Synthesis of isoquinoline MCQs With Answer

Synthesis of isoquinoline MCQs With Answer

The synthesis of isoquinoline is a core topic in pharmaceutical chemistry for B.Pharm students, covering classical routes like Pomeranz–Fritsch, Bischler–Napieralski and Pictet–Spengler, modern Pd-catalyzed annulations, reagents (POCl3, DDQ, P2O5), mechanisms (iminium formation, electrophilic cyclization, oxidative aromatization) and practical considerations such as regioselectivity, substituent effects and analytical identification. Understanding these methods is essential for designing isoquinoline derivatives in drug discovery and alkaloid synthesis. This collection of 50 targeted MCQs with answers focuses on reaction steps, intermediates, reagents and troubleshooting to strengthen your problem-solving skills. Now let’s test your knowledge with 50 MCQs on this topic.

Q1. What is isoquinoline?

• An aromatic heterocycle isomeric with quinoline, containing a nitrogen atom in the fused ring system
• A saturated bicyclic hydrocarbon used as a solvent
• A peptide used in drug formulations
• An alkane with two nitrogen atoms

Correct Answer: An aromatic heterocycle isomeric with quinoline, containing a nitrogen atom in the fused ring system

Q2. At which ring position is the nitrogen atom located in isoquinoline (relative to the fused benzene)?

• Position 1
• Position 2
• Position 3
• Position 4

Correct Answer: Position 2

Q3. Which classical method converts β-phenylethylamides into dihydroisoquinolines via cyclodehydration?

• Pomeranz–Fritsch reaction
• Bischler–Napieralski reaction
• Pictet–Spengler reaction

Correct Answer: Bischler–Napieralski reaction

Q4. Which reagent is commonly used for the dehydration step in the Bischler–Napieralski reaction?

• DDQ
• POCl3
• NaBH4
• LiAlH4

Correct Answer: POCl3

Q5. The Pomeranz–Fritsch synthesis typically proceeds via which key intermediate?

• Carbanion
• Iminium ion (or imine) intermediate
• Radical cation
• Ylide

Correct Answer: Iminium ion (or imine) intermediate

Q6. Which reaction is most commonly used to prepare tetrahydroisoquinolines from β-arylethylamines and aldehydes?

• Pomeranz–Fritsch
• Pictet–Spengler
• Bischler–Napieralski
• Skraup synthesis

Correct Answer: Pictet–Spengler

Q7. After forming dihydroisoquinoline in Bischler–Napieralski, which type of reagent is typically required to obtain aromatic isoquinoline?

• Reducing agent
• Oxidizing/dehydrogenation agent
• Acid quencher
• Nucleophilic catalyst

Correct Answer: Oxidizing/dehydrogenation agent

Q8. Which oxidant is frequently used for oxidative aromatization of dihydroisoquinolines to isoquinolines?

• DDQ
• LiAlH4
• Borane (BH3)
• Sodium borohydride

Correct Answer: DDQ

Q9. In electrophilic cyclization steps to form the isoquinoline core, the aromatic ring acts as which type of reactant?

• Nucleophile in electrophilic aromatic substitution
• Electrophile in nucleophilic aromatic substitution
• Radical initiator
• Base

Correct Answer: Nucleophile in electrophilic aromatic substitution

Q10. Which feature of the aromatic ring accelerates electrophilic cyclization during isoquinoline synthesis?

• Electron-donating substituents on the ring
• Strong electron-withdrawing substituents on the ring
• Saturated substituents
• Presence of a nitro group exclusively

Correct Answer: Electron-donating substituents on the ring

Q11. Which modern method enables isoquinoline formation via C–H activation and annulation?

• Pd-catalyzed annulation of aryl halides with alkynes
• Wurtz coupling
• Grignard addition to esters
• Friedel–Crafts acylation only

Correct Answer: Pd-catalyzed annulation of aryl halides with alkynes

Q12. Which reaction is less suitable for directly forming isoquinoline frameworks?

• Pomeranz–Fritsch
• Friedländer synthesis (designed for quinolines)
• Bischler–Napieralski
• Pictet–Spengler

Correct Answer: Friedländer synthesis (designed for quinolines)

Q13. What is the primary mechanistic role of POCl3 in the Bischler–Napieralski reaction?

