introduction to stereochemistry

Stereochemistry of Medicinal Compounds

PHRM 412

Isomers are different compounds that have the same molecular formula (no. and types of atom present) but different in structural formula.

The compounds that process the same molecular formula but differ from each other in physical and/or chemical properties are called isomers.

Compounds that have the same molecular formula but are not identical are called isomers.

This phenomena is termed as isomerism (Greek: isos-equal, meros-part).

Isomers

Constitutional isomers

Draw three constitutional isomers with molecular formula C3H8O

Stereoisomer

• Stereoisomers are isomers with the same molecular formula and same connectivity of atoms but different arrangement of atoms in space.

• In stereoisomers the atoms and/or groups are attached to the molecule in the same order, but they have a different orientation in space.

Configurational IsomersCis–Trans IsomersCis–trans isomers (also called geometric isomers) result from restricted rotation.

Restricted rotation can be caused either by a double bond or by a cyclic structure. As a result of the restricted rotation about a carbon–carbon double bond, an alkene such as 2-pentene can exist as cis and trans isomers.

The cis isomer has the hydrogens on the same side of the double bond, whereas the trans isomer has the hydrogens on opposite sides of the double bond..

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If there are more than one different groups or atoms present, the situation becomes a bit more complicated for assigning cis and trans.

To simplify this situation, the E/Z system is used for naming geometrical isomers.

Z stands for German zusammen, which means the same side, and E for German entgegen, meaning on the opposite side.

In the E and Z system, the following rules or steps are followed.

(a) On each C atom of the double bond, we have to assign the priority of the atoms bonded. The priority should be on the basis of atomic number.(b) If the two higher priority groups of the two C atoms are on the

same side of the double bond, it is called the (Z)-isomer.

(c) If the two higher priority groups of the two C atoms are on opposite sides of the double bond, it is called the (E)-isomer.

Optical isomers are characterized by compounds having the same structure but different configurations, and because of their molecular asymmetry these compounds can rotate the plane of polarized light.

Optical isomer has similar physical and/or chemical properties. The most marked different between them is their action on polarized light. Example-

Optical isomers

(-) Glyceraldehyde (+) Glyceraldehyde

It has been found that only those structures; crystalline or molecular, which are not superimposable on their mirror images are optically active.

CHO

CH2OH

H OH

CHO

CH2OH

OH H

Enantiomer

• Nonsuperimposable mirror-image molecules are called enantiomers

• They rotate the plane of polarized light in opposite direction, though in equal amounts.

• Though chemically they are identical but their rate of reaction with other optically active compounds (chiral compounds) are usually different.

Diastereomers

• Diastereomers have different physical properties (like solubility will differ)

• Diastereomers have similar chemical properties

• Diastereomers differ in specific rotation; they may have the same or opposite signs of rotation or some may be inactive

For example in 2,3 dichloropentane there are 2-chiral center present, so the no. of isomer will be 4.

CH3 / CH2 / CH / CH / CH3

Cl Cl

* *

CH3

C

C

C2H5

H

H Cl

Cl

CH3

C

C

C2H5

Cl

Cl H

H

I II

Enantiomers

CH3

C

C

C2H5

Cl

H Cl

H

CH3

C

C

C2H5

H

Cl H

Cl

III IV

Enantiomers

Relationship between-

I and II EnantiomersIII and IV EnantiomersI and III/IV DiastereomersII and III/IV DiastereomersIII and I/II DiastereomersIV and I/II Diastereomers

Drawing Enantiomers: Perspective formulas

• The solid wedges represent bonds that points out of the plane of the paper toward the viewer.

• The hatched wedges represent bonds that points back from the plane of the paper away from the viewer.

Drawing Enantiomers: Perspective formulas

• Two bonds (singled lined) in the plane of the paper are adjacent to one another, neither the solid wedge nor the hatched wedge should be drawn between them.

CH3CHCH2OH

Br

2-bromopropan 1-ol

• The first enantiomer is drawn by putting the four groups bonded to the assymetric center in any order.

• The second enantiomer is the mirror image of the first enantiomer.

Drawing Enantiomers: Perspective formulas

Drawing Enantiomers: Fischer projection

• A Fischer projection represents an asymmetric carbon as the point of intersection of two perpendicular lines;

• Horizontal lines represent the bonds that project out of the plane of the paper toward the viewer, and

• Vertical lines represent the bonds that extend back from the plane of the paper away from the viewer.

Contain chiral carbon but optically inactive.

A meso compounds is one whose molecules are superimposable on their mirror images even through they contain chiral centers.

A meso compound is optically inactive.

Meso structures

Compound C has two chiral centers but it contains a plane of symmetry, and is achiral; C is a meso compound.

» Not optically active

» Superimposable on its mirror image

» Has a plane of symmetry

Sometimes molecules with 2 or more chiral centers will have less than the maximum amount of stereoisomers. e.g.

Racemic mixture is a mixture of equal parts of enantiomer. Racemic mixtures are optically inactive since the equal and opposite rotation cancel each other.

Racemic mixture

A mixture of equal parts of enantiomers is called a racemic mixture. A racemic mixture is optically inactive: when enantiomers are mixed together, the rotation caused by a molecule of one isomer is exactly cancelled by an equal and opposite rotation caused by a molecule of its enantiomer.

A mixture is said to be racemic when it contains exactly equal amounts of two enantiomers. Such a mixture is optically inactive (zero rotation of plane polarized light).

For example, (±) Lactic acid [a mixture of (+) Lactic acid and (-) Lactic acid]

COOH

CH3

H OH

COOH

CH3

OH H

d or (+) Lactic acid

l or (-) Lactic acid

This is demonstrated by the hydrogenation of 2-butanone:Most chemical reactions which produce chiral molecules produce them in racemic form

Ibuprofen• Ibuprofen is produced industrially as a

racemate.• Indeed, the (S)-(+)-ibuprofen (dexibuprofen)

was found to be the active form both in vitro and in vivo.

• Further in vivo testing, however, revealed the existence of an isomerase (alpha-methylacyl-CoA racemase), which converted (R)-ibuprofen to the active (S)-enantiomer.

R-ibuprofen (interconvert in vivo)

S-ibuprofen (active form)This means that preparing a pure enantiomer for medication is largely pointless.

Isomers with More thanOne Asymmetric Carbon

Isomers with More thanOne Asymmetric Carbon

• When Fischer projections are drawn for stereoisomers with two adjacent asymmetric carbons (such as those for 3-chloro-2-butanol), the enantiomers with similar groups on the same side of the carbon chain are called the erythro enantiomers. Those with similar groups on opposite sides are called the threo enantiomers.

D and L system Emil Fischer

D, L-series (sugar)

The configuration of the asymmetric carbon atom furthest from the carbonyl carbon is:

identical with D-glyceraldehyde ... D-series

identical with L-glyceraldehyde ... L-series

There is no correlation between D and L configurations, and (+) and (-) rotations

Assigning R,S configurations

• Assign priorities to the four substituents.• Perform one of the two allowed motions to

place the group of lowest (fourth) priority at the top or bottom of the Fischer projection.

• Determine the direction of rotation in going from priority 1 to 2 to 3, and assign R or S configuration.