Ring synthesis strategies: 3-,4-,5-,6-membered ring construction MCQs With Answer

Ring synthesis strategies: 3-,4-,5-,6-membered ring construction MCQs With Answer

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Introduction

This set of MCQs focuses on synthetic strategies to construct 3-, 4-, 5- and 6-membered rings—key transformations in medicinal chemistry and drug design. It covers mechanistic principles, named reactions, reagents, stereochemical control, ring strain implications and ring expansion/contraction tactics relevant to M.Pharm students. Questions probe cyclopropanation methods (Simmons–Smith, diazo chemistry, Kulinkovich), [2+2] and photochemical routes to cyclobutanes and oxetanes, 1,3-dipolar cycloadditions and Nazarov/Pauson–Khand approaches to cyclopentenes, plus Diels–Alder, Robinson annulation and intramolecular condensations for six-membered rings. Expect emphasis on reactivity, selectivity and practical limitations encountered in drug discovery-oriented synthesis.

Q1. Which reagent combination is characteristic of a Simmons–Smith cyclopropanation used to convert an alkene into a cyclopropane?

  • Diazomethane with catalytic Rh2(OAc)4
  • CH2I2 with activated zinc-copper (Zn(Cu))
  • Ti(OiPr)4 with excess EtMgBr (Kulinkovich)
  • Sodium borohydride with iodine

Correct Answer: CH2I2 with activated zinc-copper (Zn(Cu))

Q2. The Kulinkovich reaction primarily affords which type of ring-containing product from esters?

  • Cyclobutanones
  • Cyclopropanols
  • Oxetanes
  • Pyrrolidines

Correct Answer: Cyclopropanols

Q3. Which mechanistic feature explains why thermal [2+2] cycloaddition of two alkenes is generally symmetry-forbidden but allowed under photochemical conditions?

  • Photochemical excitation inverts the relative energies of HOMO and LUMO, enabling allowed orbital symmetry for [2+2]
  • Heat increases entropy, making [2+2] unfavorable
  • Photons supply chlorine radicals that mediate the reaction
  • Thermal conditions lead to radical polymerization instead

Correct Answer: Photochemical excitation inverts the relative energies of HOMO and LUMO, enabling allowed orbital symmetry for [2+2]

Q4. The Paternò–Büchi reaction is commonly used to synthesize which heterocyclic 4-membered ring?

  • Cyclobutanones
  • Oxetanes
  • Azetidines
  • Cyclobutenes

Correct Answer: Oxetanes

Q5. Which reagent is most commonly used to generate carbenes for direct cyclopropanation of alkenes via a free carbene rather than a metal carbenoid?

  • Diazomethane (CH2N2)
  • CH2I2 + Zn(Cu)
  • Titanium isopropoxide + Grignard
  • MCPBA (meta-chloroperbenzoic acid)

Correct Answer: Diazomethane (CH2N2)

Q6. Which transformation is best described as a [3,3]-sigmatropic rearrangement that can be used to form five-membered rings from allylic systems?

  • Claisen rearrangement
  • Baeyer–Villiger oxidation
  • Pauson–Khand reaction
  • Wolff rearrangement

Correct Answer: Claisen rearrangement

Q7. The Pauson–Khand reaction typically produces which type of ring system from an alkyne, an alkene and CO?

  • Cyclobutanone derivatives
  • Cyclopentenone derivatives
  • Cyclohexanones
  • Pyridines

Correct Answer: Cyclopentenone derivatives

Q8. In intramolecular Diels–Alder reactions aimed at constructing six-membered rings, what factor most strongly influences endo/exo selectivity?

  • Concentration of dienophile
  • Relative tether length and transition state geometry favoring secondary orbital interactions
  • Use of radical initiators
  • Presence of strong inorganic bases

Correct Answer: Relative tether length and transition state geometry favoring secondary orbital interactions

Q9. Which ring-expansion reaction converts an oxime into a lactam (increasing ring size) and is often used to prepare azepines/lactams?

  • Beckmann rearrangement
  • Baeyer–Villiger oxidation
  • Favorskii rearrangement
  • Meerwein–Ponndorf–Verley reduction

Correct Answer: Beckmann rearrangement

Q10. The Nazarov cyclization is an important method to form which size and type of ring from divinyl ketones under acids?

