Stereochemistry

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Stereochemistry stereoisomers
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• 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

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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

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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)

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• 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).

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Isomers
constitutional isomers
stereoisomers
Optical isomers or Enantiomers
Diastereomers Configurational Cis-trans
diastereomers
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• 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.

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• 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.

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• Measurement of optical activity
• Polarimeters are used to measure the optical
  activities

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• Measurement of optical activity

• Plane polarized light passing through an
  optically active solution is rotated by a certain
  number of degrees alpha (a) called the observed
  rotation.
• If a found to be to the right (clockwise
  rotation), the optically active compound is
  designated as dextro-rotatory with the symbol
  ().
• If a found to be to the left (counter clockwise
  rotation), is termed levo-rototatory with the
  symbol (-).

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• The observed rotation (a) depends upon
• The concentration of the solution (C)
• The length of the polarimeter tube (L)
• The temperature (T)
• The wavelength of the light (?)

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• Specific Rotation aD
• The value of optical rotation of a compound under
  standard conditions is called the specific
  rotation. Thus specific rotationaDof 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.)
• aD observed rotation
  (degrees)
• Path length, L (dm) X Concentration ,
  C (g/mL)
• a
• L X C

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Specific rotation a

• The specific rotation is a physical constant
  characteristic of a compound
• Specific rotation a is mainly used for
• 1-Identification of compounds
• 2-Determining degree of purity
• 3-Determining the concentration

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aD a /L x c a 1.21 L 5 cm 0.5 dm C
1.5 g/ 10 ml 0.15 g/ml aD 1.21/ 0.5 x
0.15 16.1o
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Optical activity and structure of compounds
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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.
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• A molecule is chiral if two mirror image forms
  are not superimposable upon
• one another.
• A molecule is achiral if its two mirror image
  forms are superimosable
• The chiral centre is usually indicated by an
  asterisk ()
• A molecule with a single chiral carbon must be
  chiral
• But, a molecule with two or more chiral carbons
  may be chiral or it may not.

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Bromochlorofluoromethane is chiral

• It cannot be superimposed point for point on its
  mirror image.

Cl
Br
H
F
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Bromochlorofluoromethane is chiral
Cl
Cl
Br
Br
H
H
F
F

• To show nonimsuperposability, rotate this model
  180 around a vertical axis.

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Properties of enantiomers

• Physical properties are the same melting point,
  boiling point, density, etc.
• except properties that depend on the shape of
• molecule
• eg. 1biological-physiological
• and 2optical properties i.e, for direction of
  the
• plane polarized light.

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The chiral carbon atom

• a carbon atom with fourdifferent groups attached
  to it
• also called
• chiral center chiral carbonasymmetric center
• asymmetric carbonstereocenter
• stereogenic center

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Chirality and chiral carbons

• A molecule with a single stereogenic center is
  chiral.
• 2-Butanol is an example.

H
CH3
CH2CH3
OH
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Examples of molecules with 1 chiral carbon
one chiral alkane
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Examples of molecules with 1 chiral carbon
Linalool, a naturally occurring chiral alcohol
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Examples of molecules with 1 chiral carbon
1,2-Epoxypropane a chiral carbon can be part of
a ring

• attached to the chiral carbon are
• H
• CH3
• OCH2
• CH2O

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• 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.

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• 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

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PREFIXES USED TO DENOTE CHIRAL PROPERTIES
PREFIX PROPERTY d-/l- Rightward
(dextro), clockwise/Leftward
(leuvlo), counterclockwise, optical
rotation. Used
interchangably with ()/(-) D-/L- Rightward/leftw
ard arrangement of substituents
about chiral center (archaic,
used for amino acids carbohydrates) R-/S-
Rightward (rectus)/leftward (sinister) arrange-
ment of substituents about
chiral center (modern,
used for drugs)
e.g., R-(-)- levorotatory, but with absolute
configuration R
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• Assigning absolute configuration
• Sequence Rules for specification of Configuration
  (R S Configuration)

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• Assignning Absolute Configuration
• (R) (S) Configuration
• (Cahn-Ingold-Prelog R/S system)
• In the R,S system, groups are assigned priority
  using the Cahn-Ingold-Prelog 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
• H1, C6, N7, O8, F9, S16, Cl17, Br35
• Brgt Clgt Sgt FgtO gtNgt Cgt 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.

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• 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 gt 1 chiral center
• Inversion of 1 chiral center produces a compound
  that is not a mirror image

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DIASTEREOMERS
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• 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).
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• 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)

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• 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)

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• Examples

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• 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).

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• FISCHER PROJECTIONS AND THE EXCHANGE METHOD
• The R, S, configuration can be assigned by the
  following steps
• Assign properties to four substituents in the
  usual way
• 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, 270an enantiomer, etc.
• Determine the direction of rotation in going from
  priority 1 to 2 to 3.
• Draw a curved arrow toward the group (atom) of
  next lowest priority.
• Clockwise orientation (arrow direction) is R.
  Counterclockwise arrow direction is S.

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I-Assigning priorities and determining R or S of
compounds containing one chiral carbon
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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.

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• 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.

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• 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

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II-Assigning priorities and determining R or S
of compounds containing multiple chiral carbons
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• 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,

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The top carbon is R, and, rearranging the bottom
carbon,
Enantiomer
Identical
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• 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.

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I-The two molecules shown below are enantiomeric
at both centers, and are therefore enantiomers.
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II-The two molecules shown below are enantiomeric
at one center, and identical at the other, and
are therefore diastereomers.
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III-The two molecules shown below are identical
at one center, and identical at the other, and
are therefore identical.
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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.
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Practice Problems
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Q Find the stereochemical relationship between
the following two compounds

• Solution
• These two compounds are constitutional isomers

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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

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