Effect of substituents on acidity MCQs With Answer

Understanding the effect of substituents on acidity is vital for B. Pharm students studying drug design, pharmacokinetics and medicinal chemistry. Substituents alter acid strength through electronic influences — inductive (-I/+I), resonance (−R/+R), field effects and hyperconjugation — by stabilizing or destabilizing the conjugate base. Mastering how position (ortho/meta/para), type and number of substituents affect pKa helps predict solubility, absorption and metabolic fate of drug molecules. This topic integrates Hammett constants, resonance structures and steric or intramolecular hydrogen-bonding effects, linking theory to practical pKa estimation. Clear grasp of these principles aids rational modification of lead compounds. Now let’s test your knowledge with 50 MCQs on this topic.

Q1. Which electronic effect primarily explains why nitro groups increase acidity of benzoic acids?

• +I effect (electron donating by induction)
• -I effect (electron withdrawing by induction)
• +M effect (electron donating by resonance)
• Hyperconjugation

Correct Answer: -I effect (electron withdrawing by induction)

Q2. Which substituent pattern on phenol will generally make it most acidic?

• Para-methoxy
• Ortho-nitro
• Para-methyl
• Meta-methoxy

Correct Answer: Ortho-nitro

Q3. The resonance (mesomeric) effect that withdraws electron density from an aromatic ring is denoted as:

• +M
• -M
• +I
• -I

Correct Answer: -M

Q4. Which factor stabilizes the conjugate base and thus increases acidity?

• Electron donating group at para position
• Electron withdrawing group at ortho position
• Increased hyperconjugation from alkyl groups
• Steric hindrance preventing solvation

Correct Answer: Electron withdrawing group at ortho position

Q5. For benzoic acid derivatives, which position has the least resonance effect on the carboxylate group?

• Para
• Meta
• Ortho
• All have equal resonance effect

Correct Answer: Meta

Q6. Which substituent will most decrease the acidity of acetic acid?

• Trifluoromethyl (-CF3)
• Nitro (-NO2)
• Methyl (-CH3)
• Chloro (-Cl)

Correct Answer: Methyl (-CH3)

Q7. Which statement best describes the ortho effect on substituted benzoic acids?

• Only resonance determines acidity at ortho position
• Steric and intramolecular hydrogen bonding can alter acidity at ortho
• Ortho substituents never influence acidity
• Only inductive effects operate at ortho position

Correct Answer: Steric and intramolecular hydrogen bonding can alter acidity at ortho

Q8. Which pair shows the expected order of acidity (most to least) for substituted phenols?

• 4-NO2-phenol > phenol > 4-OH-phenol > 4-CH3-phenol
• 4-NO2-phenol > 4-Cl-phenol > phenol > 4-CH3-phenol
• phenol > 4-NO2-phenol > 4-CH3-phenol > 4-OH-phenol
• 4-CH3-phenol > phenol > 4-Cl-phenol > 4-NO2-phenol

Correct Answer: 4-NO2-phenol > 4-Cl-phenol > phenol > 4-CH3-phenol

Q9. The Hammett sigma constant for a substituent quantifies which property?

• Solubility in water
• Electronic effect relative to hydrogen
• Steric hindrance only
• Acid dissociation constant directly

Correct Answer: Electronic effect relative to hydrogen

Q10. Which substituent has a strong -M (electron withdrawing by resonance) effect on a conjugated acid?

• -NH2
• -OMe
• -NO2
• -CH3

Correct Answer: -NO2

Q11. For α-carbonyl acids (e.g., acetoacetic acid), electron-withdrawing substituents at the α-carbon generally:

• Decrease acidity by destabilizing the conjugate base
• Increase acidity by stabilizing the enolate or conjugate base
• Have no effect on acidity
• Convert acid to a base

Correct Answer: Increase acidity by stabilizing the enolate or conjugate base

Q12. Which effect predominates when a halogen is attached to an aromatic ring regarding acidity of a carboxylic acid substituent?

