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Stereochemistry

The document discusses the thalidomide disaster, which demonstrated the importance of stereochemistry. Thalidomide was prescribed to pregnant women for morning sickness but was found to be teratogenic, causing birth defects. While one enantiomer may be safe, the other can cause harm, as thalidomide undergoes racemization in the body. Now strict regulations control its use to prevent developmental deformations.

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57 views44 pages

Stereochemistry

The document discusses the thalidomide disaster, which demonstrated the importance of stereochemistry. Thalidomide was prescribed to pregnant women for morning sickness but was found to be teratogenic, causing birth defects. While one enantiomer may be safe, the other can cause harm, as thalidomide undergoes racemization in the body. Now strict regulations control its use to prevent developmental deformations.

Uploaded by

nana
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PPT, PDF, TXT or read online on Scribd
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CHAPTER 3

Stereochemistry
Thalidomide

An often cited example of the importance of stereochemistry relates to the


thalidomide disaster. Thalidomide is adrug, first prepared in 1957 in Germany,
prescribed for treating morning sickness in pregnant women. The drug was
discovered to be teratogenic, causing serious genetic damage to early embryonic
 growth and development, leading to limb deformation in babies. Some of the
several proposed mechanisms of teratogenecity involve a different biological
function for the (R)- and the (S)-thalidomide enantiomers.[3] In the human body
however, thalidomide undergoes racemization: even if only one of the two
enantiomers is administered as a drug, the other enantiomer is produced as a
result of metabolism.[4] Accordingly, it is incorrect to state that one of the
stereoisomer is safe while the other is teratogenic. [5] Thalidomide is currently used
for the treatment of other diseases, notably cancerand leprosy. Strict regulations
and controls have been enabled to avoid its use by pregnant women and prevent
developmental deformations. This disaster was a driving force behind requiring
strict testing of drugs before making them available to the public
Chapter 3 - Stereochemistry

• STRUCTURAL ISOMERISM (CONSTITUTIONAL)

• GEOMETRICAL ISOMERISM AND OPTICAL ISOMERISM (CONFIGURATIONAL)

Structural Isomerism
Chapter 3 – Stereochemistry

Structural/constitutional Isomerism
Chapter 3 – Stereochemistry
GEOMETRICAL ISOMERISM/OPTICAL ISOMERISM
(CONFIGURATIONAL)

• Isomers that have the same molecular formula


and same molecular structure: same atoms and
bonds
• However, the isomers are different because some
of the atoms are arranged differently in space
• Isomers that cannot be interconverted without
breaking and remaking covalent bonds
Chapter 3 – Stereochemistry
GEOMETRICAL ISOMERISM/OPTICAL ISOMERISM
(CONFIGURATIONAL)
Chapter 3 – Stereochemistry

GEOMETRICAL ISOMERISM/ (CONFIGURATIONAL)


Alkenes- (Z) and (E) nomenclature
E or Z alkenes
Examples
priority

8 6
H3CO CH3 8 6
C C Is it Z or E H3CO CH3
H CH2-CH3 C C no difference
1 6 H CH2-CH3
1 6

priority

8 6 priority
H3CO CH3 E-1-methoxy 2-methyl 1-butene
C C
H CH2-CH3
1 6
Substituted Cycloalkanes
Comparison of physical properties

Cis and trans isomers often have different physical properties.


Differences between isomers, in general, arise from the differences in
the shape of the molecule or the overall dipole moment.

cis-butenedioic acid trans-butenedioic acid

Oleic acid Elaidic acid

Usually, for acyclic systems trans isomers are more stable than cis isomers.


