L 9 assigment-of_configuration_pch217_2013_2014
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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
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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.
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Expressing Configuration of Enantiomers in 3-Dimensions
D
C
E
BA
D
C
E
AB
D
C
E
BA
D
C
E
AB
(a)Tetrahedral structure
(b)Three Dimensional structuresolid wedges (in front of plane)dashes (behind the plane)
E
CB
A
D
E
CA
B
D
(c)Vertical bonds are behind the planeHorizontal bonds are infront of plane
D
E
BA
D
E
AB
(d) Fischer projection
Vertical bonds are behind the planeHorizontal bonds are infront of plane Groups A/B
interchange
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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
CH3
ClBr
H
C
CH3
BrCl
(a) Tetrahedral structureof 1-Bromo-1-chloroethane
(b)Three dimensional structureSolid wedges (in front of plane)Dashes (behind the plane)
CH3
CCl
Br
H
CH3
CBr
Cl
H
H
CH3
ClBr
H
CH3
BrCl
(d) Fischer projection
Vertical bonds are behind the planeHorizontal bonds are infront of plane
Br / Cl interchange
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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.
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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)Tetrahedral structure
(b)Three Dimensional structuresolid wedges (in front of plane)dashes (behind the plane)
E
CB
AD
A
CD
EB
(c)Vertical bonds are behind the planeHorizontal bonds are infront of plane
D
E
BA
B
A
DE (d) Vertical bonds are behind the planeHorizontal bonds are infront of plane (Fischer projection)
Groups A / E and B / D are interchanged
(i) (ii)
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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”:
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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.
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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
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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
CA
D
C
Clockwise direction
R-configuration
B
CC
D
A
Counterclockwise direction
S-configuration
If the Group Priority Sequence: 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
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Determining Group Priority Sequence
Cl
CICH2CH2
CH2CH2CH3
CH2Br
Cl > CH2Br > CH2CH2I > CH2CH2CH3
Priority Order Sequency:
CF3
CHSCH2CH2
CH2Cl
CH
CH2Cl > CF3 > CH(CH3)2 > CH2CH2SH
Priority Order Sequency:
CH3
CH3
C
CH2NCH2
H
CH2OH
CH2OH > > CH2NH2 > HPriority Order Sequency:
N
C N
1.
2.
3.
3-Bromo-2-cyano-2-formylpropanoic acid
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Assigning Specific Configuration of Enantiomers
R/S configurations of bromochlorofluoromethane:
Question: What is the Configuration of the structure of bromochlorofluoromethane shown below?
R-Configuration S-Configuration
Group Priority Sequence: Br > Cl > F > H
Cl
C
HFBr
Cl
C
H
BrF
Cl
C
H
FBr
Cl
C
HBrF
F
C
Cl
HBr
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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 groupsto 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
CH3
OH HO
H3C
CH3HO
CH3
OH HO
H3C
(1S,3R)-3-methylcyclohexanol (1R,3R)-3-methylcyclohexanol
3-methylcyclohexanol
cis-2-Methylcyclohexanol (a pair of enantiomers) trans-2-Methylcyclohexanol
(a pair of enantiomers)
Stereoisomerism in Saturated Cyclic Compounds
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OH
OH HO
HO
OHHO
OH
OH HO
HO
Cyclohexane-1,3-diol
cis-1,3-Cyclohexanediol (a meso compound)
trans-1,3-Cyclohexandiol (a pair of enantiomers)
(1R,3R)-cyclohexane-1,3-diol(1R,3S)-cyclohexane-1,3-diol
Plane ofSymmetry
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Stereoisomerism in Saturated Cyclic Compounds
Plane ofSymmetry
OH
OH HO
HO
HO OH
Cyclopentane-1,2-diol
OH
OH HO
HO
(1S,2R)-Cyclopentane-1,2-diol
cis-1,2-Cyclopentanediol(meso compound)
(1S,2S)-Cyclopentane-1,2-diol
trans-1,2-Cyclopentanediol(a pair of enatiomers)
Stereoisomerism in Saturated Cyclic Compounds
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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.
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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!!.
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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
Chemicalreaction
C*
V
WU C*
V
WU
R, R S, RMixture of Diastereomers
B
C*
X
DA
B
C*
X
AD
R, R
S, S
Separation / Chemical Conversion
R
S
Separated enantiomersR-isomer
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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)-RCO2H
(S)-RCO2H
and + (S)-R'NH2
(R)-RCO2
(S)-RCO2
and
(S)-R'NH3
pureenantiomer
racemicmixture
(S)-R'NH3
The (R,S)-salts and the (S,S)-Salt are not enantiomers.
They are Diastereomeric salts and can be separated.
+
+
_
_
(R)-RCO2H
(S)-RCO2H
+
Pure enantiomers Separated
strong
base
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Resolution of a Racemic Mixture.ii. Resolution by biological means: Use of enzymes as resolving agents:
H3CO
OEt
H CH3
C
O OCH3
C
HH3C
O
EtO
NaOH, H2O
2. HCl, H2O
H3CO
C
H CH3
OH
O
Ethyl ester of (S)-naproxen Ethyl ester of (R)-naproxen(not affected by the esterase)
+
1. esterase
(S)-Naproxen
(S)-Naproxen is resolved as an insoluble salt of N-methyl-D-glucamine
H3CHN(S) (R) (R) (R)
OH
OH
OH
OH
OH
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Assign Configuration for the Enantiomers
CH3
CBr
ClH
CH3
CBr
ClH
CH3
CBr
HCl
1. 2. 3.
4. 5. 6.
7. Ibuprofen 8. Inactive enantiomer Active enantiomer
COOH
CH3H
HOOC
H3C H
H
OH
OH
H
OH
H
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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
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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
ICH3CH2CHCH3
NH2
(i) (ii)
Questions – Assignment of Configuration in Cyclic Compounds
HO CH3
Cyclopentane-1,3-diol
OH
CH3 H3C
HO OH
CH3 H3C
HO
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