• Strong +M donating effect
• -I electron withdrawing effect, weak +M donating effect
• Only steric effect
• Strong hyperconjugation

Correct Answer: -I electron withdrawing effect, weak +M donating effect

Q13. Which of the following increases acid strength of an aliphatic carboxylic acid most effectively?

• Introducing an alkyl group at alpha carbon
• Replacing a hydrogen with a nitro group at beta position
• Adding an electron-withdrawing group at alpha carbon
• Methylation of the carboxylate

Correct Answer: Adding an electron-withdrawing group at alpha carbon

Q14. Why do electron donating groups reduce acidity of carboxylic acids?

• They stabilize the conjugate base
• They increase the pKa by destabilizing the conjugate base
• They create intramolecular hydrogen bonding that increases acidity
• They remove the acidic proton directly

Correct Answer: They increase the pKa by destabilizing the conjugate base

Q15. Which compound is the most acidic?

• p-nitrobenzoic acid
• benzoic acid
• p-methoxybenzoic acid
• p-methylbenzoic acid

Correct Answer: p-nitrobenzoic acid

Q16. The field effect differs from the inductive effect in that the field effect:

• Operates through bonds only
• Is mediated by solvent and spatial proximity, not necessarily bonds
• Is identical to resonance effect
• Only occurs in aliphatic systems

Correct Answer: Is mediated by solvent and spatial proximity, not necessarily bonds

Q17. Which statement about hyperconjugation and acidity is correct?

• Hyperconjugation stabilizes carboxylate ions and increases acidity
• Alkyl groups via hyperconjugation donate electron density and decrease acidity
• Hyperconjugation is a resonance withdrawal effect
• Hyperconjugation has no influence on acidity

Correct Answer: Alkyl groups via hyperconjugation donate electron density and decrease acidity

Q18. Which is more acidic: 2,4-dinitrophenol or 4-nitrophenol?

• 4-nitrophenol
• 2,4-dinitrophenol
• They have identical acidity
• Phenol (unsubstituted) is more acidic than both

Correct Answer: 2,4-dinitrophenol

Q19. Which effect explains why para-nitrophenol is more acidic than para-methoxyphenol?

• +M of methoxy increases acidity
• -M/-I of nitro stabilizes the phenoxide ion and increases acidity
• Methyl group resonance increases acidity
• Hyperconjugation from methoxy stabilizes conjugate base

Correct Answer: -M/-I of nitro stabilizes the phenoxide ion and increases acidity

Q20. In substituted acetic acids, which substituent would give the lowest pKa (most acidic)?

• -NH2
• -CH3
• -NO2
• -OH

Correct Answer: -NO2

Q21. Meta-nitrobenzoic acid compared to para-nitrobenzoic acid is:

• More acidic due to stronger resonance stabilization
• Less acidic because meta position has no resonance stabilization of carboxylate
• Identical in acidity
• Less acidic because of steric hindrance

Correct Answer: Less acidic because meta position has no resonance stabilization of carboxylate

Q22. Which phenomenon can make ortho-substituted benzoic acids unexpectedly more acidic?

• Intramolecular hydrogen bonding that stabilizes the acid
• Steric hindrance preventing conjugate base solvation
• Certain ortho groups can form intramolecular hydrogen bonds that stabilize the conjugate base
• Ortho substituents never affect acidity

Correct Answer: Certain ortho groups can form intramolecular hydrogen bonds that stabilize the conjugate base

Q23. Which of the following best predicts acidity trends using linear free-energy relationships?

• Hückel rule
• Hammett equation
• Le Chatelier’s principle
• Arrhenius equation

Correct Answer: Hammett equation

Q24. For aromatic carboxylic acids, which substituent combination gives the greatest acidity?

• Two para electron-donating groups
• Two ortho electron-withdrawing groups
• Single para electron-donating group
• Unsubstituted ring

Correct Answer: Two ortho electron-withdrawing groups

Q25. Which of the following increases phenol acidity through resonance stabilization?

