Chemistry for Health Sciences II

Two credits
Term 3, 2022/2023
King Saud bin Abdulaziz University for Health Sciences

Stereoisomerism
(Lectures 9-11)

Organic Chemistry A Brief Course. 13th Edition, Hart Hadad and Craine Hart 1
 Objectives
• At the end of these lectures, students should be
able to:

• Differentiate between the different types of stereoisomers.

• Identify a chiral molecule by locating a stereogenic/chiral center.
 Describe how a plane of symmetry relates to whether or not a
molecule is chiral.
 Explain what is meant by the terms enantiomer and diastereomer.
 Explain optical activity as a property of chiral molecules.
 Specify the absolute configuration of a molecule using the R-S
notational system in both dash-wedge and Fischer projection
models.
 Draw Fischer projections of chiral molecules.
 Explain the meaning of the meso form.

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Stereoisomers that contain asymmetric centers
Intro to Chirality
• A molecule is chiral if its two mirror image forms
are not superimposable upon one another.
ASYMMETRIC!
• Objects that have handedness in this manner are said to
be chiral (pronounced ky-ral, from the Greek cheir,
meaning “hand”). They don't have a plane of symmetry.

Non-superimposable mirror images

 Achiral molecules

• A molecule is achiral if its two mirror image forms

are superimposable. SYMMETRIC!
• Objects that lack handedness are said to be nonchiral, or achiral.
Their mirror images are superimposable because they have a
plane of symmetry.

Superimposable mirror images

 Plane of symmetry
• A plane that passes through a molecule and can divide it into
two identical halves where one side is same as the other.
• A molecule to be achiral if it has plane of symmetry.
• A molecule will be chiral if it does not have a plane of
symmetry.
Example: Chiral or Achiral?

achiral achiral

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 Example: Chiral or Achiral?
• School desk

chiral

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 Chirality: Stereogenic Centers

A carbon atom that is both tetrahedral geometry (four single

bonds) and has four different groups attached to it is
called :

• A chiral carbon atom

• A chiral center
• An asymmetric center
• A stereoegnic center
• A stereocenter

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 Chirality and chirality centers
If any molecule contains a single chiral center or a
stereogenic center the molecule is supposed to be
chiral molecule.

Examples H H

* *
CH3 C CH2CH3 CH3 C CH2CH3

OH Cl
2-butanol 2-chlorobutane

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Example: Identify a chiral molecule by locating a stereogenic/chiral
center.

CH3
Limonene
H
* CH2CH2CH3
CH3CH2 C
*
CH3
H C CH2
3-methylhexane
CH3
—H
a chirality center can be part of a ring
—CH2CH2
attached to the chirality center are: —CH2CH=C
—C=C
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More Examples: Identify a chiral molecule by locating a
stereogenic/chiral center.
 Learning Check:
What are chiral and achiral molecules?
 Enantiomers
• A chiral compound and its mirror image are
called Enantiomers.
Enantiomers are type of configurational isomer; they are
said to have opposite configurations.

Enantiomers
 Properties of Enantiomers
Physical properties of enantiomers
Same:
melting point, boiling point, density, spectroscopy, etc.
Different:
- Biological-physiological properties
- Arrangements of atoms or groups in space
mirror
CO2H CO2H

C C
OH HO
CH3 CH3
H H

(R)-(-)-lactic acid (S)-(+)-lactic acid

mp = 53 oC mp = 53 oC
[] (H2O) = + 2.6 [] (H2O) = - 2.6
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 Examples of Enantiomers
• Asparagine: mirror
plane
O OH HO O
C C

H2N C H H C NH2

CH2 CH2
C C
H2N O O NH2
L-asparagine D-asparagine
(from asparagus) (from vetch)
bitter taste sweet taste
Enantiomers 16
 Examples of Enantiomers
• Most importantly, pairs of enantiomers often
differ in their activity as drugs.
Enantiomers Configuration/ Designation

• R (clockwise) and S (counterclockwise)

Mirror

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 Configuration and the R-S Convention

The priority order of the four groups is set in the following way:
Rule 1.
The atoms directly attached to the stereogenic center are ranked according to
atomic number: the higher the atomic number, the higher the priority.
Cl > O > C > H
high priority Low priority

Rule 2.
If a decision can not be reached with rule 1, work outward from the
stereogenic center until a decision is reached. For example, C2H5- has higher
priority than CH3-

