Hammett’s substituent constant MCQs With Answer

Hammett’s substituent constant MCQs With Answer

Hammett’s substituent constant (σ) is a cornerstone concept for B. Pharm students studying how aromatic substituents influence reactivity and drug properties. This introduction covers sigma values, sigma+, sigma–, resonance and inductive effects, the reaction constant (ρ), Hammett plots, linear free energy relationships (LFER), and applications in QSAR, SAR and medicinal chemistry. Understanding how σ correlates with acidity (pKa), reaction rates, mechanism sensitivity and limitations (steric or solvent effects) helps predict metabolic fate and optimize lead compounds. Clear grasp of these electronic descriptors strengthens rational drug design and data interpretation. Now let’s test your knowledge with 30 MCQs on this topic.

Q1. What is the Hammett substituent constant (σ)?

• A numerical value quantifying the electronic effect of a substituent relative to hydrogen
• A measure of steric hindrance caused by a substituent
• A thermodynamic constant for bond dissociation energy
• A measure of molecular lipophilicity

Correct Answer: A numerical value quantifying the electronic effect of a substituent relative to hydrogen

Q2. Which two electronic effects are primarily represented by Hammett σ values?

• Resonance and inductive effects
• Hydrophobicity and hydrogen bonding
• Stereoelectronic and steric effects
• Van der Waals and dipole interactions

Correct Answer: Resonance and inductive effects

Q3. A positive σ value for a para substituent means the group is:

• Electron-withdrawing (stabilizes negative charge)
• Electron-donating (increases electron density)
• Sterically bulky but electronically neutral
• Always resonance-donating regardless of position

Correct Answer: Electron-withdrawing (stabilizes negative charge)

Q4. What does the Hammett reaction constant (ρ) indicate?

• The sensitivity of a reaction or equilibrium to substituent electronic effects
• The steric bulk of a substituent
• The aqueous solubility of a series of compounds
• The temperature dependence of a reaction

Correct Answer: The sensitivity of a reaction or equilibrium to substituent electronic effects

Q5. If ρ is positive for a reaction series, which substituents accelerate the reaction?

• Electron-withdrawing substituents
• Electron-donating substituents
• Only bulky substituents
• Substituents that increase lipophilicity

Correct Answer: Electron-withdrawing substituents

Q6. How are classical Hammett σ values commonly determined experimentally?

• From ionization constants (pKa) of substituted benzoic acids or relative reaction rates
• By measuring melting points of substituted benzenes
• Using X-ray crystallography of substituted aromatics
• By partition coefficients (log P) measurements

Correct Answer: From ionization constants (pKa) of substituted benzoic acids or relative reaction rates

Q7. Which σ variant is used when positive charge develops at the reaction center and resonance effects are enhanced?

• σ+ (sigma-plus)
• σ– (sigma-minus)
• σI (inductive only)
• σR (resonance only)

Correct Answer: σ+ (sigma-plus)

Q8. Which pair of parameters aims to separate inductive and resonance contributions?

• σI and σR
• σ+ and σ–
• ρ and σ
• pKa and log P

Correct Answer: σI and σR

Q9. Which statement best describes the nitro group (–NO2) in Hammett terms?

• Strong electron-withdrawing group; large positive σ (e.g., para σ ≈ +0.78)
• Strong electron-donating group with negative σ
• Neutral in electronic effect (σ ≈ 0)
• Only sterically active, no electronic influence

Correct Answer: Strong electron-withdrawing group; large positive σ (e.g., para σ ≈ +0.78)

Q10. Which substituent typically has a negative para σ value indicating net electron donation through resonance?

• Para-methoxy (–OCH3)
• Para-nitro (–NO2)
• Para-cyano (–CN)
• Para-chloro (–Cl)

Correct Answer: Para-methoxy (–OCH3)

Q11. How does an electron-withdrawing substituent on benzoic acid influence its pKa compared to unsubstituted benzoic acid?

• It lowers pKa (increases acidity)
• It raises pKa (decreases acidity)
• It has no effect on pKa
• It only affects solubility, not pKa

Correct Answer: It lowers pKa (increases acidity)

Q12. Which of the following is a common limitation when applying Hammett correlations in drug chemistry?

• Steric effects, solvation changes or mechanism shifts can break linearity
• Hammett constants cannot represent resonance
• They perfectly predict metabolic stability for all drugs
• They account directly for 3D conformations of ligands

Correct Answer: Steric effects, solvation changes or mechanism shifts can break linearity

Q13. What is a linear free energy relationship (LFER) in the context of Hammett analysis?

• A linear correlation between log(rate or equilibrium constant) and substituent σ values
• A plot of molecular weight versus bioavailability
• The relationship between pH and solubility
• A direct measure of steric hindrance

Correct Answer: A linear correlation between log(rate or equilibrium constant) and substituent σ values

Q14. Why are Hammett constants useful in QSAR for medicinal chemistry?

