Nucleophilic addition in carbonyl compounds MCQs With Answer

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Nucleophilic addition in carbonyl compounds MCQs With Answer
Nucleophilic addition to carbonyl compounds is a central topic for B.Pharm students, covering mechanism, kinetics, regiochemistry and stereochemistry of reactions of aldehydes, ketones and conjugated carbonyls. This concise introduction highlights key concepts: polarization of the C=O bond, tetrahedral intermediates, acid/base and Lewis acid catalysis, hydride and organometallic additions (NaBH4, LiAlH4, RMgX), cyanohydrin formation, imine/enamine chemistry, acetal protection, and 1,2 vs 1,4 (conjugate) addition. Understanding reagent selectivity, electronic and steric effects, and named processes (Aldol, Michael, Reformatsky) is essential for drug synthesis and medicinal chemistry. Now let’s test your knowledge with 50 MCQs on this topic.

Q1. Which statement best describes the first electronic step in a typical nucleophilic addition to a carbonyl?

  • The nucleophile donates a pair of electrons to the carbonyl carbon forming a new sigma bond while the pi bond electrons move to oxygen.
  • The carbonyl oxygen donates electrons to the nucleophile creating an oxonium ion.
  • The nucleophile abstracts an alpha-hydrogen to form an enolate immediately.
  • The carbonyl is reduced by hydrogen transfer before bond formation.

Correct Answer: The nucleophile donates a pair of electrons to the carbonyl carbon forming a new sigma bond while the pi bond electrons move to oxygen.

Q2. Which of the following reagents will convert a ketone to a secondary alcohol under typical conditions?

  • Grignard reagent (RMgBr) followed by acid workup
  • LiAlH4 in ether followed by aqueous workup
  • NaBH4 in methanol
  • PCC in dichloromethane

Correct Answer: NaBH4 in methanol

Q3. Which factor increases the electrophilicity of the carbonyl carbon the most?

  • Conjugation with an aromatic ring
  • Electron-withdrawing substituents on carbonyl carbon
  • Bulky alkyl substituents adjacent to carbonyl
  • Resonance donation from neighboring lone pairs

Correct Answer: Electron-withdrawing substituents on carbonyl carbon

Q4. Which nucleophile is most likely to undergo 1,4-conjugate addition (Michael addition) to an α,β-unsaturated ketone?

  • Organocuprate (Gilman reagent, R2CuLi)
  • Grignard reagent (RMgBr)
  • Hydride from NaBH4
  • Hydroxide ion (OH–)

Correct Answer: Organocuprate (Gilman reagent, R2CuLi)

Q5. Which of the following correctly ranks reactivity toward nucleophilic addition at the carbonyl carbon (most to least) for simple carbonyl classes?

  • Aldehyde > Ketone > Ester > Amide
  • Ketone > Aldehyde > Ester > Amide
  • Aldehyde > Ester > Ketone > Amide
  • Amide > Ester > Ketone > Aldehyde

Correct Answer: Aldehyde > Ketone > Ester > Amide

Q6. What intermediate is typically formed immediately after nucleophilic attack on a carbonyl?

  • Tetrahedral alkoxide intermediate
  • Carbocation intermediate
  • Carbanion stabilized by resonance
  • Radical intermediate

Correct Answer: Tetrahedral alkoxide intermediate

Q7. Which reagent will reduce an ester to a primary alcohol?

  • NaBH4 in ethanol
  • LiAlH4 in diethyl ether followed by water
  • Pd/C hydrogenation under mild pressure
  • DIBAL-H at low temperature followed by hydrolysis

Correct Answer: LiAlH4 in diethyl ether followed by water

Q8. Formation of a cyanohydrin from an aldehyde involves which type of reaction step?

  • Nucleophilic addition of CN– to the carbonyl carbon
  • Electrophilic aromatic substitution on the aldehyde
  • Nucleophilic substitution at the carbonyl oxygen
  • Radical addition of cyanogen bromide

Correct Answer: Nucleophilic addition of CN– to the carbonyl carbon

Q9. Which condition favors acetal formation from a carbonyl compound?

