Heterocyclic Chemistry: Smiles rearrangement and Traube purine synthesis MCQs With Answer

Introduction:

This quiz-focused blog on Heterocyclic Chemistry: Smiles rearrangement and Traube purine synthesis is designed for M.Pharm students studying MPC 102T Advanced Organic Chemistry I. It provides a concise, exam-oriented set of multiple-choice questions that probe mechanism, scope, reaction conditions, intermediates, and synthetic applications of both the Smiles family of rearrangements and the Traube route to purines. Emphasis is on understanding key steps (Meisenheimer intermediates, Truce–Smiles variants, diazotization and ring closure), reagents and limitations, and practical uses in heterocycle synthesis. Use this targeted practice to reinforce conceptual mastery and problem-solving for graduate-level pharmaceutics and medicinal chemistry.

Q1. What best describes the classical Smiles rearrangement?

• An intramolecular nucleophilic aromatic substitution in which an attached nucleophile attacks the aromatic ring, producing migration of an aryl or heteroaryl group via a Meisenheimer-type intermediate
• A radical chain process that substitutes hydrogen on heterocycles by halogen atoms
• An acid-catalyzed electrophilic substitution on activated aromatics leading to Friedel–Crafts alkylation
• A photochemical [2+2] cycloaddition followed by ring opening to give rearranged products

Correct Answer: An intramolecular nucleophilic aromatic substitution in which an attached nucleophile attacks the aromatic ring, producing migration of an aryl or heteroaryl group via a Meisenheimer-type intermediate

Q2. Which structural feature most commonly activates the aromatic ring toward a Smiles rearrangement?

• A strong electron-withdrawing group (e.g., nitro) at an ortho or para position relative to the ipso site
• A strong electron-donating group (e.g., methoxy) at the ipso carbon
• A bulky tert-butyl substituent adjacent to the leaving group
• A saturated alkyl chain attached to the aromatic ring

Correct Answer: A strong electron-withdrawing group (e.g., nitro) at an ortho or para position relative to the ipso site

Q3. In the classical Smiles rearrangement which of the following is a typical leaving group?

• An aryl ether oxygen (phenoxide) or thiophenoxide derived leaving group
• A primary alkyl chloride attached to a saturated carbon
• An unactivated aromatic hydrogen
• A carboxylate that cannot stabilize negative charge

Correct Answer: An aryl ether oxygen (phenoxide) or thiophenoxide derived leaving group

Q4. The Truce–Smiles rearrangement is distinct because it typically involves:

• An anionic carbon nucleophile (carbanion) attacking an aryl sulfone leading to aryl transfer without requiring a strong nitro activation
• A radical-mediated aryl migration promoted by peroxides under aerobic conditions
• An intramolecular proton transfer followed by electrocyclic ring closure
• A photoredox-catalyzed single-electron oxidation of electron-rich arenes

Correct Answer: An anionic carbon nucleophile (carbanion) attacking an aryl sulfone leading to aryl transfer without requiring a strong nitro activation

Q5. Which intermediate is most commonly invoked in the mechanism of Smiles-type rearrangements on activated aromatic rings?

• A Meisenheimer (σ) complex formed after nucleophilic attack on the aromatic ring
• A benzyne intermediate formed by elimination of a leaving group and hydrogen
• A stabilized carbocation on the aromatic ring
• A biradical formed by homolytic cleavage of a C–X bond

Correct Answer: A Meisenheimer (σ) complex formed after nucleophilic attack on the aromatic ring

Q6. Typical reaction conditions that promote Smiles rearrangements are:

• Strong base (e.g., NaH, t-BuOK) in polar aprotic solvent or milder base (K2CO3) with activated rings
• Neutral water at room temperature in the absence of base or catalyst
• Excess Brønsted acid (HCl concentrated) and heat
• Low-temperature photochemical activation in nonpolar solvent

Correct Answer: Strong base (e.g., NaH, t-BuOK) in polar aprotic solvent or milder base (K2CO3) with activated rings

Q7. The regioselectivity of the aromatic bond cleavage/formation in the Smiles rearrangement is best described as:

• Ipso substitution where the nucleophile attacks the ipso carbon and a substituent migrates from that same carbon
• Ortho-selective electrophilic substitution to form new C–C bonds exclusively
• Meta-selective free-radical halogenation followed by migration
• Unselective fragmentation producing a statistical mixture of isomers

Correct Answer: Ipso substitution where the nucleophile attacks the ipso carbon and a substituent migrates from that same carbon

Q8. Which statement best contrasts Smiles rearrangement with classic intermolecular S_NAr?

• Smiles is typically intramolecular and often involves migration of a tethered group, whereas S_NAr is intermolecular nucleophilic aromatic substitution
• Smiles proceeds only under radical conditions, while S_NAr is only ionic
• Smiles always gives para-substitution whereas S_NAr always gives ortho-substitution
• Smiles is an electrophilic aromatic substitution pathway whereas S_NAr is nucleophilic

Correct Answer: Smiles is typically intramolecular and often involves migration of a tethered group, whereas S_NAr is intermolecular nucleophilic aromatic substitution

Q9. Which of the following bond types is least commonly formed directly by a Smiles rearrangement?

