Stereoisomerism and Chirality

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Stereoisomerism and Chirality
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Isomerism

• Constitutional Isomers Same atoms but linked
  (bonded) together differently. Spatial
  orientation not important.

No, different molecular formulae!!
Are these constitutional isomers of hexane?
Are these constitutional isomers of cis but-2-ene?
Not this one! It is 2-butene. Cis / trans does
not matter.
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Stereoisomerism

• Stereoisomers Same molecular formulae, same
  connectivity same constitutional isomer.
  Different spatial orientation of the bonds.

Are these stereoisomers of cis but-2-ene?
How does the connectivity differ between these
two?
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Enantiomers and Diastereomers

• Two kinds of Stereoisomers
• Enantiomers stereoisomers which are mirror
  objects of each other. Enantiomers are different
  objects, not superimposable.
• Diastereomers stereoisomers which are not mirror
  objects of each other.

If a molecule has one or more tetrahedral carbons
having four different substituents then
enantiomers will occur. If there are two or more
such carbons then diastereomers may also occur.
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Summary of Isomerism Concepts
Isomers, contain same atoms, same formula
Constitutional isomers, different connectivities,
bonding.
Stereoisomers, same connectivity, different three
dimensional orientation of bonds
Enantiomers, mirror objects
Diastereomers, not mirror objects
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Mirror Objects Carbon with 4 different
substituents. We expect enantiomers (mirror
objects).
Reflect!
The mirror plane still relates the two
structures. Notice that we can characterize or
name the molecules by putting the blue in the
back, drawing a circle from purple, to red, to
green. Clockwise on the right and
counterclockwise on the left. Arbitrarily call
them R and S.
Notice how the reflection is done, straight
through the mirror!
Arrange both structures with the light blue atoms
towards the rear.
These are mirror objects. Are they the same
thing just viewed differently ?? Can we
superimpose them?
We can superimpose two atoms. but not all four
atoms.
R
S
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Recap Tetrahedral Carbon with four Different
Substituents. Enantiomers
Mirror objects. Different, not superimposable. En
antiomers
Simple Rotation, Same
Simple Rotation, Same
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But the reflection might have been done
differently. Position the mirror differently.
Reflection can give any of the following
Again. all three objects on the right are the
mirror object of the structure above. They are
different views of the enantiomer. A swap of two
substituents is seen to be equivalent to a
reflection at the carbon atom.
Can you locate the mirror which would transform
the original molecule into each mirror object?
What is common to each of these reflection
operations?
In the course of each reflection, two
substitutents are swapped. The other two remain
unchanged.
All three of these structures are the same, just
made by different mirrors. The structures are
superimposable. What rotations of the whole
molecules are needed to superimpose the
structures?
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Now Superimposable mirror objects Tetrahedral
Carbon with at least two identical substituents.
Reflection can interchange the two red
substituents. Clearly interchanging the two reds
leads to the same structure, superimposable!
Remember it does not make any difference where
the mirror is held for the reflection. This
molecule does not have an enantiomer the mirror
object is superimposable on the original, the
same object.
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Summary
A reflection on a tetrahedral carbon with four
different substituents produces a different,
non-superimposable structure, the enantiomer. A
different three dimensional arrangement of the
bonds is produced, a different configuration.
Such a carbon is called chiral. The carbon is a
chiral center, a stereogenic center.
If a tetrahedral carbon has two or more
substituents which are the same then reflection
produces the same structure, the same
configuration. Such a carbon is called achiral.
The swapping two of the substituents on the
chiral carbon is equivalent to a reflection.
There is only one mirror object produced by
reflection, no matter where the mirror is
located. It is either the same as the original
structure (superimposable) or it is different
(non-superimposable), the enantiomer.
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Multiple reflections
One reflection (swap of substituents) on a chiral
carbon produce the enantiomer.
Two reflections (swaps) yields the original back
again.
Even number (0, 2, 4) of reflections (swaps) on
a chiral carbon yields the original structure.
An odd number (1, 3, 5) yields the enantiomer.
Enantiomers
Enantiomers
One swap
Second swap
Same molecule.
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Repeating.
Three different substitutents.
Reflection (in this plane) yields.
Same, not enantiomers.
Four different substituents.
Reflection (in this plane) yields.
Different, not superimposble, enantiomers.
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Is a chiral carbon needed? No!
Recall allene
Reflection (in this plane) yields.
Different, not superimposable, enantiomers.
The (distorted) tetrahedral array of the
substitutents (huh??) suffices to allow for
enantiomers.
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Naming of configurations.
S
R
A priority is assigned to each substituent on the
chiral carbon
Rotate the structure so that the lowest priority
towards the rear.
Draw an arc from the highest, to the next lower,
to the next lower.
If arc is clockwise it is R configuration. If
arc is counterclockwise it is S.
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Assigning Priorities 2
Start with first atom attached to chiral carbon
C vs. F
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When the first atom is the sameExamine what is
bonded to it.
Start with first atom attached to chiral carbon.
No decision!!
Examine atoms bonded to first atom
O vs O
N vs C
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Example assigning Priorities
S configuration
Substituents
Highest,1
Lowest, 4
3
2
Assign on the basis of the atomic number of the
first atom in the substituent.
If the atoms being compared are the same examine
the sets bonded to the atoms being compared.
C has priority over H!!
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More If the first atom is the same and the
second shell is the same then proceed to the
atoms attached to the highest priority of the
second shell.
Examine the first atom, directly attached to the
chiral atom.
Examine the atoms bonded to the first atom (the
second shell) .
N vs N
C vs C
H vs H
Examine atoms bonded to highest priority of
second shell, N
Cl vs F Cl wins!
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Unsaturation
So far have not worried about double or triple
bonds.
Double and triple bonds are expanded as shown
below.
Expanded into
becomes
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Lets investigate what happens if low priority is
positioned closer to us than chiral carbon
H towards the rear where it belongs
Now lets swap any two substituents. We know
that this produces the enantiomer, R. Swap the H
and the Cl.
Arc going in wrong direction because the low
priority substituent is closer to us than the
chiral center!!!!!! We are looking at the
molecule from the wrong side. INVERT NAMING if
LOW PRIORITY IS CLOSER THAN CHIRAL
CENTER Clockwise is S Counterclockwise is R
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Physical Properties of Enantiomers
Enantiomers different compounds but have
same Melting Point Boiling Point Density
Enantiomers rotate plane polarized light in
opposite directions. OPTICALLY ACTIVE!! The
enantiomers rotate plane polarized light the same
amount but in opposite directions. One
clockwise the other counterclockwise.
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How to know if a compound is optically
(in)active. Symmetry elements.