  • Acid catalyst, excess alcohol, removal of water
  • Strong base, low temperature, no alcohol
  • Neutral conditions with catalytic water
  • Excess amine and dehydrating agent

Correct Answer: Acid catalyst, excess alcohol, removal of water

Q10. Which of the following best explains why aldehydes are generally more reactive than ketones toward nucleophiles?

  • Aldehydes have a hydrogen instead of an alkyl, reducing steric hindrance and electron donation
  • Aldehydes are more stabilized by resonance than ketones
  • Keto form is always less stable than aldehyde form
  • Aldehydes are stronger acids than ketones

Correct Answer: Aldehydes have a hydrogen instead of an alkyl, reducing steric hindrance and electron donation

Q11. In acid-catalyzed nucleophilic addition to a carbonyl, what is the primary role of the acid?

  • Protonate the carbonyl oxygen to increase electrophilicity of the carbon
  • Convert the nucleophile into a stronger nucleophile
  • Remove an α-hydrogen to form an enolate
  • Oxidize the carbonyl to a carboxylic acid

Correct Answer: Protonate the carbonyl oxygen to increase electrophilicity of the carbon

Q12. Which statement correctly contrasts NaBH4 and LiAlH4?

  • NaBH4 selectively reduces aldehydes and ketones in protic solvents; LiAlH4 is much stronger and reduces esters and carboxylic acids.
  • LiAlH4 is milder and used in aqueous media; NaBH4 reduces esters and acids.
  • Both reagents have identical reactivity and selectivity.
  • NaBH4 reduces only conjugated double bonds while LiAlH4 only reduces nitro groups.

Correct Answer: NaBH4 selectively reduces aldehydes and ketones in protic solvents; LiAlH4 is much stronger and reduces esters and carboxylic acids.

Q13. Which product results from addition of a Grignard reagent to formaldehyde followed by acid workup?

  • Primary alcohol
  • Secondary alcohol
  • Tertiary alcohol
  • Aldehyde regenerated

Correct Answer: Primary alcohol

Q14. Which nucleophile is classified as ‘soft’ and therefore favors 1,4-addition to enones?

  • Thiolate (RS–)
  • Hydride (H– from NaBH4)
  • Alkoxide (RO–)
  • Grignard (RMgX)

Correct Answer: Thiolate (RS–)

Q15. During imine formation from a primary amine and a carbonyl, which intermediate is directly formed after nucleophilic attack?

  • Carbinolamine (hemiaminal)
  • Enamine
  • Oxocarbenium ion
  • Acetal

Correct Answer: Carbinolamine (hemiaminal)

Q16. Which reagent pair is commonly used to favor 1,2-reduction of α,β-unsaturated carbonyls (Luche reduction)?

  • NaBH4 with CeCl3
  • LiAlH4 with ether
  • DIBAL-H at −78°C
  • Pd/C with H2

Correct Answer: NaBH4 with CeCl3

Q17. Which observation indicates formation of a tetrahedral intermediate during nucleophilic addition to an acyl chloride?

  • Transient disappearance of acyl chloride IR carbonyl band and appearance of new bands from tetrahedral species
  • Immediate precipitation of a stable aldehyde
  • Formation of free radical as detected by EPR
  • Colorless solution becoming colored due to oxidation

Correct Answer: Transient disappearance of acyl chloride IR carbonyl band and appearance of new bands from tetrahedral species

Q18. Which of the following reactions is an example of nucleophilic addition followed by elimination (addition–elimination) rather than simple addition?

  • Reaction of an alcohol with an acyl chloride to give an ester
  • Formation of a cyanohydrin from an aldehyde
  • NaBH4 reduction of a ketone to an alcohol
  • Addition of HCN to formaldehyde

Correct Answer: Reaction of an alcohol with an acyl chloride to give an ester

Q19. Which effect decreases the rate of nucleophilic addition to a carbonyl?

  • Electron-donating substituents adjacent to the carbonyl
  • Electron-withdrawing substituents adjacent to the carbonyl
  • Use of a polar aprotic solvent when nucleophile is ionic
  • Lewis acid coordination to the carbonyl oxygen

Correct Answer: Electron-donating substituents adjacent to the carbonyl

Q20. In the Aldol reaction, what is the nucleophile that attacks another carbonyl?

  • Enolate ion (or enolate equivalent)
  • Alcohol solvent molecule
  • Amine catalyst only
  • Carbocation formed from aldehyde

Correct Answer: Enolate ion (or enolate equivalent)

Q21. Which analytical technique most directly identifies formation of an imine from a carbonyl and amine?

  • IR spectroscopy showing disappearance of C=O stretch and appearance of C=N stretch
  • UV-Vis showing new conjugation band
  • Mass spectrometry showing loss of nitrogen
  • Polarimetry indicating change in optical rotation

Correct Answer: IR spectroscopy showing disappearance of C=O stretch and appearance of C=N stretch

Q22. Which factor makes an aldehyde more likely to form its hydrate (gem-diol) in water?

  • Presence of strong electron-withdrawing groups on the aldehyde
  • Bulky alkyl groups adjacent to the carbonyl
  • Use of nonpolar solvents only
  • High pH with strong base

Correct Answer: Presence of strong electron-withdrawing groups on the aldehyde

Q23. Which reagent will convert a ketone into an enamine with a secondary amine?

  • Secondary amine under acid catalysis with removal of water
  • Primary amine under basic conditions
  • Hydride donor like NaBH4
  • Organolithium reagent followed by hydrolysis

Correct Answer: Secondary amine under acid catalysis with removal of water

Q24. Which statement about nucleophilicity and basicity is generally true in protic solvents?

  • Basicity correlates with nucleophilicity, but small, strongly solvated ions are less nucleophilic than expected
  • Nucleophilicity always equals basicity in all solvents
  • Large anions are always weaker nucleophiles in protic solvents
  • Solvent has no effect on relative nucleophilicity

Correct Answer: Basicity correlates with nucleophilicity, but small, strongly solvated ions are less nucleophilic than expected

Q25. Which reagent is typically used to selectively form a carbon–carbon bond by nucleophilic addition to a carbonyl and yields an alcohol after workup?

  • Grignard reagent (RMgX)
  • PCC (pyridinium chlorochromate)
  • H2 with Pd/C
  • HCl in acetone

Correct Answer: Grignard reagent (RMgX)

Q26. Which product results from the 1,4-addition (conjugate addition) of a cuprate to an α,β-unsaturated ketone followed by protonation?

  • β-substituted ketone
  • α-substituted ketone at the carbonyl carbon
  • Alcohol at the former carbonyl carbon
  • Epoxide formation

Correct Answer: β-substituted ketone

Q27. In nucleophilic addition to carbonyls, which step is often rate-determining under neutral or basic conditions?

  • Nucleophilic attack on the carbonyl carbon
  • Proton transfer to the oxygen after attack
  • Final workup with aqueous acid
  • Diffusion of solvent molecules

Correct Answer: Nucleophilic attack on the carbonyl carbon

Q28. Which carbonyl derivative is least susceptible to simple nucleophilic addition without prior activation?

  • Amide
  • Aldehyde
  • Ketone
  • Acid chloride

Correct Answer: Amide

Q29. Which of the following best explains why conjugation (resonance) with an aromatic ring reduces carbonyl reactivity?

  • Resonance delocalization reduces positive character at the carbonyl carbon
  • It increases steric hindrance only
  • It makes the carbonyl more basic
  • Aromatic conjugation always increases electrophilicity

Correct Answer: Resonance delocalization reduces positive character at the carbonyl carbon

Q30. Which reagent is commonly used for the formation of acetals as protecting groups for carbonyls?

  • Glycol or diol with catalytic acid
  • NaBH4 in methanol
  • Grignard reagent followed by acid
  • Concentrated base and heat

Correct Answer: Glycol or diol with catalytic acid

Q31. Which of the following is true about cyanide (CN–) addition to carbonyls?

  • Cyanide is a strong nucleophile that forms cyanohydrins reversibly and introduces a synthetic handle for further transformations.
  • Cyanide only oxidizes carbonyls and does not add.
  • Cyanide preferentially performs 1,4-addition to enones.
  • Cyanide is incapable of reacting with aldehydes.

