Protecting Groups: Carboxyl protection – esters, amides, hydrazides MCQs With Answer

Protecting Groups: Carboxyl protection – esters, amides, hydrazides MCQs With Answer

This quiz set focuses on carboxyl protecting strategies — particularly esters, amides and hydrazides — tailored for M.Pharm students studying MPC 102T Advanced Organic Chemistry I. It covers selection criteria, formation and cleavage methods, mechanistic aspects, orthogonality, stability under synthetic conditions and common reagents used in laboratory practice. Questions emphasize practical decision-making: which protecting group to choose for base- or acid-sensitive molecules, how to avoid racemization during activation, and how hydrazide chemistry integrates into peptide and rearrangement transformations. Use these MCQs to test and deepen your understanding of carboxyl protection in multi-step organic syntheses and pharmaceutical compound assembly.

Q1. What is the primary purpose of using carboxyl protecting groups (esters, amides, hydrazides) in multi-step organic synthesis?

• To permanently block reactivity so the group is never regenerated
• To increase the acidity of the carboxyl group for later reactions
• To temporarily mask the carboxyl functionality to prevent undesired reactions during subsequent steps
• To convert the carboxyl into a leaving group for nucleophilic substitution

Correct Answer: To temporarily mask the carboxyl functionality to prevent undesired reactions during subsequent steps

Q2. Which ester protecting group is most commonly removed by catalytic hydrogenation (H2, Pd/C)?

• Methyl ester
• Tert-butyl ester
• Benzyl ester
• Isopropyl ester

Correct Answer: Benzyl ester

Q3. Which carboxyl protecting group is classically cleaved under strong acid (e.g., trifluoroacetic acid) but is stable to basic hydrolysis?

• Methyl ester
• Benzyl ester
• Tert-butyl ester
• Allyl ester

Correct Answer: Tert-butyl ester

Q4. Which reagent is commonly used for mild and relatively racemization-free conversion of carboxylic acids to methyl esters in the laboratory?

• Thionyl chloride followed by methanol
• TMS-diazomethane
• Sodium methoxide at high temperature
• Mitsunobu reaction with methanol

Correct Answer: TMS-diazomethane

Q5. The Steglich esterification to form esters from acids and alcohols typically employs which activating reagent pair?

• SOCl2 and pyridine
• DCC and DMAP
• H2/Pd and ethanol
• LiAlH4 and methanol

Correct Answer: DCC and DMAP

Q6. Which deprotection method is orthogonal to acid cleavage and suitable for selectively removing a benzyl ester while leaving tert‑butyl ester intact?

• Acidic cleavage with TFA
• Basic hydrolysis with NaOH
• Catalytic hydrogenolysis (H2, Pd/C)
• Thermal cleavage at high temperature

Correct Answer: Catalytic hydrogenolysis (H2, Pd/C)

Q7. What is a major advantage of converting a carboxylic acid to an amide as a protecting strategy?

• Amides are very easily cleaved under neutral conditions
• Amides are typically more reactive than esters toward nucleophiles
• Amides are chemically robust and resist many conditions, providing strong protection
• Amide formation avoids the need for coupling reagents

Correct Answer: Amides are chemically robust and resist many conditions, providing strong protection

Q8. Acyl hydrazides are useful carboxyl derivatives because they can be transformed into which of the following reactive intermediates by diazotization (NaNO2/HCl)?

• Acyl chlorides
• Acyl azides
• Anhydrides
• Carboxylate salts

Correct Answer: Acyl azides

Q9. Which protecting group pair is commonly cited as orthogonal for complex syntheses because one is removed by hydrogenolysis and the other by acid?

• Methyl ester and ethyl ester
• Benzyl ester and tert-butyl ester
• Tert-butyl ester and methyl ester
• Allyl ester and methyl ester

Correct Answer: Benzyl ester and tert-butyl ester

Q10. During activation of a carboxylic acid for amide bond formation, which additive is commonly used to suppress racemization of chiral centres?

