Named Reactions: Mitsunobu reaction MCQs With Answer

Introduction

The Mitsunobu reaction is a powerful and widely used transformation in organic synthesis that converts alcohols into a variety of functional derivatives under mild conditions. For M.Pharm students, understanding this named reaction is essential because it offers stereochemical control (typically inversion at a stereocenter), broad nucleophile scope (acids, phenols, thiols, amines in modified protocols), and applicability in complex molecule construction. Key reagents include triphenylphosphine and an azodicarboxylate (DIAD or DEAD), and the mechanism proceeds via oxyphosphonium activation and SN2 displacement. This quiz set focuses on mechanistic details, reagent roles, scope, limitations and practical considerations relevant to pharmaceutical synthesis.

Q1. What are the two core reagents required for a classical Mitsunobu reaction?

• Triphenylphosphine and an azodicarboxylate (e.g., DIAD or DEAD)
• Thionyl chloride and pyridine
• Lithium aluminum hydride and ether
• Tosyl chloride and triethylamine

Correct Answer: Triphenylphosphine and an azodicarboxylate (e.g., DIAD or DEAD)

Q2. Which of the following best describes the stereochemical outcome at a secondary alcohol carbon in a standard Mitsunobu reaction?

• Retention of configuration via radical pathway
• Inversion of configuration via an SN2 displacement
• No change in stereochemistry because the alcohol is not involved
• Racemization to give a racemic mixture

Correct Answer: Inversion of configuration via an SN2 displacement

Q3. In the Mitsunobu mechanism, which species is responsible for converting the alcohol into a better leaving group (oxyphosphonium intermediate)?

• Triphenylphosphine (PPh3) after reaction with the azodicarboxylate
• The nucleophile directly attacks the alcohol
• Hydrazine byproduct forms the leaving group
• Solvent molecules (e.g., THF) activate the alcohol

Correct Answer: Triphenylphosphine (PPh3) after reaction with the azodicarboxylate

Q4. Which byproduct is formed from triphenylphosphine during the Mitsunobu reaction?

• Triphenylphosphine oxide (Ph3P=O)
• Triphenylphosphine hydride (Ph3PH)
• Triphenylphosphine chloride (Ph3PCl)
• Triphenylphosphine radical

Correct Answer: Triphenylphosphine oxide (Ph3P=O)

Q5. Which pronucleophiles are normally suitable for direct use in a Mitsunobu reaction without further activation?

• Acidic pronucleophiles such as carboxylic acids, phenols, and thiols
• Non-acidic alcohols and alkanes
• Strong bases such as alkali metal amides
• Neutral hydrocarbons and ethers

Correct Answer: Acidic pronucleophiles such as carboxylic acids, phenols, and thiols

Q6. Which azodicarboxylate reagent is commonly considered safer and more commonly used than DEAD?

• DIAD (diisopropyl azodicarboxylate)
• ADN (azodinitrile)
• TAD (triazodicarboxylate)
• DEAD is always preferred and safer

Correct Answer: DIAD (diisopropyl azodicarboxylate)

Q7. What is the approximate pKa range of pronucleophiles that typically work well in a Mitsunobu reaction?

• pKa ≤ ~15 (e.g., carboxylic acids, phenols, thiols)
• pKa > 30 (very weak acids)
• pKa between 20–30 only
• Any pKa value works equally well

Correct Answer: pKa ≤ ~15 (e.g., carboxylic acids, phenols, thiols)

Q8. Which statement best describes the role of the azodicarboxylate (e.g., DIAD) in the Mitsunobu reaction?

• Acts as an oxidant and electron acceptor, being reduced to a hydrazide
• Serves as nucleophile that substitutes the alcohol directly
• Functions as solvent stabilizer and is not chemically consumed
• Forms a radical that abstracts hydrogen from the alcohol

Correct Answer: Acts as an oxidant and electron acceptor, being reduced to a hydrazide

Q9. Which of the following alcohol classes is least suitable for a straightforward Mitsunobu reaction?

• Tertiary alcohols due to steric hindrance and difficulty of SN2
• Primary alcohols which undergo smooth SN2 displacement
• Secondary alcohols which typically invert stereochemistry
• Benzylic primary alcohols which are reactive

Correct Answer: Tertiary alcohols due to steric hindrance and difficulty of SN2

Q10. Which solvent is commonly used for Mitsunobu reactions because it dissolves reagents and is aprotic?

