STEREOCHEMISTRY

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STEREOCHEMISTRY
Dr. ABRAHAM GEORGE READER IN CHEMISTRY MAR
IVANIOS COLLEGE TRIVANDRUM
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STEREOCHEMISTRY IS CHEMISTRY IN SPACE DESCRIBES
CHEMISTRY AS A FUNCTION OF TIME CERTAIN MOLECULAR
PHENOMENA WERE OBSERVED AND TO EXPLAIN THEM, THE
PRINCIPLES OF STEREOCHEMISTRY WERE DEVELOPED
THE TERM STEREOCHEMISTRY WAS FIRST COINED BY
VICTOR MEYER
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PLANE-POLARIZED LIGHT BEAM
wavelength
All sine waves (rays) in the beam aligned in
same plane.
single ray or photon
l
.
END VIEW
SIDE VIEW
polarized beam
A beam is a collection of these rays.
NOT PLANE-POLARIZED
Sine waves are not aligned in the same plane.

unpolarized beam
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Optically Active

• Refers to molecules that interact with
  plane-polarized light

Jean Baptiste Biot French Physicist - 1815
He discovered that some natural substances
(glucose, nicotine, sucrose) rotate the plane
of plane-polarized light and that others did not.
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Optical Activity
angle of rotation, a
a
incident polarized light
transmitted light (rotated)
sample cell
(usually quartz)
a solution of the substance to be examined is
placed inside the cell
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TYPES OF OPTICAL ACTIVITY
new
older
()-
d-
Dextrorotatory
Rotates the plane of plane-polarized light to the
right.
new
older
(-)-
l-
Laevorotatory
Rotates the plane of plane-polarized light to the
left.
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Specific Rotation ?D
BIOTS LAW
This equation corrects for differences in
cell length and concentration.
a
aD
t
cl
Specific rotation calculated in this way is a
physical property of an optically active
substance.
a observed rotation
You always get the same
c concentration ( g/mL )
aD
t
value of
l length of cell ( dm )
D yellow light from sodium lamp
t temperature ( Celsius )
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POLARIZED LIGHT
and the
POLARIMETER
The instrument used to determine whether
a substance is optically active and to measure
the direction and degree of optical rotation is
called a polarimeter.
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Double Refraction
Beam A Beam B
A
B
unpolarized beam
calcite crystal
pencil line underneath crystal
The original polarimeter was based on this
property of calcite crystals.
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NICOL PRISM (polarizer)
unpolarized beam
Beam A
used to determine optical rotation
Two prisms of calcite cemented together in
a geometry that causes the two beams to
diverge at a 90-degree angle.
Beam B
discarded
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THE POLAROID FILM WORKS LIKE A NICOL PRISM
polarized light
Polaroid Film
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POLAROID SUNGLASSES
AN EXPERIMENT YOU CAN DO
Each eye is polarized in a different plane
to eliminate glare.
fold
fold
no light can pass
Try this with a flexible pair of clip-on
sumglasses (polaroid).
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The Polarimeter
observed rotation
plane-polarized light
Na lamp
sample cell
plane is rotated
chemist
rotate to null
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PASTEURS DISCOVERY
Louis Pasteur 1848 Sorbonne, Paris
2-


