Isomers Have same molecular formula,

but different structures

Constitutional Isomers Differ in the order of attachment of atoms

(different bond connectivity)

Stereoisomers Atoms are connected in the

same order, but differ in spatial orientation

Diastereomers Not related as image and

mirrorimage stereoisomers

Enantiomers Image and mirrorimage are not superimposable

CH3

H3CH

CH3H3C

CH3

H3C CH3H3C

CH3

H

H

HH

H

BrClF

H

Br ClF

What is meant by Stereoisomers?

They are any structure that have the same constitutional structure (have the same atoms bonded to the same atoms) but are arranged differently in three dimensions

Differ in the ORIENTATION of atoms in space

Have already seen this with cis and trans alkene structures

The difference in orientation can cause vastly different properties for the molecule

Trans-2-butene Cis-2-butene

H3C CH3H

HH3C

CH3

HH

Stereoisomers

How Do We Tell if Something is Chiral Chiral object has a mirror image that is different from the original object

(chiral means “handedness” in Greek)

Therefore mirror image is NONSUPERIMPOSABLE

Stereoisomers

Hands are nonsuperimposable, therefore chiral

Hammer is superimposable, therefore achiral

Importance of Chirality

When two chiral objects interact, a unique shape selectivity occurs (we will learn that with chiral organic molecules this leads to an ENERGY difference)

Consider a hand and a glove (two chiral objects)

Both are chiral, therefore there is a different energetic fit if the left hand goes into a right-handed glove compared to the right hand

This energetic difference is not present if one of the objects is achiral

Would not be able to fit opposite hand into this chiral glove

Importance of Chirality

Similar to a chiral hand interacting with a chiral glove leading to different energy interactions, when two chiral molecules interact there will be an energy difference

depending upon the chirality

Cl-Cl

When methyl groups are pointing away and hydroxy or amine groups pointing up,

chlorine interacts with chlorine and hydrogen with hydrogen

In this enantiomer, however, the chlorine is directed toward the hydrogen and the other chlorine is directed toward other hydrogen

Will obtain different energetic interactions when different chirality of compounds interact

Chirality of Molecules

Whenever a molecule cannot be superimposed on its mirror image it is chiral

nonsuperimposable therefore chiral

superimposable therefore achiral

H3C

CH3

BrHH

H

CH3

H3C

BrH H

H

2-bromobutane

H3C

CH3

BrHH

H

H3C

CH3

HBrH

H

2-bromopropane

H3C

H3C

BrH

CH3

CH3

BrH

H3C

H3C

BrH

H3C

H3C

BrH

Definition of Enantiomers

Enantiomers: any nonsuperimposable mirror image molecules

H3C

CH3

BrHH

H

CH3

H3C

BrH H

H

2-bromobutane

enantiomers

H3C

CH3

BrHH

H

H3C

CH3

HBrH

H

Nonsuperimposable mirror images

Ultimately symmetry distinguishes chiral molecules

A chiral molecule can have no internal planes of symmetry

Methane (1 of 4 planes)

(achiral)

Chloromethane (1 of 3 planes)

(achiral)

Dichloromethane (1 of 2 planes)

(achiral)

Bromochloro- methane (achiral)

Bromochloro-fluoromethane

(chiral)

Symmetry

A chiral carbon atom must have four different substituents

In order to have no internal planes of symmetry all four substituents on a carbon must be different

Therefore a double or triple bonded carbon atom is not chiral (2 or 3 substituents, respectively, would be the same)

If a compound has only one chiral atom, then the molecule must be chiral

Determining Chiral Carbon Atoms

Cahn-Ingold-Prelog Naming System for Chiral Carbon Atoms

A chiral carbon is classified as being either R or S chirality

How to name: 1)  Prioritize atoms bonded to chiral carbon atom

The higher the molecular weight the higher the priority

-if two substituents are the same at the initial substitution point continue (atom-by-atom) until a point of difference

*if there is never a difference then the carbon atom is not chiral!

