Unit 3 : Stereochemistry and types

3.1 Introduction

 Stereochemistry deals with three dimensional representation of molecule in space.

 It is a branch of chemistry which deals with three dimensional structure of
molecule and their effect on physical and chemical properties.

 The study of stereochemistry focuses on stereoisomers

 It is also known as 3D chemistry in which the prefix "stereo" means "three-
dimensionality".

 For example, most drugs are often composed of a single stereoisomer of a

compound. Among stereoisomers one may have positive effects on the body and
another stereoisomer may not or could even be toxic.
 Here we study about the various kinds of isomers, especially the
stereoisomers.
ISOMERS AND THEIR CLASSIFICATION
Isomers are compounds with the same molecular formula but different structures or
arrangements.
OPTICAL ACTIVITY

 ordinary lights are composed of rays of different wavelengths vibrating in all directions
perpendicular to the path of its propagation.
 These vibrations can be made to occur in a single plane by passing ordinary light through the
polarizing Nicol prism. Such light whose vibrations occur in only one plane is called plane
polarized light

 Compounds which rotate the plane of polarized light are called optically active
compounds.
 This property is known as optical activity. Rotation of plane of polarized light can be
of two types ,Dextrorotatory and Laevorotatory
 The change in the angle of plane of polarization is known as optical rotation. The optical
rotation is detected and measured by an instrument called polarimeter.
 The measurement of optical activity is reported in terms of specific rotation [α], which is
given as,
[α] λ t = α/lc or [α]D = α/lc

[α]D = specific rotation , t = temperature of measurement

λ=wavelength of the light used , α= observed angle of rotation
l= length of sample tube in decimeter , c=concentration of the sample in g/mL of solution

Example: A 1.20 g sample of cocaine, [α]D = - 16, was dissolved in 7.50 mL of

chloroform and placed in a sample tube having a pathlength of 5.00 cm. What
was the observed rotation in degrees?
Solution
CHIRALITY
 The term chiral (Greek word Chier,meaning hand) is used for those objects or molecules which
have right-handed and left-handed forms.
 Molecules which have “handedness” and the general property of “handedness” is termed as
chirality. An object which is not superimposable upon its mirror image is a chiral.
Chiral center

 A chiral center can be defined as an sp3 hydridized carbon which is bonded to four
different groups.
 A more contemporary term for "chiral center" (or chiral carbon) is stereogenic center or
stereocenter, and the terms will be used interchangeably.
The term Achiral
 Object or molecule which is superimposable on its mirror image is achiral.
Achiral molecule has internal plane of symmetry, a hypothetical plane which
bisects an object or molecule into mirror-reflactive halves.
 An object or molecule with an internal plane of symmetry is achiral.
 A chiral object is not identical in all respects (i.e. not superimposable) with its
mirror image. An achiral object is identical with (superimposable on) its mirror
image.
 Achiral molecules having a stereocenter are known as Meso molecules.
 Example: (meso)-2,3-dibromobutane and trans-1,2-dichloro-1,2-ethanediol are
examples of achiral molecules. They have a plane of symmetry or a centre of symmetry.
 A meso compound contains a plane of symmetry and so is achiral, regardless of whether the
molecule has a chiral center. A plane of symmetry is a plane that cuts a molecule in half,
yielding two halves that are mirror reflections of each other.
 A Meso compound or meso isomer is a non-optically active member of a set of stereoisomers,
at least two of which are optically active. This means that despite containing two or more
stereogenic centers, the molecule is not chiral.
STEREOISOMERS-
STEREOISOMERS : are compounds having the same molecular formula but
different spatial arrangement of their atoms . They are of two types:
 Configurational isomers
optical isomers ( enantiomers, diastereomers) & geometrical isomers (cis –
trans isomers)
 Conformational isomers

a) Configurational isomers: optical isomers & geometrical isomers

i) Optical isomers
Enantiomers: Stereoisomers which are non superimposable mirror images
of each other. Chirality is necessary and sufficient condition for existence of
enantiomers. These always exist as discrete pairs.
  Example : the two stereoisomers of lactic
acid

 They are enantiomers - non superimposable mirror images of each

other
stereogenic center or stereocenter
 A stereogenic center is defined as an atom on which an interchange of any
two atoms or groups result in a new stereoisomer, When the new
stereoisomers is an enantiomer ,the stereocenter is called chiral center. All
stereocenters are not tetrahedral.
III and IV are not enantiomers . they are diasteriomers hence in this case
sterio centres are not chiral centres. Also these are not tetrahedral. Thus, all
chiral centres are sterio centres but all steriocentres are not chiral centres. If
a molecule contains only one chiral centres it must be chiral. Molecule
containing two or more chiral centres may or may not be chiral
 For example: meso tartaric acid has two chiral centres but it is achiral.
Enantiomers can contain any number of stereogenic centers, as long as each center is the exact
mirror image of the corresponding center in the other molecule.
Diastereomers
 Diastereomers are defined as non-mirror image, non-identical
stereoisomers.
 They occur when two or more stereoisomers of a compound have different
configurations at one or more (but not all) of the equivalent (related)
stereocenters and are not mirror images of each other
They are stereoisomers which are not enantiomers
Diastereomers are stereoisomers that are not mirror images