This is typically due to the increased unfavourable steric interaction of the
substituents in the cisisomer. Therefore, trans isomers have a less
exothermic heat of combustion, indicating higher thermochemical stability.
Chapter 3 - Stereochemistry
CONFIGURATIONAL ISOMERS-
OPTICAL ISOMERS
OPTICAL ISOMERS
Definition
• Optical isomers are configurational isomers
that have the ability to rotate plane polarized
light clockwise or anticlockwise. They have
identical chemical and physical properties
(apart from light) but can have different
biological properties
Stereoisomers – Mirror Images
Examples of Enantiomers
Examples of Enantiomers
• Molecules that have one carbon with 4 different substituents
have a nonsuperimposable mirror image – enantiomer
• Build molecular models to see this
Examples of Enantiomers
Chirality Centers
• A point in a molecule where four different groups (or atoms)
are attached to a carbon is called a chirality center
• There are two nonsuperimposable ways that 4 different
different groups (or atoms) can be attached to one carbon
atom
– If two groups are the same, then there is only one way
• A chiral molecule usually has at least one chirality center
Chirality Centers in Chiral Molecules
• Groups are considered “different” if there is any structural
variation (if the groups could not be superimposed if
detached, they are different)
• In cyclic molecules, we compare by following in each
direction in a ring
Asymmetric carbon centers
• Carbon that have four different substituents
• Molecules having asymmetric centers will usually be
chiral (few exceptions)
• Nonsuperimposable mirror images of a molecule are
called enantiomers
• An equal mixture of two enantiomers is called a
racemate and does not rotate a plane polarized light
• Asymmetric carbon centers are only possible for sp3
carbons
Fisher diagrams
Fischer projections
R and S nomenclature
To determine the absolute configuration
at asymmetric centers
The groups attached to the asymmetric
centers are given priorities based on their
atomic weights of the atoms directly attached
to the centers
R and S configuration
X = lowest priority atom, lowest atomic weight
behind the page
P X
R C Q
*

P, Q, R are atoms attached directly to carbon center


Find which has the highest priority, second and third
Then look at the arrangement of the highest, second and third priority
whether it is clockwise (R) or anticlockwise (S)

P X P X
R C Q R C Q
* *

R configuration S configuration
R and S nomenclature
• Structure of an enantiomer can be specified using R and S
nomenclature, determined by the Cahn-Ingold-Prelog rules

highest priority lowest priority

8
HO H 8 O H1
O H1
H3C C COOH C C C O
* C C C 6
6 6
6

?
?

lowest priority
first priority
8
O H1
Clockwise
C C C O
6
6
second priority

third priority The molecule has R-configuration


R and S nomenclature
CHIRAL DRUGS

Ibuprofen (Advil, Motrin, Nuprin): an anti-inflammatory agent


CHIRAL DRUGS
(+) and (-)
• Symbols are used to show which direction an
enantiomer rotates plane polarised light
• The direction of the rotation can only be
determined by experimentation
Specific Rotation
• To have a basis for comparison, define specific
rotation, []D for an optically active compound
• []D = observed rotation/(pathlength x
concentration)
= /(l x C) = degrees/(dm x g/mL)
• Specific rotation is that observed for 1 g/mL in
solution in cell with a 10 cm path using light from
sodium metal vapor (589 nanometers)
PLANE POLARISED LIGHT


[]D = Observed Rotation (degrees) =
Path length (dm) x Concentration (g/ml) lxc
A Simple Polarimeter
• Measures extent of
rotation of plane polarized
light
• Operator lines up
polarizing analyzer and
measures angle between
incoming and outgoing
light
(+) and (-)
• Assignment of an asymmetric center as R or S has
got nothing to do with whichever direction the
molecules rotates plane-polarized light
• Molecules which rotate plane polarized light
clockwise are defined as (+) or d
• Molecules which rotate plane polarized light anti-
clockwise are defined as (-) or l
• An R enantiomer of lactic acid is found to rotate
plane-polarized light anticlockwise is defined as
(R)-(-) –lactic acid
Question
Calculate the observed rotation of a solution
of 0.5445 g of S-1-amino-1-phenylethane
diluted to a volume of 10 ml with methanol at
200C using the D line of a sodium lamp and a
1.00 dm tube. Specific rotation of this
material:
[]D = -30.00
Meso Structures
Meso Compound

HO
H
COOH rotate around C-C bond *
H * H COOH
HO OH HO
H *
*
COOH COOH
Plane of symmetry
* asymmetric centers
Diastereoisomers
• Occurs when there are two or more
asymmetric centers
• For a molecule having n asymmetric centers,
the number of possible stereoisomers
(enantiomers) is 2n and the number of
diastereoisomers is 2n-1
Example of diastereoisomer

Mirror Mirror

COOH COOH COOH COOH


H2N H H NH2 H2N H H NH2
* * * *
* * * *
H OH HO H HO H H OH
CH3 CH3 CH3 CH3
2S, 3R 2R, 3S 2S, 3S 2R, 3R

enantiomers enantiomers

Diastereoisomers
Racemic Mixture

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