This document provides information on organic chemistry concepts including: 1. Expressing the configuration of enantiomers in 2D and 3D, including Fischer projections. 2. Determining the priority order of groups around a chiral carbon using sequence rules. 3. Assigning the R and S configuration to compounds using the CIP priority rules and determining if structures are identical, enantiomers, or diastereomers. 4. Methods for resolving a racemic mixture into enantiomers including forming diastereomeric salts and using enzymes.

1. 1
Organic Chemistry
Course Number: PCH 1120-217
Lecture # 9
Thursday September 26, 2013
Assignment of Configuration (R and S),
Resolution of Racemic Mixture
Prof. Oludotun A. Phillips
Room # 2-81, 2nd Floor Pharmacy Building
Email: dphillips@hsc.edu.kw
Tel: 24986070

2. 2
Learning Objectives
At the end of the class students should be able to:
 express enantiomers in 2- and 3-Dimensions.
 draw stereoisomers in the solid wedge (Dash-Wedge)
and Fischer projection forms.
 determine the group priority sequence around a chiral
carbon.
 identify enantiomers and assign specific configuration (R
& S) using the Sequence Rules.
 discuss different methods for resolution of racemic
mixtures.

3. 3
Expressing Configuration of Enantiomers in 3-Dimensions
D
C
E
BA
D
C
E
AB
D
C
E
BA
D
C
E
AB
(a)
T etrahedral structure
(b)
T hree D im ensional structure
solid w edges (in front of plane)
dashes (behind the plane)
E
C
B
A
D
E
C
A
B
D
(c)
V ertical bonds are behind the plane
H orizontal bonds are infront of plane
D
E
BA
D
E
AB
(d)
F ischer projection
V ertical bonds are behind the plane
H orizontal bonds are infront of plane G roups A /B
interchange

4. 4
Expressing Configuration of Enantiomers in 3-Dimensions
The two isomers of 1-bromo-1-chloroethane above are enantiomers, since
two of the groups (1 pair) around the chiral carbon are interchanged.
H
C
C H 3
C lB r
H
C
C H 3
B rC l
(a)
T etrahedral structure
of 1-B rom o-1-chloroeth ane
(b)
T hree dim ensional structure
S olid w ed ges (in fron t of plane)
D ash es (behin d the plane)
C H 3
C
C l
B r
H
C H 3
C
B r
C l
H
H
C H 3
C lB r
H
C H 3
B rC l
(d)
Fischer projection
V ertical b ond s are behind the plane
H orizon tal bonds are infront of p lan e
B r / C l
in terchan ge

5. 5
Expressing Configuration of Enantiomers in 3-Dimensions
Note:
 When only one pair of the groups around the chiral
carbon are interchanged the resulting molecule is the
enantiomer (mirror image) of the former.
 But when both pairs of the groups (all the groups) or
three of the groups are interchanged, then the
resulting isomer will be identical to the former.

6. 6
Expressing Configuration of Enantiomers in 3-Dimensions
 The structures (i) and (ii) shown above are identical, since both pair of the
groups around the chiral carbon are interchanged:
D
C
E
BA
B
C
A
DE
D
C
E
BA
B
C
A
DE
(a)
T etrahedral structure
(b)
T hree D im ensional structure
solid w edges (in front of plane)
dashes (behind the plane)
E
C
B
A
D
A
C
D
E
B
(c)
V ertical bonds are behind the plane
H orizontal bonds are infront of plane
D
E
BA
B
A
DE
(d)
V ertical bonds are behind the plane
H orizontal bonds are infront of plane
(F ischer projection)
G roups A / E and
B / D are interchanged
(i) (ii)

7. 7
Assigning Specific Configuration of Enantiomers
 Configuration refers to the specific arrangement of the
four groups around the Stereocenter in space.
 The “R” and “S” descriptors are used to designate
the configuration around Chiral Carbon Atoms.
 The method of assigning configuration developed by
Cahn, Ingold and Prelog involves the Two Main Steps:
A. Assign priority order to the groups bonded directly to
the Chiral carbon using a “Set of Sequence Rules 1-
3”:

8. 8
Assigning Specific Configuration of Enantiomers
Set of Sequence Rules:
 Rule 1: The priority order of some commonly found atoms in
organic compounds are:
HighPriority_________________________Low Priority
I > Br > Cl > S > F > O > N > C > H
53 35 17 16 9 8 7 6 1
Atomic numbers
 Rule 2: If two or more of the atoms directly bonded to the
Chiral Carbon atom are identical, the priority of the groups is
determined by comparing the next atoms of the groups and so
on; working outward until the first point of difference is found.

