Coverage:

1
Chapter 9 Stereochemistry

• Coverage
• Chirality in molecules test for chirality
• Chiral carbons and absolute configuration ( R and
  S)
• Fischer projections and their meaning
• 4. Optical activity of chiral molecules
• Enantiomers and racemic mixtures
• Diastereomers and meso molecules
• Resolution of enantiomers by chemical
  modification
• Chirality in cycloalkane systems

Problems 33, 35, 39, 43, 46-54, 63, 68, 71, 76

• Goals
• Be able to determine whether a molecule is chiral
  or not.
• Be able to identify chiral centers in a molecule
• Be able to draw Fischer projections of simple
  molecules and manipulate them.
• Be able to determine absolute configuration of
  3-D structures and Fischer projections
• Be able to identify pairs of enantiomers, pairs
  of diastereomers, and meso molecules.
• Know the principles of enantiomeric resolution by
  chemical modification.
• Be able to predict the stereochemical outcome of
  addition of X2 and HX to alkenes.

2
Chirality objects that are handed and are not
superimposable are chiral objects. your hands
are chiral objects. One way of testing for
chirality is to examine the mirror image.
Chiral objects have mirror images different from
the original.
Molecules can be either chiral or achiral
mirror image mirror image
Achiral
Chiral
Superimposable mirror image
Non-superimposable mirror image
Non-superimposable mirror images are deemed
enantiomers. Any chiral molecule must have a
corresponding mirror image enantiomer.
3
Chiral Carbons
A carbon atom is chiral if it is bonded to four
different groups. The carbon is often referred
to as an asymmetric or stereocenter.
Question Are the above molecules
superimposable?
Answer No, they are not! Not convinced?
Build models and see if they are!
These molecules are therefore chiral. Each
represents an enantiomer
4
The most common cause of chirality in molecules
is the existence of a chiral carbon. This is
not the only cause, however!

• If a molecule has only one chiral carbon, it is
  chiral
• If a molecule has two or more chiral carbons, it
  may or may not be chiral
• If a molecule has no chiral carbon, it may or
  may not be chiral.

So.. what is the best way to tell if a molecule
is chiral or not?

• Test for superimposability of the mirror image.
• Chiral non-superimposable
• Achiral - superimposable

• Determine if a plane of symmetry exits.
• If it does, then molecule is achiral
• If it does not, then molecule is chiral

5
?1
Consider 2-bromobutane again.
rotate
?2

• Rotate so that one group is up and one group is
  down.

• Define a plane through the vertical groups. Is
  this a plane of symmetry?

No.
3. Define a plane through the horizontal
groups. Is this a plane of symmetry?
No.
This molecule is chiral because it lacks a plane
of symmetry
6
?1
Consider 1-bromopropane
rotate
?2
A horizontal plane of symmetry exists. The
molecule is achiral
Defining Absolute Configuration about Chiral
Carbons
How do we define the arrangement of the 4
different groups around a chiral carbon? In other
words, how do we name the individual enantiomers
of a molecule like the amino acid alanine
Name?
Name?
7
1. Prioritize the atoms using the previously
discussed Cahn-Ingold-Prelog rules.
2
1
3
Prioritize the groups
4
2. Rotate the molecule such that the lowest
priority group is placed in the back with the
other groups point toward you or out of the paper.
2
Counterclockwise S
1
3

• Examine the relationship of the three highest
  priority groups.
• Clockwise R (right or Rectus)
• Counterclockwise S (left or Sinister)

Name (S)-alanine
8
Optical Activity
Consider the interaction of plane-polarized light
with a single enantiomer of a chiral molecule.
Polarimetry technique of measuring the amount
of rotation of polarized light.
Enaniomers rotate plane-polarized light in equal
amounts but in opposite direction. Clockwise
rotation dextrorotatory (d) () Counterclockwis
e rotation levorotatory (l) (-)
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How do we quantify the amount of
rotation? Specific rotation, ? ?
?_____ C l ? -
observed rotation in degrees C - concentration,
g/mL l - cell path length, dm
(l)-(-)-2-butanol ?D25 -13.50
D D line of sodium as light source 25 -
temperature in degrees Celsius.
chiral carbon
Racemic mixture a mixture with equimolar amounts
of the two enantiomers. This
mixture does not rotate polarized light because
the two enantiomers cancel each
other out.
10
Fischer Projections provides a rapid means of
depicting molecules with chiral carbons. Allows
for convenient comparison of stereochemistry
especially when more than one chiral carbon
exists.
?
(R)-lactic acid

• The cross represents a chiral carbon
• More oxidized carbon place on top, least
  oxidized on bottom.
• Horizontal groups toward, vertical groups away.

• Determination of Stereochemistry of Chiral
  Carbons in Fischer projections.
• First, rules for allowed motions when
  manipulating
• A Fischer projection can never be removed from
  the plane of the paper.
• 1800 rotation is allowed, 900 or 2700 rotations
  are not allowed.
• Hold one group stationary, rotate others either
  clockwise or counter clockwise.

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Violating any of these rules during manipulation
will result in a change in stereochemistry of
the chiral carbon. The idea here is to
manipulate without altering the
stereochemistry. 2.
1800
R
R
900
R
S
12

• Hold one group stationary and rotate the other
  three groups either clockwise
• or counterclockwise.

