Lecture 3

Physical organic and bioorganic chemistry

CH-204

Department of Chemistry
IITDH

1
2
3
4
5
 Synthesis of amino acids
1. HVZ reaction followed by addition of ammonia
• Hell-Volhard-Zelinski (HVZ) reaction to replace an α-hydrogen of a
carboxylic acid with a bromine. The resulting α-bromocarboxylic acid
can then undergo an SN2 reaction with NH3 to form the amino acid

6
 Synthesis of amino acids
2. Reductive amination
• Amino acids can be synthesized by reductive amination of an
α-keto acid

7
 Synthesis of amino acids
3. N-Phthalimidomalonic ester synthesis
• Amino acids can be synthesized with better yields via N-phthalimidomalonic ester
synthesis, a method that combines malonic ester synthesis and Gabriel synthesis

Heating in an acidic
aqueous solution in
last step hydrolyzes
the two esters and the
two amide bonds and
decarboxylates the 3- 8
oxocarboxylic acid.
 Synthesis of amino acids
3. N-Phthalimidomalonic ester synthesis
• A variation of the N-phthalimidomalonic ester synthesis uses
acetamidomalonic ester in place of N-phthalimidomalonic ester.

9
 Synthesis of amino acids
3. N-Phthalimidomalonic ester synthesis
• Example: Synthesis of methionine

10
 Synthesis of amino acids
4. Strecker synthesis
• In the Strecker synthesis, an aldehyde reacts with ammonia to form
an imine. A nucleophilic addition reaction with cyanide ion forms
an intermediate, which, when hydrolyzed, forms the amino acid

11
12
Configuration of amino acids

L-alanine
an amino acid

13
 Resolution of a racemic mixture of amino acids
• When amino acids are synthesized in nature, only the L-enantiomer is formed. When amino
acids are synthesized in the laboratory, a racemic mixture of D- and L-amino acids is formed.
The enantiomers must be separated, which can be done by an enzyme-catalyzed reaction.
• Because an enzyme is chiral, it reacts at a different rate with each of the enantiomers. For
example, aminoacylase enzyme catalyzes the hydrolysis of N-acetyl-L-amino acids, but not N-
acetyl-D-amino acids. Therefore, if the racemic mixture of amino acids is converted to a pair of
N-acetylamino acids and is hydrolyzed with aminoacylase, the products will be the L-amino
acid and unreacted N-acetyl-D-amino acid, which are easily separated

Because the resolution (separation) of the enantiomers depends on the

difference in the rates of reaction of the enzyme with the two N- 14
acetylated compounds, this technique is known as a kinetic resolution
 The peptide bond
• The amide bonds that link amino acids are called peptide bonds.

15
The peptide bond

−NH3+
−CO2-

16
 Naming a peptide

• In naming a peptide, adjective names (ending in “yl”) are used for all the amino
acids except the C-terminal amino acid. All amino acids have L-configuration

Dipeptide

Val-Cys-Ala-Glu-His Tripeptide
Valylcysteinylalanylglutamylhistidine (Pentapeptide) 17
 Peptide bond has double bond character
• A peptide bond has about 40% double-bond character because of electron
delocalization. Steric strain causes the configuration that has the α-carbons of
adjacent amino acids on opposite side of the double bond to be more stable.

18
 Peptide bond has restricted rotation
• The partial double-bond character prevents free rotation about the peptide
bond, so the carbon and nitrogen atoms of the peptide bond and the two
atoms to which each is attached are held rigidly in a plane. This regional
planarity affects the way a chain of amino acids can fold; this has important
implications for the three-dimensional shapes of peptides and proteins.

A segment of a polypeptide chain. The red arrows indicate the peptide bonds. Colored
squares indicate the plane defined by each peptide bond. Notice that the R groups
bonded to the α-carbons are on alternate sides of the peptide backbone. 19
 Disulfide bond
• Peptide bonds and disulfide bonds are the only covalent
bonds that join amino acids together in a peptide or a protein.
• The amino acid cysteine contains a thiol group, so two cysteine
molecules can be oxidized to a disulfide called cystine.

20
 Disulfide bond cross-links protein segments
• Two cysteines in a protein can be oxidized to a disulfide, creating a bond known
as a disulfide bridge. Disulfide bridges are the only covalent bonds that are found
between nonadjacent amino acids in peptides and proteins. They contribute to the
overall shape of a protein by linking cysteines from various parts of protein.

21
Disulfide bonds in keratin (hair protein)

22
 Disulfide bonds in insulin hormone
The hormone insulin, synthesized in the pancreas by cells known as the islets of
Langerhans, maintains the proper level of glucose in blood. Insulin is a protein with two
peptide chains; one contains 21 amino acids (chain A) and the other 30 amino acids
(Chain B). The two chains are connected by two interchain disulfide bridges (between
two chains). Insulin also has one intrachain disulfide bridge (within a chain).

23
Disulfide bonds in insulin hormone

24
Identity of amino acids in protein are important:
Glu to Val change in hemoglobin causes SCA

25