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Rule 3.
Multiple bonds are treated as if they were an equal number of
single bonds. For example, the vinyl group –CH=CH2 is counted
as
H
C CH2

This carbon is treated C C This carbon is treated

as if it were singly bonded as if it were singly bonded
to two carbons to two carbons

Similarly C C

C CH is treated as C C H

C C

and
H

C O is treated as C O
H

O C
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Configuration and the R-S Convention

(in plane of the page

(dash)Away from us, out of the plane of the page

(Wedge)Towards us, out of the plane of the page

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Assign the configuration (R or S) to the following enantiomer of
3-methylhexane CH3

H
C
CH3CH2
CH2CH2CH3

The priority order of the four different groups attached to stereogenic center

–CH2CH2CH3 > -CH2CH3 > -CH3 > -H

We write the name :

(R)-3-methylhexane

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Eye image repeated

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Examples 1
Assign a priority order to each of the following sets of groups:

a. –CH3, -CH(CH3)2, -H, -NH2

-NH2 > -CH(CH3)2 > -CH3 > -H,

b. –OCH3, -NHCH3, -CH2NH2, -OH

–OCH3 > -OH > -NHCH3 > -CH2NH2

c. –OH, -F, -CH3, -CH2OH

-F > –OH > -CH2OH > -CH3

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Examples 2
Which group has the priority, isopropyl or vinyl?
The vinyl group has the higher priority, because
H
C CH2 = C CH2
H
Vinyl C C

H
CH(CH3)2 = C CH2

isopropyl
CH3 H

Assign a priority order to

–CH=O, -CH=CH2, -CH2CH3 and -CH2OH

–CH=O > -CH2OH > -CH=CH2 > -CH2CH3

The aldehyde carbon is treated as though it is bonded to two oxygens
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Examples 3
Determine the configuration (R or S) at the stereogenic center in
CH3
CH O
A. H
HO
C B. C
CH2CH2CH3 H2N H
Ph

3
2 CH3
CH O
C
1 H 4
C 1 H2N H 4
HO Ph
CH2CH2CH3 2
3

clockwise or counterclockwise or
R- S-
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Examples 4
- Draw the structure of (R)-2-bromobutane.
*
Solution CH3CHCH2CH3 -Br > –CH2CH3 > -CH3 > -H
Br
1
3
Br 2
CH3
4 C2H5
C H
C H or
C H 4 or
CH3 C H 4
3 CH2CH3 C2H5
Br Br
2 2 1 CH3
1 3

- Draw the structure of (S)-2-phenylbutane.

C6H5 > CH2CH3 > CH3 > H
3
CH3 1 C6H5
2 CH CH
4 2 3
C H C H or C H 4
C6H5 or 3 C H 4
CH3CH2
1 CH2CH3 CH3 CH3
2
3 C6H5
2 1
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 Properties of Enantiomers

1. They have same physical properties such as

melting point, boiling point, density, spectroscopy.
They differ in optical activity or optical rotation.

mirror
CO2H CO2H

C C
OH HO
CH3 CH3
H H

(R)-(-)-lactic acid (S)-(+)-lactic acid

mp = 53 oC mp = 53 oC
[] (H2O) = + 2.6 [] (H2O) = - 2.6

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 Properties of Enantiomers

2. They have different biological-physiological

properties.

CO2H
CO2H CO2H
lactic acid lactic acid C
C C H
dehydrogenese CH3
HO dehydrogenese
CH3 O CH3 HO
H
(S)-(+)-lactic acid pyruvic acid (R)-(-)-lactic acid

The enzyme lactic acid dehydrogenase oxidizes (+)-lactic acid to

pyruvic acid, but it does not oxidize (-)-lactic acid

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 Fisher Projection Formulas
A Fischer projection or Fischer projection formula is a
representation of stereoformula in two dimension
without destroying the stereochemistry at chiral centers.
Fisher Projections are used extensively in biochemistry and in
carbohydrate chemistry.

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Draw Fischer projections of chiral molecules.
Step 1: Hold the molecule so that
1.the chiral center is on the plane of the paper,
2.two bonds are coming out of the plane of the
paper and are on a horizontal plane,
3.the two remaining bonds are going into the plane
of the paper and are on a vertical plane

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 Step 2: Push the two bonds coming out of the plane of the paper onto the plane of
the paper

Step 3: Pull the two bonds going into the plane of the paper onto the plane of

paper.

