Stereochemistry Notes

Stereochemistry
Dr. Krishnaswamy. G, DOS & R in Organic Chemistry, TUT Page 1

Stereochemistry
HISTORY:
Christian Huygens (1629-1695) discovered plane polarized light.
Jean Baptiste Biot in 1815 noted that certain natural organic compounds rotate plane
polarised light.
Louis Pasteur in 1847 carried out crystallization of sodium ammonium salt tartaric acid and
separated mirror image crystals by hand. The equimolar solution of separated crystals have
equal but opposite optical activity.
In 1847 Joseph A Lebel and Jacobs H Van’t Hoff proposed carbon with four attachment is
tetrahedral and showed that carbon with four different attachments may exists as a pair of
isomers.
Thalidomide disaster showed significance of stereochemistry. This drug was used to treat
morning sickness in pregnant women. However, drug caused deformation in babies. It was

Stereochemistry
found that one isomer was safe but other had tetratogenic (agent that disturb development of
embryo) effect causing serious genetic damage.
Acts as Sedative Acts as Tetratogenic

R-(+)-Thalidomide S-(-)-Thalidomide
What is Stereochemistry?
It is branch of chemistry that involves the study of the different spatial orientation or
arrangement of atoms or groups in the molecule.
This branch of chemistry is commonly referred to as 3-Dimensional chemistry. Since, it

focuses on stereoisomers (i.e. chemical compounds with same molecular formula but
different spatial arrangement in three dimensions).
Enantiomers - Non-superposable mirror images or chiral molecules which are mirror

images.
Enantiomers have identical: b.p.’s, m.p.’s, solubilities, index of refraction, IR, NMR in
achiral solvent, etc.
Enantiomers differ when they interact with other chiral substances and when they interact
with plane polarized light
Chiral or asymmetric carbon - a tetrahedral carbon atom bearing four different

substituent’s.
Diastereomers - stereoisomers which are not enantiomers (or mirror images), that is non-
super imposable not mirror images.
Diastereomers have different physical properties.
Optical activity - the ability of chiral substances to rotate the plane of polarized light by a
specific angle

Stereochemistry
Racemic mixture - an equimolar (1:1) pair of enantiomers is called a racemic mixture. A

racemic mixture has an optical rotation of zero.
Device used to measure optical rotation: Polarimeter
Dextrorotatory (+): an optically active compound that rotates plane polarized light in a
clockwise direction.
Levorotatory (-): an optically active compound that rotates plane polarized light in a counter
clockwise direction.
The specific rotation of a compound is calculated using the following formula:
Molecules with one stereocenter can be R or S = 2 possible stereoisomers.
Molecules with n stereocenters can have all the possible combination of R and S for each
stereocenter = 2n possible stereoisomers.
Representation of three dimensional molecules
Configuration of a chiral molecule is three dimensional structure and it is not ver easy to
depict on a paper having only two dimensions. To overcome this problem four 2dimesional
structures known as projections have been used.
(1) Dashed Wedge or Flying Wedge formula

(2) Fischer projection
(3) Sawhorse formula
(4) Newmann projection.

Stereochemistry
(1) Dashed-Wedge or Flying Wedge formula
In this representation a solid continuous lines represent bond is in the plane.
A solid wedge line represent bond is above the plane i.e. towards the observer.
( )
A broken wedge / dashed line represent the bond is below the plane i.e. away from the
observer.
( )
CH3 CH3
H CH2CH3 H CH2CH3
OH OH
Dash-Wedge formula
(2) Fischer projection:
In this representation, bonds are drawn as solid lines. The bonds are placed vertical and
horizontal to each other.
A tetrahedral carbon is represented using just two crossed lines represents the stereo center.

Stereochemistry
Horizontal line is coming out of the plane of the page (towards observer) and vertical line is
going back behind the plane of the paper (away from observer).
In Fischer representation most oxidized carbon atom is placed on the vertical line at the top.
Most oxidize carbon
COOH COOH
H NH2 H NH2
CH3 CH3
D-Alanine D-Alanine
There are some regular relationships that are "short cuts" to recognizing stereochemical
relationships:
• A 180° rotation gives the same stereochemistry.

Stereochemistry
• A 90° rotation gives the inverted stereochemistry.
• Exchanging any two positions gives the inverted stereochemistry.
• Pairwise exchange of two sets of positions gives back the same stereochemistry.
Disadvantage:
➢ These projections can be turned or rotated only in certain specified way.

➢ In compounds more than one stereocenters, a Fischer projection implies an eclipsing
relationship of groups attached to two stereo centers but staggered is more stable than
eclipsed.
(3) Saw-horse representation
In this representation each carbon atoms may be viewed as a letter “Y”.
Rear carbon H OH
CHO
H OH CHO
H Cl
H Cl
CH2OH CH2OH
Front carbon

Stereochemistry
1 CHO
2
H OH
2 2
3 3 3
H Cl CHO
1 CH2OH 1
4 CH OH 4 4
2
Fischer projection
1 CHO
H OH
H Cl H Cl
2
2
3 HO H 3
Rotate C-2 CHO
by 180o CH2OH 1
CH2OH
4 4
Staggered Eclipsed
Sawhorse projection
(4) Newmann Projections

In this representation the molecule is viewed along the bond joining the two carbon atoms.
The front carbon shown by three solid lines i.e. “Y”
The rear carbon is shown by a circle with three bonds pointing out from it i.e.
Combining the front and rear results in the eclipsed Newmann projection which on rotation
through 180o results in stable staggered Newmann projection

Stereochemistry
Eclipsed Staggered
Newmann projection
Propane staggered Newmann projection from two views is shown below.
INTER CONVERSION OF REPRESENTATIONS

Conversion of Dash Wedge formula to Fischer projection
By viewing the molecule in between dash line and wedge line one can convert Dash formula
to Fischer projection as shown below
D C
B
C B

Stereochemistry
COOH
COOH
H OH
CH3
HO CH3
One more method for converting the dash formula into Fischer projection is to see whether
the solid continuous line is left or right side as follows.
If the solid lines are on right side in the first step solid line is written vertical line. In the
second step horizontal line is drawn and substituent which is placed on wedge bond will be
placed on right side.
CH3 Right side CH3 CH3
Br
Step-1 Br H
CHO Step-2
H
CHO CHO
NOTE: Finally look for whether the most oxidized carbon is placed on top of the vertical
line. If not rotate the Fischer projection through 180o in the plane of the paper.

Stereochemistry
CH3 Right side CH3 CH3
Br
Step-1 Br H
CHO Step-2
H
CHO CHO
Rotate 180o in the

plane of the paper
CHO
H Br
CH3
If the solid lines are on left side in the first step solid line is written vertical line. In the
second step horizontal line is drawn and substituent which is placed on wedge bond will be
placed on left side.
Left side COOH COOH

COOH
CH3 H CH3
Step-1 Step-2
H2N H
NH2 NH2
Conversion of Fischer projection to Dash Wedge formula

The reverse of the above discussed method will be used to covert Fischer projection to Dash
Wedge formula.
In this conversion first step is Fischer vertical line will be written in solid line of Dash
formula. In the second step horizontal line will be written in dashed line and wedge line. To
place the substituent on dash and wedge line configuration of Fischer projection is used.

Stereochemistry
Left side
COOH COOH
COOH
H CH3 CH3
Step-1
H2N Step-2 H 2N H
NH2
(S)-Alanine (S)-Alanine
COOH
Step-1 COOH Right side
NH2 Step-2 H
NH2
H3C
(S)-Alanine
Conversion of Fischer projection to Newmann projection to Sawhorse

formula:
Fischer projection is viewed either from front carbon or rear cabon atom which results in
eclipsed Newmann projection. Rotation of either front carbon or rear carbon 180o gives
staggered Newmann projection. This Newmann projection viewed through central bonds
results in sawhorse formula.