The difference between enantiomers and diastereomers:

 enantiomers have opposite configurations at all chirality centers, whereas
diastereomers have opposite configurations at some (one or more) chirality
centers but the same configuration at others.
A molecule that is not identical to its mirror image is said to be chiral, mean
ing“handed.” A chiral molecule is one that does not contain a plane of symmetry.
The usual cause of chirality is the presence of a tetrahedral carbon atom bonded
to four different groups—a so-called chirality center. Chiral compounds can exist
as a pair of mirror-image stereoisomers called enantiomers, which are related
to each other as a right hand is related to a left hand. When a beam of plane
Polarized light is passed through a solution of a pure enantiomer, the plane of
polarization is rotated, and the compound is said to be optically active.
Assigning (R) and (S): The Cahn-Ingold-Prelog Rules

Priority Rules for Naming Chiral Centers - The R,S System

1. Prioritize the four atoms, or groups of atoms, attached to the chiral center
based on the atomic number of the atom that is bonded directly to the chiral
center. The higher the atomic number, the higher the priority. Number the four
atoms, or groups of atoms, such that “1” has the highest priority and “4” has the
lowest priority.

2. If two or more of the atoms that are bonded directly to the chiral center are the
same, then prioritize these groups based on the next set of atoms (i.e., atoms
adjacent to the directly bonded atoms). Continue until priorities can be assigned.
Priority is assigned at the first point of difference.
If two atoms have substituents of the same priority, higher priority is assigned
to the atom with more of these substituents.
A larger group (i.e., more atoms) may not necessarily have a higher priority over
another (smaller) group.

-CH2Cl has higher priority than -CH2CH2CH2CH3

3. Atoms participating in double/triple bonds are considered to be bonded to
an equivalent number of similar “phantom” atoms by single bonds. Note:
“phantom” atoms are bonded to no other atoms.
Phantom atoms are those atoms that are placed in order to understand clearly
the number of bonds for priority selection in naming and R/S configuration.
Please look at the example below: Here, the C=O is represented as 2 single
bonds, being equivalent to this double bond.
4. Orient the molecule in space so that the lowest priority group (#4) is
directed away from you. The three remaining groups then project toward you.
If the three groups projecting toward you are ordered from highest priority (#1)
to lowest priority (#3) clockwise, then the configuration is “R”. If the three groups
projecting toward you are ordered from highest priority (#1) to lowest priority
(#3) counterclockwise, then the configuration is “S”.
 We should know that the designations (R) and (S) bear no relationship to
whether a molecule rotates plane-polarized light clockwise (+) or
counterclockwise (-).
 For example the most common naturally occurring configuration of the amino
acid alanine is (S), but its optical rotation (in aqueous acid solution) is (+).
 Summary to name a chiral center using the Cahn-Ingold-Prelog rules:
 Identify a carbon with four different groups attached to it
 Put the lightest group at the back (i.e. pointing away from you
 Give the heaviest group attached the highest priority (number
 Give the second heaviest group attached the number
 Give the third heaviest group attached the number
 If, with the lightest group or atom pointing away from you, the
highest priority to the lowest priority (1→2 → 3) goes clockwise, the
center is named R- , counterclockwise it’s called S
SUMMARY OF RELATIONSHIPS BETWEEN MOLECULES WITH TWO OR MORE
CHIRAL CENTERS
If n = number of chiral centers, the maximum possible number of stereoisomers is 2n
Summary on configurational etereoisomers

Asymmetric carbon is a carbon atom that is bonded to four different groups. It is

also called chiral carbon.
Diastereomers :are optical isomers that are not mirror images.
Enantiomers : are optical isomers that are mirror images.
Meso Compound: is a compound that has more than one asymmetric carbon and
that is superimposable on its mirror image. Meso compounds are optically inactive.
Optically active molecule : is a molecule that cannot be superimposed on its
mirror image. It is also called chiral molecule.
 The three-dimensional confi guration of a chirality center is specifi ed as either R or S.
 Sequence rules are used to rank the four substituents on the chiral carbon, and the
molecule is then oriented so that the lowest-ranked group points directly away from the
viewer. If a curved arrow drawn in the direction of decreasing rank for the remaining
three groups is clockwise, the chirality center has the R confi guration. If the direction is
counterclockwise, the chirality center has the S configuration.
 Some molecules have more than one chirality center. Enantiomers have opposite
configurations at all chirality centers, whereas diastereomers have the same
configuration in at least one center but opposite configurations at the others.
 Meso compounds contain chirality centers but are achiral overall because they contain
a plane of symmetry.
 Racemates are 50 :50 mixtures of (+) and (-) enantiomers.
Racemic mixtures and individual diastereomers differ in both their physical properties and
Properties of Stereoisomers
 Enantiomers: have same chemical and physical properties in an achiral environment but
they differ on the sign of rotation of plane polarized light.
For example : Enantiomers of Epinephrine (Adrenaline)