• Aromatic C–F bond formed via direct Smiles migration
• C–N bond formed by attack of oxygen- or sulfur-bound nucleophiles and migration of aryl groups
• C–O bond formation through O-to-O or O–aryl reorganizations in certain variants
• C–S bond formation in sulfur-containing Smiles variants

Correct Answer: Aromatic C–F bond formed via direct Smiles migration

Q10. In mechanistic studies of Smiles reactions the rate-determining step is generally considered to be:

• The initial nucleophilic attack on the aromatic ring to form the Meisenheimer complex
• The expulsion of the leaving group after Meisenheimer formation
• The final proton transfer to regenerate aromaticity
• The diffusion-controlled encounter between substrates in very dilute solution

Correct Answer: The initial nucleophilic attack on the aromatic ring to form the Meisenheimer complex

Q11. A common synthetic application of the Smiles/Truce–Smiles strategies in medicinal chemistry is:

• The construction of diarylamines and heteroaryl–carbon connections as core motifs in drug scaffolds
• The polymerization of monomers to form polyethylene
• The direct conversion of alkanes to alcohols under mild conditions
• The selective hydrogenation of aromatic rings to cyclohexanes

Correct Answer: The construction of diarylamines and heteroaryl–carbon connections as core motifs in drug scaffolds

Q12. A limitation often encountered in Smiles rearrangements is:

• Need for an electron-deficient aromatic ring or good leaving group to stabilize the σ-complex, limiting substrate scope
• Incompatibility with any polar solvents, forcing exclusive use of hydrocarbons
• Mandatory use of photoredox catalysts which are expensive and unstable
• Requirement that reactions be conducted at cryogenic temperatures (below −78 °C)

Correct Answer: Need for an electron-deficient aromatic ring or good leaving group to stabilize the σ-complex, limiting substrate scope

Q13. The Traube purine synthesis classically uses which starting material class?

• 5-Aminopyrimidine derivatives that are elaborated to a fused imidazole–pyrimidine system (purine)
• Benzene derivatives that undergo Friedel–Crafts alkylation to form purines
• Carbohydrate derivatives that cyclize to purine rings under acidic conditions
• Aliphatic amines that are oxidized directly to purines

Correct Answer: 5-Aminopyrimidine derivatives that are elaborated to a fused imidazole–pyrimidine system (purine)

Q14. Which reagent is most commonly associated with initial functionalization in Traube purine syntheses (e.g., transformation of the 5-amino group)?

• Nitrous acid (HNO2) used for nitrosation/diazotization steps preceding cyclization
• Lithium aluminum hydride (LiAlH4) for exhaustive reduction
• Ozone (O3) to cleave double bonds
• Hydroboration–oxidation reagents for alkene functionalization

Correct Answer: Nitrous acid (HNO2) used for nitrosation/diazotization steps preceding cyclization

Q15. The key transformation in the Traube purine synthesis that builds the purine bicyclic system is best described as:

• Formation of an imidazole ring fused to the existing pyrimidine by intramolecular condensation/cyclization
• Oxidative cleavage of the pyrimidine ring to give two separate heterocycles
• Diels–Alder cycloaddition between pyrimidine and an alkene partner
• Direct metal-catalyzed C–H activation of pyrimidine to attach an imidazole fragment

Correct Answer: Formation of an imidazole ring fused to the existing pyrimidine by intramolecular condensation/cyclization

Q16. A typical sequence in Traube purine synthesis includes:

• Diazotization/nitrosation of the 5-amino site, generation of a reactive intermediate, and intramolecular closure to form the imidazole ring
• Radical chlorination followed by Sandmeyer-type substitution to install chlorine at multiple positions
• Electrophilic aromatic substitution at the pyrimidine ring with acyl chlorides under Friedel–Crafts conditions
• Direct photochemical fusion of an imidazole onto pyrimidine without prior functional group modification

Correct Answer: Diazotization/nitrosation of the 5-amino site, generation of a reactive intermediate, and intramolecular closure to form the imidazole ring

Q17. Which reagent is least likely to be employed in Traube purine synthesis?

• Grignard reagent used for large-scale nucleophilic additions to unactivated pyrimidines
• Nitrous acid for diazotization steps
• Cyanamide or equivalent C–N building blocks in some Traube protocols

Correct Answer: Grignard reagent used for large-scale nucleophilic additions to unactivated pyrimidines

Q18. A practical limitation of Traube purine syntheses in preparative heterocyclic chemistry is:

• Requirement for a suitably substituted 5-aminopyrimidine precursor, which can limit access to some substitution patterns
• Mandatory use of strong photochemical irradiation and rare earth catalysts
• Complete incompatibility with all nitrogen-containing solvents
• Ineffectiveness at temperatures above −100 °C

Correct Answer: Requirement for a suitably substituted 5-aminopyrimidine precursor, which can limit access to some substitution patterns

Q19. Which application best exemplifies why Traube purine synthesis remains relevant to medicinal chemists?

• It provides a modular route to substituted purines and purine analogs that serve as nucleoside mimics and kinase inhibitors
• It is routinely used to polymerize monomers for plastic manufacture
• It exclusively produces natural nucleosides with no scope for substitution
• It is primarily a method to prepare saturated cyclohexane derivatives

Correct Answer: It provides a modular route to substituted purines and purine analogs that serve as nucleoside mimics and kinase inhibitors

Q20. When combining knowledge of Smiles and Traube strategies in heterocyclic synthesis, an advanced synthetic plan might involve:

• Using Smiles or Truce–Smiles tactics to assemble aryl–heteroatom linkages followed by Traube-type cyclizations to construct fused purine frameworks
• Relying solely on high-pressure hydrogenation to create both aryl–heteroatom bonds and fused purines in one step
• Avoiding any intramolecular rearrangements and using only intermolecular radical halogenations
• Performing Smiles rearrangement under aqueous acidic conditions and then applying photochemical Traube coupling without intermediate purification in all cases

Correct Answer: Using Smiles or Truce–Smiles tactics to assemble aryl–heteroatom linkages followed by Traube-type cyclizations to construct fused purine frameworks

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