Stereoisomerism

Types of Isomer
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 Types of Isomers

(Cis & Trans)

Isomers divide broadly into two main types – structural isomers

and stereoisomers. We will be looking mainly at Stereoisomers
and in particular optical isomers (enantiomers).
 Structural Isomers
Chain Isomers Positional Isomers
Rearrangement of carbon chain. Repositioning of functional group

CH3-CH2-CH2-CH3 CH3CH2CH2OH
n-butane 1-propanol
and
and
CH3
OH
/ │
CH3-CH CH3-C-CH3
\
CH3 │
2 methyl propane H 2-propanol
 Structural Isomers
Functional Isomers
Rearrangement of atoms that leads to change in functional group(s).
• C2H6O has two functional isomers.
• These have the same number of carbon, hydrogen and oxygen
atoms, but they are arranged in different functional groups to give
either ethanol (CH3CH2OH) or dimethyl ether (CH3OCH3).
 Functional Isomers
(Tautomers)
• Tautomers are functional isomers that exist in an
equilibrium that allows them to be easily
interconverted.
• An example is keto-enol tautomerism.

Ethanal Ethenol
 Stereoisomers
Geometric Isomers
Maleic acid (cis isomer) Fumaric acid (trans isomer)

• H-C-OOH • H-COOH
║ ║
H-C-OOH HOO-C-C-H
m.p. 130 C m.p. 287 C
pKa1 = 1.92
pKa1 = 3.02
• Doesn’t form internal
• Forms internal anhydride
anhydride
 Stereoisomers
Enantiomers

R & S Enantiomers of 1-bromoethane

 Definition of Enantiomers
• Enantiomers are molecules that have the
same order of attachment of atoms, but
different arrangements of the atoms in
space.
• In other words central carbon atom have
the same groups attached, but these
groups are arranged in a different order
around the central carbon atom
Tetrahedral Carbon Atom
How to draw stereochemical features
 Exercise 1
• Draw Newman projections of
– CH3CH2OH
– CH2ClCH2Cl
– CH3CHClCOOH
– CH3CH2CH3
– CH3CHOHCH2CH3
 Chirality & Enantiomers
• Any tetrahedral carbon that has four different
substituents is a chiral centre
• This is because there are two different ways to
place the four different substituents in a
tetrahedral arrangement.
• These two arrangements are non-
superimposable mirror images and are called
enantiomers.
 Exercise 2
• Circle the four chiral
centres in the
molecular structure
of testosterone.
 Exercise 3
• Look at the structures you have drawn in
answer to Exercise 1:
• Do any of these contain chiral centres?
• If they do draw the resultant pair of
enantiomers.
 R & S and D & L notation
• Enantiomers are named either R & S (or
D & L) depending on the arrangement of
the groups around the central chiral
carbon.
• Every group that is bonded to a chiral
carbon is given a priority:
– OR > OH > NH2 > CH2SH > COOH > CHO >
CH2OH > CH3 > H
 Assigning R & S Notation
• Look at the molecule with the group of lowest
priority (e.g. H) furthest away (Newman
Projection)
– If the priority of the remaining groups decreases
clockwise we call that enantiomer R (from Latin
rectus, right)
– If the priority decreases anti-colckwise we call that
enantiomer S (from Latin sinister, left)
• D & L is assigned the same; D = R and L = S
 Enantiomers of Lactic Acid

HOOC COOH

S-Lactic Acid R-Lactic Acid

 Exercise 4
• Draw Newman Projections of both
enantiomers of Lactic Acid
 Polarised light & optical activity
• It is possible to distinguish between
enantiomers by observing how they
affect plane polarised light.
–R enantiomer rotates light in a
clockwise direction.
–S enantiomer rotates light in an anti-
clockwise direction.
 Measurement of Rotation of Light
• Rotation of polarised light can be measured by a
polarimeter.
 Stereoisomerism

Applications to Biochemistry
 Pasteur & Tartaric Acid
• In 1848 Louis Pasteur resolved (separated) an
optically inactive substance (tartaric acid) into
two optically active components.
• Each of the optically active components had
properties identical to tartaric acid
(density, melting point, solubility, etc.) except
that one of the components rotated the polarized
light clockwise (+) while the other component
rotated the polarized light by the same amount
counter-clockwise (-).
 Pasteur & Tartaric Acid
• Pasteur made a proposal that still stands as the
foundation of stereochemistry: The twin molecules of
tartaric acid were mirror images of each other!
• Additional research by Pasteur revealed that one
component of tartaric acid could be utilized for
nutrition by micro-organisms but the other could not.
• On the basis of these experiments, Pasteur concluded
that biological properties of chemical substances
depend not only on the nature of the atoms
comprising the molecules but also on the manner in
which these atoms are arranged in space.
 Amino Acids
• Amino acids have
the general
formula:
Glycine
• R-CH-COOH
|
NH2

General Formula of Amino Acid

 Enantiomers of Amino Acids
• All amino acids (with the exception of glycine)
have chiral centres and therefore have D & L
enantiomers
• Although D-amino acids exist in nature only
L-amino acids are used by organisms as the
building blocks for proteins.
• No definite explanation as to why. Possibly
due to L-enantiomers being chosen by chance
in early days of evolution.
D & L enantiomers of analine
 Exercise
• Draw the enantiomer pairs of the following
amino acids:
• Valine R = CH(CH3)2
• Serine R = CH2OH
• Tyrosine R = CH2C6H5OH
• Aspargine R = CH2CNH2
||
O
 Receptor Site Binding
• According to the modern receptor-site theory,
drugs attach themselves to specific sites by
means of three dimensional bonding
capabilities.
• The fit of a drug onto a receptor site was
compared by Fisher to the fit of a key into a
lock: The right drug is the "key" which can fit
the receptor "lock" and turn on the desired
biological response.
 Receptor Site Binding
• Sometimes two slightly different keys will fit inside
the same lock, but only one will open the door.
When subjected to a chiral environment such as the
human body, how are mirror image twins
differentiated?
• Discrimination between enantiomers, called chiral
recognition, depends on the degree of interaction
exhibited between each enantiomer and the chiral
bonding site. In a way, chiral recognition resembles
the matching of a right hand with a right-handed
glove.
Receptor Site Bonding
• The illustration opposite
represents interactions
between chiral bonding site -
CXYZ and enantiomers
CWXYZ.
• For one enantiomer, a three-
point interaction is possible at
X-X, Y-Y, and Z-Z;
• the other enantiomer can only
accommodate a two-point
interaction at X-X and Y-Y with
the same chiral binding site.
• In this instance, chiral
recognition relies on the
absence of a Z-Z fit in
conjunction with the other
two interactions.
 Other examples of optical activity
• In the 1960s, many pregnant women who had
taken racemic thalidomide gave birth to
deformed babies. Ensuing investigations showed
only the R-enantiomer version of the drug to
cause the same birth defects in rat embryos.
• Sold over the counter in a number of pain
remedies such as Advil and Nuprin, ibuprofen
contains therapeutic activity only in the R isomer.
• Our bodies can only metabolize D-glucose and
not L-glucose.
• D-leucine tastes sweet while L-leucine bitter.