Stereochemistry
Conversion of Sawhorse formula to Newmann projection to Fischer

projection:
Staggered Sawhorse formula is viewed either from front carbon or rear cabon atom which
results in staggered Newmann projection. Rotation of either front carbon or rear carbon 180o
gives eclipsed Newmann projection. This Newmann projection holding in vertical plane
results in Fischer projection.
Conversion of Sawhorse formula to Fischer projection:

Staggered Sawhorse formula is converted into eclipsed projection by rotating either front
carbon or rear carbon 180o. It is then held in vertical plane in such manner that the two
groups pointing upwords are shown on the vertical line results in Fischer projection.

Stereochemistry
Configuration: Three dimensional arrangements of atoms or groups around an asymmetric

carbon atom or chiral centre are known as configuration.
Two systems have been developed to study the configuration of organic compounds.
(1) Relative configuration (D-L configuration): Prior to 1951, there was no method
available for determining the absolute configuration of a compound. So, configuration
relative to that of standard ((+)-Glyceraldehyde) were determined. This system of
configuration is known as D-L configuration.
CHO CHO
H OH HO H
CH2OH CH2OH
D-Glyceraldehyde L-Glyceraldehyde
(2) Absolute Configuration (R-S system): Due to some draw backs of D-L configuration
a new system called R-S system of configuration was developed by Robert. S. Cahn
(Royal Institute of Chemistry, London), Christopher K. Ingold (University College,
London), and Vladimir Prelog (Swiss Federal Institute of Technology, Zurich) in the
1950's, and is thus called the Cahn-Ingold-Prelog convention.
D-L Conventions:
D-L system is seldom used today except for some class of compounds like carbohydrates and
amino acids.
D- & L - Glyceraldehyde are used as standard references for D-L system of configuration of
carbohydrates.
D- & L - Alanine are used as standard reference for alpha amino acid with D-L system of
configuration.
D-series of sugars are those with –OH group attached to highest numbered stereo center on
the right side in Fischer projection.

Stereochemistry
1 CHO CHO
2
H OH HO H
3
HO H HO H
4
1 CHO H OH H OH
2 5
H OH H OH H OH
3 CH2OH 6 CH2OH CH2OH
D-Glyceraldehyde D-Glucose D-Mannose
L-series are those with –OH group attached to highest numbered stereo center on the left side
in Fischer projection.
CHO CHO
H OH HO H
HO H HO H
CHO H OH H OH
HO H HO H HO H
CH2OH CH2OH CH2OH
L-Glyceraldehyde L-Glucose L-Mannose
D- & L- configuration of α-amino acid refers to the configuration of the regardless of the
number of asymmetric carbon in the molecule.

Stereochemistry
1 COOH 1 COOH
2 2
H NH2 H NH2
3
3 CH3 H OH
D-Alanine 4
CH3
D-Threonine
COOH COOH
H2N H H2N H
CH3 H OH
L-Alanine
CH3
L-Threonine
The D- & L- system has the disadvantage of specifying configuration of only one
stereocenter.
D- & L- configurations are not related to the optical rotation of sugars.
Threo and Erythro system:

A molecule with two adjacent stereocenters and with two groups are common to each carbon
while third group is different i.e. Cabx-Caby gives rise to threo and erythro diastereomers.
When similar groups are on the same side = Erythro

Stereochemistry
CH3
H Br
H OH
CH3
erythro-3-Bromo-2-butanol
When similar groups are on the opposite side = Threo
CH3
Br H
H OH
CH3
threo-3-Bromo-2-butanol
3-bromo-2-butanol has two asymmetric centres. So, the total number of stereoisomers = 2n =
22= 4
NOTE:
The term erythro and threo are generally applied only to those molecules which do not have
symmetric ends. Instead Meso or (d, l) will be used.

Stereochemistry
Plane of symmetry
CH3 CH3
H Br Br H
H Br H Br
CH3 CH3
Meso-2, 3-Dibromobutane (d,l)-2, 3-Dibromobutane
R-S system:
The Sequence (CIP) Rule is the actual method whereby the four substituents on an
asymmetric carbon may be assigned priorities 1, 2, 3 or 4 so that the absolute configuration R
or S may be determined.
Rule-1: Rank the groups or atoms boned to the asymmetric carbon in order of priority.
Priorities depend on atomic number; the atom of higher atomic number is assigned higher
priority.
If two atoms are isotopes of same element, the atom of higher mass number has the higher
priority.
Rule-2: If the relative priority of two groups can note be determined as above, then look for
next atom, often it may be necessary to proceed atom by atom till a point of difference is
obtained.

Stereochemistry
Rule-3: In the case of double or triple bond, either atoms or groups are considered as
duplicate or triplicate.
Rule-4: Orient the molecule so that the groups or atoms with lowest priority are directed
away from the observer.
Rule-5: Draw an arrow from the group or atom with highest priority to the group or atom
with next priority (decreasing priority). If you trace a circular path from 1 to 2 to 3 and the
path describes a clockwise rotation, then the center is called R (Latin: rectus means right). If
the path shows a counter clockwise rotation, then the chiral center is called S (L.: sinister
means left).
NOTE:
Case-1: When the group or atom of lowest priority is on continuous solid line, one can look
along C-lowest priority group bond.

Stereochemistry
4
4
H H
1 I 2
1 Br
I
CH3 3
Br CH3
2 3
View the molecule

along C-H bond
OR
If the fourth group is on the plane then do double interchange in such a way that the 4 th group
goes below the plane.
1 1
4
I I
H
4 4
1 H 3 H 2
I CH3 Br
CH3 3 First Second
interchange Br H3 C
Br interchange
2 3
2
R
Case-2: When the group or atom of lowest priority is oriented towards the observer, one may
rotate the molecule so that priority 4th group point back.

Stereochemistry
1 1
Rotate
3 4
2 3
4 2
OR
If fourth group is above the plane, then clock wise movement is “S”, while counter clock
wise movement is “R”.
The R & S system of nomenclature can be applied to isomers with more than one asymmetric
carbon. If a compound has more than one asymmetric carbon, the steps followed to determine
whether an asymmetric carbon has R / S configuration must be applied to each of asymmetric
carbon individually.

Stereochemistry
R-S nomenclature for Fischer projection:

Case-I: If the 4th group is present on top or bottom of the vertical line in the Fischer
projection.
1 4
NH2 H
3 2 3 2
COOH H3C COOH
H NH2
4 1
R S
Case-II: If the 4th group is present on left or right of the horizontal line in the Fischer
projection.

Stereochemistry
2 2
COOH Ph
4 H CH3 3 4 H 3C OH 1
NH2 C2H5
1 3
S R
Helical descriptors-M & P:
Many chiral molecule lack conventional center that cannot be described by R/S system can be
viewed as helical and may have propeller or screw shaped structure.
To assign descriptor in such molecules highest priority at near group and highest priority at
far group were determined separately.
Sighting down the axis, if moving from near group highest priority to corresponding far
group highest priority requires clock wise rotation then the helix is right handed and is
described as P (Plus). A counter clockwise rotation implies helix is left handed and
designated as M (Minus).
3 4
NO2 H
O2N CH3 H3C H

1 2 1 2
CH3 Cl
4 3
P M

Stereochemistry
These M-P convention has relation with R-S configuration as shown in the formula
P = aS M = aR
P = pS M = pR
aS & aR represents Axial chirality

pS & pR represents Stereoplanar chirality
Chirality is also observed in compounds that lack a stereogenic carbon atom.
• Quaternary ammonium salts
R4 R4
R1 N R1
R3 N
R3
R2 R2
Cl Cl

Stereochemistry
• Phosphine oxides
O O
R1 P R1
R3 P
R3
R2 R2
• Silicon containing compounds
R4 R4
R1 Si R1
R3 Si
R3
R2 R2
• Sulfones due to different isotopes
O16
H3C S CH3
O18
Optical activity in compounds without stereogenic center

The chiral compounds discussed so far contains one or more stereocenter and have their
chirality specified at one or more such centers. There are other chiral compounds without
stereocenter like axial chirality (Stereoaxis), Planar chirality (Stereoplanar) and Helicity.
The central tetrahedron usually occupied by a tetracoordinate atoms e.g. C in Cabcd.

Stereochemistry
a a
d
d
b
b c
c
Regular Tetrahedron
If this centre is replaced by a linear grouping such as C-C or C=C=C, the tetrahedral becomes
elongated along the axis. Such elongated tetrahedron (D2d point group with 3C2 axes and 2σ
planes) has lesser symmetry than a regular tetrahedral (Td). Elongate tetrahedron approach
can be applied to a variety of compounds like allenes, spiranes and biphenyls which are chiral
not due to presence of stereocenter but due to stereoaxis.
a a
d d
c c
b b
Elongated Tetrahedron
This extended tetrahedron will be chiral if the pair of ligands or substituent’s at one end of
one axis and the pair at other end are different i.e. the minimum condition for chirality is that
ligand a ≠ b.
Allenes:
Suitable substituted allenes could be chiral was made by Van’t Hoff in 1875 and verified by
Matlan and Mills in 1935.
Allenes contain cumulative double bonds and have general formula
a a a a
C C C C C C
b b b b

Stereochemistry
Simplest allene i.e. propa-1,2-diene is achiral due to presence of two plane of symmetry.
H H
C C C
H H
Allenes has two types of carbon based on hybridization i.e. two Sp2 hybridized carbon atom
at terminal and one Sp hybridized carbon atom in the middle.
Sp hybridized
H
H
C C C
H H
Sp2 hybridized Sp2 hybridized
To make allene chiral unlike substituents at either end and also on carbon are added.
H H
C C C
H3C CH3 H ≠ CH3

An allene with substituents on one terminal carbon atom are unlike and substituent on other
terminal carbon atoms are same, then it will be achiral due to one symmetry plane.
H H
C C C One plane of
symmetry
H3C H
(Achiral)

Stereochemistry
Allene with all the four different substituent’s are also chiral.
H Cl
C C C
H3C C(CH3)3
(Chiral)
Types of Allenes
(1) Asymmetric allenes: Allenes having asymmetric carbon / C1 point group exhibit
chirality.
H H R2 R3
R1
C C C C C C
C H R1 R4

R2 (Chiral due to (Chiral due to
asymmetric center) C1 point group)
R3
(2) Dissymmetric allenes: Allenes having C2 point group exhibit chirality.
H H R1
R1
R2 R2 C C C
C C C C C
R1 R1  
R2 R2
R3
R3
(Chiral due to C2 point group)
Conditions for chirality of allenes:

(1) Proper substitution i.e. two different substituents at either end and also on carbon.
(2) Number of double bonds should be even.

Stereochemistry
The Cumulene with odd number of double bond with terminal carbon atoms having unlike
substituent also will be achiral because both terminal planes will be same.
R
R'
C C C C
R' R
Substituent at two ends of cumulated double bonds now lies in the same plane. Hence, they
exhibit geometrical isomerism instead of optical isomerism.

Stereochemistry
R/S nomenclature for the Allenes:

1. Viewing of molecule from left side
(a) Groups near to the observer are drawn on the bold line and away groups are on the
thin line.
(b) Priority will be given to near group according to CIP rule than far group.
2. Viewing of molecule from right side

thin line.
OR
❖ Always the groups on the solid lines are given priority then priority given to dashed
and wedge lines.
4 1
CH3
H
C C C
H
H3C
3 2

Stereochemistry
2 3
CH3
H
C C C
H
H3C
4
1
R
Hemispiranes or Alkylidenecycloalkanes:
The replacement of one double bond in an allene by a ring gives alkylidenecycloalkanes
referred to as hemispiranes, does not alter the basic geometry of the allene and exists as
optical form if suitabley substituted.
CH3
H
C C C
H3C
H
For such a system, Optical activity arises if
(1) Number of ring + double bonds should be even.

(2) Proper substitution i.e. two different substituents at either end and also on carbon.
Spiranes:
If both double bonds in the allene system are replaced by rings the resulting molecules are
spiranes. In spirane molecule two rings are perpendicular to each other due to steric crowding
by the hydrogen atoms.

Stereochemistry
H H
H
H
H
H
H
H
H H
Spiranes has two types of hydrogen

1. Lateral - 8 hydrogens are lateral
2. Terminal – 4 hydrogens are terminal
H H H H
H
H
Terminal Hydrogens
H
H
H H H H
Lateral Hydrogens
Essential criteria for exhibiting optical activity
1. Even number of ring in spiro compound (Odd number of spiro carbon)

2. Proper substitution at only terminal H.
❖ Chirality due to chiral centre can be generated in any spirane compound (even or odd
number of ring) by substitution at lateral hydrogen (Plane of symmetry should not be
there).

Stereochemistry
R/S nomenclature for the Spiranes:

thin line.

thin line.
OR
❖ Always the groups on the solid lines are given priority then priority given to dashed and
wedge lines.

Stereochemistry
2 3
CH3
H
H3C H
1 4
S
Biphenyls:
Biphenyls itself is not planar, one benzene ring being slightly twisted in relation to other as a
consequence of steric crowd.
Dihedral angle 45o
Conformation having a 90o dihedral angle is achiral as a consequence of plane of symmetry.

If each of the phenyl rings of biphenyl has two different ortho / meta substituent, even the
twisted 90o dihedral angle conformer becomes chiral.
In order to interconvert such conformation with their mirror image structure, a rotation
through the higher energy coplanar form must be made. The ease with which this
interconversion occurs will depend on the size of ortho substituents.
Conformational isomers that are isolable due to high energy barrier are called atropisomers (a
= not, tropos = turn).
The name was introduced by Kuhn i 1933, but atropisomerism was first detected in 6, 6’-
dinitro-2, 2’-diphenic acid by Cristie in 1922.
The C-C sigma bond is known as pivotal bond.
Biphenyls are classified into two categories
1. Bridged biaryls

Stereochemistry
C
H2
n
n > 2, leads to atropisomersim irrespective of bulkiness of two ortho
substituents
2. Non bridged biaryls
R R
R' R'
Conditions for biphenyls to be enantiomeric or resolvable:
1. Two aryl ring must be non planar. This can be done by introducing bulky group in
ortho position.
2. Most tetra substituted biphenyls can be resolved and quite stable to racemisation.
Buttressing effect (BE-effect):

The substituent in meta position tend to enhance the racemisation barrier i.e. preventing the
outward bending of an ortho substituent, which could otherwise occur in the transition state
for racemisation.
In simple the extra meta-group prevents that the ortho-group can bend and therefore makes
the transition state higher in energy. (The meta group ‘buttresses’ or ‘reinforces’ the bond of
the ortho-substituent). This is known as buttressing effect.

Stereochemistry
The rate of racemisation of the 3-nitro derivative is much lower compared to 5’-nitro
derivative. The meta substituent increases the effective size of the ortho substituent.
NO2
NO2
NO2 MeO
MeO
H
H NO2
COOH
COOH
NO2 gp in meta increase effective NO2 gp in meta does not have
size of ortho OMe hence much influence on ortho H
racemization rate decreases hence racemization rate is more
R/S nomenclature for the Biphenyls:

thin line.
NO2 1
H3C NO2
4 3
H3C NO2
O2N
CH3
CH3 2
S
Stereochemistry

thin line.
3 NO2
NO2 H3C
1 2
O2N CH3
O2N
CH3
4 CH3
S
OR
❖ Always the groups on the solid lines are given priority then priority given to dashed and
wedge lines.
1
NO2
4
H3C
O2N
3
CH3
2

Stereochemistry
Classification of cyclic compounds

Cyclic compounds are classified, according to the number of atoms in the ring and properties,
as small rings with 3 or 4 atoms, common rings with 5–7, medium rings 8–11, and large rings
with 12 or more.
Types of strain
Conformational analysis of simple alkanes revealed two types of strain—torsional and steric.
According to Hendrickson and separately Allingerthe total strain of a conformation is the
sum of:
Bond strain - stretching or compression of chemical bonds. This type of strain is rather
severe and is not encountered very often in organic compounds. To minimize bond strain, a
molecule adopts conformations that have other, less energy-demanding, types of strain.
Torsional strain (eclipsing strain, Pfitzer strain) is caused by eclipsing interactions.

Torsional strain is considerably higher compared to steric or angle strain, which are explained
next.
Steric strain (Van der Waals strain, Prelog strain) is caused by atoms forced too close to
each other. Transannular strain (Prelog strain) is a form of steric strain characteristic of
medium rings.
Angle strain (Bayer strain, classical strain) is a result of deviation from the ideal bond
angle. Compared to other types of strain, increase in energy of a conformation caused by
angle strain is relatively low. As a result, a molecule can accommodate relatively large
deviation from an ideal bond angle and still be stable.
Van’t Hoff and Lebel proposed tetrahedral geometry of carbon. The bond angel is of 109˚ 28'
(or 109.5˚) for carbon atom in tetrahedral geometry (methane molecule). Baeyer observed
different bond angles for different cycloalkanes and also observed some different properties
and stability.
On this basis, he proposed angle strain theory.
The theory explains reactivity and stability of cycloalkanes.
Baeyer proposed that the optimum overlap of atomic orbitals is achieved for bond angel of
109.5o. In short, it is ideal bond angle for alkane compounds. Effective and optimum overlap

Stereochemistry
of atomic orbitals produces maximum bond strength and stable molecule. If bond angles
deviate from the ideal then ring produce strain. Higher the strain higher will be instability.
Higher strain produce increased reactivity and increases heat of combustion.
Baeyer proposed “any deviation of bond angle from ideal bond angle value (109.5o) will
produce a strain in molecule. Higher the deviation lesser will be instability.
Baeyer’s theory is based upon some assumptions as following.

1. All ring systems are planar. Deviation from normal tetrahedral angles results in to
instable cycloalkanes.
2. The large ring systems involve negative strain hence do not exists.
3. The bond angles in cyclohexane and higher cycloalkanes (cycloheptane,
cyclooctane, cyclononane……..) are not larger than 109.5o because the carbon
rings of those compounds are not planar (flat) but they are puckered (Wrinkled).
According to Baeyer, the relative order of stability for some common cycloalkanes is as
under.
Cyclopentane > Cyclohexane >Cyclobutane> Cyclopropane
Actual observed order of stability for these cycloalkanes is as under.

Cyclohexane > Cyclopentane >Cyclobutane> Cyclopropane
According to Baeyer, the bond angle in cyclopentane is 108˚ (the geometry is

pentagonal) that is very close to tetrahedral angle (109.5˚), so it is almost free from ring
strain.
Heat of Combustion and Relative Stability of Cycloalkanes
The amount of heat evolved when one mole of compound is burned in carbon
dioxide and water is referred as heat of combustion.
Heat of combustion is important property to know the stability and other valuable
information. The information from heat of combustion is important to understand the
Baeyer’s theory and its limitations.

Stereochemistry
Calculation of heat of combustion (Bomb calorimeter)

Stereochemistry
Successfulness of Baeyer’s angle strain theory

• Baeyer rightly proposed that cyclopropane and cyclobutaneare flat molecule and
having angle of 60˚ and 90˚ those are much deviated from the ideal tetrahedral
value of 109.5˚ hence these ring systems are unstable and easily undergo ring
opening reactions. There is much angle strain in cyclopropane and cyclobutane.
• Baeyer also proposed that cyclopentane is not need to be planar but it is planar as in
that condition the angle is much near to ideal tetrahedral angle
Unsuccessfulness of Baeyer’s angle strain theory

• Baeyer was not able to explain the effect of angle strain in larger ring systems.
• According to Baeyer cyclopentane should be much stable than cyclohexane but
practically it is reversed.
• Larger ring systems are not possible according to Baeyer as they have negative
strain but they exist and much stable.
• Larger ring systems are not planar but puckered to eliminate angle strain.
Coulson-Moffitt Model or Concept of Maximum Overlap of Carbon

Orbitals (Bent bond/Banana bond Theory)
• A bent bond, also known as a banana bond, is a type of covalent chemical bond with
geometry somewhat indicative of a banana.
• The term itself is a general representation of electron density or configuration
resembling a similar "bent" structure within small ring molecules, such as
cyclopropane (C3H6) or as a representation of double or triple bonds within a
compound that is an alternative to the sigma and pi bond model.

Stereochemistry
Sachse-Mohr Theory (Theory of Strainless Rings)

Sachse Mohr’s theory proposed that higher member ring can become free from strain if all
the ring carbons are not forced into one plane. They exhibit in two non-planar ‘folded’ or
‘puckered’ conformations both of which are completely free from strain. These are
strainless as the carbon atoms lie in different planes and the normal valency angle (109.5o)
is retained. These are called the ‘Chair’ Form or the ‘Z’ Form and the ‘Boat’ Form or the
‘C’ Form because of their shapes.
The chair conformation is the most stable conformation of cyclohexane.
Conformational analysis
The various arrangements in space that is available for a molecule by rotation about single
bond its conformation. There are in principle an infinite number of conformations, but a
molecule will adopt a geometry that minimises total energy; this minimum energy is given by
Esteric = E(r) + E(q) + E(f) + E(d))
Where, E(r) = stretching energy, E(q) = strain energy, E(f) = torsion energy, E(d) = non-
bonding interactions.
The investigation of various conformations of a molecule and their stabilities is known as

conformational analysis.

Stereochemistry
Understanding the differences in energy with conformational analysis allows prediction of

relative rates of compounds.
Conformation of Cyclopropane:
In cyclopropane, the three carbon atoms lie in a plane. All C-C bond lengths are same and
three carbons form an equilateral triangle. The hybridization at each carbon atom is Sp3.
The bonding electrons principally lie outside the triangular internuclear line resulting in bent
bonds. There are three strained bonds and six eclipsed hydrogens.
Newmann projection of cyclopropane.

Stereochemistry
Conformation of Cyclobutane:
Cyclobutane has internuclear angle of 90o. There are four strained bonds and eight eclipsed
hydrogens.
Cyclobutane is not planar but puckered i.e. one –CH2- group bent at an angle of about 25o.
The molecule flips from one puckered conformation to other.
Due to bent at angle of about 25o from plane of three ring carbons there will be reduction in
the eclipsed hydrogen interaction and compensate for the increase in bond angle strain.

Stereochemistry
Conformation of Cyclopentane:
If the structure of cyclopentane is planar, the C-C-C bond angle will be 108o which is so close
to normal tetrahedral bond angle of 109o.28’ that is no significant strain effect would be
expected.
However, in such structure all of the hydrogens are completely eclipsed and it would have
considerable torsion strain resulting from ten H---H eclipsing interactions.
Torsional strain is reduced by moving one or two carbon away from the plane. This
results in an increase in angular strain. Carbon atoms move in and out of the plane
rapidly, resulting in an illusion of rotation of the molecule. This phenomenon is termed
as pseudo-rotation. The actual structure is of open envelope shape. In which four carbon
atoms lie in plane and one above or below it.

Stereochemistry
Conformation of Cyclohexane:
A planar structure of cyclohexane is clearly improbable. The bond angle would be 120o i.e.
10.5o larger than the ideal tetrahedral angle. Also every C-C bond in such structure would be
eclipsed. The resulting angle and eclipsing strain would severely destabilize this structure.
Planar
Erel = Very large
If two carbon atoms on opposite side of six member ring are lifted out of the plane, much of
the angle strain can be eliminated. It can form Chair conformation or Boat conformation.
In 1950, interconversion of chair conformation and the different orientation bond was
elucidated by D. H. R. Barton.
Chair conformation:
It is non planar puckered conformation. All bonds are fully staggered therefore Pitzer strain is
minimized. The bond angles are not exactly 109o.28’ but 111o. Relative energy is zero (four
carbons are planar, one puckered up and one puckered down)
Cyclohexane forms a number of different conformers. However, structure other than

the chair conformation suffers torsional strain, angular strain or both.
Boat Conformation:
Even though boat conformation is free from angular strain. However, in addition to the
torsional strain resulting from 4 H---H eclipsing interactions, it also has a flagpole interaction
between the hydrogen atoms on 1- and 4-carbon atoms. Hence, it has higher energy than
chair conformation of about 25 KJ/mol or 6.0 Kcal/mol.

Stereochemistry
The eclipsing interaction can be relieved by slightly twisting two C-C bonds resulting in new
conformation called twist boat conformation.
In boat conformation there are four types of hydrogens

1. Flag pole hydrogen – 2 Nos (Hfp)
2. Bow spirit hydrogen – 2 Nos (Hbs)
3. Quasi axial hydrogen – 4 Nos (Hqa)
4. Quasi equatorial hydrogen – 4 Nos (Hqe)
Hfp Hfp
Hbs Hbs
Hqe Hqe
Hqa Hqa
Twist Conformation:
It is more stable than the boat conformation, but less stable than
than chair conformation. The flagpole interactions and torsional strain in the boat
conformation are reduced in the twist conformer.
The twist boat has energy of about 21 KJ/mol or 5.5 Kcal/mol which is lower than boat
conformer.
Half chair conformation:

It is a transition state conformation. The half chair conformer lies about 43 KJ/mol or 10
Kcal/mol above chair conformation. It has five carbons lie in plane and one puckered out of
plane.

Stereochemistry
Stability order of cyclohexane conformers:
Chair > Twist boat > Boat > Half chair
On careful examination of cyclohexane we find that the twelve hydrogens are not structurally
equivalent.
Equatorial Bonds: These are three sets of two parallel bonds, each of which are
parallel to two of the bonds in the ring. Equatorial bonds alternate from slightly up to
slightly down orientation on moving from one carbon to the next.

Stereochemistry
Axial Bonds: They are parallel to each other and to the principal axis, but
perpendicular to the average plane of the ring. There are three bonds facing up and
three facing down.
An inversion of a cyclohexane chair involves all of the conformations of cyclohexane.

Starting with a chair conformation a, cyclohexane first passes through a “half-chair”
conformation b. The half-chair, as expected, has a very high energy and is only a transition
state, which gives rise to the actual conformation—twist-boat c. Next, the twist-boat
conformation flips into the alternative twist-boat conformation e. The transition state for this
flip is the boat conformation d. Then, the cyclohexane molecule passes through another half-
chair transition state f (mirror image of the first one) and finally arrives at the alternative
chair conformation g. At room temperature cyclohexane interconvert from one chair form to
another referred to as ring inversion or ring flipping.
Axial and equatorial bonds also undergo interconversion, when a chair conformation flips to
the other. However, their relative orientations in space do not change.

Stereochemistry
Since two equilibrium chairs are in rapid equilibrium all twelve hydrogen have 50%
equatorial and 50% axial character.
Conformations of substituted cyclohexanes:

Monosubstituted cyclohexanes:
The axial and equatorial positions have different spatial orientations. In chair-chair
interconversion, substituent’s moves from equatorial to axial and vice versa. Bigger
substituent’s has more steric interaction in an axial position than in equatorial. Hence, the
chair conformation which has the larger group on equatorial is more stable.
Steric repulsion
H H Y H
H H
Y H
Y = equitorial Y = axial
When larger group occupies the axial position there is a steric repulsion between the
substituent and the axial hydrogens which are three carbons away. These repulsive effects are
called 1, 3 –diaxial interactions. It destabilizes the axial conformer about 1.8 Kcal/mol
compared to equatorial conformer.
1, 3 –diaxial interactions is approximately equivalent to one gauche butane interaction of 0.9

Kcal/mol. Since in axial methyl cyclohexane two gauche butane type of interaction between
axial methyl and two ring C-C bond destabilizes the axial conformer while such interactions
does not exists when methyl group is in equatorial.

Stereochemistry
H
H
H C
H
H
View from this side
View from this side
C H
Due to difference in energy between placing a substituent in the axial vs equatorial position,
the two chair conformers are no longer equal energy.
With methyl substituent a hydrogen a hydrogen is directed towards 1, 3 – hydrogens. As the

substituent becomes larger, steric interaction with 1, 3-hydrogen increases.
With ethyl substituent, if the extra methyl is pointed towards 1, 3-hydrogens can rotate to
move away. Has energy similar to methyl cyclohexane i.e. 1.8 Kcal/mol.

Stereochemistry
H H
H3C H
H C H C
H CH3
H H
With isopropyl substituent, can still have a conformer with hydrogen pointed towards 1, 3-
hydrogens. Has energy of about 2.1 Kcal/mol.
H CH3
H3C H
H C H C
CH3 CH3
H H
With tertiary butyl group must have methyl group towards 1, 3-hydrogens. Its energy is
greater than 4.5 Kcal/mol.
CH3
H3 C
H C
CH3
H
The relative population of the two chair conformers can be calculated by the equation,
The free-energy difference between conformers is referred to as the conformational free

energy. For substituted cyclohexanes it is conventional to specify the value of -Gc for the
equilibrium:
[Equatorial] [Axial]

Stereochemistry
As - Gc is negative when the equatorial conformation is more stable than the axial, the value
of - Gc is positive for groups that favor the equatorial position. The larger the - Gc, the greater
the preference for the equatorial position.
The equatorial conformer of ethyl cyclohexane is 7.4 KJ/mol more stable than the axial
conformer. Calculate the percentage of ethyl cyclohexane which is in equatorial at 25oC.
∆G = -RT ln Keq
Keq = e-∆G/RT
= e-7.4 / 0.0083 x 298
= e-2.99
Keq = 0.0504

Stereochemistry
Disubstituted Cyclohexanes and Diastereoisomerism:

In a disubstituted cyclohexane, the most stable conformation is the one in which the largest
number of substituents are in equatorial positions. If the number of equatorial and axial
substituents of the same size in two conformations is the same, then the two conformations
are equally stable.
1, 1 -Disubstituted cyc1ohexanes:
The two identical groups, like in 1, 1-dimethylcyc1ohexane, occupy an equatorial and an
axial position in both conformations. Hence, both are equally stable and so identical.
When two different substituents are present, the bulkier one preferentially occupies the
equatorial position. Example is 1-methyl-1-cyc1ohexanol. The conformation with the larger
methyl group in the equatorial position is more stable, so the two conformers are present in
unequal amounts. Because the substiiuents are present in different positions, the two
conformations are diastereomers. However, since they interconvert very fast, they cannot be
separated.
1,2-, 1,3- and 1,4-disubstituted cyclohexanes exhibit cis–trans isomerism. In

a cis isomer, both substituents are on the same side of the ring, while in a trans isomer the
two substituents are on the opposite sides. Cis–trans isomerism is a consequence of restricted
rotation about carbon–carbon bonds in cyclic compounds. Note that in a cis isomer both
substituents point “up” (or “down”) and that in a trans isomer one substituent points “up” and
the other one “down”. The chair flip does not change the orientation of substituents. One that
was pointing “up” still points “up” and the one that was pointing “down” still points “down”.

Stereochemistry
Substitution Pattern and Cis/Trans Isomerism
Substitution Position Isomer

1, 2- and 1, 4- e, e & a, a trans
disubstituted e, a & a, e cis
e, e & a, a cis
1, 3-disubstituted
e, a & a, e trans
1, 2- disubstituted
H H
CH3
CH3
CH3
H
H CH3
(e, e) (a, a)
Erel = 0.9 Kcal/mol Erel = 2 x 1.8 = 3.6 Kcal/mol
No axial methyl but Two axial methyl

one gauche butane i.e. two 1,3-diaxial
interaction between interaction
to methyl groups

Stereochemistry
1, 4- disubstituted
1, 3-disubstituted
Two substitutions by bulky groups, ring distortion takes place. In the chair conformation of
1,4-di-t-butylcyclohexane the bulky t-butyl groups even in diequatorial positions cannot
avoid steric interactions with the adjacent hydrogens. Hence, the molecule prefers to pucker
into a twist boat form so that these groups are away from all the adjacent hydrogens. In the
twist boat form, the groups are not exactly equatorial as in the chair conformation, but are
directed away from the ring and are known as the pseudoequatorial positions.
Another factor which predominates in deciding the stability of the conformations is the
intramoleculer H-bonding e.g. in the 1, 3- and 1, 4- dihydroxy cyclohexanes. The diaxial
chair contormation of cis-l, 3-dihydroxycyclohexane is preferred due to stabilization by
intramolecular H-bonding, as the two hydroxy groups are closer, while this is not possible in
the diequatorial form.

Stereochemistry
More interesting is the example of cis-l, 4-dihydroxycyclohexane where the unfavourable

boat form is the preferred conformation due to intramolecular H-bonding and the molecule
exists in only one form.
Conformational effect on reactivity:

In cyclic system to satisfy a particular mechanism a suitable conformation may be of higher
energy is adopted.
Substitution reactions:
SN1: Acetolysis of cis-4-t-butylcyclohexyltosylate. Axial conformer reacts faster due to
relieve in the steric strain due to 1,3-diaxial interaction and forms carbocation very easily.

Stereochemistry
OTs
Fast
Slow
OTs
SN2 reaction: Axial conformer reacts faster due to relieve in the steric strain due to 1,3-
diaxial interaction and leads to more stable (e, e) conformation with two bulky in equatorial
position. Displacement equatorial X group by PhS- leads to the formation of less stable (e, a)
conformation.
PhSNa
SPh
PhS
SPh
PhS
PhSNa
X
Less stable product
Saponification of an ester: If the ester is in the axial position or in a equatorial position what
is the rate. The equatorial acetate will be hydrolysed faster as compared to the axial ester.
Reaction of axial ester decelerated due to severe developing 1,3-diaxial interactions in
transition state.

Stereochemistry
NaOH OEt
COOEt
-
O OH
COOH
-
O OH
OEt
H
COOEt
NaOH H
COOH
Alcohol oxidation: Destabilizing 1,3-diaxial interactions in cis chromate ester accelerated its
break down to the ketone.

Stereochemistry
E2 elimination reaction: occurs through anti periplanar transition state. In cyclic

compounds, two leaving groups must be diaxial so as to assume anti periplanar arrangement.
1-Chloro-2methylcyclohexane undergoes elimination reaction in presence of base to give 3-

methylcyclohexene and 2-methylcyclohexene is not all formed.
Cl
CH3 CH3 CH3

Base
Only prodct formed
1-Chloro-2methylcyclohexane undergoes elimination reaction to give 3-methylcyclohexene

through less stable conformer. Since less stable conformer has two groups in diaxial position
i.e. one axial hydrogen and one axial chloro group and hence it assume anti periplanar
arrangement must for elimination reaction.
2-methylcyclohexene is not formed at all because the hydrogen is in equatorial position and
anti periplanar arrangement is not possible.
Axial
:B
Cl
H
CH3 H3C
Cl H
CH3
Axial Cl
More stable Less stable

conformer conformer
Base
CH3 H3C
CH3

Stereochemistry
Pyrolytic elimination (Syn):
Pyrolytic elimination reaction of acetate, benzoate and xanthates take place through cyclic six
membered transition states which require cis rearrangement.
(1S, 2R)-Ethyl-2-acetoxycyclohexanecarboxylate undergoes syn elimination reaction through

cyclic six membered transition state to give ethylcyclohex-2-enecarboxylate.
COOEt H H
OCOCH3
COOEt COOEt
H
H H H
(1S,2R)-ethyl 2- OCOCH3 O
O
acetoxycyclohe
xanecarboxylate
(e, a) Cis to each other
CH3
6-membered cyclic TS
-CH3COOH
COOEt
ethyl cyclohex-2-enecarboxylate
Conformation of Cycloheptane:
Cycloheptane is the largest common ring and it exhibits some features associated with
medium rings such as a more difficult preparation and steric strain in some conformations.
Hendrickson in 1961 distringusihed two general type of conformation of cycloheptane-chair

and boat.
Chair Boat

Stereochemistry
Both chair and boat of cycloheptane exhibit torsional strain are quite flexible that easily
undergo pseudorotation to lower energy conformations twist char and twist boat. The
interconversion barrier between the chair and boat is computed to be 8 Kcal/mol.
The lowest energy conformation is a twist-chair, while a twist-boat has slightly higher energy
due to the presence of the intraannular “flagpole” hydrogen

Stereochemistry
Earlier part of stereochemistry was concentrated on the stereo center.

Stereo center
X
*
A C B
Y
Now we start to see the relationship between the ligands attached to stereo center if the
attached ligands are homomorphic in nature.
X
Relation
A C B between
X&Y
Y
Homomorphic Groups / Ligands / Atoms:
The Groups / ligands / atoms which are in isolation look the same or super imposable mirror
images of each other are called homomorphic groups / ligands / atoms.
Homo in greek means same
Morph in greek means form
CH3
H C H Homomorphic
groups
CH3
Homomorphic atoms
In case of atoms, they must be of same element example two H’s or two Br atoms. If we
isolate the two H’s, then they are same and super imposable to each other hence they are
called homomorphic hydrogen's.

Stereochemistry
Isolated CH3 Isolated
H C H
CH3
H H
Identical and super imposable
In case of groups, they must have same constitution and configuration. For example two
methyl or two Ph groups of same chirality R or S. They are called homomorphic groups /
ligands / atoms.
TOPICITY: (TOPOs in Greek means place) can be defined as geometrical or

sterochemical relationship between homorphic groups / ligands / atoms and structure of the
molecule.
Different types of relationships are possible for homorphic ligands / groups / atoms.
1. Homo topic (Homo-same; topo-place)
2. Hetero topic (Hetero-different; topo-place)
Ligands can not by itself be called homotopic or heterotopic, in order to use this
terminologies a comparison with other homomorphic ligand or ligands present either in the
same molecule (internal comparison) or in a different molecule (external comparison) is
necessary.
Two criteria are used to decide whether the ligands / groups are equivalent or not
1. Substitution-addition criteria
2. Symmetry criteria
Are employed to determine the topic relationship of homomorphic ligands

Stereochemistry
(a) Homo topic ligands:

Two or more ligands that are identical when viewed in isolation but individual replacement of
two identical ligands by another give rise to identical molecule, then they are called
homotopic ligands.
Two homomorphic ligands are homotopic if substitution (replacement) of first one and other
by different test ligand leads to homomers or identical product.
Example-1:
Example-2:
H X
Ha X
C C C
H Ha H H
Identical product
C C C
H Hb H H
C C C
Hb X
H X

Stereochemistry
Example-3:
COOH
Ha F
F H
H
COOH COOH
Identical
Ha Hb H F products
Hb F
Hc H
COOH
H H
Hc F
F
Example-4:
COOH
Ha D D OH
HO H
COOH COOH
Ha OH
Identical
products
HO Hb
COOH COOH
H OH
Hb D HO D
COOH

Stereochemistry
(b) Homo topic faces

Two faces of a pi system or a double bond are homotopic if addition to either face gives same
or identical product.
Example-1:
Example-2:

Stereochemistry
(a) Homo topic ligands
Two homomorphic ligands are homotopic if they can interchange position by rotation around
Cn axis.
Example-1:
Example-2:

Stereochemistry
(b) Homo topic faces

Two faces of pi system are homotopic if they can interchange face result in same structure by
rotation around C2 axis.
Example-1:
Example-2:

Stereochemistry
NMR Spectroscopy of Homotopic Hydrogen

If the hydrogen atoms in the molecule are homotopic, then they are chemically equivalent.
Hence they will resonate at same chemical shift values.
SUMMARY
Between homotopic groups and faces no differentiation is possible either by enzyme or by
NMR or by human being because they are homomers or identical.
Substitution-
Topicity Symmetry criteria Reactivity
addition criteria
Homotopic
Homomers / No differentiation
groups and Cn or C2
Identical possible
faces

Stereochemistry
Hetero topic ligands

Two or more ligands that are identical when viewed in isolation but individual replacement of
two identical ligands by another ligand give rise to two structurally different (isomeric)
molecules, then they are called heterotopic ligands.
Constitutionally Hetero topic ligands

Two or more ligands in a molecule that are identical on individual replacement by another
ligand give rise to two molecule that constitutional isomers of each other, then the original
two ligands are said to be constitutionally heterotopic ligands.

Stereochemistry
Example-1:
H COOH
C C
H3C CH3
CH3 X CH3 X
H COOH H COOH
1 1
C C C C
3 2 3 2
X CH3 H 3C X
Example-2:
NO2
H F H F
NO2 NO2
F H
H F

Stereochemistry
Stereo chemically heterotopic

ligand give rise to two molecule that are enantiomers / super imposable mirror images of each
other, then the original two ligands are said to be enantiotopic ligands.
(a) Enantiotopic ligands
Two homomorphic ligands are enantiotopic if substitution (replacement) of first one and
other by different test ligand leads to enantiomers.
Example-1:
Example-2:
Hb Cl
C C C
Ha H
Ha Cl Hb Cl
4 1 4 1
H Cl H Cl
C C C C C C
Cl H Cl H
3 2 3 2
(S) (R)
They are enantiomers and hence enantiotopic ligands

Stereochemistry
Example-3:
Hb Ha
OH
Ha D Hb D
H D
D H
OH
OH
O
O
(R) (S)
They are enantiomers and hence Ha & Hb are enantiotopic ligands
Example-4:
Hb
Ha
CH3
H3C
H H
Ha D Hb D
H D
D H
CH3 CH3
H3C H3C
H H H H
(S) (R)
They are enantiomers and hence Ha & Hb are enantiotopic ligands

Stereochemistry
(b) Enantiotopic faces

Two faces of a pi system or a double bond are enantiotopic if addition to either face gives
enantiomeric product.
Example-1:
Top face
O
Ph Addition reaction
Bottom face
from either face leads
to formation of
EtMgBr
enantiomers and
EtMgBr
hence two faces are
enantiotopic
Et OH
H H
 
Ph OH Ph Et
(R) (S)
Example-2:
CN
H
Top face 
HCN Ph OH
H (S)
O
OH
Ph H
HCN
Bottom face

Ph CN
(R)
Addition reaction from either face leads to formation of
enantiomers and hence two faces are enantiotopic

Stereochemistry
Molecules having stereo heterotopic ligands (enantiotopic) exhibit prostereoisomerism or

prochirality
Prostereoisomerism or Prochirality
Prochiral molecules are those which are achiral can be converted into chiral molecule in a
single step.
Prochirality may be the result of substitution reaction of Sp3 carbon substituent (usually
hydrogen) with other substituent results in chiral center.
OR
Prochirality may be the result of addition reaction of a Sp2 carbon to a chiral Sp3 carbon
with nucleophile.
Prochirality may be the result of substitution reaction of Sp3 hybridized

carbon substituent.
CH3 PROCHIRAL
C
Hb PROCHIRAL
HYDROGENS
Ha
Ha Cl Hb Cl
CHIRAL 3 CHIRAL
3 CH CH3
3
2 C 2 C 1
4
H Cl
Cl H
1 4
4th group on wedge bond hence
clock wise "S" configuration
(R) (S)

Stereochemistry
Prochirality may be the result of addition reaction of Sp2 hybridized

carbon.
H3C PROCHIRAL
C O
H3C CH2
NaBH4 NaBH4
CHIRAL 1
H4 OH CHIRAL
3
3 H3C H3C
C C
H3C C OH H3C C H
H2 1 H2 4
2 2
(S) (R)
View the molecule through C-H bond for assigning the
configuration
(a) Enantiotopic ligands
Two homomorphic ligands are enantiotopic if they can interchangeable through plane of
symmetry or center of inversion or Sn axis.
Example-1: Molecule with plane of symmetry (σ) containing homomorphic ligand is

enantiotopic. COOH
Ha OH
plane of symmetry
Hb OH
COOH

Stereochemistry
Example-2: Molecule with Improper axis of symmetry (Sn) containing homomorphic

ligand is enantiotopic.
Ha Hb Hb
Hb Ha Ha
H3C OH HO CH3 H3C OH
Rotation Reflection
Example-3: Molecule with Center of inversion (i) containing homomorphic ligand
enantiotopic.
OH
Cl
Inversion center
Cl
OH
(b) Enantiotopic faces:

Two faces are enantiotopic if they can interchangeable through plane of symmetry or center
of inversion or Sn axis.
Top face Top face

H Ph
O O
Ph H
Bottom face Bottom face
Structure is not same upon rotation hence mirror plane

exists.

Stereochemistry
Top face
Ph
O Molecular mirror plane exists
H
Bottom face
NMR Spectroscopy of Enantiotopic Hydrogen

If the hydrogen atoms in the molecule are enantiotopic, then they are chemically equivalent.
Hence they will resonate at same chemical shift values.
SUMMARY
Between enantiotopic groups and faces differentiation is possible either by enzyme or by
NMR in chiral reagent or catalyst.
Substitution- Symmetry
Topicity Reactivity
addition criteria criteria
Enantiotopic
Differentiation
groups and Enantiomers σh or Sn
possible
faces

Stereochemistry
(a) Diastereotopic ligands

ligand give rise to two molecule that are diastereomers / non super imposable not mirror
images of each other, then the original two ligands are said to be diastereotopic ligands.
Substitution-addition criteria
Two homomorphic ligands are diastereotopic if substitution (replacement) of first one and
other by different test ligand not already attached to the molecule leads to diastereomers / non
super imposable not mirror images.
Example-1:
H Cl
C C
Cl
Ha
H3C H
H Ha
-CH3 & -Cl
C C are
Trans
H3C Hb H H
Hb
Cl C C
H3C Cl
-CH3 & -Cl
are
Cis
Substitution of Ha & Hb by Cl leads to formation of trans

and cis products which are diastereomers and hence two
hydrogens are diastereotopic

Stereochemistry
Example-2:
Br
Cl
H
Cl H
Br -Br & -Cl
are
Ha
Ha Cis
Hb Br
H
Cl H
Hb
H
Cl
-Br & -Cl
are
Trans
Substitution of Ha & Hb by Cl leads to formation of trans
and cis products which are diastereomers and hence two
hydrogens are diastereotopic
Geminal methylene protons adjacent to a stereocenter on substitution test

by other ligands not already present in the molecule usually leads to
diastereomers and are usually diastereotopic.
O Stereo center

Hb Ha
Adjacent to a stereo
center hence they are
usually diastereotopic

Stereochemistry
Example-1:
O
Enantiomers
 RR SS
Diastereomers
Diastereomers
Hb Ha
Diastereomers
Hb
Ha RS SR
Enantiomers
Cl Cl
O O Substitution of Ha

 & Hb by Cl leads to
 formation of

diastereomers and
Cl H H Cl
hence two
(R) (R) hydrogens are
diastereotopic
(S) (R)
Example-2:
(R)
CH3
 Substitution of Ha
H Cl
& Hb by D leads to
Hb Ha
formation of
Cl diastereomers and
hence two
hydrogens are
Hb diastereotopic
Ha
D D
(R) (R)
CH3 CH3
 
H Cl H Cl
D H H D
Cl Cl
(R) (S)

Stereochemistry
(b) Diastereotopic faces

Two faces of a carbonyl group adjacent to a stereo center upon addition reaction leads to
diastereomers and possess diastereotopic face.
CH3
Two faces of a
O carbonyl group
adjacent to a stereo
 center
H3C H
C6H5 Stereo center
NMR Spectroscopy of Diastereotopic Hydrogen

If the hydrogen atoms in the molecule are diastereotopic, then they are chemically and
magnetically non equivalent. Hence they will resonate at different chemical shift values.
Diastereotopic hydrogens
H
H Due to non equivalent nature of protons
H it splits into multiplet.
CH3
HO

Stereochemistry
SUMMARY
Between diastereotopic groups and faces differentiation is possible either by enzyme or by
reagent or by NMR.
Substitution- Symmetry
Topicity Reactivity
addition criteria criteria
Diastereotopic
Differentiation
groups and Diastereomers Not applicable
possible
faces
EXAMPLES FOR HOMOTOPIC, ENANTIOTOPIC AND

DIASTEREOTOPIC LIGANDS
H D
Substitution of Ha &
trans Hb by D leads to
H Ha Br H formation of
diastereomers and
H H hence two hydrogens
are diastereotopic.
Br Hb
Br D Cis

Stereochemistry
D
H
Ha Substitution of Ha & Hb by D
Hb leads to formation of
homomers and hence two
H hydrogens are homotopic.
D
D H
MeO OMe Substitution of H & H by D
H H leads to formation of
H D hydrogens are homotopic.
MeO OMe
MeO OMe
Cl Cl
R R
D H Substitution of H & H by D
Cl Cl
leads to formation of
R R Cl Cl hydrogens are homotopic.
H H
R R
H D

Stereochemistry
C2
H H H H H & H are
interchangeable by C2
rotation and hence two
O O O O hydrogens are homotopic.
Ph CH3 Ph CH3
H3C Ph H3 C Ph
H
D
H Substitution of H & H by D
leads to formation of homomers
H
D and hence two hydrogens are
homotopic.
H
D
H
Substitution of H & H by D
leads to formation of
H
H enantiomers and hence two
hydrogens are enantiotopic.
H
D
D
H
Substitution of H & H by D
H leads to formation of
H diastereomers and hence two
H
hydrogens are diastereotopic.
D

Stereochemistry Notes

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Stereochemistry

Dr. Krishnaswamy. G, DOS & R in Organic Chemistry, TUT Page 1

Christian Huygens (1629-1695) discovered plane polarized light.

Dr. Krishnaswamy. G, DOS & R in Organic Chemistry, TUT Page 2

Acts as Sedative Acts as Tetratogenic

This branch of chemistry is commonly referred to as 3-Dimensional chemistry. Since, it

Enantiomers - Non-superposable mirror images or chiral molecules which are mirror

Chiral or asymmetric carbon - a tetrahedral carbon atom bearing four different

Diastereomers have different physical properties.

Dr. Krishnaswamy. G, DOS & R in Organic Chemistry, TUT Page 3

Racemic mixture - an equimolar (1:1) pair of enantiomers is called a racemic mixture. A

Device used to measure optical rotation: Polarimeter

The specific rotation of a compound is calculated using the following formula:

Molecules with one stereocenter can be R or S = 2 possible stereoisomers.

stereocenter = 2n possible stereoisomers.

Representation of three dimensional molecules

(1) Dashed Wedge or Flying Wedge formula

Dr. Krishnaswamy. G, DOS & R in Organic Chemistry, TUT Page 4

(1) Dashed-Wedge or Flying Wedge formula

In this representation a solid continuous lines represent bond is in the plane.

(2) Fischer projection:

Dr. Krishnaswamy. G, DOS & R in Organic Chemistry, TUT Page 5

Most oxidize carbon

• A 180° rotation gives the same stereochemistry.

Dr. Krishnaswamy. G, DOS & R in Organic Chemistry, TUT Page 6

• A 90° rotation gives the inverted stereochemistry.

• Exchanging any two positions gives the inverted stereochemistry.

➢ These projections can be turned or rotated only in certain specified way.

Dr. Krishnaswamy. G, DOS & R in Organic Chemistry, TUT Page 7

(4) Newmann Projections

The front carbon shown by three solid lines i.e. “Y”

Dr. Krishnaswamy. G, DOS & R in Organic Chemistry, TUT Page 8

Propane staggered Newmann projection from two views is shown below.

INTER CONVERSION OF REPRESENTATIONS

Dr. Krishnaswamy. G, DOS & R in Organic Chemistry, TUT Page 9

CH3 Right side CH3 CH3

Dr. Krishnaswamy. G, DOS & R in Organic Chemistry, TUT Page 10

CH3 Right side CH3 CH3

Rotate 180o in the

Left side COOH COOH

Conversion of Fischer projection to Dash Wedge formula

Dr. Krishnaswamy. G, DOS & R in Organic Chemistry, TUT Page 11

Conversion of Fischer projection to Newmann projection to Sawhorse

Dr. Krishnaswamy. G, DOS & R in Organic Chemistry, TUT Page 12

Conversion of Sawhorse formula to Newmann projection to Fischer

Conversion of Sawhorse formula to Fischer projection:

Dr. Krishnaswamy. G, DOS & R in Organic Chemistry, TUT Page 13

Configuration: Three dimensional arrangements of atoms or groups around an asymmetric

Dr. Krishnaswamy. G, DOS & R in Organic Chemistry, TUT Page 14

3 CH2OH 6 CH2OH CH2OH

D-Glyceraldehyde D-Glucose D-Mannose

CH2OH CH2OH CH2OH

L-Glyceraldehyde L-Glucose L-Mannose

Dr. Krishnaswamy. G, DOS & R in Organic Chemistry, TUT Page 15

D- & L- configurations are not related to the optical rotation of sugars.

Threo and Erythro system:

Dr. Krishnaswamy. G, DOS & R in Organic Chemistry, TUT Page 16

Dr. Krishnaswamy. G, DOS & R in Organic Chemistry, TUT Page 17

Meso-2, 3-Dibromobutane (d,l)-2, 3-Dibromobutane

Dr. Krishnaswamy. G, DOS & R in Organic Chemistry, TUT Page 18

Dr. Krishnaswamy. G, DOS & R in Organic Chemistry, TUT Page 19

View the molecule

Dr. Krishnaswamy. G, DOS & R in Organic Chemistry, TUT Page 20

Dr. Krishnaswamy. G, DOS & R in Organic Chemistry, TUT Page 21