Step 4: Delete the chiral atom symbol for convenience.

This is the Fischer Projection of (R)-Lactic acid.
Rules for Fischer projections
4
H
1 2
Br Cl

F
3
Clockwise = (R)-configuration

Projection of molecule on page is a cross.

When represented this way it is understood that horizontal
bonds project outward, vertical bonds are back.
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Determine the absolute configuration of the following enantiomers:
1
4
Cl H
3 2 3 2
CH3 CH2CH3 CH3 CH2CH3

H OH
4 1
clockwise = (R)-configuration counterclockwise = (S)-configuration
3 3
CH3 CH3
1 enantiomers 1 4
4H OH HO H

CH2CH3 CH2CH3
2 2
(S)-configuration (R)-configuration
Note:- lowest priority group is on the horizontal; R is changed to S
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 Properties of Enantiomers: Optical activity

• The enantiomer that rotates the plane of polarized

light in a clockwise direction is called dextrorotatory
(D) and is called the (+) enantiomer.
• The other enantiomer (counterclockwise rotation) is
levorotatory (L), the (-) enantiomer.
• Racemic Mixture: A 50:50 mixture of two
enantiomers: no optical rotation!
A polarimeter is used to make such measurements.

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 Properties of Enantiomers: Optical activity
𝑡 𝛼
Specific rotation = 𝛼 𝜆 =
𝑐.𝑙

Specific rotation, 𝛼 𝑡𝜆 , is an intrinsic property of chiral molecule

at specific temperature of the solution (t) , nature of the solvent,
and wavelength of the light (𝝀).

Observed rotation, 𝛼 , is function of concentration of the chiral

molecules (c, in unit of g/mL) and length of the sample tube (𝒍 , in
unit of decimeter (1 dm =10 cm))
Compound Rotation Compound Rotation
azidothymidine +99 Na glutamate +25.5
Cefotaxine +55 Morphine -132
Cholesterol +31.5 Progesterone +172
Codeine -136 Sucrose +66.5
epinephrine -5.0 testosterone +109
 Example: Optical activity
A 3.20 g sample of morphine ([α]D = -132) was dissolved in 10.0 mL of acetic acid ([α]D = 0).
If it is put into a sample tube with a path length of 2.00 cm, what would be its observed
rotation (α)?

Answer

([α]D = -132) x (l = 2.00 cm = 0.200 dm) x (c = 3.20 g / 10.0 cm3 = 0.320 g/cm3)
α = -132 x 0.200 dm x 0.320 g/cm3 = -8.45 o
 Compounds with More Than One
Stereogenic Center; Diastereomers
• How many stereoisomers when a particular molecule
contains two chiral centers?
Stereoisomers = 2n where n is the number of chiral centers
H H
1 2 * 3 * 4
CH3 C C CH3

Br Cl

2-bromo-3-chlorobutane

4 Combinations = 4 Stereoisomers
What is the relationship between these stereoisomers?
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 mirror
mirror
1 CH3 1 CH3 1 CH3 1 CH3
2 2 2 2
Br C H H C Br Br C H H C Br

3 3 3 3
H C Cl Cl C H Cl C H H C Cl

4 CH3 4 CH3 4 CH3 4 CH3

enantiomers enantiomers
(2R,3R) (2S,3S) (2R,3S) (2S,3R)
1 2 3 4
1 and 2 are enantiomers. 3 and 4 are enantiomers.
but not all relationships are enantiomeric
Diastereomers are stereoisomers that are not enantiomers.
1 and 3 are diastereomers. 2 and 3 are diastereomers.
1 and 4 are diastereomers. 2 and 4 are diastereomers.

Diastereomers have different physical and chemical properties.

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 Meso Compounds
• Consider the stereoisomers of 2,3-dichlorobutane.

A compound with two asymmetric centers that have the same four groups
bonded to each asymmetric center will have three stereoisomers:
a meso compound and a pair of enantiomers. 40
 Meso Compounds
this structure and its
mirror image are the
same
it is called a meso form
a meso form is an achiral molecule that has chirality centers

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 Summary of Meso Compounds

Any meso compound should have the following:

 Has more than one stereogenic center
 Achiral molecule
 Plane of symmetry

 The molecule and its mirror image are superimposable (e.g. same
compound)

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