dr. sapna guptadrsapnag.manusadventures.com/chemistry/organic-chemistry/... · 2017-10-22 ·...

StereochemistryDr. Sapna Gupta

Introduction

• Stereo – left and right handedness

• Any carbon that has four different groups will show chirality.

• Chirality: the mirror image of the compound will not superimpose on the original molecule.

Dr. Sapna Gupta/Stereochemistry 2

Chirality• When two mirror images are non imposable on each other.

• When the tetrahedral carbon has four different groups it is called a chiral center.

• The mirror image pair of the compounds are called enantiomers.

• The only thing different about the two molecules is how they rotate the plane polarized light. The rotation would be in equal and opposite direction.

• Drawing chiral molecules: draw dash (behind the plane) and wedges (coming out of paper) and plane line (in the plane) for bonds.

• Here are four representations of one compound.

• Here are two representations for the enantiomer of (4).

OH

CH3 C

CH2 CH3

H

OH

CH3 C CH2CH3

HH OH OH

(1) (2) (3) (4)

OH

(4)

OH OH

representations for theenantiomer of (4)


Some Enantiomers

• 2-Chlorobutane

• 3-Chlorocyclohexene

CH3 CHCH2 CH3

Cl

ClH Cl H

Cl Cl


Another Example

How many chiral centers in the following compound?


• Louis Pasteur discovered that sodium ammonium salts of tartaric acid crystallize into right handed and left handed forms

• The optical rotations of equal concentrations of these forms have opposite optical rotations

• The solutions contain mirror image isomers, called enantiomers and they crystallized in mirror image shapes – such an event is rare

Pasteur’s Discovery of Enantiomers


Naming Enantiomers- The R,S System

• Also called the Cahn-Ingold-Prelog system

• The four groups attached to the stereogenic/chiral carbon are assigned priorities from highest (a) to lowest (d)

• Priorities are assigned as follows

• Atoms directly attached to the chiral center are compared

• Atoms with higher atomic mass are given higher priority

• If priority cannot be assigned based on directly attached atoms, the next layer of atoms is examined

• Example


Naming Enantiomers- The R,S System, contd..

• The molecule is rotated to put the lowest priority group back

• If the groups descend in priority (a,b then c) in clockwise direction the enantiomer is R

• If the groups descend in priority in counterclockwise direction the enantiomer is S


Assigning Priority1. Look at the atom (not the group) directly attached to the carbon and

arrange according to atomic weight

2. If priority cannot be assigned per the atoms bonded to the chiral center, look to the next set of atoms; priority is assigned at the first point of difference

3. Groups with double or triple bonds are assigned priorities as if their atoms were duplicated or triplicated

(53)(35)(17)(16)(8)(7)(6)(1)

Increasing priority

- H -CH3 -NH2 - OH - SH - Cl - Br - I

Increasing priority

(8)(7)(6)(1)

- CH2 -OH- CH2 -NH2- CH2 -CH3- CH2 -H

-CH=CH2

O

-CH

C CH

O

H

C

C

O

C

-CH-CH2

C

C C H

C

C

C

C

is treated as

is treated as

is treated as

-CH=CH2

O

-CH

C CH

O

H

C

C

O

C

-CH-CH2

C

C C H

C

C

C

C

is treated as

is treated as

is treated as

-CH=CH2

O

-CH

C CH

O

H

C

C

O

C

-CH-CH2

C

C C H

C

C

C

C

is treated as

is treated as

is treated as


Examples

• (S)-2-Chlorobutane

• (R)-3-Chlorocyclohexene

• (R)-Mevalonic acid

ClH2 3

S1

4

2

3

R

1

Cl

H

1

2

3

4

23

41

HO OH

OHO CH3

23

1

R


Identical or Not?• Are A and B identical or enantiomers?

Manipulate B to see if it will become superimposable with A

Exchange 2 groups to try to convert B into A


• Light restricted to pass through a plane is plane-polarized. Phenomenon discovered by Jean-Baptiste Biot in the early 19th century

• Plane-polarized light that passes through solutions of achiral compounds retains its original plane of polarization

• Solutions of chiral compounds rotate plane-polarized light and the molecules are said to be optically active

• The instrument is called a polarimeter

• Rotation is measured in degrees, is []

• Clockwise rotation is called dextrorotatory (d)

• Anti-clockwise is levorotatory (l)

Optical Activity


• The source passes through a polarizer and then is detected at a second polarizer

• The angle between the entrance and exit planes is the optical rotation.

