Organic Chemistry

ByDr. Mehnaz KamalAssistant Professor,

Pharmaceutical ChemistryPrince Sattam Bin Abdulaziz University

1-What is Optical Isomerism2-What is Polarimeter?3- Chirality4-Enantiomers and diastereomers

Isomers

Structural isomerism(Constitutional isomers)

Position of function groups

Skeleton or chain of carbon Functional group

Stereoisomerism

Optical isomers

(Diastereomers(Enantiomers

GeometricalCis & trans

ConformationalConfigurational

Type of Isomerism

Optical Isomerism

Optical isomerismAn isomerism resulting from ability of certain molecules to rotate plane of polarized light

-- the light is rotated plane-polarized light to either to the right or left

right ( clockwise ( + d ( dexter ( dextro

left ( anticlockwise ( - l ( laevous ( levo

Any material that rotates the plane of polarized light.

Optically active compound is non-

superimposable on its mirror image.

C COOHH2N

CH3

H

Types of Optical isomerism1-Optically active.

If a molecule is super-imposable on its mirror image, the compound does not rotate the plane polarized light.

Example: Alanine)amino acid(

2-Optically inactive

B D

C C

D

A

B

MirrorMirror

Mirror imageReal molecule

Mirror image

C

DB

A

C

BD

A Mirror image

C

DB

A

A

DB

C

A

Enantiomers Have Equal And Opposite Rotations

W

CX

ZY

W

CXY

Z)+( dextrorotatory )-( levorotatory

Enantiomers

All Other Physical Properties Are The Same

Enantiomers )from Greek enantio, “opposite” and merso , “part”( have opposite configuration

Optically active.

Enantiomers: isomers that are nonsuperimposable mirror images of each other

Types of Optical isomerism

If one stereoisomer is “right-handed,” its enantiomer is “left-handed.”

Optical Isomerism

Optically active

Non SuperImposable(Enantiomers(

Optically inactive

Non-Superimposable(Diastereomers(

Chirality And

Chiral Compounds

If a molecule is not superimposable on its mirror image, it is chiral.

If it is superimposable on its mirror image, it is achiral.

What is chirality?Chirality )cheir, Greek for hand(.

The property of nonsuperimposability of an object on its mirror image is called chirality.

Things that are chiral have non superimposable mirror images

What is Chiral carbon?

Chiral carbon: It is an sp3-hybridized carbon atom with four different groups

attached to it. Chiral compound exists in a pair of enantiomers.Chiral carbons have no symmetry they are asymmetricChiral center is indicated by an *.

If one stereoisomer is “right-handed,” its enantiomer is “left-handed.”

Chiral CentersOne of the ways a molecule can be chiral is to have a stereocenter.

A point in a molecule where four different groups )or atoms( are attached to carbon is called a chiral center

also called:asymmetric centerstereocenterstereogenic center

• To locate a stereogenic center, examine each tetrahedral carbon atom in a molecule, and look at the four groups—not the four atoms—bonded to it.

• Always omit from consideration all C atoms that cannot be tetrahedral stereogenic centers. These include

*CH2 and CH3 groups * Any sp or sp2 hybridized C

Stereogenic Carbons

stereocenter

*

What is the relationship between chirality and enantiomers?

A chiral molecule always has an enantiomer.

An achiral molecule never has an enantiomer.

Recall that enantiomers are non-superimposable mirror images.

Enantiomers have identical physical and chemical properties except in two important respects:

1. They rotate the plane polarized light in opposite directions, however in equal amounts. The isomer that rotates the plane to the left

)anticlockwise( is called the levo isomer and is designated )-(

While the one that rotates the plane to the right )clockwise( is called the dextro isomer and designated )+(.

2. They react at different rates with other chiral compounds.

This is the reason that many compounds are biologically active while their enantiomers are not.

They react at the same rates with achiral

compounds.

Summary of the Basic Principles of Chirality:• Everything has a mirror image. The fundamental question is whether

the molecule and its mirror image are superimposable.• If a molecule and its mirror image are not superimposable, the

molecule and its mirror image are an enatiomers.• The terms stereogenic center and chiral molecule are related but

distinct. In general, a chiral molecule must have one or more stereogenic centers.

