Synthetic Reagents: DCC and peptide coupling chemistry MCQs With Answer

Synthetic Reagents: DCC and peptide coupling chemistry MCQs With Answer

This focused quiz set covers DCC-mediated peptide coupling and related reagent chemistry tailored for M.Pharm students studying advanced organic chemistry. Through 20 carefully designed multiple-choice questions the quiz probes fundamental mechanisms—formation of O-acylisourea intermediates, pathways to N-acylurea side-products, and strategies to minimize racemization. It also examines the roles of common additives (HOBt, HOAt, Oxyma), nucleophilic catalysts (DMAP), and alternative carbodiimides (EDC, DIC), plus practical concerns like solvent choice, byproduct removal, and reaction troubleshooting. Answers include concise explanations to reinforce learning. Whether preparing for exams or refining laboratory technique this resource deepens conceptual understanding and practical competence in peptide coupling chemistry and safety.

Q1. What is the primary role of DCC in peptide bond formation?

• Acts as a reducing agent to convert amides to amines
• Serves as a dehydrating/activating reagent converting carboxyl groups to reactive O-acylisourea intermediates
• Functions as an acid catalyst to protonate amines
• Oxidizes alcohols to carbonyls

Correct Answer: Serves as a dehydrating/activating reagent converting carboxyl groups to reactive O-acylisourea intermediates

Q2. Which reactive intermediate is formed first when a carboxylic acid reacts with DCC?

• N-acylurea
• Acyl chloride
• O-acylisourea
• Anhydride

Correct Answer: O-acylisourea

Q3. The common irreversible side-product formed from O-acylisourea rearrangement is:

• Acyl azide
• N-acylurea
• Acyl chloride
• Carboxylate salt

Correct Answer: N-acylurea

Q4. Which additive is most classically used with DCC to suppress racemization and form a more stable active ester?

• DMAP
• HOBt (1-hydroxybenzotriazole)
• EDC
• TFA

Correct Answer: HOBt (1-hydroxybenzotriazole)

Q5. What is the mechanistic role of DMAP when used in acylation reactions?

• Acts as a strong oxidizing agent
• Serves as a nucleophilic acyl transfer catalyst by forming acyl-pyridinium intermediates
• Neutralizes DCC to form soluble ureas
• Protects amines by reversible protonation

Correct Answer: Serves as a nucleophilic acyl transfer catalyst by forming acyl-pyridinium intermediates

Q6. Compared to DCC, EDC (EDC·HCl) is often preferred in aqueous peptide couplings because:

• EDC forms an insoluble urea that is easier to remove
• EDC is a stronger base than DCC
• EDC gives a water-soluble urea byproduct that can be removed by aqueous washes
• EDC converts carboxyls directly to acid chlorides

Correct Answer: EDC gives a water-soluble urea byproduct that can be removed by aqueous washes

Q7. Which solvent is commonly used for DCC/HOBt peptide couplings due to its ability to dissolve both reagents and peptides?

• Water
• Diethyl ether
• Dimethylformamide (DMF)
• Hexane

Correct Answer: Dimethylformamide (DMF)

Q8. Oxyma Pure (ethyl cyano(hydroxyimino)acetate) is used as an additive in peptide coupling primarily because it:

• Is more explosive than HOBt and should be avoided
• Increases racemization compared to HOBt
• Reduces racemization and is a safer alternative to HOBt
• Converts carboxyls into acyl chlorides

Correct Answer: Reduces racemization and is a safer alternative to HOBt

Q9. Epimerization during carbodiimide-mediated coupling commonly proceeds via formation of which intermediate?

• Acyl chloride intermediate
• Oxazolone intermediate
• Imine intermediate
• Acetal intermediate

Correct Answer: Oxazolone intermediate

Q10. The most practical method to remove dicyclohexylurea (DCU) formed after a DCC coupling is:

• Steam distillation
• Vacuum sublimation directly from the reaction mixture
• Filtration of the precipitated DCU followed by solvent washes
• Complete evaporation of solvent leaving pure DCU

Correct Answer: Filtration of the precipitated DCU followed by solvent washes

Q11. Which base is commonly chosen for peptide couplings to deprotonate the amine while being sterically hindered and non-nucleophilic?