Correct Answer: Cyanide is a strong nucleophile that forms cyanohydrins reversibly and introduces a synthetic handle for further transformations.

Q32. In nucleophilic addition to a carbonyl, what happens to the oxygen atom in the C=O bond during attack?

  • It becomes negatively charged (alkoxide) as the pi bond electrons relocate to oxygen.
  • It is expelled as a leaving group immediately.
  • It is reduced to water instantly without proton transfer.
  • It forms a radical cation that stabilizes the intermediate.

Correct Answer: It becomes negatively charged (alkoxide) as the pi bond electrons relocate to oxygen.

Q33. Which reagent combination will convert an α,β-unsaturated aldehyde largely into the corresponding allylic alcohol via 1,2-addition?

  • Grignard reagent (RMgBr) followed by acid workup
  • Gilman reagent (R2CuLi)
  • Soft thiolate nucleophile
  • Organocopper reagent followed by oxidation

Correct Answer: Grignard reagent (RMgBr) followed by acid workup

Q34. Which mechanistic pathway describes formation of hemiacetal from an aldehyde and one equivalent of alcohol under acid catalysis?

  • Nucleophilic addition of alcohol to protonated carbonyl giving an oxonium that deprotonates to hemiacetal
  • Direct radical combination between alcohol and aldehyde
  • Hydride transfer from alcohol to carbonyl
  • SN1 substitution at the carbonyl carbon

Correct Answer: Nucleophilic addition of alcohol to protonated carbonyl giving an oxonium that deprotonates to hemiacetal

Q35. Which process competes with nucleophilic addition when strong base is present with α-hydrogen containing carbonyls?

  • Enolate formation (deprotonation at the α-position)
  • Direct radical polymerization
  • Formation of acetal under neutral conditions
  • Immediate oxidation to carboxylic acid

Correct Answer: Enolate formation (deprotonation at the α-position)

Q36. Which reagent is used for nucleophilic 1,2-addition to carbonyls but is tolerant of esters and nitriles (often via chemoselectivity)?

  • Organolithium and Grignard reagents are not chemoselective; NaBH4 is chemoselective for carbonyls
  • LiAlH4 is highly chemoselective for ketones only
  • DIBAL-H cleaves esters readily at room temperature
  • Strong acid catalysts selectively add to nitriles

Correct Answer: Organolithium and Grignard reagents are not chemoselective; NaBH4 is chemoselective for carbonyls

Q37. Which technique can be used to favor the formation of imine (Schiff base) from an aldehyde and a primary amine?

  • Remove water (e.g., molecular sieves) and use acid catalyst to drive dehydration
  • Use excess water to shift equilibrium toward imine formation
  • Perform reaction at extremely low temperatures with strong base
  • Add NaBH4 to reduce intermediate

Correct Answer: Remove water (e.g., molecular sieves) and use acid catalyst to drive dehydration

Q38. Which named reaction involves nucleophilic addition of an enolate to another carbonyl compound?

  • Aldol reaction
  • Wittig reaction
  • Clemmensen reduction
  • Hofmann rearrangement

Correct Answer: Aldol reaction

Q39. Which structural change at the carbonyl-bearing carbon results from stereoselective nucleophilic addition to a prochiral carbonyl?

  • Formation of a new stereogenic center (chiral center) at the carbonyl carbon
  • Loss of the carbonyl carbon entirely
  • Instant racemization of adjacent stereocenters only
  • Only formation of an achiral product

Correct Answer: Formation of a new stereogenic center (chiral center) at the carbonyl carbon

Q40. Which reagent set is appropriate for stereoselective 1,2-reduction of α,β-unsaturated carbonyls to give allylic alcohols selectively?

  • Sterically hindered hydride donors like L-Selectride at low temperature
  • DIBAL-H always gives saturated alcohols only
  • Using aqueous acid alone
  • Use of organocuprates to give allylic alcohols

Correct Answer: Sterically hindered hydride donors like L-Selectride at low temperature

Q41. Which statement correctly describes the role of a Lewis acid like BF3 in nucleophilic additions?