• Para-amino group (+M)
• Para-nitro group (-M)
• Para-alkyl group (+I)
• Ortho-alkyl group (steric)

Correct Answer: Para-nitro group (-M)

Q26. Which substituent shows strong +I (inductive donating) effect?

• Fluorine
• Methyl
• Nitro
• Carboxyl

Correct Answer: Methyl

Q27. Which is the most acidic among the following carboxylic acids?

• Formic acid (HCOOH)
• Acetic acid (CH3COOH)
• Benzoic acid (C6H5COOH)
• Propionic acid (CH3CH2COOH)

Correct Answer: Formic acid (HCOOH)

Q28. The presence of multiple electron-withdrawing groups on a molecule typically:

• Decreases acidity by destabilizing conjugate base
• Increases acidity by stabilizing conjugate base
• Has no cumulative effect
• Always converts acid to base

Correct Answer: Increases acidity by stabilizing conjugate base

Q29. Which substituent would most increase acidity of a β-diketone like acetylacetone?

• Tert-butyl group
• Nitro group adjacent to carbonyl
• Methyl group at gamma position
• Phenyl group at remote position

Correct Answer: Nitro group adjacent to carbonyl

Q30. Which statement is true regarding electron-withdrawing substituents and solvation of conjugate base?

• EWGs decrease solvation and reduce acidity
• EWGs often increase negative charge delocalization and improve solvation, enhancing acidity
• EWGs convert conjugate base to neutral species
• Solvation is unaffected by substituents

Correct Answer: EWGs often increase negative charge delocalization and improve solvation, enhancing acidity

Q31. Which substituent at para position will most weaken acidity of benzoic acid?

• -NO2
• -CN
• -OCH3
• -F

Correct Answer: -OCH3

Q32. How does resonance donation (+M) by an aryl substituent affect acidity of a nearby acid group?

• It withdraws electron density and increases acidity
• It donates electron density and usually decreases acidity
• It has no effect
• It always converts acid to stronger acid

Correct Answer: It donates electron density and usually decreases acidity

Q33. Which is more acidic: p-chlorobenzoic acid or p-methoxybenzoic acid?

• p-chlorobenzoic acid
• p-methoxybenzoic acid
• They have identical acidity
• Neither is acidic

Correct Answer: p-chlorobenzoic acid

Q34. Intramolecular hydrogen bonding in ortho-substituted phenols typically:

• Always increases acidity by stabilizing phenoxide
• Can decrease apparent acidity by stabilizing the neutral form
• Has no effect on acidity
• Makes phenol insoluble

Correct Answer: Can decrease apparent acidity by stabilizing the neutral form

Q35. Which descriptor quantitatively relates substituent effects to reaction or acidity changes?

• pKa only
• Hammett sigma constant
• Boiling point
• Molecular weight

Correct Answer: Hammett sigma constant

Q36. Which aromatic substituent combination would most stabilize a negative charge on a conjugate base via resonance?

• Para-OMe
• Para-NO2
• Ortho-CH3
• Meta-CH3

Correct Answer: Para-NO2

Q37. Which functional group attached to benzene is most likely to decrease acidity of benzoic acid via +M effect?

• -NO2
• -NH2
• -CF3
• -Cl

Correct Answer: -NH2

Q38. For pharmaceuticals, why is pKa prediction using substituent effects important?

• It predicts color of the drug
• It helps forecast ionization state, solubility and absorption
• It determines melting point only
• It only affects synthetic yield

Correct Answer: It helps forecast ionization state, solubility and absorption

Q39. Which effect is most responsible for increased acidity when fluorine atoms are attached near an acid group?

• Strong +I effect
• Strong -I inductive electron-withdrawing effect
• Resonance donation
• Hyperconjugation donation

Correct Answer: Strong -I inductive electron-withdrawing effect

Q40. Which is the correct trend in acidity for substituted benzoic acids with increasing electron-withdrawing ability?