9. 9
Assigning Specific Configuration of Enantiomers
Set of Sequence Rules:
 Rule 3: If a Double bond or Triple bond is considered, the
atoms involved are treated as being duplicate or triplicate,
respectively:
B. Then visualize the molecule in such a way that the group of
lowest priority is directed away from the observer; and the
remaining groups are in a plane projected toward the viewer.
 When using Fischer Projection formula, the group of lowest
priority is placed at the bottom of the projection formula.
C O equals C O
O
C N equals C
N
N
N

10. 10
Assigning Specific Configuration of Enantiomers
i. If the groups are arranged in a “Clockwise” version from the
highest priority to the lowest priority group – the Configuration is R
(Latin, Rectus, right)
ii. If the groups are arranged in a “Counterclockwise” direction, the
Configuration is S (Latin, Sinister, left)
B
C
A
D
C
C lo ck w ise d irectio n
R -co n fig u ra tio n
B
C
C
D
A
C o u n terclo ck w ise d irectio n
S -co n fig u ra tio n
If th e G ro u p P rio rity S eq u en ce: A > B > C > D
(1 )
(2 )
(3 )
(4 )
(2 )
(1 )(3 )
(4 )
In Fischer projects the lowest
priority order group (D) is
at the bottom of the structure

11. 11
Determining Group Priority Sequence
Cl
CICH2CH2
CH2CH2CH3
CH2Br
Cl > CH2Br > CH2CH2I > CH2CH2CH3
Priority Order Sequency:
C F3
CHSCH2CH2
C H2C l
C
H
C H 2C l > CF3 > CH (C H 3)2 > CH 2CH 2SH
Priority O rder Sequency:
CH3
C H3
C
CH2NCH2
H
CH2O H
CH 2OH > > CH 2NH 2 > H
Priority O rder Sequency:
N
C N
1.
2.
3.
3-Bromo-2-cyano-2-
formylpropanoic acid

12. 12
Assigning Specific Configuration of Enantiomers
 R/S configurations of bromochlorofluoromethane:
 Question: What is the Configuration of the structure of
bromochlorofluoromethane shown below?
R -C onfiguration S-C onfiguration
G roup Priority Sequence: B r > C l > F > H
C l
C
H
FB r
C l
C
H
B rF
C l
C
H
FB r
C l
C
H
B rF
F
C
C l
HB r

13. 13
Assigning Specific Configuration of Enantiomers
 A molecule identical to that shown above can be obtained
by interchanging two pairs of groups, in order to place the
group of lowest priority at the bottom of the Fischer
Projection Structure (i.e. away from the viewer) to give:
F
C
Cl
HBr
Interchange the two pairs of groups
to allow the group of lowest priority
to be at the bottom of the Fischer
projection Structure
Br
C
H
ClF
(1)
(2)(3)
(4)
Clockwise direction
R-Configuration

14. C H 3
O H H O
H 3C
C H 3H O
C H 3
O H H O
H 3C
(1S,3R)-3-m ethylcyclohexanol
(1R,3R)-3-m ethylcyclohexanol
3-m ethylcyclohexanol
cis-2-M ethylcyclohexanol
(a pair of enantiom ers) trans-2-M ethylcyclohexanol
(a pair of enantiom ers)
Stereoisomerism in Saturated Cyclic Compounds
14

15. O H
O H H O
H O
O HH O
O H
O H H O
H O
C yclohexane-1,3-diol
cis-1,3-C yclohexanediol
(a m eso com pound)
trans-1,3-C yclohexandiol
(a pair of enantiom ers)
(1R ,3R )-cyclohexane-1,3-diol(1R ,3S)-cyclohexane-1,3-diol
Plane of
Symmetry
15
Stereoisomerism in Saturated Cyclic Compounds

16. Plane of
Symmetry
O H
O H H O
H O
H O O H
C yclopentane-1,2-diol
O H
O H H O
H O
(1S,2R )-C yclopentane-1,2-diol
cis-1,2-C yclopentanediol
(m eso com pound)
(1S,2S)-C yclopentane-1,2-diol
trans-1,2-C yclopentanediol
(a pair of enatiom ers)
Stereoisomerism in Saturated Cyclic Compounds
16

17. 17
Resolution of a Racemic Mixture (Racemate)
 Racemic mixture: equimolar mixture of two enantiomers.
 Racemic mixture (racemate) contains equal amounts of
dextrorotatory and levorotatory enantiomers, hence, its
specific activity is zero.
 Resolution: the separation of a racemic mixture into its
enantiomers.
 However, conventional separation methods based on
differences in solubility and boiling points are usually
ineffective for separation of enantiomers; because they
have identical physical properties.