• Oxidant to aromatize the ring
• Dehydrating agent that generates an iminium/nitrilium species
• Hydrogen donor
• Nucleophilic catalyst

Correct Answer: Dehydrating agent that generates an iminium/nitrilium species

Q14. Which intermediate is commonly formed during Pictet–Spengler cyclization before ring closure?

• Carbocation at benzylic position (iminium ion)
• Carbanion stabilized by metal
• Free radical stabilized by light
• Peroxide intermediate

Correct Answer: Carbocation at benzylic position (iminium ion)

Q15. For regioselective functionalization of isoquinoline, formation of the N-oxide is useful because:

• It permanently deactivates the ring for further reactions
• It directs lithiation to specific positions on the ring
• It converts isoquinoline to an alkane
• It removes nitrogen from the ring

Correct Answer: It directs lithiation to specific positions on the ring

Q16. Which reagent combination is commonly used to form Vilsmeier-type intermediates for ring functionalization (formylation) of isoquinolines?

• DMF and POCl3
• LiAlH4 and THF
• NaBH4 and ethanol
• H2 and Pd/C

Correct Answer: DMF and POCl3

Q17. Which transformation converts tetrahydroisoquinoline to isoquinoline?

• Oxidative aromatization (dehydrogenation)
• Hydrogenation
• Acylation of the nitrogen
• Alkylation at C-4

Correct Answer: Oxidative aromatization (dehydrogenation)

Q18. Which reagent is frequently used to oxidize dihydro- or tetrahydroisoquinolines to the aromatic isoquinoline?

• Manganese dioxide (MnO2)
• Sodium cyanoborohydride
• Hydrazine
• Borane

Correct Answer: Manganese dioxide (MnO2)

Q19. In an acid-catalyzed Pomeranz–Fritsch cyclization, what is the typical role of strong acid?

• To generate the iminium/activated species and promote cyclization
• To act as a reducing agent
• To stabilize carbanions
• To act as a nucleophile

Correct Answer: To generate the iminium/activated species and promote cyclization

Q20. Which statement about isoquinoline basicity is correct?

• Isoquinoline is typically more basic than pyridine
• Isoquinoline is typically less basic than pyridine
• Isoquinoline is a strong base comparable to alkylamines
• Isoquinoline is non-basic

Correct Answer: Isoquinoline is typically less basic than pyridine

Q21. Which analytical technique gives a characteristic downfield proton signal for the proton adjacent to nitrogen in isoquinoline?

• 1H NMR spectroscopy
• Infrared spectroscopy
• Mass spectrometry
• Elemental analysis

Correct Answer: 1H NMR spectroscopy

Q22. Which commercial oxidizing catalyst can mediate hydrogen removal (dehydrogenation) to form aromatic heterocycles?

• Pd/C under heating with acceptor
• LiAlH4 in ether
• NaBH4 in methanol
• Grignard reagent

Correct Answer: Pd/C under heating with acceptor

Q23. In directed ortho-metalation (DoM) strategies on isoquinoline derivatives, which functional group often acts as the directing group after N-oxidation?

• N-oxide functionality
• Terminal alkyne
• Methyl group
• Nitro group only

Correct Answer: N-oxide functionality

Q24. Which natural product class commonly contains the isoquinoline or tetrahydroisoquinoline core?

• Isoquinoline alkaloids (e.g., papaverine)
• Steroids
• Peptides
• Polyketides exclusively

Correct Answer: Isoquinoline alkaloids (e.g., papaverine)

Q25. What is a common synthetic challenge when making highly substituted isoquinolines?

• Regioselective cyclization and controlling electronic effects
• Lack of reagents
• Isoquinolines spontaneously polymerize in all cases
• They cannot be characterized by NMR

Correct Answer: Regioselective cyclization and controlling electronic effects

Q26. Which of the following best describes the Pomeranz–Fritsch–Bobbitt variant?

• An acid-catalyzed method using aminoacetals and aldehydes to form isoquinolines
• A radical polymerization method
• A metal-free hydrogenation
• A photochemical ring-opening

Correct Answer: An acid-catalyzed method using aminoacetals and aldehydes to form isoquinolines

Q27. For synthesizing 1-substituted isoquinolines selectively, which approach is often applied?