• Acidity decreases as EWG strength increases
• Acidity increases as EWG strength increases
• Acidity is unaffected by EWG strength
• Acidity oscillates unpredictably

Correct Answer: Acidity increases as EWG strength increases

Q41. Which substituent will have a greater effect on acidity: para-nitro or ortho-nitro, and why?

• Para-nitro due to better resonance stabilization of conjugate base
• Ortho-nitro because steric effects always increase acidity
• Ortho-nitro because it cannot participate in resonance
• Neither; both have no effect

Correct Answer: Para-nitro due to better resonance stabilization of conjugate base

Q42. Which of the following leads to decreased acidity of an alcohol?

• Electron-withdrawing substituent on adjacent carbon
• Electron-donating substituent on adjacent carbon
• Increased hydrogen bonding with solvent
• Conjugation with an electron-withdrawing group

Correct Answer: Electron-donating substituent on adjacent carbon

Q43. In the Hammett equation log(k/k0) = ρσ, what does a positive ρ indicate for a reaction sensitive to substituents?

• Reaction rate decreases with electron-withdrawing substituents
• Reaction or equilibrium is stabilized by electron-withdrawing substituents
• Substituents have no effect
• Only steric effects matter

Correct Answer: Reaction or equilibrium is stabilized by electron-withdrawing substituents

Q44. Which is the most acidic phenol derivative among these?

• 2,4-dichlorophenol
• Phenol
• 4-methoxyphenol
• 2,6-dimethylphenol

Correct Answer: 2,4-dichlorophenol

Q45. Which substituent effect is distance-dependent and decays rapidly with increasing separation from the functional group?

• Resonance (mesomeric) effect
• Inductive effect
• Hammett sigma constant
• Hyperconjugation

Correct Answer: Inductive effect

Q46. Which aromatic position allows both resonance and inductive effects to influence acidity of a substituent most effectively?

• Meta position
• Para position
• Remote position (beyond para)
• Substituent position does not matter

Correct Answer: Para position

Q47. Which property of a conjugate base is most directly related to increased acidity of the parent acid?

• Larger molecular weight
• Greater stabilization/delocalization of the negative charge
• Higher boiling point
• Less solvation in solvent

Correct Answer: Greater stabilization/delocalization of the negative charge

Q48. Which substituent would increase acidity of pyridinium-like acids by resonance?

• Para-amino on an attached phenyl ring (+M)
• Para-nitro on an attached phenyl ring (-M)
• Tert-butyl on attached ring (+I)
• Methyl on attached ring (+I)

Correct Answer: Para-nitro on an attached phenyl ring (-M)

Q49. Which of the following best describes why trifluoroacetic acid (TFA) is much stronger than acetic acid?

• CF3 is electron-donating and stabilizes the acid
• CF3 is strongly electron-withdrawing by induction, stabilizing conjugate base
• CF3 increases hyperconjugation making acid stronger
• TFA has higher molecular weight only

Correct Answer: CF3 is strongly electron-withdrawing by induction, stabilizing conjugate base

Q50. When designing a drug with a required acidic group, which substituent strategy helps lower pKa to favor ionization at physiological pH?

• Introduce electron-donating groups near the acid
• Introduce electron-withdrawing groups and conjugation to stabilize the conjugate base
• Increase bulky lipophilic alkyl groups adjacent to the acid
• Remove any resonance possibilities

Correct Answer: Introduce electron-withdrawing groups and conjugation to stabilize the conjugate base

G S Sachin

I am a Registered Pharmacist under the Pharmacy Act, 1948, and the founder of PharmacyFreak.com. I hold a Bachelor of Pharmacy degree from Rungta College of Pharmaceutical Science and Research. With a strong academic foundation and practical knowledge, I am committed to providing accurate, easy-to-understand content to support pharmacy students and professionals. My aim is to make complex pharmaceutical concepts accessible and useful for real-world application.

Mail- Sachin@pharmacyfreak.com