Pharmaceutical OrganicChemistry

Lec 3

StereochemistryOptical isomerism

Absolute Configuration ( AC )

Is the actual spatial arrangement of atoms or groups around a chiral carbon

In 1891 German chemist [ Emil Fisher ] introduce formula showing the spatial arrangement ………

configuration – the arrangement in space of the four different groups about a chiral center.

How do we show configurations?

“wedge” formulas Fischer projections“cross structures”use only for chiral centers!

Br

F

HCl

Br

F ClH

Rules for Fischer projections

Arrange the molecule so that horizontal bonds at chiral carbon point toward you and vertical bonds point away from you.

H

F

ClBr

Projection of molecule on page is a cross. When represented this way it is understood that horizontal bonds project outward, vertical bonds are back.

StereochemistryOptical isomerism

(±)- Ethanolamine CH3CH(OH)NH2

has one chiral carbon, so 2- enantiomers

H2N

CH3

H

OH H2NOH

H

CH3

Mirror Fischer projection formula

Determination of ( AC ) by ( R ) and ( S ) system

Groups are assigned a priority ranking using the

same set of rules as are used in ( E ) and

( Z ) system

CH3CH(OH)NH2

1. Draw Fischer Projection formula

H2N

CH3

OH

H

Determination of ( AC ) by ( R ) and ( S ) system

Groups are assigned a priority ranking using the

same set of rules as are used in ( E ) and

( Z ) system

CH3CH(OH)NH2

2. Rank the substitution according to the priority order

H2N

CH3

OH

HOH > NH2 > CH3 > H

1 2

3

Determination of ( AC ) by ( R ) and ( S ) system

3. The group (atom) with lowest priority [H] should

be away from the observer , if not do an even

number of changes to get H away from the observer

H2N

CH3

OH

H1

OH OH

CH3

CH3

H2N H2N

H

H

2

Determination of ( AC ) by ( R ) and ( S ) system

4. Draw an arrow from group with highest priority ( OH ) to second highest priority ( NH2 ) . if the arrow is …… a- clockwise, the configuration is R b- anti-clockwise, the configuration S

HO

H

NH2

CH3

(R)-ethanolamine(+)- ethanolamine

The viewing rule

Switching Substituents on a Fischer Projection

1) Any single (odd #) exchange of 2 substituents gives the other enantiomer

2) Any two (even #) of exchanges gives the same enantiomer

H

CH3

Br CH2CH3

H/CH3

exchange

CH3

H

Br CH2CH3

CH3

H

CH3CH2 BrBr/Et

exchange

R RS

Draw the formulas for the two enantiomers of each of the following compunds then assign each as R or S

CH

Br

CH3

OH

CH

CH3H3CH2Ca- b-

a) Analyze compounds A, B, and C. Which are identical Which are enantiomers

b) How are the following pairs of compounds related                                                                                                                                                                                                                                     

Stereochemistry(±)- CH3CH(Cl)CH(Br)NH2

n = 2 ….. So No. of stereoisomer 4

CH3

H Cl

NH2

H Br

CH3

Cl H

NH2

Br H

CH3

H Cl

NH2

Br H

CH3

Cl H

NH2

H Br

1 2 3 4

Enantiomers Enantiomers

mirror mirror

1,3 and 1,4 2,3 and 2,4 are diastereoisomers

Stereochemistry

Determination of ( AC ) in enatiomer 1

a. At C1 :

H

NH2

C2

C2NH2

H

Br

Br

2

1

AC at C1 is S

Br > NH2 > C2 > H

Stereochemistry

Optical isomerism

Stereochemistry

Optical isomerismDetermination of ( AC ) in enatiomer 1

a. At C2 :

H

C1

CH3

ClCH3

H

Cl

C1

2

1

AC at C2 is S

Cl > C1 > CH3 > H

Enantiomers and diastereomers:

EXAMPLE:

2-Bromo-3-chlorobutane

Meso compounds

In the simplest case, they are compounds which have internal plan of symmetry.

EXAMPLE: Tartaric acid

COOH

H OH

COOH

H OH

StereochemistryOptical isomerism

Meso-compound are : - superimposable mirror images - only 3 stereoisomers - optically inactive

COOHCH(OH)CH(OH)COOH tartaric acid

COOH

HO H

COOH

HO H

COOH

H OH

COOH

H OH

COOH

H OH

COOH

HO H

COOH

HO H

COOH

H OH

1 2 3 4

Mesocompounds Enantiomers

mirror mirror

2R,3R-(+) 2S,3S-(-)

Racemic Mixture

• A racemic mixture dose not rotate the plane of polarization

of plane-polarized light because the rotation by each

enantiomer is cancelled by the equal and opposite rotation

by the other.

• A solution of either a racemic mixture or of achiral compound

said to be optically inactive

• Many drugs are optically active, with one enantiomer

only having the beneficial effect.

• In the case of some drugs, the other enantiomer can

even be harmful, e.g. thalidomide.

• In the 1960’s thalidomide was given to pregnant women to reduce the effects of morning sickness.

• This led to many disabilities in babies and early deaths in many cases.

• Thalidomide was banned worldwide when the effects were discovered.

• However, it is starting to be used again to treat leprosy and HIV.

• Its use is restricted though and patients have to have a pregnancy test first (women!) and use two forms of contraception.

Stereochemistry

Resolution of racemic mixture

1- treat the mixture with microorganism

N

N

H

CH3

N

N

H

CH3

(R,S) nicotine (R)

PseudomonasPutida

2- using chiral reagent

( R) RCOOH ( R) RCOO - (S) R’NH3+

+ ( S) R’NH2 ( S) RCOOH ( S) RCOO - (S) R’NH3

+

Resolution of Enantiomers

React a racemic mixture with a chiral compound to form diastereomers, which can be separated.

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Examine the following structural formulas and select those that are chiral.