Isomers Have same molecular formula, but different structures

Constitutional Isomers Stereoisomers Differ in the order of Atoms are connected in the attachment of atoms same order, but differ (different bond connectivity) in spatial orientation

CH3

CH3 H H3C H3C CH3

Enantiomers Diastereomers Image and mirrorimage Not related as image and are not superimposable mirrorimage stereoisomers

H H H CH3

F F H3C H3C Br Cl Cl Br CH3 H H H Stereoisomers

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

H CH3 H3C H3C CH3 H H H

Trans-2-butene Cis-2-butene

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

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

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

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

2-bromobutane

H C CH H C H C 3 Br Br 3 3 Br 3 H H H H H H H H Br H H H H CH3 H3C CH3 CH3

nonsuperimposable therefore chiral 2-bromopropane

H C CH H C H C 3 Br Br 3 3 Br 3 Br H H H H H3C CH3 H3C H3C

superimposable therefore achiral Definition of Enantiomers

Enantiomers: any nonsuperimposable mirror image molecules

2-bromobutane

H C CH H C H C 3 Br Br 3 3 Br 3 H H H H H H H H Br H H H H CH3 H3C CH3 CH3

enantiomers Nonsuperimposable mirror images Symmetry

Ultimately symmetry distinguishes chiral molecules

A chiral molecule can have no internal planes of symmetry

Methane Chloromethane Dichloromethane Bromochloro- Bromochloro- (1 of 4 planes) (1 of 3 planes) (1 of 2 planes) methane fluoromethane (achiral) (achiral) (achiral) (achiral) (chiral) Determining Chiral Carbon Atoms

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 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

1 Br 2 4 CH=CH H 2 CH2CH3 3 Cahn-Ingold-Prelog Naming System for Chiral Carbon Atoms

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

1 1 Br 2 Br 3 4 CH=CH 4 CH CH H 2 H 2 3 CH2CH3 CH=CH2 3 2

1 1 Br Br

H3CH2C CH=CH2 H2C=HC CH2CH3 3 2 2 3

R S

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

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 H OH

(R)-2-butanol -13.5˚ (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 Racemic Mixtures

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

O H2 HO H H OH

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.

[(R – S) / (R + S)] (100%) = 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% Fischer Projection

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

CO H HO 2 H CH3

** 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

CO2H HO H

CH3 Fischer Projection

Important Points

- Crosses are always pointing out of the page

- Extended chain is directed away from the page

CO2H CO2H HO H HO H

CH3 CH3 Rotation of Fischer Projections

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

CO2H 180˚ CH3 Convention is to place HO H H OH more oxidized carbon at top, but obtain same CH3 CO2H stereoisomer

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

CO2H 90˚ OH HO H H3C CO2H CH3 H

CO2H CO2H H C H H C OH 3 OH 3 H Fischer Projection

Fischer projections are extremely helpful with long extended chains with multiple stereocenters Orient view at each chiral center

H C CH3 3 Br H Br H H H Cl Cl CH 3 CH3

An enantiomer is easily seen with a Fischer projection

CH3 CH3 H Br Br H H Cl Cl H

CH3 CH3

Merely consider the “mirror” image of the Fischer projection Number of Stereoisomers

With n Stereocenters there are a Maximum Possible 2n Stereoisomers

Therefore with two stereocenters there are a possible four stereoisomers

enantiomers enantiomers

CH3 CH3 CH3 CH3 H Br Br H H Br Br H H Cl Cl H Cl H H Cl

CH3 CH3 CH3 CH3

These two stereoisomers are not related by a mirror plane, therefore they are not 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

H CH3 H3C H3C CH3 H H H

Stereoisomers, but not mirror images therefore diastereomers 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)

Enantiomers Diastereomers Identical (nonsuperimposable (not mirror related) (meso) mirror images)

CH3 CH3 CH3 CH3 HO H H OH HO H H OH H OH HO H HO H H OH

CH3 CH3 CH3 CH3

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

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

CH3 HO H 2,3-(2R,3S)-butanediol has an internal plane of HO H symmetry as shown

CH3

Any compound with an internal plane of symmetry is achiral Number of Stereoisomers

Determining number of stereoisomers of HO2CCH(OH)CH(OH)CH(OH)CO2H using Fischer projections Maximum number is 2n, therefore 23 = 8

1 2 3 2

CO2H CO2H CO2H CO2H HO H HO H HO H HO H HO H HO H H OH H OH HO H H OH HO H H OH

CO2H CO2H CO2H CO2H

4 3 4 1

CO2H CO2H CO2H CO2H H OH H OH H OH H OH HO H HO H H OH H OH HO H H OH HO H H OH

CO2H CO2H CO2H CO2H

Compound has only 4 stereoisomers Stereoisomers 1 and 3 are meso due to internal plane of symmetry Stereoisomers 2 and 4 are enantiomers 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

CH H3C 3 H H H H

CH3 CH3 H CH3 H3C H H H H H H H

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

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

H H H H Br Br H H H H H H

These two conformers of the compound are nonsuperimposable mirror images

H H H H Rotate 180˚ Br Br H H H H H H

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

Therefore compound is not configurationally chiral Energy Differences

Remember enantiomers have the same energy value

Diastereomers can have vastly different energies

CO2H CO2H Br H H Br H Br H Br

CO2H CO2H

diastereomers

m.p. 158˚C m.p. 256˚C

Therefore separation of diastereomers is easier 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

O O CH3OH H2O R OH R OCH3

Using this reaction we can create diastereomers in order to separate Resolving Enantiomers

HO H H OH

R S Since enantiomers, have same energy

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

H OCH3 HO H H OCH3 O H3C H3C CO2H S,R O H CH3 R S

H OCH3 H OH H OCH3 O H3C S,S H3C CO2H O H CH3 S S

This generates DIASTEREOMERIC esters Resolving Enantiomers

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

H OCH 3 H O H OH O 2 H3C O H CH3

Overall Scheme for Resolving Enantiomers

create diastereomer Enantiomers (R+S) (R,S) + (S,S)

separate

(R,S) (S,S)

cleave cleave resolving agent resolving agent

Pure R Pure S 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

H CH3 C C C H3C H 1,3-dimethyl allene enantiomers

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

CO2H HO2C HO2C CO2H

O2N NO2 NO2 O2N 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 CH3

H H CH3 CH3

Odor of lemon Odor of orange Taste

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

Consider two enantiomers of Asparagine

O O H N NH 2 OH HO 2 O H NH2 H2N H O

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

O O

HS OH HO SH H2N H H 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

O R Glycine has R=H, OH therefore achiral H2N H

α-amino acids

Natural chiral amino acids have an (S) designation (*except cysteine – due to sulfur atom) compare three-dimensional structures Proteins are polymers of these chiral amino acid building parts

OH O O CH H H 3 N N OH N N H H O O SH

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