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Stereochemistry: A Brief Review of Isomerism

• Isomers are
different structures
with the same
molecular formula.
• Constitutional
isomers are isomers
with different bond
connectivity.
• The flowchart
summarizes the
types of isomers we
have seen

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Constitutional Isomers
• Different order of connections gives different
carbon backbone and/or different functional
groups

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Stereoisomers
• Same connections, different spatial arrangement of atoms
– Enantiomers (nonsuperimposable mirror images)
– Diastereomers (all other stereoisomers)
• Includes cis, trans and configurational

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Stereochemistry
• Some objects are not the same as their mirror images
(technically, they have no plane of symmetry)
– A right-hand glove is different than a left-hand glove
– The property is commonly called “handedness”
• Organic molecules (including many drugs) have handedness
that results from substitution patterns on sp3 hybridized
carbon

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Chirality
• If an object has a plane of symmetry it is necessarily
the same as its mirror image
• The lack of a plane of symmetry is called
“handedness”, chirality
• Hands, gloves are prime examples of chiral object
– They have a “left” and a “right” version

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Enantiomers – Mirror Images

• Molecules exist as three-dimensional
objects
• Some molecules are the same as their
mirror image
• Some molecules are different than their
mirror image
–These are stereoisomers called
enantiomers
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Chiral Carbons
• A molecule with a single tetrahedral carbon bonded to four different
groups will always be chiral
• Switching two groups at the tetrahedral center leads to the enantiomeric
molecule in a molecule with one tetrahedral carbon
• Tetrahedral carbons with 4 different attached groups are chiral.
• Its mirror image will be a different compound (enantiomer).
• An atom bearing groups of such nature that an interchange of any two
groups will produce a stereoisomer

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Chirality Centers
• A point in a molecule where four different groups (or
atoms) are attached to carbon is called a chirality center
• There are two non-superimposable ways that 4 different
groups (or atoms) can be attached to one carbon atom
– If two groups are the same, then there is only one way
• A chiral molecule usually has at least one chirality center

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Chirality Centers in Chiral Molecules

• Groups are considered “different” if there is any structural
variation (if the groups could not be superimposed if
detached, they are different)
• In cyclic molecules, we compare by following in each
direction in a ring

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The Biological Importance of Chirality

• Chirality or handedness is common in nature. On the

macroscopic level, helical seashells generally spiral like a right-
handed screw and are chiral. Climbing vines wind in a specific
direction.
• On the molecular level, most biologically important molecules
are chiral. The biological activity of chiral molecules is
specifically associated with specific enantiomer. This
specificity results from reaction between a chiral molecule
and a chiral receptor that only accomodates one enantiomer.
This enantioselectivity is a key factor in drug design.
• The binding specificity of a chiral receptor site for a chiral
molecule is usually only favorable in one way.
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The Biological Importance of Chirality

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Enantiomers and the Tetrahedral Carbon

• Enantiomers are molecules that are not the same as their
mirror image
• They are the “same” if the positions of the atoms can
coincide on a one-to-one basis (we test if they are
superimposable, which is imaginary)
• This is illustrated by enantiomers of lactic acid

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Examples of Enantiomers
• Molecules that have one carbon with 4 different
substituents have a nonsuperimposable mirror image –
enantiomer
• Build molecular models to see this

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Mirror-image Forms of Lactic Acid

• When H and coincide
OH substituents match up,
COOH and CH3 don’t
• when COOH and CH3 coincide,
H and OH don’t

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The Reason for Handedness: Chirality

• Molecules that are not superimposable with their

mirror images are chiral (have handedness)
• A plane of symmetry divides an entire molecule into
two pieces that are exact mirror images
• A molecule with a plane of symmetry is the same as
its mirror image and is said to be achiral

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Plane of Symmetry
• The plane has the same thing on both sides
for the flask
• There is no mirror plane for a hand

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Fischer Projections Formula

• Flat drawing that represents a 3D molecule
• A chiral carbon is at the intersection of
horizontal and vertical lines.
• Horizontal lines are forward, out-of-plane.
• Vertical lines are behind the plane.

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Fischer Projection Formula

• Vertical lines represent bonds that
project behind the plane of the
paper
• Horizontal lines represent bonds
that project out of the plane of the
paper

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Optical Activity
• Light restricted to pass through a plane is plane-
polarized
• Plane-polarized light that passes through solutions of
achiral compounds remains in that plane
• Solutions of chiral compounds rotate plane-polarized
light and the molecules are said to be optically
active
• Phenomenon discovered by Biot in the early 19th
century

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Optical Activity
• Light passes through a plane polarizer
• Plane polarized light is rotated in solutions of
optically active compounds
• Measured with polarimeter
• Rotation, in degrees, is []
• Clockwise rotation is called dextrorotatory
• Anti-clockwise is levorotatory

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Measurement of Optical Rotation

• A polarimeter measures the rotation of plane-polarized
that has passed through a solution
• The source passes through a polarizer and then is
detected at a second polarizer
• The angle between the entrance and exit planes is the
optical rotation.