Treat double and triple bonded species as multiple bonds to site

Br

H CH2CH3CH=CH2

12

3

4

2)  Place lowest priority substituent towards the back and draw an arrow from the highest priority towards the second priority

If this arrow is clockwise it is labeled R (Latin, rectus, “upright) If this arrow is counterclockwise it is labeled S (Latin, sinister, “left”)

Cahn-Ingold-Prelog Naming System for Chiral Carbon Atoms

Br

H CH2CH3CH=CH2

12

3

4Br

H CH=CH2CH2CH3

1

2

34

Br

CH=CH2H3CH2C

1

23

Br

CH2CH3H2C=HC

1

2 3

R S

Enantiomers have Identical Energies

Most typical physical properties are identical (melting point, boiling point, density, etc.)

How can we distinguish enantiomers? Usually to characterize different compounds we would record the physical properties

of a pure sample and compare, but this does not distinguish enantiomers

One important characteristic – their optical activity is different

Chiral compounds rotate plane polarized light

Amount (and direction) of Optical Rotation distinguishes enantiomers

Enantiomeric compounds rotate the plane of polarized light by exactly the same amount but in OPPOSITE directions

A compound will be labeled by its specific rotation ([α])

[α] = α(observed) / (c • l)

HO H

(R)-2-butanol -13.5˚

H OH

(S)-2-butanol +13.5˚

Optical Rotation

Diagram for a polarimeter

Chiral compounds will rotate plane polarized light

Achiral compounds do not rotate plane polarized light

Optical Rotation

Few Chiral Compounds are Obtained in Only One Enantiomeric Form

A solution of a chiral molecule might contain a majority of one enantiomer but a small fraction of the opposite enantiomer

If there are equal amounts of both enantiomers present it is called a RACEMIC mixture (or RACEMATE)

The optical rotation will be zero (since each enantiomer has opposite sign of optical rotation)

Racemic Mixtures

A racemate can be formed in two ways:

1) Add equal amounts of each pure enantiomer (hard)

2) React an achiral molecule to generate a chiral center using only achiral reagents

Racemic Mixtures

HO H H OHO H2

achiral Chiral products

Enantiomeric Excess (or optical purity)

For many cases where there is an abundance of one enantiomer relative to the other the sample is characterized by its enantiomeric excess (e.e.)

The enantiomeric purity is defined by this e.e.

Therefore if a given solution has 90% of one enantiomer (say R) and 10% of the other enantiomer (S) then the enantiomeric excess is 80%

[(90 – 10) / (90 + 10)](100%) = 80%

[(R – S) / (R + S)] (100%) = e.e.

Another convenient way to represent stereochemistry is with a Fischer projection

To draw a Fischer projection: 1) Draw molecule with extended carbon chain in continuous trans conformation

2) Orient the molecule so the substituents are directed toward the viewer

** Will need to change the view for each new carbon position along the main chain

3) Draw the molecule as flat with the substituents as crosses off the main chain

Fischer Projection

CO2H

CH3

HOH

CO2HHHO

CH3

Important Points

- Crosses are always pointing out of the page

- Extended chain is directed away from the page

Fischer Projection

CO2HHHO

CH3

CO2HHHO

CH3

Rotation of Fischer Projections

A Fischer projection can be rotated 180˚, but not 90˚

A 90˚ rotation changes whether substituents are coming out or going into the page It changes the three dimensional orientation of the substituents

CO2HHHO

CH3

CH3OHH

CO2H

CO2HHHO

CH3

OHCO2HH3C

H

CO2H

H3C OHH

CO2H

H3C HOH

Convention is to place more oxidized carbon at

top, but obtain same stereoisomer

180˚

90˚

Fischer projections are extremely helpful with long extended chains with multiple stereocenters