The Polarimeter


• To have a basis for comparison, define specific rotation, []D for an optically active compound

• Specific rotation is that observed for 1 g/mL in solution in cell with a 10 cm path using light from sodium metal vapor (589 nm)

Specific Rotation

DD

H3 C

C

OH

H

COOH

CH3

C

HO

H

COOH

[ ]21

= -2.6°= +2.6°21

[ ]

(R)-(-)-Lactic acid(S)-(+)-Lactic acid


• A compound must be chiral for it to be optically active.

• The specific rotation of the enantiomer pair is equal in magnitude but opposite in sign

• There is no correlation between the R,S designation of an enantiomer and the direction [(+) or (-)] in which it rotates plane polarized light

• ([+ = d] and [– = l])

• Racemic mixture

• A 1:1 mixture of enantiomers

• No net optical rotation

• Often designated as (+)

Specific Rotation and Molecules


Two Chiral Centers - Diastereomers

• Molecules that have two or more chiral centers.

• Each of the two chiral centers will have a pair of enantiomers.

• The other stereoisomers are called diastereomers.

• Enantiomers rotate plane polarized in opposite direction.

• Diastereomers have no optical relationship.

• The number of isomers are given by 2n, where n is the number of chiral centers.

• It is important to understand the concept of symmetry. If a molecule has internal symmetry then it will not be optically active – it will be achiral.


Two Chiral Centers

• There are two pairs of enantiomers (1, 2) and (3,4)

• Enantiomers are not easily separable so 1 and 2 cannot be separated from each other

• Diastereomers: stereoisomers that are not mirror images of each other

• For instance 1 and 3 or 1 and 4

• Have different physical properties and can be separated


Meso Compounds

• Compounds with two or more chiral centers but not the maximum number of stereoisomers (2n)

• This is because two enantiomers may be superimposable – i.e. achiral (not optically active)

• This superimposability comes from the molecule having a plane of symmetry.

Has a plane of symmetry


Naming more than one Chiral Center

• The molecule is manipulated to allow assignment of each stereogenic center separately

• This compound is (2R, 3R)-2,3-dibromobutane


More Examples

2-Methylcyclopentanol 1,2-Cyclopentanediol

H H

CH3 OH

H H

HO H3 C

H OH

CH3 H

HO H

H H3 C

cis-2-Methylcyclopentanol

(a pair of enantiomers)

trans- 2-Methylcyclopentanol


diastereomers

H H

OH HO

H H

OH HO

H HO

OH H

OH H

H HO

cis-1,2-Cyclopentanediol

(one meso compound)

trans- 1,2-Cyclopentanediol


diastereomers


Six Membered Rings

• 1,4-dimethylcyclohexane (shown on the right)• Neither the cis not trans isomers

is optically active

• Each has a plane of symmetry

• 1,3-dimethylcyclohexane• The trans and cis compounds

each have two stereogeniccenters

• The cis compound has a plane of symmetry and is meso

• The trans compound exists as a pair of enantiomers


Fisher Projections

• A 2-dimensional representation of chiral molecules

• Vertical lines represent bonds that project behind the plane of the paper

• Horizontal lines represent bonds that project out of the plane of the paper


Stereoisomers With no Chiral Centers

If the conformer is sterically hindered, it may exist as enantiomers. Examples given below and allenes.


Properties of Stereoisomers• Enantiomers have identical physical and chemical properties in achiral

environments.

• Diastereomers are different compounds and have different physical and chemical properties.• meso tartaric acid, for example, has different physical and chemical properties

from the R,R and S,S enantiomers

• Some properties of the stereoisomers of tartaric acid.

CH OH

COOH

C

COOH

HHOCH OH

COOH

C

COOH

HHO CH OH

COOH

C

COOH

OHH

(S,S)-Tartaric acid

0-12.7+12.7specific rotation

4.824.344.34

3.232.982.98

125139139

1.6601.75981.7598

146-148171-174171-174

pK 1 (25°C)

solubility in water at 20°C (g/100 mL)

density at 20°C (g/cm 3)

m elting point (° C)

Meso tartaric acid

pK 2 (25°C)

(R,R)-Tartaric acid


Resolution• Racemic mixture: An equimolar mixture of two enantiomers.