• HOBt (1-hydroxybenzotriazole)
• Br2
• Hydrazine
• LiAlH4

Correct Answer: HOBt (1-hydroxybenzotriazole)

Q11. Which deprotection protocol selectively removes allyl esters under mild conditions without hydrogenolysis?

• Acidic TFA cleavage
• Pd(0)-catalyzed allyl transfer (e.g., Pd(PPh3)4 + nucleophile)
• Strong base hydrolysis at elevated temperature
• Radical hydrogen abstraction

Correct Answer: Pd(0)-catalyzed allyl transfer (e.g., Pd(PPh3)4 + nucleophile)

Q12. In the Steglich esterification mechanism the initially formed O-acylurea may rearrange unless trapped; which catalyst helps accelerate acyl transfer and reduces side reactions?

• DMAP (4-dimethylaminopyridine)
• Pd/C
• H2O
• NaOH

Correct Answer: DMAP (4-dimethylaminopyridine)

Q13. Which statement best describes acyl hydrazides as carboxyl protecting groups in synthesis?

• Acyl hydrazides are extremely labile to base and cannot withstand neutral conditions
• Acyl hydrazides are stable and can be readily converted to acyl azides or activated derivatives for further transformations
• Acyl hydrazides are removed exclusively by catalytic hydrogenation
• Acyl hydrazides cannot be formed from activated esters

Correct Answer: Acyl hydrazides are stable and can be readily converted to acyl azides or activated derivatives for further transformations

Q14. Which protecting group would you avoid if your synthetic sequence includes prolonged exposure to strong acids?

• Tert-butyl ester
• Benzyl ester
• Methyl ester
• Amide

Correct Answer: Tert-butyl ester

Q15. A straightforward method to convert a carboxylic acid to an amide under mild conditions involves which combination?

• Formation of acid chloride (SOCl2) followed by reaction with primary/secondary amine
• Hydrolysis with aqueous NaOH
• Hydrogenation with Pd/C
• Mitsunobu reaction with an alcohol

Correct Answer: Formation of acid chloride (SOCl2) followed by reaction with primary/secondary amine

Q16. For a molecule that is base-sensitive but must have its carboxyl temporarily masked, which ester protecting group is most suitable?

• Methyl ester (cleaved by base)
• Tert-butyl ester (cleaved by acid)
• Benzyl ester (requires hydrogenolysis)
• Ethyl ester (identical to methyl in base lability)

Correct Answer: Tert-butyl ester (cleaved by acid)

Q17. Which statement about methyl esters is correct regarding typical deprotection?

• Methyl esters are commonly removed by catalytic hydrogenation
• Methyl esters are generally resistant to strong acid but easily cleaved by mild acids
• Methyl esters are typically cleaved by base-catalyzed saponification or by stronger acidic conditions
• Methyl esters can be selectively removed in the presence of tert‑butyl esters using TFA

Correct Answer: Methyl esters are typically cleaved by base-catalyzed saponification or by stronger acidic conditions

Q18. Which modern coupling reagent combination is known for efficient amide bond formation with low racemization in peptide chemistry?

• HATU with a tertiary amine base (e.g., DIPEA)
• SOCl2 alone
• Thionyl chloride with pyridine
• Strong base (NaH) in absence of coupling additives

Correct Answer: HATU with a tertiary amine base (e.g., DIPEA)

Q19. How are acyl hydrazides most commonly prepared from carboxylic acids in the laboratory?

• Direct heating of carboxylic acid with hydrazine hydrate or reaction via activated ester/acid chloride followed by hydrazine
• Direct hydrogenation of the acid
• Oxidation of the corresponding alcohol
• Photochemical rearrangement of esters

Correct Answer: Direct heating of carboxylic acid with hydrazine hydrate or reaction via activated ester/acid chloride followed by hydrazine

Q20. Which carboxyl protecting group is typically resistant to base hydrolysis and therefore useful when strong base is present in later steps?

• Methyl ester
• Ethyl ester
• Benzyl ester
• Acyl chloride

Correct Answer: Benzyl ester

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