An enantiomer is easily seen with a Fischer projection

Fischer Projection

H3C

CH3

BrH

ClH

Orient view at each chiral center

CH3BrHClH

CH3

Merely consider the “mirror” image of the Fischer projection

CH3HBrHCl

CH3

CH3BrHClH

CH3

With n Stereocenters there are a Maximum Possible 2n Stereoisomers

Therefore with two stereocenters there are a possible four stereoisomers

These two stereoisomers are not related by a mirror plane,

therefore they are not enantiomers

Number of Stereoisomers

CH3BrHClH

CH3

CH3HBrHCl

CH3

CH3BrHHCl

CH3

CH3HBrClH

CH3

enantiomers enantiomers

Diastereomers

- Any stereoisomer that is not an enantiomer

Therefore the two stereoisomers are not mirror images

Remember enantiomers: mirror images that are not superimposable

Already observed diastereomers with cis and trans alkenes

Stereoisomers, but not mirror images therefore diastereomers

H3C CH3H

HH3C H

H

CH3

Meso Compounds

Sometimes there are compounds that are achiral but have chiral carbon atoms (called MESO compounds)

Maximum number of stereoisomers for a compound is 2n

(where n is the number of chiral atoms)

This compound has only 3 stereoisomers even though it has 2 chiral atoms

CH3HHOOHH

CH3

CH3OHHHHO

CH3

CH3HHOHHO

CH3

CH3OHHOHH

CH3

Enantiomers (nonsuperimposable

mirror images)

Diastereomers (not mirror related)

Identical (meso)

The meso compounds are identical (therefore not stereoisomers) therefore this compound has 3 stereoisomers

Meso compounds are generally a result of an internal plane of symmetry bisecting two (or more) symmetrically disposed chiral centers

Meso Compounds

CH3HHOHHO

CH3

2,3-(2R,3S)-butanediol has an internal plane of symmetry as shown

Any compound with an internal plane of symmetry is achiral

Determining number of stereoisomers of HO2CCH(OH)CH(OH)CH(OH)CO2H ���using Fischer projections

Maximum number is 2n, therefore 23 = 8

HHOCO2H

HHOHHO

CO2H

HHOCO2H

HHOOHH

CO2H

HHOCO2H

OHHHHO

CO2H

HHOCO2H

OHHOHH

CO2H

OHHCO2H

HHOHHO

CO2H

OHHCO2H

HHOOHH

CO2H

OHHCO2H

OHHHHO

CO2H

OHHCO2H

OHHOHH

CO2H

1   2   3   2  

4   3   4   1  

Compound has only 4 stereoisomers Stereoisomers 1 and 3 are meso due to internal plane of symmetry

Stereoisomers 2 and 4 are enantiomers

Number of Stereoisomers

Chirality of Conformationally Flexible Molecules

A molecule CANNOT be optically active if its chiral conformations are in equilibrium with their mirror image

In butane, for example, two conformers are nonsuperimposable mirror images

H

H CH3CH3

HH

H

H3C

H

CH3

HH

H

H3C HCH3

HH

But these two conformers can interconvert upon bond rotation and cannot be isolated at room temperature (called conformational enantiomers)

Therefore if a mirror image is conformationally accessible then the molecule is not chiral

These two conformers of the compound are nonsuperimposable mirror images

However, rotation about the single bond can rotate one conformer to the mirror image

Therefore compound is not configurationally chiral

Stereoisomers

H

Br

HHH

H H

Br

HH H

H

H

Br

HH H

HH

Br

HHH

HRotate 180˚

Energy Differences

Remember enantiomers have the same energy value

Diastereomers can have vastly different energies

Therefore separation of diastereomers is easier

CO2HHBrBrH

CO2H

CO2HBrHBrH

CO2H

diastereomers

m.p. 158˚C m.p. 256˚C

How can Enantiomers be Separated?

Optical rotation can distinguish between two enantiomers, but it does not separate enantiomers

Need a way to change the relative energy of the enantiomers (if the energy of the two remain the same separation becomes nearly impossible)

Resolution of Enantiomers

To “resolve” (separate) the enantiomers can be reacted to form diastereomers (which have different energies!)