• Triethylamine (TEA)
• HCl
• DIPEA (N,N-diisopropylethylamine, Hünig’s base)
• Sodium hydroxide

Correct Answer: DIPEA (N,N-diisopropylethylamine, Hünig’s base)

Q12. In the carbodiimide coupling mechanism the first covalent bond-forming event is:

• Nucleophilic attack of the amine on the carboxylic acid
• Electrophilic attack of carbodiimide on the amine
• Nucleophilic attack of the carboxylate oxygen on the carbodiimide to form O-acylisourea
• Radical formation from carbodiimide decomposition

Correct Answer: Nucleophilic attack of the carboxylate oxygen on the carbodiimide to form O-acylisourea

Q13. Which additive provides higher coupling efficiency and typically less racemization than HOBt?

• HOAt (1-hydroxy-7-azabenzotriazole)
• Pyridine
• Sodium bicarbonate
• Acetic acid

Correct Answer: HOAt (1-hydroxy-7-azabenzotriazole)

Q14. Formation of N-acylurea from O-acylisourea is considered a dead-end because:

• It immediately hydrolyzes back to starting materials
• It cannot be converted back into an activated species for amide formation under normal coupling conditions
• It forms highly reactive species that over-acylate solvents
• It is a transient intermediate that enhances coupling

Correct Answer: It cannot be converted back into an activated species for amide formation under normal coupling conditions

Q15. Which carbodiimide is especially noted for its water solubility and is preferred for aqueous bioconjugation?

• DCC (dicyclohexylcarbodiimide)
• DIC (diisopropylcarbodiimide)
• EDC (1‑ethyl‑3‑(3‑dimethylaminopropyl)carbodiimide)
• Carbonyldiimidazole (CDI)

Correct Answer: EDC (1‑ethyl‑3‑(3‑dimethylaminopropyl)carbodiimide)

Q16. For an efficient DCC-mediated coupling with minimal waste, typical stoichiometry of DCC to carboxylic acid is:

• 0.1 equivalent (catalytic)
• 1.0 equivalent exactly
• 1.1–1.2 equivalents (slight excess)
• 5–10 equivalents (large excess)

Correct Answer: 1.1–1.2 equivalents (slight excess)

Q17. To minimize racemization of a sensitive α‑chiral amino acid during carbodiimide coupling you should:

• Activate for long periods at elevated temperature
• Use HOAt or Oxyma additives and perform activation at low temperature with short reaction times
• Omit additives and use a large excess of base
• Convert the carboxyl to acid chloride with thionyl chloride first

Correct Answer: Use HOAt or Oxyma additives and perform activation at low temperature with short reaction times

Q18. HOBt helps DCC couplings by:

• Forming an acyl benzotriazole active ester from the O-acylisourea, which is less prone to rearrangement and racemization
• Converting amines to imines prior to coupling
• Reducing DCC to dicyclohexylamine
• Serving as the primary solvent for the reaction

Correct Answer: Forming an acyl benzotriazole active ester from the O-acylisourea, which is less prone to rearrangement and racemization

Q19. A notable safety concern associated with HOBt is:

• It is highly volatile and flammable at room temperature
• Its dry salts can be shock-sensitive and potentially explosive if mishandled
• It emits toxic chlorine gas upon contact with DCC
• It polymerizes violently in common solvents

Correct Answer: Its dry salts can be shock-sensitive and potentially explosive if mishandled

Q20. For very sterically hindered amide bond formations where DCC performs poorly, which modern reagent is often chosen for higher efficiency?

• Thionyl chloride
• HATU (O‑(7‑azabenzotriazol‑1‑yl)‑N,N,N’,N’‑tetramethyluronium hexafluorophosphate)
• Sodium cyanoborohydride
• Hydrogen peroxide

Correct Answer: HATU (O‑(7‑azabenzotriazol‑1‑yl)‑N,N,N’,N’‑tetramethyluronium hexafluorophosphate)

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