R
same as original allowed motion
13
So, how do you determine whether a Fischer
projection is R or S?
Using an allowed motion, place the lowest
priority group either on the top or the bottom
of the molecule. Then, look at the relationship
of the other three groups Clockwise
R Counterclockwise - S
What is the stereochemistry of this molecule?
3
Clockwise R
1
2
4
14
What about this one?
Two chiral carbons. What are their designations?
15
1
3
hold
2
1
3
16
Answer
S R
R S
mirror image
What is the stereochemistry of the mirror image?

• The above molecule is an example of a chiral
  molecule with two chiral carbons.
• How do we know it is chiral?
• Mirror image is not superimposable with original
• No plane of symmetry.

17
More detail Chiral molecule with two chiral
carbons

4 3 2 1
2,3-dihydroxybutanoic acid
How many stereoisomers are possible? Answer
2n
where n is
number of chiral carbons
So, there are 4 stereoisomers possible.
C-2 R or S C-3 R or S
(2R, 3R) (2S, 3S) (2R, 3S) (2S, 3R)
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(2R, 3R) (2S,
3S) (2R, 3S)
(2S, 3R)
enantiomers
(2R, 3R) (2S,
3S) (2R, 3S)
(2S, 3R)
diastereomers
diastereomers
enantiomers
19
Diastereomers stereoisomers that are not
enantiomers they are not mirror
images and they are non-superimposable.
Diastereomers possess different physical
properties, e.g. boiling point,
melting point, solubility,
etc Enantiomers - possess identical physical
properties.
To represent these isomers using Fischer
projections, first recognize that a Fischer
projection is an eclipsed conformation
This is an eclipsed conformation!
is
20
So, in order to draw a Fischer projection from a
3-D structure, it must first be converted from a
staggered conformation into an eclipsed
conformation
(2R, 3R) (2S, 3S)
(2R, 3S) (2S, 3R)
chiral chiral
chiral chiral
21
Achiral molecule with two chiral carbons

2,3-butanediol
chiral chiral
achiral
meso molecule
Total number of Stereoisomers 3
Meso molecule an achiral molecule with chiral
carbons
22
Resolution of Enantiomers
Enantiomers have the same physical properties so
they can not be separated directly. A possible
technique for separation is chemical modification
into diastereomers, which possess different
physical properties. Once in hand, diastereomers
can be separated by physical means, such as
boiling point or recrystallization and then
converted back into enantiomers.

• Two key requirements
• The reaction must be reversible so that the
  enantiomers can be released.
• The reagent that reacts with the enantiomers must
  be stereochemically pure.

Example The resolution of (S) and (R)-2-butanol
via esterification with enantiomerically pure
(R,R)-tartaric acid.
Key reaction Esterification
acid alcohol
ester
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Reaction Scheme
S
R R
R
R R
The initial product esters are diastereomers of
each other and can be separated by selective
recrystallization (i.e. different solubilities in
a solvent). The alcohols are recovered by
hydrolysis of the esters (reversible reaction).
24
Analysis of Cyclohexane Systems
Cyclohexanes exits predominantly in the chair
conformation and thus are considered
conformationally mobile. Consider
methylcyclohexane.
Methylcyclohexane is conformationally mobile with
the equatorial conformer favored at equilibrium.
Is this molecule chiral?
No, a plane of symmetry exists, regardess of
which conformation you consider.
Achiral
25
Lucky for us, it works just as well if you
consider the cyclohexane to be flat in your
analysis of its chirality.
The plane of symmetry is easy to see here.
Achiral
Does methylcyclohexane possess a chiral carbon?
No!
The circled CH2 groups are identical
26
Consider cis-1,2-dimethylcyclohexane
Is this molecule chiral?
No, a plane of symmetry exists
Does this molecule possess chiral carbons?
Yes, there are two.

Wow! An achiral molecule with two chiral
carbons.
Meso molecule
What about the mirror image? Since this molecule
is achiral, its mirror image should be
superimposable, i.e. identical to original. Is
it?
27
Consider trans-1,2-dimethylcyclohexane
Is this molecule chiral?
Yes, a plane of symmetry does not exist
Does this molecule possess chiral carbons?
Yes, there are two.

Wow! An chiral molecule with two chiral carbons.

What about the mirror image? Since this molecule
is chiral, its mirror image should be
non-superimposable, i.e. different from the
original Is it?
28
Allenes
Allenes possess cumulated double bonds, with the
central carbon being sp hybridized. This unique
structure results in a perpendicular relationship
of the two end CH2 groups of the unsubstituted
allene, shown below,
Achiral, two planes of symmetry, one in the plane
of the paper, another perpendicular to it.
Achiral, one plane of symmetry perpendicular to
plane of paper.
Chiral, no plane of symmetry
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Reactions where the Stereochemistry matters
1. Reaction of HBr with 2-butene

50 R/50 S Racemic

• Markovnikov addition
• New chiral carbon is produced
• Product mixture is racemic.

2. Reaction of cyclohexene with Br2.

• Anti addition results in trans stereochemistry
• Product is chiral with two chiral carbons
• Product is racemic