• Use of substituted starting benzaldehydes or directed metalation followed by cross-coupling
• Random alkylation under basic conditions
• Complete oxidation followed by reduction
• Direct nitration at position 1

Correct Answer: Use of substituted starting benzaldehydes or directed metalation followed by cross-coupling

Q28. What product results from catalytic hydrogenation of isoquinoline under typical conditions?

• Tetrahydroisoquinoline (partial hydrogenation)
• Complete ring cleavage to give benzene derivatives
• Oxidized isoquinoline N-oxide
• Unchanged isoquinoline because it is inert

Correct Answer: Tetrahydroisoquinoline (partial hydrogenation)

Q29. Which solvent type is commonly used in acid-catalyzed cyclizations for isoquinoline synthesis?

• Non-polar solvents always
• Acidic media or dichloromethane/CHCl3 with strong acid catalyst
• Strongly basic aqueous solution
• Purely aqueous neutral conditions

Correct Answer: Acidic media or dichloromethane/CHCl3 with strong acid catalyst

Q30. Which change in substrate substituents typically decreases the rate of electrophilic cyclization?

• Introduction of strong electron-donating groups
• Introduction of strong electron-withdrawing groups
• Addition of an ortho-methyl group that is electron-donating sterically favorable
• Replacing hydrogen with deuterium

Correct Answer: Introduction of strong electron-withdrawing groups

Q31. In the Pictet–Spengler reaction, which type of bond formation creates the new ring?

• C–C bond formation via electrophilic aromatic substitution
• Formation of an ether linkage
• Formation of a disulfide bond
• Salt formation only

Correct Answer: C–C bond formation via electrophilic aromatic substitution

Q32. Which reagent is commonly used to oxidize tertiary amines or dihydroheterocycles during synthesis?

• Oxone or DDQ depending on substrate
• NaBH4 in ethanol
• HCl gas
• Sodium hydroxide only

Correct Answer: Oxone or DDQ depending on substrate

Q33. For late-stage functionalization of isoquinolines, which catalysis strategy offers high regioselectivity?

• Transition-metal-catalyzed C–H activation with directing groups
• Random thermal cracking
• Non-selective radical chlorination without control
• Classical acidic nitration only

Correct Answer: Transition-metal-catalyzed C–H activation with directing groups

Q34. Which of the following is an advantage of using N-oxide intermediates in isoquinoline chemistry?

• They facilitate regioselective electrophilic substitution and metalation
• They deactivate all positions permanently
• They cannot be reduced back to isoquinoline
• They make the molecule insoluble

Correct Answer: They facilitate regioselective electrophilic substitution and metalation

Q35. Which oxidant should be avoided for sensitive substrates due to overoxidation risk during aromatization?

• Excess strong oxidants like nitric acid or peroxides
• Mild oxidants like DDQ in controlled amounts
• Biocatalytic oxidations under mild conditions
• Using oxygen with Pd catalysts under mild heat

Correct Answer: Excess strong oxidants like nitric acid or peroxides

Q36. Which step in classical isoquinoline synthesis is most influenced by solvent polarity?

• Formation and stabilization of iminium intermediates during cyclization
• Elimination of water only
• Atom transfer radical polymerization
• Hydrogenolysis only

Correct Answer: Formation and stabilization of iminium intermediates during cyclization

Q37. Which catalyst is commonly used for Pd-catalyzed annulation routes to isoquinolines?

• Pd(OAc)2 (palladium acetate)
• ZnCl2 only
• NaBH4 only
• Mg metal

Correct Answer: Pd(OAc)2 (palladium acetate)

Q38. When designing an isoquinoline synthesis for a drug lead, which property is most critical to consider early?

• Regioselectivity of substitution and functional group compatibility
• Color of the final compound only
• Price of laboratory centrifuge
• Shape of glassware

Correct Answer: Regioselectivity of substitution and functional group compatibility

Q39. Which of the following is a common spectroscopic indicator of successful aromatization to isoquinoline?

