Named Reactions: Vilsmeier–Haack reaction MCQs With Answer

Named Reactions: Vilsmeier–Haack reaction MCQs With Answer

Introduction: The Vilsmeier–Haack reaction is a powerful and widely used method for formylating activated aromatic and heteroaromatic compounds using N,N-dimethylformamide (DMF) activated by a chlorinating agent (commonly POCl3). For M.Pharm students, understanding this reaction is essential because it connects mechanistic organic chemistry with practical synthesis of pharmaceutical intermediates bearing formyl groups. This blog-style MCQ set focuses on mechanism, reagent roles, scope, regioselectivity, limitations, workup and comparisons with other formylation methods. The questions are designed to deepen conceptual knowledge and prepare students for application in drug discovery and synthetic route planning.

Q1. What is the active electrophilic species generated in the Vilsmeier–Haack reaction when DMF reacts with POCl3?

• N,N-Dimethylcarbamoyl chloride
• Chloroiminium salt [(Me2N=CHCl)+ X-]
• Formyl chloride (HCOCl)
• Dimethylamine hydrochloride

Correct Answer: Chloroiminium salt [(Me2N=CHCl)+ X-]

Q2. Which step best describes the key transformation of the aromatic substrate in the Vilsmeier–Haack reaction?

• Nucleophilic aromatic substitution followed by elimination
• Radical halogenation followed by rearrangement
• Electrophilic aromatic substitution giving an iminium-substituted intermediate
• Pericyclic [4+2] cycloaddition

Correct Answer: Electrophilic aromatic substitution giving an iminium-substituted intermediate

Q3. After formation of the iminium-substituted aromatic intermediate, what is the usual final step to obtain the aldehyde product?

• Oxidation with KMnO4
• Hydrolytic workup with aqueous base or water
• Reduction with NaBH4
• Dehydration with molecular sieves

Correct Answer: Hydrolytic workup with aqueous base or water

Q4. Which of the following substrates is most readily formylated by the Vilsmeier–Haack reaction?

• Benzene
• Nitrobenzene
• Anisole (methoxybenzene)
• Benzoic acid

Correct Answer: Anisole (methoxybenzene)

Q5. What is the primary role of POCl3 in the classical Vilsmeier–Haack protocol?

• Oxidizing agent to convert alcohols to aldehydes
• Chlorinating/dehydrating agent that activates DMF to the chloroiminium electrophile
• Base to deprotonate the aromatic σ-complex
• Solvent for the reaction

Correct Answer: Chlorinating/dehydrating agent that activates DMF to the chloroiminium electrophile

Q6. Which regioselectivity is typically observed when anisole undergoes the Vilsmeier–Haack formylation?

• Predominantly ortho substitution due to resonance
• Predominantly para substitution due to steric and resonance factors
• Exclusive meta substitution
• Random mixture of ortho, meta and para

Correct Answer: Predominantly para substitution due to steric and resonance factors

Q7. Which heterocycle is commonly formylated at the 2-position by the Vilsmeier–Haack reaction?

• Pyridine at C-3
• Pyrrole at C-2
• Pyridine at C-4
• Benzothiazole at C-5

Correct Answer: Pyrrole at C-2

Q8. Which functional group on an aromatic ring usually prevents Vilsmeier–Haack formylation under standard conditions?

• Halogen (Cl, Br)
• Electron-donating methoxy
• Nitro group
• Alkyl group

Correct Answer: Nitro group

Q9. What is a common alternative reagent combination that can generate the Vilsmeier reagent besides POCl3 + DMF?

• SOCl2 + DMF
• Oxalyl chloride (COCl)2 + DMF
• PBr3 + DMF
• LiAlH4 + DMF

Correct Answer: Oxalyl chloride (COCl)2 + DMF

Q10. In the mechanistic sequence, which intermediate is formed immediately after electrophilic attack of the Vilsmeier reagent on the aromatic ring?

• σ-Complex (Wheland intermediate) bearing an iminium substituent
• Carbanion stabilized by DMF
• Benzyl radical intermediate
• Epoxide intermediate

Correct Answer: σ-Complex (Wheland intermediate) bearing an iminium substituent

Q11. How does the Vilsmeier–Haack reaction compare with the Gattermann–Koch reaction for aromatic formylation?