• The presence of a plane of symmetry makes a molecule achiral.

Any material which rotates the plane of the polarized light is termed "optically active.“

Compounds featuring chiral centers are optically active.

An isomer of optically active compound can rotate the plane of polarized light

to the left )levorotatory(, in which case it will be designated )l, or -(, or to the

right )dextrorotatory( in which case it will be termed )d, or +(.

Label the stereogenic centers in each molecule and decide if it is chiral.

a( CH3CH2CH)Cl(CH2CH3

H Clachiral

b( CH3CH)OH(CH=CH2

H OH

chiral

c( )CH3(2CHCH2CH2CH)CH3(CH2CH3

H CH3

chiral

A molecule that has a plane of symmetry or a center of symmetry is superimposeabl

◦ Plane of symmetry plane bisect molecule so one half is the mirror of the other half.

Another test for chirality is to assess whether the object itself has a mirror plane of symmetry or center of symmetry )point of inversion(.

Symmetry

plane ofsymmetry

Examples

plane of symmetry :

R. S. Cahn, Sir Christopher Ingold, and V. Prelog

)according to Cahn-Ingold-Prelog(

Absolute Configuration ( AC (

The system that is used was devised by R. S. Cahn, Sir Christopher Ingold, and V. Prelog. Called “sequence rule”

Two requirements for a system for specifying absolute configuration

1-Need rules for ranking substituents at stereogenic center in order of decreasing precedence

2-Need convention for orienting molecule so that order of appearance of substituents can be compared with rank

Absolute Configuration ( AC (

Absolute Configuration ( AC (

1. Rank the substituents at the stereogenic center according to same rules used in E-Z notation )Assign each group priority 1-4.(

2. Orient the molecule so that lowest-ranked substituent points away from you )lowest priority group )4( is in the back, look at remaining 3 groups in a plane.

3. If the order of decreasing precedence traces a clockwise path, the absolute configuration is R. If the path is anticlockwise, the configuration is S.

Sequence Rules

Rotate to the right-hide the hydrogen, and that will look like this-------->

1

)S(-Bromochlorofluoromethane )R(-Bromochlorofluoromethane

2

3 4

Absolute Configuration ( AC (

Absolute Configuration ( AC (The Cahn-Ingold-Prelog Rules

First, we assign priorities:

we next make sure that the #4 priority group )the hydrogen( is pointed back away from ourselves, into the plane of the page )it is already(.

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 of atoms

Horizontal lines come out of the pageVertical lines go back into page

Method to project a tetrahedral carbon onto a flat surface

Tetrahedral carbon represented by two crossed lines

to show configuration at stereogenic center without necessity of drawing wedges and dashes or using models.

Absolute Configuration ( AC (Fischer projections

Fischer projections Absolute Configuration ( AC (

Rules

1. Draw Fischer Projection formula

2. Rank the substitution according to the priority order)1-4(

3-Place the group of lowest priority, usually H, at the top of the Fischer projection by using one of the allowed motions The lowest-priority group is thus oriented back away from viewer

4. Draw an arrow from group with highest priority to second highest priority. if the arrow is …… a- clockwise, the configuration is R b- anti-clockwise, the configuration S

(±(- Ethanolamine CH3CH(OH(NH2

has one chiral carbon, so 2- enantiomers

H2N

CH3

H

OH H2NOH

H

CH3

Mirror Fischer projection formula

Fischer projections Absolute Configuration ( AC (

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

Fischer projections Absolute Configuration ( AC (

2. Rank the substitution according to the priority order

H2N

CH3

OH

H

OH > NH2 > CH3 > H

1 2

3

Fischer projections Absolute Configuration ( AC (

(R(-ethanolamine(+(- ethanolamine

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

H2

Absolute Configuration ( AC (Fischer projections

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

Absolute Configuration ( AC (Fischer projections

Draw the formulas for the two enantiomers of each of the following compunds then assign each as Ror S