• Appearance of characteristic downfield 1H NMR signals and changes in UV absorbance consistent with conjugation
• A single peak at 0 ppm in 1H NMR
• Loss of all carbon signals in 13C NMR
• Complete absence of mass spectral peaks

Correct Answer: Appearance of characteristic downfield 1H NMR signals and changes in UV absorbance consistent with conjugation

Q40. Which protecting strategy is often used for the isoquinoline nitrogen to enable certain transformations?

• Oxidation to N-oxide, or N-acylation/protection
• Alkylation to permanently block the ring without removal
• Conversion to a nitro group
• Formation of an ether at the nitrogen

Correct Answer: Oxidation to N-oxide, or N-acylation/protection

Q41. Which synthetic route is most suitable for preparing 3-substituted isoquinolines via annulation with alkynes?

• Pd-catalyzed oxidative annulation of aryl amides with alkynes
• Simple nucleophilic substitution on benzene
• Direct halogenation at position 3 without catalyst
• Friedel–Crafts alkylation of isoquinoline

Correct Answer: Pd-catalyzed oxidative annulation of aryl amides with alkynes

Q42. What is a Green Chemistry approach to isoquinoline synthesis?

• Using catalytic transition metals, atom-economic annulations, and milder oxidants
• Using stoichiometric heavy metal oxidants exclusively
• Running reactions at extremely high temperatures for long times
• Using excess toxic solvents always

Correct Answer: Using catalytic transition metals, atom-economic annulations, and milder oxidants

Q43. Which moiety in starting materials is essential for Bischler–Napieralski cyclization?

• β‑Phenylethylamide (or equivalent amide precursor)
• Allylic alcohol only
• Epoxide ring
• Terminal alkyne only

Correct Answer: β‑Phenylethylamide (or equivalent amide precursor)

Q44. In practical lab work, what common problem may be encountered during acid-catalyzed cyclizations to form isoquinolines?

• Polymerization or decomposition under strongly acidic conditions
• Immediate crystallization of pure product only
• Complete inertness with no reaction even at high temperature
• Colorless gases evolving without mass change

Correct Answer: Polymerization or decomposition under strongly acidic conditions

Q45. Which of the following reagents can convert an isoquinoline to its N-oxide?

• m-CPBA (meta-chloroperbenzoic acid) or hydrogen peroxide with catalyst
• LiAlH4
• NaBH4 only
• Pd/C under hydrogen

Correct Answer: m-CPBA (meta-chloroperbenzoic acid) or hydrogen peroxide with catalyst

Q46. Which property of isoquinoline makes it useful as a ligand in coordination chemistry?

• The lone pair on nitrogen available for coordination to metals
• Its inability to coordinate metals
• Its high volatility only
• Being a strong acid

Correct Answer: The lone pair on nitrogen available for coordination to metals

Q47. During synthetic planning, converting an isoquinoline to a more reactive intermediate for substitution often uses:

• N‑oxide formation to activate positions for electrophilic substitution
• Reducing the molecule to an alkane
• Cleaving the bicyclic core entirely
• Adding inert salts to the mixture

Correct Answer: N‑oxide formation to activate positions for electrophilic substitution

Q48. Which type of spectroscopy can help confirm the presence of an isoquinoline ring by showing a characteristic C=N stretch?

• Infrared (IR) spectroscopy
• Thin-layer chromatography only
• Paper chromatography only
• Polarimetry only

Correct Answer: Infrared (IR) spectroscopy

Q49. Which transformation converts benzaldehyde derivatives and aminoacetals into isoquinoline frameworks when acid-catalyzed?

• Pomeranz–Fritsch cyclization
• Bischler–Napieralski without amide formation
• Wittig reaction
• Aldol condensation exclusively

Correct Answer: Pomeranz–Fritsch cyclization

Q50. Which of these is a practical safety or environmental consideration in isoquinoline syntheses?

• Avoiding excessive use of corrosive dehydrating agents and managing oxidant waste
• Using unlimited volumes of chlorinated solvents without controls
• Discarding metal catalysts directly into drains
• Always performing reactions with open flames in presence of volatile oxidants

Correct Answer: Avoiding excessive use of corrosive dehydrating agents and managing oxidant waste

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