Date post: | 23-Dec-2015 |
Category: |
Documents |
Upload: | gertrude-welch |
View: | 260 times |
Download: | 0 times |
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.
=>
Examine the following structural formulas and select those that are chiral.