Stereochemistry &
stereoisomers
Stereochemistry
The Arrangement of Atoms in Space or
three dimensional structure of atoms.
Stereoisomerism: is one aspect of
stereochemistry.
Isomers are compounds that have the
same molecular formula but with different
structures.
There are two main classes of isomers:
1- Structural isomers (or constitutional
isomers)
2- Stereo-isomers
I-Constitutional isomers:
These are compounds whose atoms are connected
differently .
Different connections among atoms which may be due
to difference in:
A- Skeleton of carbon or
B- Functional groups or
C- Position of functional groups
II-Stereoisomers:
These are compounds whose atoms are
connected in the same order but with
different geometry or arrangements.
Types of Stereoisomers are:
A- Optical isomers (e.g. enantiomers &
configurational diastereomers)
B- Geometric isomers or Cis &trans isomers or
cis &trans stereomers (both in alkenes and
cycloalkanes)
• Enantiomers :
•
These are non-superimposable mirror image
stereoisomers.
•
Diastereomers: Steroisomers which are not
enantiomers are called diastereomers.
• A- configurational diastereomers:
• These are non-superimposable non-mirror image
stereomers.
• B- cis-trans diastereomers:
• These contain substituents on same side or opposite
side of double bond or ring (cyclic structure).
Isomers
constitutional
isomers
Optical isomers
or Enantiomers
stereoisomers
Diastereomers:
Configurational &
Cis--trans diastereomers
Cis
Optical Isomerisms
• Optical Isomerisms:
• It manifests itself by its effect on plane-polarized
light.
• Polarizers are used to produce plane-polarized light (e.g.
polaroid film, nicol prism).
• Optical Activity
• Any compound that has the ability to change the
direction of plane polarized light or to rotate it, is said
to be optically active compound.
• Optical isomers are optically active substances.
• The rotation itself is called optical activity.
• The diffrence between ordinary or plane-polarized
light:
• A beam of ordinary light is vibrating in all
possible planes perpendicularly, but
• Plane-polarized light is vibrating in only one of
these possible planes.
Measurement of optical activity
Polarimeters are used to measure the optical activities
Measurement of optical activity
oPlane polarized light passing through an optically active
solution is rotated by a certain number of degrees alpha (α)
called the “observed rotation”.
oIf α found to be to the right (clockwise rotation), the
optically active compound is designated as dextro-rotatory
with the symbol (+).
oIf α found to be to the left (counter clockwise rotation), is
termed levo-rototatory with the symbol (-).
The observed rotation (α) depends upon:
•
•
•
•
The concentration of the solution (C)
The length of the polarimeter tube (L)
The temperature (T)
The wavelength of the light (λ)
Specific Rotation [α]D:
• The value of optical rotation of a compound under standard
conditions is called the specific rotation. Thus specific
rotation[α]Dof a compound is defined as the observed
rotation when light of 589 nm wavelength is used with a
sample path length (L) of 1 decimeter ( 1 dm = 10 cm) and a
sample concentration (C) of 1 g/mL . (light of 589 nm, the so
called sodium D line, is the yellow light emitted from
common sodium lamps; 1 nm= 10-9 m.)
[α]D =
observed rotation (degrees)
Path length, L (dm) X Concentration , C (g/mL)
=
α
LXC
Specific rotation [α]
• The specific rotation is a physical constant
characteristic of a compound
•
•
•
•
Specific rotation [α] is mainly used for
1-Identification of compounds
2-Determining degree of purity
3-Determining the concentration
[α]D = α /L x c
α = + 1.21
L= 5 cm = 0.5 dm
C= 1.5 g/ 10 ml = 0.15 g/ml
[α]D = + 1.21/ 0.5 x 0.15 = + 16.1o
Optical activity and structure of
compounds
Optical activity and structure of
compounds
Chiral carbon atoms
4 different substituents on carbon, then it is no longer superimposable on
its mirror image and we say that carbon is chiral .
Carbon with 1,2,3 different atoms or groups attached can be superimposed
on its mirror image and is achiral.
CO
CO
2
2
H
H
H
3
CH
C
NH
2
L -(+ ) a la n in e
H
2N
D - ( -) a la n in e
3
oA molecule is chiral if two mirror image forms are not superimposable upon
oone another.
oA molecule is achiral if its two mirror image forms are superimosable
oThe chiral centre is usually indicated by an asterisk (*)
oA molecule with a single chiral carbon must be chiral
oBut, a molecule with two or more chiral carbons may be chiral or it may not.
