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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
CH3
H
CH3
H3C
CH3
H3 C
Enantiomers
Image and mirrorimage are not superimposable
H
Br
Diastereomers
Not related as image and
mirrorimage stereoisomers
H
F
Cl
F
Cl
CH3
H
Br
H 3C
CH3
H
H 3C
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
H 3C
CH3
CH3
H
Trans-2-butene
H 3C
H
H
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
H3C
H
H
Br
H
CH3
Br
H
CH3
H3 C
H
H
H3C
H
H
Br
H
CH3
H3 C
H
H
H
Br
CH3
nonsuperimposable
therefore chiral
2-bromopropane
H3C
H3C
Br
H
Br
H
CH3
H3C
CH3
H3C
Br
H
H3C
H3C
Br
H
superimposable
therefore achiral
Definition of Enantiomers
Enantiomers: any nonsuperimposable mirror image molecules
2-bromobutane
H3C
H
H
Br
H
CH3
Br
H
CH3
H3 C
enantiomers
H
H
H3C
H
H
Br
H
CH3
H3 C
H
H
H
Br
CH3
Nonsuperimposable mirror images
Symmetry
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)
Bromochlorofluoromethane
(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=CH2
H
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
Br 2
4
CH=CH2
H
CH2CH3
3
1
Br 3
4
CH2CH3
H
CH=CH2
2
1
Br
1
Br
H3CH2C
3
CH=CH2
2
R
H2C=HC
CH2CH3
2
3
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
(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
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
achiral
H2
HO H
H OH
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
HO
H
CO2H
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
H
HO
CH3
Fischer Projection
Important Points
- Crosses are always pointing out of the page
- Extended chain is directed away from the page
CO2H
H
HO
CH3
CO2H
H
HO
CH3
Rotation of Fischer Projections
A Fischer projection can be rotated 180˚, but not 90˚
CO2H
H
HO
CH3
180˚
CH3
H
OH
CO2H
Convention is to place
more oxidized carbon at
top, but obtain same
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
H
HO
CH3
90˚
OH
H3C
CO2H
H
CO2H
H3C
H
OH
CO2H
H3C
OH
H
Fischer Projection
Fischer projections are extremely helpful with long extended chains with multiple stereocenters
Orient view at each chiral center
H3 C
H
Cl
Br
H
CH3
CH3
H
Br
H
Cl
CH3
An enantiomer is easily seen with a Fischer projection
CH3
H
Br
H
Cl
CH3
CH3
Br
H
H
Cl
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
CH3
H
Br
H
Cl
CH3
CH3
Br
H
H
Cl
CH3
enantiomers
CH3
H
Br
H
Cl
CH3
These two stereoisomers are not
related by a mirror plane, therefore they are not enantiomers
CH3
Br
H
H
Cl
CH3
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
H3 C
CH3
CH3
H
H3 C
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
(nonsuperimposable
mirror images)
CH3
H
HO
H
OH
CH3
Diastereomers
(not mirror related)
CH3
H
OH
H
HO
CH3
CH3
H
HO
H
HO
CH3
Identical
(meso)
CH3
H
OH
H
OH
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
H
HO
H
HO
CH3
2,3-(2R,3S)-butanediol has an internal plane of
symmetry as shown
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 CO2H
H
HO
H
HO
H
HO
CO2H
2 CO2H
H
HO
H
HO
H
OH
CO2H
4 3 CO2H
H
OH
H
HO
H
HO
CO2H
CO2H
H
OH
H
HO
H
OH
CO2H
3 CO2H
H
HO
H
OH
H
HO
CO2H
4 CO2H
H
OH
H
OH
H
HO
CO2H
2 CO2H
H
HO
H
OH
H
OH
CO2H
1 CO2H
H
OH
H
OH
H
OH
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
H3C CH3
H
H
CH3
CH3
H
H
H
H
H
H
H3C
CH3
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
HH
H
H
HH
Br
H
Br
H
H
H
These two conformers of the compound are nonsuperimposable mirror images
HH
H
H
Br
H
Rotate 180˚
HH
Br
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
Br
H
H
Br
CO2H
CO2H
H
Br
H
Br
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
R
O
CH3OH
OH
R
OCH3
H2 O
Using this reaction we can create diastereomers in order to separate
Resolving Enantiomers
HO H
R
H OH
S
Since enantiomers, have same energy
These two enantiomers, however, can be reacted with a chiral acid
HO H
H OCH3
H3C
R
H OH
CO2H
S
H OCH3
H3C
S
CO2H
S
H OCH3
O
H3 C
O H CH3
H OCH3
O
H3C
O H CH3
This generates DIASTEREOMERIC esters
S,R
S,S
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 OCH3
O
H3C
O H CH3
H2 O
H OH
Overall Scheme for Resolving Enantiomers
Enantiomers (R+S)
create
diastereomer
(R,S) + (S,S)
separate
(R,S)
cleave
resolving agent
Pure R
(S,S)
cleave
resolving agent
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
H 3C
H
1,3-dimethyl allene
enantiomers
Can also observe with conformational enantiomers if the energy to interconvert is too high
CO2H
HO2C
HO2C
CO2H
O 2N
NO2
NO2
O 2N
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
CH3
H
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
H2 N
O
OH
O
H NH2
bitter
HO
H2N H
sweet
NH2
O
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
HS
H2 N H
O
OH
antiarthritic
HO
SH
H NH2
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
OH
H2 N H
Glycine has R=H,
therefore achiral
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
H
N
O
N
H
OH
H
N
O
O
CH3
N
H
SH
OH
O
(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?