1. PRESENTATION ON
STEREOCHEMISTRY
MO.SHAHANAWAZ
M.PHARM (CHEMISTRY)
200102926

2. CONTENT
 INTRODUCTION
 CLSSIFICATION
 OPTICAL ACTIVITY
 RACEMIC PHARMACEUTICALS
 RESOLUTION OF RACEMIC MIXTURE
 CAHN-INGOLD-PRELOG PRIORITY (CIP) RULES
 FISCHER D AND L NOTATIONS
 CIS-TRANS ISOMERISM
 CHIRALITY

3. INTRODUCTION
 Isomerism finds its importance in the field of clinical pharmacology and
pharmacotherapeutics, as isomers differ in their pharmacokinetic and pharmacodynamics
properties. Currently,knowledge of isomerism has helped us in introducing safer and more
effective drug alternatives of the newer as well as existing drugs. Many existing drugs have
gone chiral switch i.e., switching from racemic mixture to one of its isomers.
 The branch of chemistry which deals with three dimensional structure of molecule and their
effect on physical and chemical properties is known as stereochemistry. To represent
molecule as three dimensional object we need at least one carbon sp3- hybridized.
 Among stereoisomers one may have positive effects on the body and another stereoisomer
may not or could even be toxic.

4.  An example of this is the drug thalidomide which was used during the 1950s to suppress the
morning sickness. The drug unfortunately, was prescribed as a mixture of stereoisomers, and
while one (S)-stereoisomer actively worked on controlling morning sickness, the other (R)-
stereoisomer caused serious birth defects.

5. 3D STRUCTURE 2D STRUCTURE
 2D drawing Not appropriate for stereochemistry
 3D drawing appropriate for stereochemistry

6. CLASSIFICATION

7. OPTICAL ACTIVITY
 Optical activity is the ability of a compound to rotate the plane of polarized light. This
property arises from an interaction of the electromagnetic radiation of polarized light with
the unsymmetric electric fields generated by the electrons in a chiral molecule
 Compounds which rotate the plane of polarized light are called optically active compounds
and this property is known as optical activity. Rotation of plane of polarized light can be of
two types.
 DEXTROROTATORY : If the compound rotates the plane of polarization to the right(clockwise)
it is said to be dextrorotatory (Latin: dexter-right) and is denoted by (+), or ‘d’.
 LEVOROTATORY : If the compound rotates the plane of polarization to the left(anticlockwise)
it is said to be levorotatory (Latin: laevus-left) and is denoted by (-) or ‘l’

8. LEVOCETIRIZINE DEXTROCETIRIZINE
EXAMPLE
 Levocetirizine has a high affinity and selectivity for H1 receptors (two-fold that of cetirizine),
whereas the dextro-enantiomer of cetirizine is show sedation

9. RACEMIC PHARMACEUTICALS
 racemic mixture, also called racemate, a mixture of equal quantities of two enantiomers, or
substances that have dissymmetric molecular structures that are mirror images of one another.
 Some drug molecules are chiral, and the enantiomers have different effects on biological
entities. They can be sold as one enantiomer or as a racemic mixture. Examples
include thalidomide, ibuprofen, cetirizine and salbutamol. A well known drug that has different
effects depending on its ratio of enantiomers.
 In some cases (e.g., ibuprofen and thalidomide), the enantiomers interconvert or racemize in
vivo. This means that preparing a pure enantiomer for medication is largely pointless. However,
sometimes samples containing pure enantiomers may be made and sold at a higher cost in
cases where the use requires specifically one isomer.

10. RESOLUTION OF RACEMIC MIXTURE
 The separation of a racemic mixture into the individual pure enantiomers is called resolution.
 Since enantiomers have identical physical properties, such as solubility, boiling point and
chromatographic retention time, they can not be resolved by common physical techniques such
as crystallization, distillation or basic chromatography.
 The most commonly used procedure for separating enantiomers is to convert them to a mixture
of diastereomers that will have different physical properties.
 For example, if you have a racemic or (R)/(S) mixture of enantiomers of a carboxylic acid and
convert this to a salt with a chiral amine base having the (R) configuration, the salt will be a
mixture of two diastereomers, ((R)-acid・(R)-base) and ((S)-acid・(R)-base). These
diastereomeric salts are not identical. If the diastereomeric salts can be completely separated,
the carboxylic acid regenerated from each salt will be either exclusively the (R) or the (S)
enantiomer.