• The symmetry of an object is described in terms
  of symmetry elements. The use of a symmetry
  element may only interchange identical atoms.

Proper Rotation. Rotation about an axis. Think
of a propeller.
Reflection plane (mirror plane).
Inversion Point. An equidistant line through the
center of the molecule.
Improper Rotation. Rotation followed by
reflection in plane perpendicular to axis.
If a molecule has a reflection plane, inversion
point, or improper rotation axis inactive
The presence of any of these symmetry elements
except for proper rotation rules out enantiomers.
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Rotational Axis
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Reflection Plane
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Inversion Point
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Improper Rotational Axis
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Allene, lets find the symmetry elements in it.
Two Proper Rotational Axes, 180 deg.
Reflection Plane
Reflection Plane
We recognize this molecule as being achiral
because of the reflection planes or because of
the improper rotational axis. Usually they go
together. Can you, however, design a molecule
having an improper axis but not reflection planes.
Proper Rotational Axis, 180 deg
Improper Rotational Axis, 90 and 270 deg
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Polarimeter
before
after
Concentration pure liquid in g/mL solution in g
per 100 mL of solvent
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Optical Activity

• Optically Active compounds rotate plane polarized
  light. Chiral compounds (compounds not
  superimposable on their mirror objects) are
  expected to be optically active.
• Optically Inactive compounds do not rotate plane
  polarized light. Achiral compounds are optically
  inactive.

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Problems

• If the specific rotation of pure R 2-bromobutane
  is 48 degrees what is the specific rotation of
  the pure S enantiomer?

The pure S enantiomer has a specific rotation of
-48 degrees. Equal but opposite!!
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Mixtures of Enantiomers

• These are high school mixture problems.
• If you know the specific rotation of the pure
  enantiomers and the composition of a mixture then
  the specific rotation of the mixture may be
  predicted. And conversely the specific rotation
  of the mixture may be used to calculate the
  composition of the mixture.

Specific rotation of mixture (fraction which is
R)(specific rotation of R) (fraction which
is S)(specific rotation of S)
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Example

• Mixture of 30 R and 70 S enantiomer.
• The pure R enantiomer has a specific rotation of
  -40 degrees.
• What is the specific rotation of the mixture?

Contribution from R
Contribution from S
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• Using the specific rotation to obtain the
  composition of the mixture.
• For the same two enantiomers (a of R -40) ,
  suppose the specific rotation of a mixture is 8.
  degrees what is the composition?

Specific rotation of mixture (fraction which is
R)( specific rotation of R) (fraction which
is S)( specific rotation of S)
-40.
8.
40.
(1. fraction which is R)
Fraction which is R 40 fraction which is S is
60.
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Racemic Mixtures, Racemates

• The racemic mixture (racemate) is a 5050 mixture
  of the two enantiomers.
• The specific rotation is zero.
• The racemic mixture may have different physical
  properties (m.p., b.p., etc.) than the
  enantiomers.