tartaric acid
sodium ammonium tartrate
( found in wine must )
Pasteur crystallized this substance on a cold day.
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Crystals of Sodium Ammonium Tartrate
Pasteur found two different crystals.
hemihedral faces
mirror images
(-)
()
Biots results
Louis Pasteur separated these and gave them to
Biot to measure.
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THERE IS AN ELEMENT OF SERENDIPITY IN PASTEURS
DISCOVERY. THE TWO TYPES OF CRYSTALS ARE FORMED
ONLY AT THE CONDITIONS WHICH FAVOURED
PASTEUR. TARTARIC ACID IS ALSO KNOWN AS RACEMIC
ACID. RACEMUS IN LATIN MEANS A BUNCH OF
GRAPES HE MADE THIS DISCOVERY AT THE AGE OF
26. (SEE REFLECTIONS ON MY LIFE)
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Enantiomers
non-superimposable mirror images
(also called optical isomers)
W
W
C
C
Y
X
X
Y
Z
Z
Pasteur decided that the molecules that made the
crystals, just as the crystals themselves, must
be mirror images. Each crystal must contain a
single type of enantiomer.
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Pasteurs hypothesis eventually led to the
discovery that tetravalent carbon atoms are
tetrahedral.
tetrahedral carbon
Vant Hoff and LeBel (1874)
Only tetrahedral geometry can lead to mirror
image molecules
Square planar, square pyrimidal or trigonal
pyramid will not work
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ENANTIOMERS HAVE EQUAL AND OPPOSITE
ROTATIONS
W
W
Enantiomers
C
C
Y
X
X
Y
Z
Z
()-nno
(-)-nno
dextrorotatory
laevorotatory
ALL OTHER PHYSICAL PROPERTIES ARE THE SAME
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TARTARIC ACID
from fermentation of wine
Enantiomers
()-tartaric acid
(-)-tartaric acid
IF A COMPOUND WITH TWO CHIRALITY CENTRES HAS THE
SAME FOUR GROUPS BONDED TO EACH OF THE CHIRALITY
CENTRES, ONE OF ITS STEREOISOMERS WILL BE A MESO
COMPOUND
ALSO FOUND
(as a minor component)
aD 0
meso -tartaric acid
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THE NEXT IMPORTANT DEVELOPMENT IN STEREOCHEMISTRY
WAS THE CONCEPT OF CONFORMATIONAL ANALYSIS (1950).
THEN 3D STEREOCHEMISTRY BECAME TIME DEPENDENT
(TEMPORAL) AND MARKED THE ADVENT OF DYNAMIC
STEREOCHEMISTRY
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MOLECULAR SYMMETRY AND CHIRALITY
STEREOCHEMISTRY IS PRIMARILY CONCERNED WITH
MOLECULAR GEOMETRY AND MOLECULAR GEOMETRY IS BEST
EXPLAINED IN TERMS OF SYMMETRY
SYMMETRY OPERATION AND ELEMENTS OF SYMMETRY
AXIS OF SYMMETRY, PLANE OF SYMMETRY (sv, sh
sd) CENTRE OF SYMMETRY SIMPLE AND COMPOUND
ELEMENTS OF SYMMETRY ROTOREFLECTION - Sn
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A SYMMETRIC OBJECT HAS A PLANE OF SYMMETRY
- ALSO CALLED A MIRROR PLANE
plane of symmetry
Mirror Plane
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CHIRAL
An object without symmetry is
no symmetry
The mirror image of a chiral object is different
and will not superimpose on the original object.
OBJECTS WHICH ARE CHIRAL HAVE A SENSE OF
HANDEDNESS AND EXIST IN TWO FORMS
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STEREOCENTERS
One of the ways a molecule can be chiral is to
have a stereocenter.
A stereocenter is an atom, or a group of atoms,
that can potentially cause a molecule to be
chiral.
stereocenters - can give rise to chirality
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STEREOGENIC CARBONS
( called chiral carbons in older literature )
stereocenter
A stereogenic carbon is tetrahedral and has
four different groups attached.
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plane of symmetry
side view
edge view
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PRESENT ACHIRAL MOLECULES
Sn AXIS
ABSENT CHIRAL, DISSYMMETRIC