CH

Br

CH3

OH

CH

CH3H3CH2Ca- b-

H .W

A Fischer projection can have one group held steady while the other three rotate in either a clockwise or a counterclockwise direction◦ Effect is to simply rotate around a single bond

Absolute Configuration ( AC (Fischer projections

Rules for manipulating Fischer projections: A Fischer projection can be rotated on the page by 180°, but

not by 90° or 270°◦ Only a 180° rotation maintains the Fischer convention by

keeping the same substituent groups going into and coming out of the plane

Absolute Configuration ( AC (Fischer projections

A 90° rotation breaks the Fischer convention by exchanging the groups that go into and come out of the plane◦ A 90° or a 270° rotation changes the representation to the

enantiomer

Absolute Configuration ( AC (Fischer projections

Determination of Number of stereoisomers

2n where n = number of chiral carbons

n = zero no possible stereoisomers 1 2 stereoisomers are possible 2 4 ~ ~ ~ ~ ~ ~ ~ 3 8 ~ ~ ~ ~ ~ ~ 4 16 ~ ~ ~ ~ ~ ~ 5 32 ~ ~ ~ ~ ~ ~

Optical isomerism

DiastereomersDiastereomers are stereoisomers that are not mirror images of one another and are non-superimposable on one another. Stereoisomers with two or more stereocenters can be diastereomers. It is sometimes difficult to determine whether or not two molecules are diastereomers

Example:2-bromo-3-chlorobutane

(±(- 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

Optical isomerism

Diastereomers

Determination of Absolute configuration(AC( in enatiomer 1

a. At C1 :

H

NH2

C2

C2NH2

H

Br

Br2

1

So , AC at C1 is S

Br > NH2 > C2 > H

Diastereomers

Optical isomerism

a. At C2:

H

C1

CH3

ClCH3

H

Cl

C1

2

1

AC at C2 is S

Cl > C1 > CH3 > H

Determination of (AC( in enatiomer 1

Diastereomers

Optical isomerism

So for overall

1 ( 1S, 2S ( 2 ( 1R, 2R (

Similarly:

3 ( 1R, 2S ( 4 ( 1S, 2R (

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

The solutions contain mirror image isomers, called enantiomers and they crystallized in distinctly different shapes

A )50:50( racemic mixture of both crystal types dissolved together was not optically active

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

the effect of each molecule is cancelled out by its enantiomer

Racemic mixture Optical isomerism

*It is optically inactive as it shows no rotation of PP light)because the

rotation by each enantiomer is cancelled(

*It is often designated as being )±( or )dl( or )RS(.

*A solution of either a racemic mixture or of achiral compound said to be

optically inactive* Can be separated )resolved( into 2 optically active enantiomers .

a sample that is optically inactive can be either an achiral substance or a racemic mixture

Racemic mixture

Thus

Optical isomerism

Resolution of racemic mixture

1- Treat the mixture with microorganism

N

N

H

CH3

N

N

H

CH3

(R,S) nicotine (R)

PseudomonasPutida

( R( RCOOH ( R( RCOO- (S( R’NH3

+

+ ( R( R’NH2 ( S( RCOOH ( R( RCOO- (R( R’NH3

+

Racemic mixture

2- Using chiral reagent

Optical isomerism

The pure compounds need to be separated or resolved from the mixture )called a racemate(

Using a Chiral amine changes the relationship of the productsNow we can separate the Diastereomeric Salts

*To separate components of a racemate )reversibly( we make a derivative of each with a chiral substance that is free of its enantiomer )resolving agent(*This gives Diastereomers that are separated by their differing solubility*The resolving agent is then removed

Optical isomerism

Meso-compound A meso compound is an achiral compound that has chiral centers. It is superimposed on its mirror image and is optically inactive although it contains two or more stereocenters.