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Specific Rotation and Molecules

• Characteristic property of a compound that is optically
active – the compound must be chiral
• The specific rotation of the enantiomer is equal in
magnitude but opposite in sign

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Relative 3-Dimensionl Structure

• The original method was a
correlation system,
classifying related
molecules into “families”
focused on carbohydrates
– Correlate to D- and L-
glyceraldehyde
– D-erythrose is the mirror
image of L-erythrose
• This does not apply in
general

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Sequence Rules for Specification of

Configuration
• A general method applies to the configuration at
each chirality center (instead of to the whole
molecule)
• The configuration is specified by the relative
positions of all the groups with respect to each
other at the chirality center
• The groups are ranked in an established priority
sequence and compared
• The relationship of the groups in priority order in
space determines the label applied to the
configuration, according to a rule
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Sequence Rules (IUPAC)

• Assign each group priority according to the Cahn-
Ingold-Prelog scheme With the lowest priority group
pointing away, look at remaining 3 groups in a plane
• Clockwise is designated R (from Latin for “right”)
• Counterclockwise is designated S (from Latin word
for “left”)

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(R) or (S), Nomenclature of Enantiomers

1. Assign priority, according to the Cahn-Ingold-Prelog rules, to the 4 substituents on
the stereocenter, in order of (1) > (2) > (3) > (4).
2. Arrange the molecule so that the lowest priority group, (4), is in the back, and then
draw a Newman projection looking along the bond from the stereocenter C down to
(4).
3. Draw a circular arrow from highest (1) through (2) to the third priority group (3).
• Clockwise arrow, assign “R” to the stereocenter.
• Counterclockwise arrow, assign “S” to the stereocenter.

(1)

(2) (3)
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Priority assignment: Cahn-Ingold-

Prelog Rules
• The higher atomic number has a higher priority than the
lower one.
– e.g., Br > Cl > F > O > N > C > H
• The higher mass isotope has higher priority than the lower
mass.
– e.g., T > D > H
• For the same atoms directly attached to the stereocenter,
move along the two chains until a point of difference, and
use the above priority rules to determine which group has
higher priority.
• Double (triple) bonds are treated by assuming that each such
bonded atoms is duplicated (triplicated).

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Examples of Applying Sequence Rules

• If lowest priority is back,
clockwise is R and
counterclockwise is S
– R = Rectus
– S = Sinister

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Diastereomers
• Molecules with more
than one chirality
center have mirror
image stereoisomers
that are enantiomers
• In addition they can 2R,3R 2S,3S
have stereoisomeric
forms that are not
mirror images, called
diastereomers
2R,3S 2S,3R
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Properties of Diastereomers
• Diastereomers have different physical
properties: m.p., b.p.
• They can be separated easily.
• Enantiomers differ only in reaction with other
chiral molecules and the direction in which
polarized light is rotated.
• Enantiomers are difficult to separate.

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Meso Compounds
• Tartaric acid has two chirality centers and two diastereomeric forms
• One form is chiral and the other is achiral, but both have two chirality
centers
• An achiral compound with chirality centers is called a meso compound
– it has a plane of symmetry
• The two structures on the right in the figure are identical so the
compound (2R, 3S) is achiral

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Molecules with More Than Two Chirality

Centers
• Molecules can have very many chirality centers
• Each point has two possible permanent arrangements (R or S),
generating two possible stereoisomers
• So the number of possible stereoisomers with n chirality
centers is 2n

Cholesterol has eight chirality centers

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Physical Properties of Stereoisomers

• Enantiomeric molecules differ in the direction in which
they rotate plane polarized but their other common
physical properties are the same
• Daistereomers have a complete set of different common
physical properties

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Racemic Mixtures and Their Resolution

• A 50:50 mixture of two chiral compounds that are mirror
images does not rotate light – called a racemic mixture
(named for “racemic acid” that was the double salt of (+) and
(-) tartaric acid
• The pure compounds need to be separated ot resolved from
the mixture (called a racemate)
• To separate components of a racemate (reversibly) we make a
derivative of each with a chiral substance that is free of its
enantiomer (resolving agent)
• This gives diastereomers that are separated by their differing
solubility
• The resolving agent is then removed

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• An equal amount of two enantiomers is called

a racemic mixture or a racemate. A racemic
mixture is optically inactive. Because two
enantiomers rotate plane-polarized light to an
equal extent but in opposite directions, the
rotations cancel, and no rotation is observed.

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