NO Cn
ASYMMETRIC
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CONFIGURATION
ABSOLUTE CONFIGURATION ( R / S )
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CONFIGURATION
The three dimensional arrangement of the groups
attached to an atom
Stereoisomers differ in the configuration at one
or more of their atoms.
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CONFIGURATION - relates to the three
dimensional sense of attachment for groups
attached to a chiral atom or group of atoms
(i.e., attached to a stereocenter).
1
2
counter clockwise
2
clockwise
1
C
C
4
4
3
3
view with substituent of lowest priority in back
R
S
(rectus)
(sinister)
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SPECIFICATION OF CONFIGURATION
Enantiomers are assigned a CONFIGURATION using
the same priority rules we developed for E/Z
stereoisomers.
1. Higher atomic number has higher priority.
2. If priority cannot be decided based on the
first atom attached move to the next atom,
following the path having the highest prioity
atom.
3. Expand multiple bonds by replicating the
atoms attached to each end of the bond.
CAHN-INGOLD-PRELOG
SEQUENCE RULE
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Bromochlorofluoroiodomethane
1
1
4
4
2
3
3
2
R
S
Enantiomers
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How Many Stereoisomers Are Possible?
maximum number of stereoisomers 2n, where n
number of stereocenters (sterogenic carbons)
sometimes fewer than this number will exist
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22 4 stereoisomers