• They quantify electronic effects that correlate with biological activity and reactivity
• They directly measure receptor binding affinity
• They determine the crystal structure of a drug-target complex
• They provide exact metabolic clearance rates

Correct Answer: They quantify electronic effects that correlate with biological activity and reactivity

Q15. What does a large magnitude of ρ (reaction constant) signify?

• High sensitivity of the reaction to substituent electronic effects
• Large steric hindrance in the series
• Low correlation between σ and kinetics
• That resonance effects are absent

Correct Answer: High sensitivity of the reaction to substituent electronic effects

Q16. A Hammett plot is typically constructed by plotting which two quantities?

• log(k / k0) or log(K / K0) versus σ
• pKa versus log P
• Molecular weight versus melting point
• Log D versus target potency

Correct Answer: log(k / k0) or log(K / K0) versus σ

Q17. Which substituent effect generally accelerates nucleophilic aromatic substitution (SNAr) at an activated ring?

• Electron-withdrawing substituents at ortho/para positions
• Strong electron-donating substituents
• Bulky alkyl groups irrespective of electronics
• Nonpolar alkyl chains increasing lipophilicity

Correct Answer: Electron-withdrawing substituents at ortho/para positions

Q18. Which substituents accelerate electrophilic aromatic substitution (EAS)?

• Electron-donating substituents
• Strong electron-withdrawing substituents
• Polar neutral substituents with high σ+
• Substituents that increase molecular weight only

Correct Answer: Electron-donating substituents

Q19. Which common substituent typically has a slightly negative σp indicating weak electron donation?

• Para-methyl (–CH3)
• Para-nitro (–NO2)
• Para-cyano (–CN)
• Para-fluoro (–F)

Correct Answer: Para-methyl (–CH3)

Q20. σ– (sigma-minus) values are most appropriate for correlating reactions in which:

• Negative charge is developed or stabilized in the transition state
• Positive charge is developed at the reaction center
• Only steric effects are important
• The reaction is purely photochemical

Correct Answer: Negative charge is developed or stabilized in the transition state

Q21. In a Hammett plot, what does the intercept (when σ = 0) represent?

• The log of the rate or equilibrium constant for the unsubstituted compound
• The steric hindrance of the substituent
• The resonance contribution isolated from induction
• The partition coefficient of the compound

Correct Answer: The log of the rate or equilibrium constant for the unsubstituted compound

Q22. A poor linear correlation in a Hammett plot may indicate which of the following?

• A change in mechanism, significant steric or solvation effects, or inappropriate σ type
• That electronic effects perfectly dominate reactivity
• The presence of identical substituents on all compounds
• That ρ is exactly zero

Correct Answer: A change in mechanism, significant steric or solvation effects, or inappropriate σ type

Q23. How can Hammett analysis assist in predicting sites of metabolic oxidation in a drug candidate?

• By indicating how electronic density at aromatic positions affects susceptibility to enzymatic attack
• By measuring the drug’s plasma protein binding directly
• By providing exact metabolic half-life in humans
• By predicting only steric accessibility, ignoring electronics

Correct Answer: By indicating how electronic density at aromatic positions affects susceptibility to enzymatic attack

Q24. What does a ρ value near zero imply for a reaction series?

• The reaction rate or equilibrium is insensitive to electronic substituent effects
• The reaction is highly sensitive to electronics
• All substituents have identical steric bulk
• The Hammett plot must be nonlinear

Correct Answer: The reaction rate or equilibrium is insensitive to electronic substituent effects

Q25. If introduction of electron-donating substituents increases the reaction rate, what is the sign of ρ?

• ρ is negative
• ρ is positive
• ρ is zero
• ρ is undefined

Correct Answer: ρ is negative

Q26. Which method can be used to separate field/inductive and resonance contributions quantitatively?

• Swain–Lupton equation (field and resonance parameters)
• Partition coefficient measurement only
• Melting point correlation
• NMR chemical shift of water

Correct Answer: Swain–Lupton equation (field and resonance parameters)

Q27. Which substituent is a classical example of resonance donation to an aromatic ring?

• Methoxy (–OCH3)
• Nitro (–NO2)
• Cyano (–CN)
• Trifluoromethyl (–CF3)

Correct Answer: Methoxy (–OCH3)

Q28. In drug optimization, a large absolute value of ρ for a metabolic reaction suggests what about modifying substituents?

• Electronic changes will strongly influence the metabolic rate
• Only steric modifications will affect metabolism
• Substituent changes have no effect on metabolism
• Lipophilicity is the sole determinant of metabolism

Correct Answer: Electronic changes will strongly influence the metabolic rate

Q29. In correlating para-substituted benzoic acid pKa values with σp, which axis contains σp values?

• The x-axis
• The y-axis
• Both axes contain σp
• Neither axis; σp is not used in pKa correlations

Correct Answer: The x-axis

Q30. Which factor is NOT explicitly accounted for by classical Hammett σ constants?

• Steric hindrance and 3D conformational effects
• Inductive electronic effects
• Resonance electronic effects
• Relative electronic withdrawing/donating power

Correct Answer: Steric hindrance and 3D conformational effects

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