Amino Acids, Peptides and Proteins | Organic Chemistry 3

Amino acids, peptides and proteins are studied in this chapter: structure and properties of amino acids, synthesis of amino acids (Hell-Volhard-Zelinsky , Gabriel and Strecker synthesis), structure and properties of peptides and proteins, amino acids sequencing, synthesis of polypeptides, Merrifield solid-phase peptide synthesis

Structure and Properties of Amino Acids

Amino acids: carboxylic acids bearing an amine group

α-amino acids (or 2-amino acids): amine group on the α-carbon. These are the most common amino acids in nature and the α-carbon has the S configuration:

Properties of amino acids:

Amine (pKa ~ 9-10) and carboxylic acid (pKa ~ 2-3) groups ⇒ amino acids are both basic and acidic. The structure of an amino acid depends on the pH:


Isoelectric pH (or isoelectric point pI): pH with the maximum number of amino acids with net zero charge

pI = pKa COOH + pKa NH22

Synthesis of Amino Acids

Hell-Volhard-Zelinsky Synthesis:



Gabriel Synthesis:



Strecker synthesis:


All these methods produce amino acids in racemic form. Optically pure amino acids can be obtained by:

  • resolution of a racemic mixture (resolution of their diastereomeric salts)
  • enantioselective formation of the C2 stereocenter

Peptides and Proteins

Peptides and proteins are polypeptides (polymers of α-amino acids). Polypeptides are formed by repeated reaction between COOH and NH2 to form amide bonds called peptide bonds:


Polypeptides are characterized by their sequence of amino acid from the amino end (left) to the carboxy end (right). They are organized in 4 different structures:

  • primary structure ⇒ sequence of amino acids
  • secondary structure (pleated sheet + α helix) ⇒ folding of the primary structure
  • tertiary structure (pleated sheet + α helix) ⇒ further folding and coiling
  • quaternary structure ⇒ aggregation of several polypeptides

Amino Acids Sequencing

Amino acids sequencing is a technique for determining the primary structure of polypeptides

  1. Purification of the polypeptide:

    gel-filtration chromatography, ion-exchange chromatography, electrophoresis ...
  2. Determination of which the amino acids are present

    - complete hydrolysis

    - amino acid analysis (amino acid analyzer)
  3. Sequencing from the amino end to the carboxy end

    Repeated Edman degradation ⇒ access to the sequence of short polypeptides
    For long polypeptides: cleavage with enzymes then Edman degradation

    Edman degradation:

Synthesis of Polypeptides

The synthesis of polypeptides consists in a coupling between an amino-protected amino acid and a carboxy-protected amino acid:


  • Protection of the carboxy group: esterification
  • Protection and deprotection of the amino group:

Merrifield Solid-Phase Peptide Synthesis

The synthesis of polypeptides has been automated: solid-phase synthesis using a solid support of polystyrene ⇒ a carboxy-anchored peptide chain is built up from amino protected monomers


  1. Cycles of coupling and deprotection:

    Attachment of protected amino acid:

    Deprotection of amino terminus:

  2. At the end of the synthesis, disconnection from polymer: