L 9 assigment-of_configuration_pch217_2013_2014

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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: [email protected]

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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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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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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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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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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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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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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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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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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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)


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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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L 9 assigment-of_configuration_pch217_2013_2014

Technology

c h c h

c b r c

r h c c h

h h c h

plane c h

d c e ba b c

plane e c b

b r h c h