A meso compound, should have :*two or more stereocenters, * an internal plane, *the stereochemistry should be R and S.*They are diastereomers of the )R,R( and )S,S( isomer.*Only 3 stereoisomers

It is a general rule that any molecule with at least one stereocenter is chiral – but as with most rules, there is an exception.  Some molecules have more than one stereocenter but are actually achiral – these are called meso compounds. Tartaric acid, a byproduct of the wine-making process, provides a good example

With two stereocenters, there should, in theory, be four stereoisomers of tartaric acid.  In fact, there are only three.  First of all, there is a pair of enantiomers with )2R,3R( and )2S, 3S( stereochemistry

Meso-compound Optical isomerism

Now, carefully consider a )2S, 3R( stereoisomer.  You may notice that, when it is rotated into just the right conformation, this isomer has a plane of symmetry passing through the C2-C3bond

That means that this molecule is not chiral, even though it has two stereocenters!  It also means that )2R,3S( tartaric acid and )2S,3R( tartaric acid are not enantiomers, as we might have expected – they are in fact the very same molecule, meso-tartaric acid.  This achiral molecule is, however, still a diastereomer of both R,R and S,S tartaric acid. Notice that the two ‘stereocenters’ of )meso(-tartaric acid have the same four substituents – this is a prerequisite for meso compounds; otherwise there would be no plane of symmetry

49

Tartaric acid has 2 chiral centers, 2 enantiomeric forms and 1 meso form Enantiomeric forms are chiral and meso form is achiral, but both have two chiral centers The two structures on the right in the figure are identical so the compound )2R, 3S( is

achiral Identical substitution on both chiral centers.

Optical isomerismMeso-compound

Applications of isomersem

In living organisms, virtually every molecule that contains a chiral center is found as a single enantiomer, not a racemic mixture.

At the molecular level, our bodies are chiral and interact differently with the individual enantiomers of a particular compound.

For example, the two enantiomers of carvone produces very different responses in humans:

(−(-carvone is the substance responsible for the smell of spearmint oil,

and )+(-carvone—the major flavor component of caraway seeds—is responsible for the characteristic aroma of rye bread.

Chirality in Nature

The sedative thalidomide, was sold in Europe from 1956 to the early 1960s. It was prescribed to treat nausea during pregnancy, but unfortunately only the )+( enantiomer was safe for that purpose. The )−( enantiomer was discovered to be a relatively potent teratogen, which caused the children of many women who had taken thalidomide to be born with missing or undeveloped limbs. As a result, thalidomide was quickly banned for this use. It is currently used to treat leprosy, however, and it has also shown promise as a treatment for AIDS )acquired immunodeficiency syndrome(.

A racemic mixture

Ibuprofen, a common analgesic and anti-inflammatory agent that is the active ingredient in pain relievers The drug is sold as a racemic mixture that takes approximately 38 minutes to achieve its full effect in relieving pain and swelling in an adult human. Because only the )+( enantiomer is active in humans, however, the same mass of medication would relieve symptoms in only about 12 minutes if it consisted of only the )+( enantiomer. Unfortunately, isolating only the )+( enantiomer would substantially increase the cost of the drug. Conversion of the )−( to )+( enantiomer in the human body accounts for the delay in feeling the full effects of the drug

A pharmaceutical example of a chiral compound

https://www.google.com.sa/imgres?imgurl&imgrefurl=http://www.clipartbest.com/post-it-note-clipart&h=0&w=0&tbnid=vZwTtMn5HLp6aM&zoom=1&tbnh=190&tbnw=266&docid=vPfmhr_9PgjahM&hl=en&tbm=isch&ei=bus4VNCqIMfBPJzsgJgN&ved=0CAQQsCUoAA

Extra examples

Step 1: Hold the molecule so that

1-The chiral center is on the plane of the paper,

2-Two bonds are coming out of the plane of the paper and are on a horizontal plane,

3-The two remaining bonds are going into the plane of the paper and are on a vertical plane

To convert this stereoformula into a Fischer projection use the following proced

Steps

Step 2: Push the two bonds coming out of the plane of the paper onto the plane of the paper

Step 3:  Pull the two bonds going into the plane of the paper onto the plane of the paper.

Step 4:  Omit the chiral atom symbol for convenience

To determine the absolute configuration of a chiral center in a Fisher projection, use the following two-step procedure.