  • Three-membered cyclopropanes via carbene insertion
  • Four-membered oxetanes via photochemistry
  • Five-membered cyclopentenones via 4π electrocyclization
  • Six-membered morpholines via nucleophilic addition

Correct Answer: Five-membered cyclopentenones via 4π electrocyclization

Q11. Which 1,3-dipolar cycloaddition is commonly employed to synthesize isoxazoles or isoxazolines, which are five-membered heterocycles?

  • Azide–alkyne Huisgen cycloaddition
  • Nitrile oxide cycloaddition to alkenes
  • Fischer indole synthesis

Correct Answer: Nitrile oxide cycloaddition to alkenes

Q12. For constructing cyclobutanes with defined stereochemistry in complex molecules, which approach offers best stereochemical control?

  • Nonselective thermal [2+2] of simple alkenes
  • Intramolecular photochemical [2+2] cycloaddition with rigid tethering
  • Random radical polymerization
  • Base-catalyzed aldol condensation

Correct Answer: Intramolecular photochemical [2+2] cycloaddition with rigid tethering

Q13. The Favorskii rearrangement is mechanistically associated with formation of which strained ring intermediate when applied to α-halo ketones?

  • Cyclopropanone or its anionic equivalent (three-membered ring)
  • Oxetane intermediate (four-membered ether)
  • Pyran intermediate (six-membered oxygen heterocycle)
  • Aziridine intermediate (three-membered nitrogen ring)

Correct Answer: Cyclopropanone or its anionic equivalent (three-membered ring)

Q14. Which tactic is often used to decrease ring strain and favor formation of larger rings (5–6) over smaller ones during intramolecular cyclizations?

  • Using high dilution to favor intramolecular over intermolecular reactions
  • Increasing temperature to drive entropic collapse to smaller rings
  • Adding radical initiators to break tether
  • Employing rigid short linkers to enforce small rings

Correct Answer: Using high dilution to favor intramolecular over intermolecular reactions

Q15. In Robinson annulation, which sequence of steps constructs a six-membered ring fused to a five-membered ring commonly used to make steroid-like frameworks?

  • Aldol condensation followed by intramolecular Michael addition and dehydration
  • Pericyclic [4+2] cycloaddition followed by hydrogenation
  • Oxidative cleavage of alkenes followed by esterification
  • Radical cyclization then ozonolysis

Correct Answer: Aldol condensation followed by intramolecular Michael addition and dehydration

Q16. Which reagent combination is typically used to convert a ketene into a cyclobutanone via [2+2] cycloaddition with an alkene?

  • Ketenes generated thermally or from acid chlorides and triethylamine reacting with alkenes
  • Diazomethane with copper catalysts
  • CH2I2 with Zn(Cu)
  • Hydrazine and base

Correct Answer: Ketenes generated thermally or from acid chlorides and triethylamine reacting with alkenes

Q17. Which strategy is best for selective synthesis of enantiomerically enriched cyclopropanes useful in drug molecules?

  • Use of racemic diazomethane and column chromatography
  • Chiral metal carbenoid catalysts (e.g., Rh or Cu with chiral ligands)
  • Photochemical [2+2] cycloadditions
  • Thermal Diels–Alder followed by decarboxylation

Correct Answer: Chiral metal carbenoid catalysts (e.g., Rh or Cu with chiral ligands)

Q18. Baeyer–Villiger oxidation of cyclic ketones is frequently used to expand ring size by one. Which product results from this oxidation of cyclopentanone?

  • Cyclobutanone
  • γ-Lactam
  • δ-Lactone (five-membered ketone to six-membered lactone)
  • Cyclopropanol

Correct Answer: δ-Lactone (five-membered ketone to six-membered lactone)

Q19. For synthesis of substituted pyrrolidines (five-membered N-heterocycles), which method uses an iminium-type intermediate formed from aldehydes and amines followed by intramolecular trapping?

  • Pauson–Khand reaction
  • Mannich-type or intramolecular aza-Michael cyclization
  • Simmons–Smith cyclopropanation
  • Wittig olefination

Correct Answer: Mannich-type or intramolecular aza-Michael cyclization

Q20. Which limitation is especially important when planning synthesis of highly strained three-membered rings for drug candidates?

  • Three-membered rings never undergo ring-opening reactions in vivo
  • High ring strain can lead to instability and undesired ring-opening or metabolic liabilities
  • They are always the least reactive functional groups
  • They preferentially form six-membered rings under all conditions

Correct Answer: High ring strain can lead to instability and undesired ring-opening or metabolic liabilities

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