• Vilsmeier–Haack uses CO and HCl; Gattermann–Koch uses DMF and POCl3
• Vilsmeier–Haack is better for strongly deactivated rings; Gattermann–Koch is for activated rings
• Vilsmeier–Haack uses a chloroiminium electrophile from DMF; Gattermann–Koch uses CO/HCl with a Lewis acid and is limited by CO handling
• They are identical in mechanism and reagents

Correct Answer: Vilsmeier–Haack uses a chloroiminium electrophile from DMF; Gattermann–Koch uses CO/HCl with a Lewis acid and is limited by CO handling

Q12. What is a typical solvent choice for running a Vilsmeier–Haack reaction?

• Water
• DMF often serves both as reagent and solvent; dichloromethane or chloroform are sometimes used as co-solvents
• Methanol
• Liquid ammonia

Correct Answer: DMF often serves both as reagent and solvent; dichloromethane or chloroform are sometimes used as co-solvents

Q13. Which safety or handling issue is particularly relevant when using POCl3 in the Vilsmeier–Haack reaction?

• POCl3 is a strong oxidizer and explosive
• POCl3 is highly corrosive and reacts violently with water releasing HCl
• POCl3 is inert and non-toxic
• POCl3 is pyrophoric in air

Correct Answer: POCl3 is highly corrosive and reacts violently with water releasing HCl

Q14. Which statement best describes why tertiary amines (e.g., -NMe2 substituents) on the aromatic ring can interfere with Vilsmeier–Haack formylation?

• Tertiary amines strongly deactivate the ring toward electrophiles
• Tertiary amines are protonated or alkylated by the Vilsmeier reagent and lose directing ability
• Tertiary amines undergo oxidation to nitro groups under conditions
• Tertiary amines are unchanged and do not affect the reaction

Correct Answer: Tertiary amines are protonated or alkylated by the Vilsmeier reagent and lose directing ability

Q15. Which by-product is commonly formed when the Vilsmeier reagent is hydrolyzed during workup?

• Dimethylformamide (DMF) regenerates unchanged
• Dimethylamine and formyl derivatives leading to formic acid or salts
• Molecular chlorine
• Carbon monoxide as the major liquid-phase by-product

Correct Answer: Dimethylamine and formyl derivatives leading to formic acid or salts

Q16. For which transformation is the Vilsmeier–Haack reaction NOT well-suited?

• Formylation of electron-rich aromatics
• Formylation of pyrroles and indoles at their reactive positions
• Formylation of strongly electron-poor aromatics bearing multiple electron-withdrawing groups
• Synthesis of salicylaldehydes from activated phenols

Correct Answer: Formylation of strongly electron-poor aromatics bearing multiple electron-withdrawing groups

Q17. What happens if excess POCl3 remains when the reaction mixture is quenched with water?

• Nothing particular; reaction is unaffected
• Violent exotherm with release of HCl and possible decomposition of product
• POCl3 spontaneously becomes inert on contact with water
• It converts aldehyde into its acetal quantitatively

Correct Answer: Violent exotherm with release of HCl and possible decomposition of product

Q18. Which structural feature of the Vilsmeier electrophile stabilizes the positive charge and affects its reactivity?

• Resonance delocalization into a carbonyl group
• Resonance stabilization by the N,N-dialkylamino group forming an iminium-like system
• Hyperconjugation from multiple alkyl substituents only
• Coordination to a metal center

Correct Answer: Resonance stabilization by the N,N-dialkylamino group forming an iminium-like system

Q19. Which experimental modification can improve regioselectivity toward ortho formylation when sterics favor para substitution?

• Running the reaction at very high temperature (>150 °C)
• Using bulky Lewis acids to block para-site
• Using stoichiometric amounts of water during reaction
• Using excess DMF only

Correct Answer: Using bulky Lewis acids to block para-site

Q20. Which analytical technique is most useful to confirm conversion of the iminium intermediate to the aldehyde after hydrolytic workup?

• IR spectroscopy showing C=O stretch near 1700 cm-1 and disappearance of C=N stretch
• UV-Vis only
• Polarimetry showing optical rotation change
• Gas evolution monitoring alone

Correct Answer: IR spectroscopy showing C=O stretch near 1700 cm-1 and disappearance of C=N stretch

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