23 8 stereoisomers
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CONSTITUTIONAL ISOMERS
ISOMERS
Different compounds with the same molecular
formula
Isomers with a different order of attachment
of the atoms in their molecules
each isomer could
have stereoisomers
STEREOISOMERS
Isomers with the same order of attachment, but a
different configuration (3D arrangement) of
groups on one or more of the atoms
double bond or ring
with a ring
cis/trans ISOMERS
both can apply
TYPES OF ISOMERISM
(geometric)
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IMPORTANCE OF STEREOCHEMISTRY
AN ACHIRAL REAGENT REACTS IDENTICALLY WITH BOTH
ENANTIOMERS. AN ACHIRAL SOCK FITS ON EITHER
FOOT A CHIRAL REAGENT REACTS DIFFERENTLY WITH
EACH ENANTIOMERS A CHIRAL SHOE FITS ON ONLY ONE
FOOT
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RECEPTORS ARE PROTEINS THAT BIND PARTICULAR
MOLECULES BECAUSE A RECEPTOR WILL RECOGNISE ONLY
ONE OF A PAIR OF ENANTIOMERS, ENANTIOMERS CAN
HAVE DIFFERENT PHYSIOLOGICAL PROPERTIES.
RECEPTORS LOCATED ON THE EXTERIOR OF NERVE CELLS
IN THE NOSE ARE ABLE TO PERCIEVE AND
DIFFERENTIATE THE ESTIMATED 10000 SMELLS TO WHICH
THEY ARE EXPOSED. (R)-(-)-CARVONE IS FOUND IN
SPEARMINT OIL AND (S)-()- CARVONE IS FOUND IN
CARAWAY SEED OIL. EACH HAS A DIFFERENT SMELL AS
IT FITS INTO DIFFERENT RECEPTORS.
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ABOUT HALF THE COMMERCIALLY AVAILABLE DRUGS HAVE
ONE OR MORE CHIRALITY CENTRES. SYNTHETIC DRUGS
ARE RACEMIC MIXTURES. THEY ARE MARKETED AS SUCH
BECAUSE OF THE HIGH COST OF SEPARATION. DRUGS
FROM NATURAL SOURCES ARE SINGLE ENANTIOMERS. ONE
ENANTIOMER MAY BE MORE POTENT AND THE OTHER MAY
HAVE SIDE EFFECTS. SOMETIMES SEPARATION IS NOT
DONE TO AVOID OVERDOSAGE.
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(S)-(-)-KETAMINE IS FOUR TIMES MORE POTENT THAN
(R)-(-)-KETAMINE AND HAS LESS SIDE EFFECTS. THE
ACTIVE INGREDIENT OF IBUPROFEN IS THE
(S)-()-ISOMER.
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THE STEREOCHEMISTRY OF REACTIONS ARE VERY
IMPORTANT. A REGIOSELECTIVE REACTION FORMS MORE
OF ONE CONSTITUTIONAL ISOMER THAN THE OTHER. A
B C MORE B IS FORMED THAN C, WHERE B
AND C ARE CONSTITUTIONAL ISOMERS. A
STEREOSELECTIVE REACTION FORMS MORE OF ONE
STEREOISOMER THAN THE OTHER. A B C
MORE B IS FORMED THAN C, WHERE B AND C ARE
STEREOISOMERS.
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IN A STEREOSPECIFIC REACTION, EACH STEREOISOMERIC
REACTANT FORMS A DIFFERENT STEREOISOMERIC PRODUCT
OR A DIFFERENT SET OF STEREOISOMERIC PRODUCTS. A
B C D A AND C ARE
STEREOISOMERS B AND D ARE STEREOISOMERS A
STEREOSPECIFIC REACTION IS ALSO STEREOSELECTIVE.
A STEREOSELECTIVE REACTION IS NOT NECESSARILY
STEREOSPECIFIC
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ALL THE REACTIONS THAT OCCUR IN BIOLOGICAL
SYSTEMS ARE CATALYSED BY ENZYMES. AN ENZYME
CATALYSED REACTION FORMS ONLY ONE STEREOISOMER
BECAUSE AN ENZYME POSSESSES A CHIRAL BINDING
SITE. THEY ARE COMPLETELY STEREOSELECTIVE. THE
ENZYME FUMARASE, WHICH CATALYSES THE ADDITION OF
WATER TO FUMARATE, FORMS ONLY (S)-MALATE.
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ENZYME CATALYSIS IS STEREOSPECIFIC. AN ENZYME
CATALYSES THE REACTION OF ONLY ONE
STEREOISOMER. FUMARASE CATALYSE THE ADDITION OF
WATER TO FUMARATE BUT NOT TO MALEATE
AN ENZYME CAN DIFFERENTIATE STEREOISOMERS BECAUSE
OF THE CHIRAL BINDING SITE
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FISCHER PROJECTIONS
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EVOLUTION OF THE FISCHER PROJECTION
Sawhorse Projection
O
H
H
Fischer Projection
Orient the main chain vertically with the
most oxidized group at the top.
C
H
O
O
H
H
H
O
H
C
H
O
H
2
Substituents will stick out toward you like prongs
Main chain bends away from you
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OH
H
ORIENTATION OF THE MAIN CHAIN AND THE
SUBSTITUENTS IN A FISCHER PROJECTION
OH
H
H
OH
continuation of the main chain
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INCREASING OXIDATION STATE
CO on carbon-2 increases the priority of C-OH
increasing oxidation state
In the Fisher projection the main chain is
oriented with the most highly oxidized group at
the top.
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rotate 90o
CH3
Cl
H
main chain in red
H
orient main chain vertically
Br
CH3
H
Cl
Br
convert to Fischer Projection
H
CH3
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DETERMINATION OF R / S CONFIGURATION IN
FISCHER PROJECTIONS
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PLACE THE PRIORITY4 GROUP IN ONE OF THE
VERTICAL POSITIONS, THEN LOOK AT THE OTHER THREE
2
4
H
CHO
1
H
O
H
OHC
C
H
O
H
4
2
2
3
C
H
O
H
O
H
R
2
3
1
BOTH IN BACK SAME RESULT
alternatively
1
2
O
H
R
CHO
2
3
1
CHO
HOCH2
H
O
H
4
H
C
H
O
H
2
4
3
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FOR THE MENTALLY AGILE
WHY BOTHER INTERCHANGING?
JUST REVERSE YOUR RESULT!
Same molecule as on previous slide.
2
S
R
reverse
CHO
H
O
H
1
Same result as before.
4
C
H
O
H
2
3
H coming toward you
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THE SIMPLEST WAY OF ASSIGNING RS CONFIGURATION
WAS GIVEN BY EPLING (1982) 1. FIX THE PRIORITY 2.
TRACE A SEMICIRCLE JOINING a b c
IGNORING d. 3. CLOCKWISE IS R AND ANTICLOCKWISE
S IF d IS VERTICAL (TOP OR BOTTOM) 4. IF d
IS ON THE HORIZONTAL LINE REVERSE THE NOTATION.