• because a racemic mixture contains equal numbers of dextrorotatory and levorotatory molecules, its specific rotation is zero.

• Resolution: The separation of a racemic mixture into its enantiomers.

• One means of resolution is to convert the pair of enantiomers into two diastereomers. • Diastereomers are different compounds and have different physical properties.

• A common reaction for chemical resolution is salt formation.

• After separation of the diastereomers, the enantiomerically pure acids are recovered by addition of an achiral acid.

• Racemic acids can be resolved using commercially available chiral bases such as 1-phenylethanamine.

• Racemic bases can be resolved using chiral acids such as

RCOOH B RCOO-

HB+

(R,R)-Salt + ( S,R)-Salt)(R)-Base(R + S)-Carboxylic

acid

+ :

NH2 NH2

(S)-1-Phenylethanamine (R)-1-Phenylethanamine

H3 C CH3

COOHHOOC

CH3

OHHO

O

OOH

OH

OHHO

O

O

OH

(2S,3S)-(+)-Tartaric acid (S)-(-)-Malic acid (1S,3R)-(+)-Camphoric acidDr. Sapna Gupta/Stereochemistry 25

Review of all Isomers

• Here is a flowchart of all isomers we have done so far.

Compounds with the

same molecular formula

Conformational

Isomers

rotation about

single bonds

with chiral centers

Stereoisomers

Meso

Compounds

Enantiomers

Constitutional

Isomers

Cis,Trans

(E,Z) Isomers

(can be called

diastereomers)

Conformations

rotation

restricted

different

connectivity

Diastereomers

stereocenters

but no chiral centers

Enantiomers

one chiral centerm ore than

one chiral center

chiralachiral

not mirror

images

mirror

images

Atropisomers

same

connectivity


Determining Stereochemistry


• Enantiomers have exactly the same chemical properties except for their reaction with chiral non-racemic reagents.

• Many drugs are chiral and often must react with a chiral receptor or chiral enzyme to be effective. One enantiomer of a drug may effectively treat a disease whereas its enatiomer may be ineffective or toxic.

Chemical Properties of Enantiomers


Amino Acids and Proteins• The 20 most common amino acids have a central carbon, called an -carbon,

bonded to an NH2 group and a COOH group.

• In 19 of the 20, the -carbon is a chiral center.

• 18 of the 19 -carbons have the R configuration, one has the S configuration.

• At neutral pH, an amino acid exists as an internal salt.

• The symbol R = a side chain.

• Proteins: Long chains of amino acids connected by amide bonds (here shown in red) formed between the carboxyl group of one amino acid and the amino group of another amino acid

O-

O

H3 N

R

side chain

Ionized or zwitterionform of an amino acid

O

HN

NH

O R

HN

O-

OO

H3N

R R

Rn

for most proteins, n= 150-750

Amide bond


Chirality in the Biological World

• Except for inorganic salts and a few low-molecular-weight organic substances, the majority of molecules of living systems are chiral.

• Although these molecules can exist as a number of stereoisomers, generally only one is produced and used in a given biological system.

• Consider chymotrypsin, a protein-digesting enzyme in the digestive system of animals.

• chymotrypsin contains 251 chiral centers.

• the maximum number of stereoisomers possible is 2251

• there are only 238 stars in our galaxy!

• Enzymes are like hands in a handshake.

• The substrate fits into a binding site on the enzyme surface.

• A left-handed molecule, like hands in gloves, will only fit into a left-handed binding site and

• a right-handed molecule will only fit into a right-handed binding site.

• Because of the differences in their interactions with other chiralmolecules in living systems, enantiomers have different physiological properties.


Chirality in the Biological World…..

A schematic diagram of an enzyme surface capable of binding with (R)-glyceraldehyde but not with (S)-glyceraldehyde.


Key Words/Concepts

•Stereoisomers•Chiral Center•Chirality•Enantiomer•Plane polarized light•Dextrorotatory (d)•Laevorotatory (l)•Diastereomers•Meso compounds

•Cahn Ingold and Prelog nomenclature•Configurations (R and S)•Racemic mixtures•Fisher projections•Enantiomeric excess•Absolute configuration•Resolution

dr. sapna guptadrsapnag.manusadventures.com/chemistry/organic-chemistry/... · 2017-10-22 ·...

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