• Tetrahydrofuran (THF)
• Water
• Ethanol (protic solvent)
• Hydrochloric acid

Correct Answer: Tetrahydrofuran (THF)

Q11. What is a common practical problem in workup of Mitsunobu reactions encountered in medicinal chemistry labs?

• Removal of triphenylphosphine oxide (Ph3P=O), which is polar and often sticky
• Large volumes of gaseous byproducts that require scrubbing
• Formation of insoluble metallic salts
• Excessive polymerization of the desired product

Correct Answer: Removal of triphenylphosphine oxide (Ph3P=O), which is polar and often sticky

Q12. How does an intramolecular Mitsunobu reaction commonly benefit synthetic strategy?

• It enables lactone or cyclic ether formation with stereochemical control
• It always gives racemates, complicating synthesis
• It prevents ring closure due to competing elimination
• It avoids formation of any cyclic products

Correct Answer: It enables lactone or cyclic ether formation with stereochemical control

Q13. Which modification is commonly used when a weakly acidic nucleophile (e.g., an amine) is required in Mitsunobu-type chemistry?

• Convert the nucleophile into a more acidic derivative (e.g., phthalimide) or use activating additives
• Use more DIAD to force the reaction without modification
• Use water as co-solvent to increase acidity
• Replace PPh3 with sodium borohydride

Correct Answer: Convert the nucleophile into a more acidic derivative (e.g., phthalimide) or use activating additives

Q14. Which of the following is a common alternative method if the Mitsunobu reaction fails due to steric hindrance?

• Convert the alcohol to a sulfonate (e.g., tosylate) then perform nucleophilic substitution
• Try direct radical chlorination of the alcohol
• Perform direct dehydrogenation to form an alkene
• Use catalytic hydrogenation to invert the stereochemistry

Correct Answer: Convert the alcohol to a sulfonate (e.g., tosylate) then perform nucleophilic substitution

Q15. Which byproduct(s) arise from reduction of the azodicarboxylate during the Mitsunobu reaction?

• A hydrazine-type derivative (e.g., diisopropyl hydrazinedicarboxylate)
• Carbon dioxide and methane exclusively
• Elemental nitrogen gas only
• No byproduct is formed from the azodicarboxylate

Correct Answer: A hydrazine-type derivative (e.g., diisopropyl hydrazinedicarboxylate)

Q16. In a Mitsunobu reaction converting a secondary alcohol to an ester using benzoic acid, what is the nucleophile?

• Benzoate anion derived from benzoic acid
• The alcohol itself acting as nucleophile
• Triphenylphosphine as nucleophile
• DIAD acting as nucleophile

Correct Answer: Benzoate anion derived from benzoic acid

Q17. Under which condition might a Mitsunobu reaction give retention of configuration instead of inversion?

• If double inversion occurs via sequential transformations or when intramolecular SN1-like processes intervene
• When a primary alcohol is used under standard conditions
• When no azodicarboxylate is present
• When the reaction is performed at −78 °C only

Correct Answer: If double inversion occurs via sequential transformations or when intramolecular SN1-like processes intervene

Q18. For which pharmaceutical synthesis scenario is the Mitsunobu reaction particularly valuable?

• Installing an ester or ether at a stereogenic center with inversion, useful for preparing stereodefined prodrugs or analogues
• Large-scale hydrogenation of aromatic rings
• Generating primary amines by direct amination without protection
• Oxidizing alcohols to carbonyls efficiently

Correct Answer: Installing an ester or ether at a stereogenic center with inversion, useful for preparing stereodefined prodrugs or analogues

Q19. Which precaution is important when handling DEAD in a laboratory setting?

• DEAD is potentially explosive and toxic; handle at small scale with proper PPE and ventilation
• DEAD is inert and requires no special precautions
• DEAD must be handled under strongly basic aqueous conditions only
• DEAD should be heated above 200 °C before use

Correct Answer: DEAD is potentially explosive and toxic; handle at small scale with proper PPE and ventilation

Q20. How many equivalents of PPh3 and azodicarboxylate are typically used relative to the alcohol and pronucleophile in a stoichiometric Mitsunobu reaction?

• Approximately 1 equivalent of PPh3 and 1 equivalent of azodicarboxylate per alcohol/pronucleophile pair
• 10 equivalents of PPh3 and 0.1 equivalents of azodicarboxylate
• No PPh3 is required; azodicarboxylate alone suffices
• Only catalytic amounts of both reagents are used (ppm level)

Correct Answer: Approximately 1 equivalent of PPh3 and 1 equivalent of azodicarboxylate per alcohol/pronucleophile pair

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