Bromochlorofluoromethane is chiral
Cl
Br
H
F
It cannot be
superimposed point
for point on its
mirror image.
Bromochlorofluoromethane is chiral
Cl
Cl
Br
Br
H
F
H
F
To show
nonimsuperposability,
rotate this model 180°
around a vertical axis.
Properties of enantiomers
oPhysical properties are the same:
melting point, boiling point, density, etc.
except properties that depend on the shape of
molecule
oeg. [1]biological-physiological
o and [2]optical properties i.e, for direction of the
plane polarized light.
The chiral carbon atom
a carbon atom with four
different groups attached to it
w
x
C
z
y
also called:
chiral center; chiral carbon
asymmetric center
asymmetric carbon
stereocenter
stereogenic center
Chirality and chiral carbons
A molecule with a single stereogenic
center is chiral.
2-Butanol is an example.
H
CH3
C
OH
CH2CH3
Examples of molecules with 1 chiral carbon
CH3
CH3CH2CH2
C
CH2CH2CH2CH3
CH2CH3
one chiral alkane
Examples of molecules with 1 chiral carbon
OH
Linalool, a naturally occurring chiral alcohol
Examples of molecules with 1 chiral carbon
H2C
CHCH3
O
1,2-Epoxypropane: a chiral carbon
can be part of a ring
attached to the chiral carbon are:
—H
—CH3
—OCH2
—CH2O
•
•
•
•
•
Enantiomers rotate light in equal amounts in
opposite directions.
(+) Dextrorotatory (Latin dexter is "right")
(-) Levrorotatory (Latin levus is "left")
A mixture consisting of equal parts of any pair of
enantiomers is called a racemic mixture (or racemic
modification) and is designated by (+/-).
A racemic mixture does not rotate plane-polarized
light because (+)-rotation caused by one enantiomer
is canceled by rotation in the opposite direction by
the (-)-enantiomer. A solution of a racemic mixture
of enantiomers is optically inactive.
• In racemic mixtures of drugs, the better fitting
enantiomer is called the eutomer (Eu) while the lower
affinity enantiomer is called the distomer (Dist).
• In racemic mixtures of drugs, the distomer should be
viewed as an impurity comprising 50% of the mixture.
An impurity that is by no means inert. Several
implications of racemic drug treatment should be
considered:
• Side effects
• Antagonist
• Metabolized to unfavorable metabolite
• Metabolized into a toxic metabolite
PREFIXES USED TO DENOTE
CHIRAL PROPERTIES
PREFIX
d-/l-
D-/L-
R-/S-
PROPERTY
Rightward (dextro), clockwise/Leftward
(leuvlo), counterclockwise, optical rotation.
Used interchangably with (+)/(-)
Rightward/leftward arrangement of
substituents about chiral center (archaic,
used for amino acids & carbohydrates)
Rightward (rectus)/leftward (sinister) arrangement of substituents about chiral center
(modern, used for drugs)
e.g., RR-(-)- levorotatory, but with absolute configuration R
31
Assigning absolute configuration
Sequence Rules for specification of Configuration (R & S
Configuration)
Assignning Absolute Configuration
(R) & (S) Configuration
(Cahn-Ingold-Prelog R/S system)
In the R,S system, groups are assigned priority using the Cahn-IngoldPrelog system just as in the E,Z system for naming alkenes.
To assign (R) or (S) configuration to a chiral carbon:
1. Rank the 4 atoms (groups) attached to the carbon .
2. Project the molecule so that the group (atom) of lowest priority is to
the rear.
The most probable atoms used are:
H=1, C=6, N=7, O=8, F=9, S=16, Cl=17, Br=35
Br> Cl> S> F>O >N> C> H
3. Select the group (atom) of highest priority and draw a curved arrow
toward the group (atom) of next lowest priority. (assign priority in
order of decreasing atomic number).
4. Clockwise orientation (arrow direction) is R. Counterclockwise arrow
direction is S.
CO
CO
2
2
H
H
CH
H 3C
NH
2
L - ( + ) a l a n in e
3
H 2N
D - ( -) a l a n in e
A compound with n chiral carbon atoms can have a maximum
of 2n stereoisomers.
Example: a compound has 2 chiral carbons and 22 (= 4)
stereoisomers. A compound with 3 chiral carbons and 23 (=
8) stereoisomers.
Diastereomers
Stereoisomers which are not mirror-image isomers are
called diastereomers. Diastereomers have different
chemical and physical properties.