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Optical Purity, Enantiomeric Excess
Consider a mixture which is 80 R (and 20 S).
Assume the specific rotation of the pure R
enantiomer is 50 degrees.
As before Specific rotation of mix 0.80 x 50.
.20 x (-50.) 30.
R R R R R R R R S S
Now, recall that a racemic mixture is 50 R and
50 S. Mixture is 60 R and 40 racemic.
Specific rotation of mix 0.60 x 50. .40 x
(0.) 30.
The optical purity (or enantiomeric excess) is
60.
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Fischer Projection
Cl to Ethyl to Methyl
Reposition to
Look from this point of view.
Standard Fischer projection orientation vertical
bonds recede horizontal bonds come forward
H,low priority substituent, is closer so CCW is R.
R and S designations may be assigned in Fischer
Projection diagrams. Frequently there is an H
horizontal making R CCW and S CW.
Standard short notation
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Manipulating Fischer Projections
Even number of swaps yields same structure odd
number yields enantiomer.
1 swap
or
R
or
Etc.
S
All of these represent the same structure, the
enantiomer (different views)!!
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Manipulating Fischer Projections
Even number of swaps yields same structure odd
number yields enantiomer.
2 swaps
or
R
or
Etc.
R
All of these represent the same structure, the
original (different views)!!
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Rotation of Entire Fischer Diagrams
Rotate diagram by 180 deg
Same Structure simply rotated H Br still
forward CH3 C2H5 in back.
This simple rotation is an example of proper
rotation.
Rotation by 90 (or 270) degrees.
Enantiomers. Non superimposable structures! Not
only has rotation taken place but reflection as
well (back to front). For example, the H is now
towards the rear and ethyl is brought forward.
This combination of a simple rotation and
reflection is called an improper rotation.
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Multiple Chiral Centers
S
R
Do a single swap on each chiral center to get the
enantiomeric molecule.
S
R
Each S configuration has changed to R.
Now do a single swap on only one chiral center to
get a diastereomeric molecule (stereoisomers but
not mirror objects).
R
S
S
R
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Multiple Chiral Centers
S
R
S
R
R
S
S
R
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Multiple Chiral Centers
S
R
Diastereomers
S
R
R
S
Diastereomers
S
R
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Diastereomers

• Everyday example shaking hands. Right and Left
  hands are mirror objects
• R --- R is enantiomer of L --- L
• and have equivalent fit to each other.
• R --- L and L --- R are enantiomeric, have
  equivalent fit, but fit differently than R
  --- R or L L.

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Diastereomers

• Require the presence of two or more chiral
  centers.
• Have different physical and chemical properties.
• May be separated by physical and chemical
  techniques.

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Meso Compounds
Must have same set of substituents on
corresponding chiral carbons.
S
R
R
S
As we had before here are the four structures
produced by systematically varying the
configuration at each chiral carbon.
S
R
S
R
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Meso Compounds
What are the stereochemical relationships?
S
R
Enantiomers Mirror images, not superimposable.
R
S
Diastereomers.
S
R
S
R
Mirror images! But superimposable via a 180
degree rotation. Same compound.
Meso
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Meso Compounds Characteristics
Has at least two chiral carbons. Corresponding
carbons are of opposite configuration.
Can be superimposed on mirror object, optically
inactive.
Can demonstrate mirror plane of symmetry
Molecule is achiral. Optically inactive.
Specific rotation is zero.
R
S
S
R
Meso
Can be superimposed by 180 deg rotation.
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Meso Compounds Recognizing
What of this structure? It has chiral carbons.
Is it optically active? Is it meso instead?
Assign configurations. Looks meso. But no mirror
plane.
R
S
Rearrange by doing even number of swaps on upper
carbon.
Now have mirror plane.
R
Original structure was meso compound. In checking
to see if meso you must attempt to establish the
plane of symmetry.
S
Meso
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Cycloalkanes
Vertical reflection plane.
Horizontal reflection plane.
Look for reflection planes!
There are other reflection planes as well. Do you
see them?
Based on these planar ring diagrams we observe
reflection plane and expect optical inactivity.
But the actual molecule is not planar!! Examine
cyclohexane.
This plane of symmetry (and two similar ones) are
still present. Achiral. Optically inactive. The
planar diagrams predicted correctly.
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Substituted cyclohexanes
The planar diagram predicts achiral and optically
inactive. But again we know the structure is not
planar.
cis
Mirror objects!!
This is a chiral structure and would be expected
to be optically active!!
But recall the chair interconversion.
Earlier we showed that the two structures have
the same energy. Rapid interconversion. 5050
mixture. Racemic mixture. Optically Inactive.
Planar structure predicted correctly
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More
trans
No mirror planes. Predicted to be chiral,
optically active.
Enantiomer.
Ring Flips??????
R,R
R,R
trans 1,2 dimethylcyclohexane
Each structure is chiral. Not mirror images! Not
the same! Present in different amounts. Optically
active!
Other isomers for you 1,3 cis and trans, 1,4
cis and trans.
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Resolution of mixture into separate enantiomers.
Mixtures of enantiomers are difficult to separate
because the enantiomers have the same boiling
point, etc. The technique is to convert the pair
of enantiomers into a pair of diastereomers and
to utilize the different physical characteristics
of diastereomers.
Formation of diastereomeric salts. Racemic
mixture of anions allowed to form salts with pure
cation enantiomer.
Racemic mixture reacted with chiral enzyme. One
enantiomer is selectively reacted.
Racemic mixture is put through column packed with
chiral material. One enantiomer passes through
more quickly.
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Chirality in the Biological World
All three substituents match up with sites on
the enzyme.
If two are matched up then the third will fai!

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