Same melting/boiling point, same rate of reaction with achiral reagents, same degree of rotation
of plane polarized light with achiral reagents, thus difficult to separate!
Diastereomers : have different chemical and physical properties in any type of environment.
Biological Significance of Chirality
Since most of the natural (biological) environment consists of enantiomeric molecules (amino
acids, nucleosides, carbohydrates and phospholipids are chiral molecules), then enantiomers

will display different properties. Then, in our body:

 The case of Thalidomide

Thalidomide was synthesized in West Germany in 1953 by Chemie Grünenthal. It

was marketed (available to patients) from October 1, 1957(West Germany) into the
early 1960's. Sold in at least 46 countries (US not included), Thalidomide was
hailed as a "wonder drug" that provided a "safe, sound sleep". It was a sedative
that was found to be effective when given to pregnant women to combat many of
the symptoms associated with morning sickness. No clinical testing was available
to show that Thalidomide molecules could cross the placental wall affecting the
fetus until it was too late.
Thalidomide was a catastrophic drug with tragic side effects. Not only did a

percentage of the population experience the effects of peripheral neuritis, a

devastating and sometimes irreversible side effect, but Thalidomide became notorious

as the killer and disabler of thousands of babies. When Thalidomide was taken

during pregnancy (particularly during a specific window of time in the first trimester),

it caused startling birth malformations, and death to babies. Any part of the fetus

that was in development at the time of ingestion could be affected.

Why did the two enantiomers display different biological activity?

Enantiomers differ in the arrangement of atoms in space. Therefore, the

S enantiomer of Thalidomide can fit the active site of a specific enzyme

(like a “key” for a specific “lock”) producing the desired effect (sedative).

On the other hand, the R enantiomer cannot interact with the same site

due to a different arrangement of atoms (3D shape). As consequence, it

fits a different enzyme active pocket triggering a different biological

effect (toxic).
 ii) Geometrical isomers (cis- /trans- isomers)

It is a form of stereoisomerism

These isomers occur where there is restricted rotation somewhere in a molecule. In

molecules where there is unrestricted rotation about carbon bonds - in other words where
the carbon-carbon bonds are all single. The next diagram shows two possible
configurations of 1,2-dichloroethane.
These two models represent exactly the same molecule. You can get from one to the other
just by twisting around the carbon-carbon single bond. These molecules are not isomers.

But what happens if you have a carbon-carbon double bond - as in 1,2-dichloroethene?

These two molecules aren't the same. The carbon-carbon double bond won't rotate
 Drawing structural formulae for the last pair of models gives two possible isomers.
 In one, the two chlorine atoms are locked on opposite sides of the double bond. This is
known as the trans isomer. (trans : from latin meaning "across" - as in transatlantic).
 In the other, the two chlorine atoms are locked on the same side of the double bond. This
is know as the cis isomer. (cis : from latin meaning "on this side")
Another example : geometrical isomers of 2-butene

In one case, the CH3 groups are on opposite sides of the double bond, and in
the other case they are on the same side.
The effect of geometric isomerism on physical properties
 The table shows the melting point and boiling point of the cis and trans isomers of 1,2-
dichloroethene.

isomer melting point (°C) boiling point (°C)

cis -80 60

trans -50 48

The trans isomer has the higher melting point;

The cis isomer has the higher boiling point.
You can see the same effect with the cis and trans isomers of but-2-ene:

isomer melting point (°C) boiling point (°C)

cis-but-2-ene -139 4

trans-but-2-ene -106 1
Why is the boiling point of the cis isomers higher?
 There must be stronger intermolecular forces between the molecules of the cis isomers
than between trans isomers.
 Taking 1,2-dichloroethene as an example:
Both of the isomers have exactly the same atoms joined up in exactly the same order. That
means that the van der Waals dispersion forces between the molecules will be identical in both
cases.
 The difference between the two is that the cis isomer is a polar molecule whereas the trans
isomer is non-polar.
 Both molecules contain polar chlorine-carbon bonds, but in the cis isomer they are both on
the same side of the molecule. That means that one side of the molecule will have a slight
negative charge while the other is slightly positive. The molecule is therefore polar.
b) Conformational isomers:
 Conformational isomers : are the isomers that can be converted into one another by rotation
around a single bond.
Example: eclipsed, gauche and anti butane are all conformational isomers of one another.
(eclipsed means that identical groups are all directly in line with one another, gauche means
that identical groups are 60 degree from one another and anti means that identical groups are
180 degree from one another.)

These molecules can be interconverted by rotating around the central carbon-carbon

single bond.