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Question 60

The correct structure of the product 'P' in the following reaction is

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The starting material is a dipeptide composed of two amino acids: Asparagine (Asn) at the N-terminus and Serine (Ser) at the C-terminus. Combined, they contain several nucleophilic functional groups capable of reacting:

  • N-terminal alpha-amine group: Found on the Asparagine residue (-NH2).
  • Side-chain amide group: Found on the Asparagine side chain (-CONH2).
  • Side-chain hydroxyl group: Found on the Serine side chain (-OH).
  • C-terminal carboxylic acid group: Found on the Serine residue (-COOH).
  • Peptide bond amide group: The linkage holding the two amino acids together (-CONH-).

2. The Reagents and Reaction Type

The reagents are acetic anhydride (CH3CO)2O in excess and triethylamine (NEt3) as a base.

This is an acetylation reaction. Acetic anhydride introduces acetyl groups (CH3CO-) to nucleophilic atoms like nitrogen and oxygen. Because it is explicitly added in excess, every nucleophilic group that is strong enough to react will become fully acetylated.

3. Comparing Nucleophilicity: What Reacts and What Doesn't?

Not all nitrogen and oxygen atoms in a peptide react equally with acetic anhydride. Here is how they behave:

  • The N-terminal Amine (-NH2) Reacts: Primary aliphatic amines are highly nucleophilic. It readily attacks acetic anhydride to form a stable amide group (-NH-COCH3).
  • The Serine Hydroxyl (-OH) Reacts: The aliphatic alcohol group on Serine is nucleophilic enough to attack acetic anhydride, converting the alcohol into an ester group (-O-COCH3).
  • The Amide Groups Do NOT React: Both the side-chain amide (-CONH2) of Asparagine and the internal peptide backbone amide (-CONH-) are very poor nucleophiles. This is because the lone pairs on these nitrogen atoms are heavily delocalized into their adjacent carbonyl groups through resonance. Therefore, they remain unchanged.
  • The Carboxylic Acid (-COOH) Does NOT get permanently acetylated: While it can form a temporary mixed anhydride, under these standard conditions it reverts back or remains as the free carboxylic acid (-COOH) in the final isolated peptide product.

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