Diastereoomers:
Possess > 1 chiral center
Inversion of 1 chiral center produces a compound that is
not a mirror image
DIASTEREOMERS
Meso Compounds
A meso compound is an optically inactive compound even through it
possesses more than one chiral centre.
The two mirror
Images of a meso
Compound are
Identical
(superimposable).
One simple way of recognizing a meso compound is to note that the
molecule possess a plane of symmetry (The upper half is the
mirror image of its lower half in the previous example)
Fischer Projections
Emil Fischer (late 1800's) introduced formulas depicting the
spatial arrangement of groups around chiral carbon atoms.
Fisher projection is the two-dimensional structure
representation of stereochemical compound.
A tetrahedral carbon atom is represented in a Fisher
projection by two perpendicular lines.
The intersection of horizontal and vertical lines (+)
represents the chiral center
The horizontal lines represent bonds coming out of the page
(directed towards the reader)
The vertical lines represent bonds going into the page
(directed a way from the readers)
Examples:
FISCHER PROJECTIONS AND THE
EXCHANGE METHOD
1-To assign absolute R, S configuration to
Fisher Projections
2-To compare sets of compounds to
determine their stereochemical
relationship (enantiomers,
diastereomers, identical, or meso).
FISCHER PROJECTIONS AND THE EXCHANGE METHOD
The R, S, configuration can be assigned by the following steps:
1.
Assign properties to four substituents in the usual way
2.
Perform one of the two allowed motions to place the group of lowest
(fourth) priority at the top of the Fisher projection
[ the single most important rule regarding rotation a Fischer is that
90° rotations are disallowed because rotating 90° generates the
enantiomer of the molecule you started with. A 180° rotation
regenerates the identical configuration, 270°an enantiomer, etc].
3.
Determine the direction of rotation in going from priority 1 to 2 to
3.
4.
Draw a curved arrow toward the group (atom) of next lowest priority.
5.
Clockwise orientation (arrow direction) is R. Counterclockwise arrow
direction is S.
I-Assigning priorities and determining
R or S of compounds containing one
chiral carbon
I-Assigning priorities and determining
R or S of compounds containing one
chiral acrbon
• It can then be done in the conventional manner. You
should note, however, that in the drawing below,
connecting the priorities in the original Fischer
projection gives the same rotation as in the drawing
on the right (both are S). This method will always
work if the lowest priority group is oriented either up
or down on your Fischer projection.
• If the groups are oriented improperly in the
original drawing, the Fischer can be
“rearranged” using the following set of rules:
• 1-Exchanging any two groups around a Fischer
projection ("one exchange") generates the
enantiomer of the original compound, and
• 2-Exchanging groups twice ("two exchanges")
regenerates the original stereochemistry.
• In the example shown above, the original molecule (R
configuration) is re-drawn with two of the groups
"exchanged" so that the hydrogen (the lowest priority
group) is placed in the "top" position; this new molecule now
has S configuration.
• The second exchange regenerates the original R
configuration.
• A third exchange would again generate S, a fourth, R, etc.
• An example of converting a drawing into a Fischer, and
using it to assign configuration is shown below:
II-Assigning priorities and determining
R or S of compounds containing multiple
chiral carbons
• For compounds with multiple chiral
centers, written as extended Fischer
projections, assignments can be made in
the same manner, as shown below.
• In the following compound,
The top carbon is R, and, rearranging the bottom
carbon,
Enantiomer
Identical
• The "exchange method" can also be
utilized to compare stereochemistry
among Fischer projections by simply
keeping track of the number of
exchanges which are necessary to
convert each chiral center into a
reference structure.
I-The two molecules shown below are enantiomeric at
both centers, and are therefore enantiomers.
II-The two molecules shown below are enantiomeric at
one center, and identical at the other, and are
therefore diastereomers.
III-The two molecules shown below are identical at one
center, and identical at the other, and are therefore
identical.
54
IV-The two molecules shown below are enantiomeric at both
centers, and are therefore enantiomers, but one molecule can
be seen to have an internal plane of symmetry, making this a
meso compound. Since a meso compound is superimposible on
its mirror image, the two molecules must be identical and
meso.
55
Practice Problems
56
Q: Find the stereochemical relationship
between the following two compounds
• Solution:
These two compounds are constitutional isomers
57
Q: Find the stereochemical relationship
between the following two compounds
Solution:
The two molecules differ in the stereochemistry of the
alkene which is connected to the chiral center. But the
two molecules, have the same bonding sequence
(constitution) differing only in the arrangement of
those atoms in space, making them stereoisomers. Since
they are not enantiomeric, they must be diastereomers 58