18. 18
Resolution of a Racemic Mixture (Racemate)
 Resolution of a Racemic Mixture can be can be
achieved by 3 main methods:
i. Resolution through Diastereomers: proceed via Chemical
reactions – reaction of the racemate with other optically pure
enantiomer to give the diastereomers; followed by separation
of the diastereomers and reconverting back to the
enantiomers – using chiral derivatizing agents.
ii. Resolution by biological means: Use of enzymes as
resolving agents or use of microorganisms that produce
certain enzymes.
iii. Resolution by Chromatographic Separation methods on
HPLC (High Performance Liquid Chromatography) using
chiral stationary phases – rather tideous process!!.

19. 19
Resolution of a Racemic Mixture (Racemate)
i. Resolution through Diastereomers:
B
C*
X
DA
B
C*
X
AD
Physically inseparable
racemic mixtture
(50:50 enatiomers)
R S
Pair of diastereomers.
top of molecules are the
mirror images.
B
C*
X
DA
B
C*
X
AD
O
C*
V
WU
Single optically
active enantiomer
Chemical
reaction
C*
V
WU C*
V
WU
R, R S, R
M ixture of Diastereomers
B
C*
X
DA
B
C*
X
AD
R, R
S, S
Separation / Chemical Conversion
R
S
Separated enantiomersR-isomer

20. 20
Resolution of a Racemic Mixture (Racemate)
i. Resolution through Diastereomers: Racemic (R)(S)-acid can
be Resolved by reaction with Pure Enantiomer (S)-amine to
give the Diastereomeric salts, which can then be separated. And
then converted to the respective pure isomers by treating with
strong base:
(R)-RC O2
H
(S)-RC O2
H
and + (S)-R'NH2
(R)-RC O2
(S)-RC O2
and
(S)-R'NH3
pure
enantiom er
racem ic
m ixture
(S)-R'NH3
The (R,S)-salts and the (S,S)-Salt
are not enantiom ers.
They are Diastereom eric salts
and can be separated.
+
+
_
_
(R)-RC O2
H
(S)-RC O2
H
+
Pure enantiom ers
Separated
strong
base

21. 21
Resolution of a Racemic Mixture.
ii. Resolution by biological means: Use of enzymes as resolving agents:
H 3 CO
OEt
H CH3
C
O OCH3
C
HH3 C
O
Et O
N aO H , H 2O
2. H Cl, H 2 O
H 3 CO
C
H CH3
OH
O
Eth yl e ste r o f (S)-n apro xe n Eth yl e s te r o f (R )-n apro xe n
(no t af f e cte d by th e e ste ras e )
+
1. e ste ras e
(S)-N ap roxe n
H3CO
COOH
H CH3
R/S racemic mixture of Naproxen
Esterification
reaction
Physically
inseparatable
mixture
(S)-Naproxen is resolved as an
insoluble salt of N-methyl-D-
glucamine

22. 22
Assign Configuration for the Enantiomers
C H 3
C
B r
C l
H
C H 3
C
B r
C l
H
C H 3
C
B r
H
C l
1. 2. 3.
4. 5. 6.
7. Ibuprofen 8.
Inactive enantiom er A ctive enantiom er
C O O H
C H 3
H
H O O C
H 3C H
H
O H
O H
H
O H
H

23. 23
Questions – Assignment of Configuration
1. Match the following compounds as identical or mirror
images:
CH3
C
CH2CH3
ClH
CH3
C
CH2CH3
HCl
(a) (b) (c) (d)
CH3
C
CH2CH3
ClH
CH3
C
Cl
CH2CH3H

24. 24
Questions – Assignment of Configuration
ii. Determine the R/S configuration for the following compounds:
iii. Draw the Fischer Projection R configuration for the following
compounds:
CH2Br
C
CH2CH2CH3
CH2CH2ICl
CH2NH2
C
C
CH2OHH
N
(A) (B) (C)
CH3
C
CH2CH3
CHO OH
O
CH3CH2CHCH3
I
CH3CH2CHCH3
NH2
(i) (ii)

25. Questions – Assignment of Configuration in Cyclic Compounds
H O CH 3
Cyclopentane-1,3-diol
O H
C H 3 H 3C
H O O H
C H 3 H3C
HO
25