Can reversibly create an ester from an alcohol and an acid

Using this reaction we can create diastereomers in order to separate

R

O

OHCH3OH

R

O

OCH3H2O

These two enantiomers, however, can be reacted with a chiral acid

This generates DIASTEREOMERIC esters

Resolving Enantiomers

HO H H OH

R S Since enantiomers, have same energy

HO H

H OH

H3C CO2H

H OCH3

H3C CO2H

H OCH3H3C

H OCH3

O

O

H CH3

H3C

H OCH3

O

O

H CH3R

S

S

S

S,R

S,S

The two diastereomers can now be separated due to their energy differences

Once separated the alcohol can be obtained in pure form by hydrolyzing the ester

Overall Scheme for Resolving Enantiomers

Resolving Enantiomers

Enantiomers (R+S) (R,S) + (S,S)

(R,S) (S,S)

creatediastereomer

cleaveresolving agent

separate

cleaveresolving agent

Pure R Pure S

H3C

H OCH3

O

O

H CH3

H2O H OH

Determination of Absolute Configuration

Once a chemist resolves two enantiomers to the pure R and S forms, how does the chemist know which pure form is R and which is S?

Easy to determine that the two are enantiomers by taking an optical rotation, one will rotate the plane of light in a clockwise direction (called dextrorotatory [+])

and one in a counterclockwise direction (called levorotatory [-])

Dextrorotatory or levorotatory do not distinguish which is R and which is S

A X-ray crystal structure could determine the absolute configuration but not all samples are solids (also need a special type of X-ray determination called anomalous dispersion)

Often chemists predict the absolute configuration for new compounds by relating them to the known absolute configuration of other molecules

(usually through reactions but then the chemist must know exactly how the reactions proceed – things we will learn as course continues)

Chiral Compounds Without Chiral Carbons

We have already seen compounds that are not chiral that do contain chiral carbon atoms (meso compounds are an example)

It is also possible to obtain chiral compounds that do not contain any chiral atoms

Remember that chirality is dependent upon the shape of the molecule

Some shapes can cause the mirror image to be nonsuperimposable upon itself and thus chiral

C C CH

H3C

CH3

H

1,3-dimethyl allene enantiomers

Can also observe with conformational enantiomers if the energy to interconvert is too high

NO2

CO2HHO2C

O2NO2N

HO2CCO2H

NO2

Importance of Chirality

Remember that two enantiomers have the same physical properties but when two enantiomers interact with another chiral object

distinct energetic interactions occur (a diastereomeric interaction)

Same consideration as when a left or right hand is inserted into a baseball glove, the hands and the glove are chiral – hence a diastereomeric interaction occurs

In biological interactions often an organic molecule will interact with a receptor The receptors are often proteins which are chiral (are made from chiral building blocks,

α-amino acids, and form a chiral three-dimensional shape)

If the organic molecules interacting with the protein are also chiral, then there will be an energy difference depending upon which enantiomer is interacting with the protein

Consequence of Diastereomeric Interactions

These stereochemical interactions lead to potentially vastly different properties

Some examples: Smell

Two enantiomers of Limonene

CH3

HCH3

CH3

HCH3

Odor of lemon Odor of orange

Taste

Taste is a brain response to when molecules bind with taste receptors

Consider two enantiomers of Asparagine

OH

O

O

H2N

NH2HHO

O

O

NH2H2N H

bitter sweet

Drug Interactions

A potentially more serious consequence of chirality is the interaction of drugs Drugs are often chiral and they interact with chiral protein receptors in the body

Enantiomers, therefore have different physiological responses

Consider Penicillamine

OH

O

HSHH2N

HO

O

SHH NH2

antiarthritic toxic

Chirality of Proteins

Proteins are biopolymers of α-amino acids

There are 20 natural α-amino acids that are used to make proteins

- Of the 20 amino acids, 19 are chiral

Natural chiral amino acids have an (S) designation (*except cysteine – due to sulfur atom) compare three-dimensional structures

O

OHR

H2N H

α-amino acids

Glycine has R=H, therefore achiral

Proteins are polymers of these chiral amino acid building parts

Short peptide segment

The chiral building blocks make a chiral environment

When chiral molecules interact with the peptide, one enantiomer can have different energetic interactions

What would happen if the protein was made with the opposite chirality of the amino acids?

OH

ONH

OHN

ONH

OHN

CH3

SH

OH

(NH2-Phe-Ser-Cys-Gly-CO2H)