Step 1: Assign priority numbers to the four ligands on the chiral cente

Step 2:If the lowest priority ligand is on a vertical bond, meaning that it is pointing away from the viewer, trace the three highest-priority ligands starting at the highest-priority ligand

If the lowest-priority ligand is on a horizontal bond, meaning that it is pointing toward the viewer, trace the three highest-priority ligands starting at the highest-priority ligand

A Fischer projection restricts a three-dimensional molecule into two dimensions.  Consequently, there are limitations as to the operations that can be performed on a Fischer projection without changing the absolute configuration at chiral centers.  The operations that do not change the absolute configuration at a chiral center in a Fischer projections can be summarized as two rules.

Rule 1:  Rotation of the Fischer projection by 180º in either direction without lifting it off the plane of the paper does not change the absolute configuration at the chiral center.

Rule 2:  Rotation of three ligands on the chiral center in either direction, keeping the remaining ligand in place, does not change the absolute configuration at the chiral center.

The operations that do change the absolute configuration at a chiral center in a Fischer projection can be summarized as two rules.

Rule 1:  Rotation of the Fischer projection by 90º in either direction changes the absolute configuration at the chiral center.

Rule 2:  Interchanging any two ligands on the chiral center changes the absolute configuration at the chiral center.

Assign R or S configuration to the following Fischer projection of alanine

StrategyFollow the steps listed in the text

1. Assign priorities to the four substituents on the chiral carbon

2. Manipulate the Fischer projection to place the group of lowest priority at the top by carrying out one of the allowed motions

3. Determine the direction 1→2→3 of the remaining three group

Configuration of alanine

Absolute Configuration ( AC (

Solution The priorities of the groups are )1( –NH2, )2( –CO2H, )3( –CH3,

and )4( –H To bring the lowest priority )–H ( to the top we might want to hold

the –CH3 group steady while rotating the other three groups counterclockwise

Absolute Configuration ( AC (Configuration of alanine

Exercises

Draw the formulas for the two enantiomers of each of the following compunds then assign each as Ror S

CH

Br

CH3

OH

CH

CH3H3CH2Ca- b-

Examine the following structural formulas and select those that are chiral.

Label the stereogenic centers in each molecule and decide if it is chiral.

a( CH3CH2CH)Cl(CH2CH3

H Clachiral

b( CH3CH)OH(CH=CH2

H OH

chiral

c( )CH3(2CHCH2CH2CH)CH3(CH2CH3

H CH3

chiral

How many stereogenic centers does each molecule have?a)

Br

Br

b)

Q: Decide the chiral carbons in the following formulas?

HC CH2CH3

CH3CHCOH

NH2

O

O

CH

CH

CH2OH

HO

CH3CCH2CH

Cl

Br

CHCH3

a.

c.

b.

d.

Practice ExerciseHow many chiral carbon atoms are there in the open-chain form of fructose

Answer: three

Solve: The carbon atoms numbered 2, 3, 4, and 5 each have four different groups attached to them, as indicated here:

How many chiral carbon atoms are there in the open-chain form of glucose

CH3 C

CH2OH

CH3

CH2 CH CH

CH3

CH3

OH*

Identify the stereocenters )chiral carbon atoms( in the following molecule?

*

OH

C CH2OH

BrH

CH3

CH3

C CO2H

NH2

H

CH)CH3(2

C

C CO2H

ClH

NH2

C CH3

CH2CH2CH3

H

OCH3

H

CH2CH3

CO2H

NH2

H

ValineAlanine

**

2-aminopentane2-Chloro- propanoic acid

2-Bromo-2- hydroxyethanol

*

***

Carvone (caraway(

Amino acids

http://chemwiki.ucdavis.edu/Organic_Chemistry/Chirality/Absolute_Configuration,_R-S_Sequence_Rules

http://www2.chemistry.msu.edu/faculty/reusch/VirtTxtJml/sterism3.htm

http://catalog.flatworldknowledge.com/bookhub/4309?e=averill_1.0-ch24_s02

http://colapret.cm.utexas.edu/courses/Nomenclature_files/Stereochemistry.htm