  • Coordinates to carbonyl oxygen, increasing electrophilicity and accelerating nucleophilic attack
  • Supplies nucleophiles by dissociation
  • Works as a base to deprotonate nucleophiles
  • Acts as a radical initiator

Correct Answer: Coordinates to carbonyl oxygen, increasing electrophilicity and accelerating nucleophilic attack

Q42. Which reaction demonstrates nucleophilic addition of an organometallic reagent to ester giving a tertiary alcohol upon excess reagent and hydrolysis?

  • Reaction of ester with two equivalents of Grignard reagent followed by acid workup
  • NaBH4 reduction of ester
  • Acetal formation from ester and diol
  • Wittig olefination of ester

Correct Answer: Reaction of ester with two equivalents of Grignard reagent followed by acid workup

Q43. Which solvent type generally increases the rate of anionic nucleophilic addition by better solvating the cation but not the nucleophile?

  • Polar aprotic solvents (e.g., DMSO, DMF)
  • Nonpolar solvents (e.g., hexane)
  • Protic solvents (e.g., water, alcohols) that strongly solvate nucleophiles
  • Supercritical CO2 exclusively

Correct Answer: Polar aprotic solvents (e.g., DMSO, DMF)

Q44. Which of the following is true about Reformatsky reaction?

  • An organozinc enolate adds to carbonyls to form β-hydroxy esters after workup
  • It uses Grignard reagents to form tertiary alcohols exclusively
  • It reduces carbonyls to alcohols using sodium borohydride
  • It forms imines from aldehydes and primary amines

Correct Answer: An organozinc enolate adds to carbonyls to form β-hydroxy esters after workup

Q45. Which experimental change would most likely increase the yield of a nucleophilic addition equilibrium when the reaction is reversible?

  • Remove one product (e.g., water) from the reaction mixture
  • Add inert gas to the reaction flask
  • Lower the temperature only without changing concentrations
  • Use a stoichiometric excess of solvent

Correct Answer: Remove one product (e.g., water) from the reaction mixture

Q46. Which of the following is NOT typically formed by simple nucleophilic addition to a carbonyl?

  • Alkene via direct addition without elimination
  • Alcohol after hydride addition and workup
  • Hemiacetal from alcohol addition
  • Imine from amine addition and dehydration

Correct Answer: Alkene via direct addition without elimination

Q47. Which of the following is a correct mechanistic description of a Michael addition?

  • Conjugate (1,4) addition of a nucleophile (often stabilized carbanion or enolate) to an α,β-unsaturated carbonyl
  • Direct nucleophilic attack at the carbonyl carbon (1,2 addition) by a hard nucleophile
  • Oxidative addition of hydrogen to a carbon–carbon double bond
  • Formation of an imine by condensation

Correct Answer: Conjugate (1,4) addition of a nucleophile (often stabilized carbanion or enolate) to an α,β-unsaturated carbonyl

Q48. Which choice best describes why steric hindrance around a carbonyl decreases its rate of nucleophilic addition?

  • Bulky substituents hinder approach of the nucleophile and stabilize the carbonyl by hyperconjugation
  • Steric hindrance increases electrophilicity dramatically
  • Steric hindrance converts the carbonyl into a carboxylic acid
  • Large groups cause immediate elimination reactions only

Correct Answer: Bulky substituents hinder approach of the nucleophile and stabilize the carbonyl by hyperconjugation

Q49. Which reagent converts an aldehyde to a geminal diol (hydrate) more readily?

  • Water with acidic or basic catalysis, especially when aldehyde contains electron-withdrawing groups
  • Dry ether with molecular sieves
  • Anhydrous alcohol without acid
  • Strong reducing agent like NaBH4

Correct Answer: Water with acidic or basic catalysis, especially when aldehyde contains electron-withdrawing groups

Q50. Which strategy is commonly used in pharmaceutical synthesis to protect a carbonyl group during multi-step sequences?

  • Convert the carbonyl into an acetal or ketal via nucleophilic addition of a diol under acid catalysis
  • Oxidize the carbonyl to a carboxylic acid
  • React it with NaBH4 to an alcohol and leave unprotected
  • Expose it to strong base to form enolate permanently

Correct Answer: Convert the carbonyl into an acetal or ketal via nucleophilic addition of a diol under acid catalysis

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