11. 1. Enzymatic Resolution
2. Chromatographic separations

12. CAHN-INGOLD-PRELOG PRIORITY (CIP) RULES
 Look at the four atoms directly attached to the stereo genic center . Assign partition based on
atomic number to all four atoms . Priority 1 is assign to the atom or group of highest atomic
number, priority 4 to the lowest
 Use the Cahn-Ingold-Prelog Rules to assign priority to the four group. Orient the molecule so
that the lowest priority group is in the back.
 Look at the remaining three groups of priority 1-2-3. If the remaining three groups are
arranged so that numbering the priorities 1-2-3 are in a clockwise fashion, then assign the
steriogenic center as R (rectus or right).
 If the remaining three groups are arranged 1-2-3 in a counterclockwise manner , then assign
the steriogenic center S (sinister or left).

14. FISCHER D AND L NOTATIONS
 The notations D and L are used to describe the configurations of carbohydrates and amino acids.
Glyceraldehyde has been chosen as arbitrary standard for the D and L notation in sugar
chemistry. Because, this has an asymmetric carbon and can exist as a pair of enantiomers.
 In a Fischer projection, the carbonyl group is always placed on the top position for
monosaccharide. From its structure if the OH attached to the bottom-most asymmetric center
(the Carbon that is second from the bottom) is on the right then the compound is a D-Sugar if
the OH group on the left then the compound is a L-Sugar. Almost all sugar found in nature is D-
Sugar
 Like R and S ,D and L indicate the configuration of any asymmetric carbon , but they do not
indicate whether the compound rotate the polarized light to the right or left . For example D-
glyceraldehyde is dextrorotatory, whereas D-lactic acid is levorotatory.

15. L-GLUCOSE D-GLUCOSE D-FRUCTOSE L-FRUCTOSE

16. GEOMATRICAL ISOMERS
 Geometrical isomers occurs as a result of restricted rotation about a carbon-carbon bond.
This is also called cis-trans isomerism.
 This isomerism exhibited by variety of compounds such as compound containing double
bond C=C, C=N, N=N, compound containing cyclic structure or compound containing
restricted rotation due to steric hindrance.
Cis isomer Trans isomer

17. E-Z NOTATION
 E–Z configuration, or the E–Z convention, is the IUPAC preferred method of describing
the absolute stereochemistry of double bonds in organic chemistry. It is an extension of cis–
trans isomer notation (which only describes relative stereochemistry) that can be used to
describe double bonds having two, three or four substituents.
 Following the Cahn–Ingold–Prelog priority rules (CIP rules), each substituent on a double bond
is assigned a priority, then positions of the higher of the two substituents on each carbon are
compared to each other. If the two groups of higher priority are on opposite sides of the
double bond (trans to each other), the bond is assigned the configuration E .
 If the two groups of higher priority are on the same side of the double bond (cis to each
other), the bond is assigned the configuration Z .

18. CHIRALITY
 The term Chiral- The word chiral (Greek word Chier,meaning hand) is used for those objects
which have right-handed and left-handed forms, i.e., molecules which have “handedness” and
the general property of “handedness” is termed chirality. An object which is not superimposable
upon its mirror image is chiral.

19.  The term Asymmetric center and chiral center- Three terms are used to designate, a
carbon atom bonded tetrahedrally to four different substituents in a chiral molecule:
Asymmetric atom, chiral center or stereo center.
Chiral centre

20. WHY WE STUDY THE STERIOCHEISTRY IN PHARMACEUTICAL CHEMISTRY
 Stereoisomers differ in pharmacokinetic and pharmacodynamics properties. Pharmacokinetics
different resulting out of stereoisomerism can be in absorption like L-Methotrexate is better
absorbed than D-Methotrexate.
 S-Warfarin is more extensively bound to albumin than R-Warfarin, hence it has lower volume of
distribution.
 Levocetrizine has smaller volume of distribution than its dextroisomer.
 In metabolism like S-Warfarin more potent and metabolized by ring oxidation while R-Warfarin is
less potent and metabolized by side chain reduction, half life of S-Warfarin is 32 hours while it Is
54 hours for R-Warfarin.

21.  Pharmacodynamics differences resulting out of stereoisomerism can be in pharmacological
activity and potency like l-Propanol has beta-adrenoreceptor blocking action while d-Propanol
is inactive.
 Carvedilol is a racemic mixture, the S(-) isomer is nonselective beta-adrenoreceptor blocker,
while both R(+) and S (-) isomers have approximately equally alpha-blocking potency.
 Labetalol is formulated as a racemic mixture of four isomers, two of these isomers-the (S,S)-
and (R,S)-isomer are relatively inactive, a third (S,R)-is a potent alpha-blocker and the fourth
one (R,R)-is a potent beta-blocker.
 Isomerism can lead to different therapeutic uses and adverse drug reactions like Quinine has
antimalarial activity while quinidine has an antiarrhythmic property.
 Levomethorphan is a potent opiod analgesic while dextromethorphan is a cough suppressant.

22. THANK YOU