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Ochem question from TPR

starbaduk

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10+ Year Member
Mar 22, 2009
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  1. Pre-Medical
    Passage 45 (last passage!)
    Problem 2

    Which one of the following would NOT be used to synthesize the Met-Ala-Leu tripeptide?

    The solution says: "A. Met amino acid and Ala-Leu peptide"

    Explanation: "Fast acid-base reaction prevents addition-elimination reactions from occurring between amines and carboxylic acid".

    I'm totally confused. I thought that's how peptides are usually made, between amino acid (Met, in this case) and an existing peptide!
     
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    sleepy425

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    10+ Year Member
    Mar 6, 2008
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    1. Fellow [Any Field]
      Passage 45 (last passage!)
      Problem 2

      Which one of the following would NOT be used to synthesize the Met-Ala-Leu tripeptide?

      The solution says: "A. Met amino acid and Ala-Leu peptide"

      Explanation: "Fast acid-base reaction prevents addition-elimination reactions from occurring between amines and carboxylic acid".

      I'm totally confused. I thought that's how peptides are usually made, between amino acid (Met, in this case) and an existing peptide!

      The whole point of this is that, if I add mix an amine and a carboxylic acid, even if I add an acid catalyst or w/e, the reaction will not proceed because of the acid base properties of the two reactants.

      Let's break it down:

      We would need the amine to be a nucleophile, and the carboxylic acid to be an electrophile. For the amine to be a nucleophile, it has to be deprotonated. For the carboxylic acid to be reasonably electrophilic, it has to be protonated (if it is deprotonated, it'll be way too poor of an electrophile).

      Anyway, so there is no way for you to have a solution where you would have a deprotonated amine and a protonated carboxylic acid, because the pKa of an amine is between 9 and 10 (usually, although amines like aniline, with good electron withdrawing groups attached, can have pKas down to 4 or lower, but with a typical amine, including amino acids, it's between 9 and 10), while the pKa of a carboxylic acid is between 1.5 and 4.5 (for amino acids, it's usually around 2ish). Anyway, so if you add the carboxylic acid in its protonated form, and the amine in its deprotonated form, the amine will pull off the carboxylic acid's proton and you're screwed.

      Ok, so that's why just adding an amine and a carboxylic acid, or even adding an acid or base catalyst, will NOT give you an amide.

      People who synthesize peptides usually use what's known as coupling reagents. The most well known coupling reagent is DCC, dicyclohexylcarbodiimide. Usually a catalytic base is also added (like DMAP, 4-dimethylaminopyridine). The coupling reagent reacts first with the carboxylic acid. This effectively turns the carboxylic acid into an ester with an awesome leaving group, and esters will react with amines to make amides. As loveoforganic said, you usually protect the termini that you don't want to react, because amino acids will polymerize if unprotected since they can react on both ends.

      So the reason that answer choice is right (in other words, just adding them will not work) is because the acid base properties prevent the two reactants from being in the correct protonation states for a reaction to occur.
       

      neil100

      anti-dummies
      10+ Year Member
      Jan 8, 2008
      1,367
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        The whole point of this is that, if I add mix an amine and a carboxylic acid, even if I add an acid catalyst or w/e, the reaction will not proceed because of the acid base properties of the two reactants.

        Let's break it down:

        We would need the amine to be a nucleophile, and the carboxylic acid to be an electrophile. For the amine to be a nucleophile, it has to be deprotonated. For the carboxylic acid to be reasonably electrophilic, it has to be protonated (if it is deprotonated, it'll be way too poor of an electrophile).

        Anyway, so there is no way for you to have a solution where you would have a deprotonated amine and a protonated carboxylic acid, because the pKa of an amine is between 9 and 10 (usually, although amines like aniline, with good electron withdrawing groups attached, can have pKas down to 4 or lower, but with a typical amine, including amino acids, it's between 9 and 10), while the pKa of a carboxylic acid is between 1.5 and 4.5 (for amino acids, it's usually around 2ish). Anyway, so if you add the carboxylic acid in its protonated form, and the amine in its deprotonated form, the amine will pull off the carboxylic acid's proton and you're screwed.

        Ok, so that's why just adding an amine and a carboxylic acid, or even adding an acid or base catalyst, will NOT give you an amide.

        People who synthesize peptides usually use what's known as coupling reagents. The most well known coupling reagent is DCC, dicyclohexylcarbodiimide. Usually a catalytic base is also added (like DMAP, 4-dimethylaminopyridine). The coupling reagent reacts first with the carboxylic acid. This effectively turns the carboxylic acid into an ester with an awesome leaving group, and esters will react with amines to make amides. As loveoforganic said, you usually protect the termini that you don't want to react, because amino acids will polymerize if unprotected since they can react on both ends.

        So the reason that answer choice is right (in other words, just adding them will not work) is because the acid base properties prevent the two reactants from being in the correct protonation states for a reaction to occur.

        The last paragraph says it all. The acid-base rxn. will indeed happen before addition and elimination. Btw, if the OP had posted the original question then things would have been a lot more clearer.
         
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