CY2002D : ORGANIC CHEMISTRY
S4 [Link], WINTER SEMESTER 2021-22
MODULE 1: PRINCIPLES OF STEREOCHEMISTRY
• Symmetry elements, chirality and nomenclature
• Concept of chirality and molecular dissymmetry
• Projection formulae and their interconversions
• Prochiral relationships
• Geometrical isomerism, E and Z nomenclature
• Conformational analysis : cyclohexane derivatives
• Conformation, stability and reactivity
STEREOCHEMISTRY
STEREOCHEMISTRY ??!!!!
STEREOCHEMISTRY AND
DRUG ACTION
STEREOCHEMISTRY AND DRUG ACTION
Sedative
Teratogenic
STEREOCHEMISTRY AND DRUG ACTION
L-Methamphetamine D-Methamphetamine
SYMMETRY
SYMMETRY IN NATURE
SYMMETRY ELEMENTS AND OPERATIONS
No Element Operation Symbol
1 Plane of symmetry Reflection through plane σ
2 Rotational axis of Rotation about axis by 360/n degrees Cn
symmetry
3 Inversion Centre Inversion: every point x,y,z translated to - i
x,-y,-z
4 Alternating axis of Rotation by 360/n degrees followed by Sn
symmetry reflection through plane perpendicular to
rotation axis
ROTATIONAL AXIS OF SYMMETRY
Rotation by 360°/n leaves the molecule unchanged
ROTATIONAL AXIS OF SYMMETRY
How many C2 axes?
Tetrachloroplatinate
ROTATIONAL AXIS OF SYMMETRY
C2 H H
H Cl
Cl H
Cl H H Cl
H H
H H C2
H H
cis-1,3-dichlorocyclobutane trans- 1,3-dichlorocyclobutane
contains a C2 axis contains a C2 axis
H H
H Cl
Cl H
Cl H H Cl
H H
H H
H H
cis-1,3-dichlorocyclobutane trans- 1,3-dichlorocyclobutane
C2 H C3
H
H Br H
H
Br H C2 H
H
trans-1,2-dibromoethane Cyclopropane
contains a C2 axis contains a C3 axis perpendicular
to three C2 axes: D3h
PLANE OF SYMMETRY (REFLECTION σ)
Plane that divides the molecule into two equal halves such that one half is the
exact mirror image of the other.
PLANE OF SYMMETRY
• Vertical plane (v) The principal axis of symmetry lies in this plane
• Horizontal plane (h) The principal axis of symmetry is perpendicular
to this plane
• Dihedral plane (d) The plane containing the principal axis and
passing in between two subsidiary axis
PLANE OF SYMMETRY
v h d
CENTRE OF SYMMETRY (INVERSION i)
An operation that transforms a coordinate (x, y, z) into (-x, -y, -z)
Centre of
inversion
ALTERNATING AXIS OF SYMMETRY (IMPROPER ROTATION
AXIS, Sn)
Involves two steps
• 1. Rotation about an axis through certain angle
• 2. Subsequent reflection in a plane perpendicular to this axis
ALTERNATING AXIS OF SYMMETRY (IMPROPER ROTATION
AXIS, Sn)
ALTERNATING AXIS OF SYMMETRY (IMPROPER ROTATION
AXIS, Sn)
Relation between Sn / / i
S1 = Plane of symmetry ()
S2 = Center of symmetry (i)
CHIRALITY
CHIRALITY
SYMMETRY AND CHIRALITY
ASYMMETRIC MOLECULES
Asymmetric molecules: Do not possess any symmetry elements other than
the C1 axis
SYMMETRY AND CHIRALITY
DISSYMMETRIC MOLECULES
Molecules which have one or more proper rotation axes(Cn, n > 1), but no improper
rotation axes (Sn), plane of symmetry, and centre of symmetry are said to be
dissymmetric
SYMMETRY AND CHIRALITY
Chiral Molecules
Absence of
ASYMMETRIC
• plane
MOLECULES • Centre of inversion DISSYMMETRIC
MOLECULES
• Alternating axis of symmetry
But can have axis of rotation
CHIRAL MOLECULES ARE OPTICALLY ACTIVE
SYMMETRY AND CHIRALITY
cis-2-butene:
H3C CH3
H3C CH3 Superimposable
C C C C
H H
cis -2-butene is optically inactive
H H
mirror mirror image
trans-2-butene:
????
Twistane
Chiral or achiral?
Asymmetric or dissymmetric?
Case of trans-1,3-dimethylcyclobutane:
H H H H
Me H H Me Superimposable
H
trans-1,3-dimethylcyclobutane
Me Me
H is optically inactive.
H H H H
mirror
Case of propionic acid:
COOH COOH
C C
Superimposable
H CH3 H Propionic acid is optically inactive
H H3C H
mirror image
mirror
Case of lactic acid:
COOH COOH
Nonsuperimposable
C C
H H
Lactic acid with the molecular
CH3 H3C
HO OH configuration (A) is optically active
(A) (B)
mirror mirror image
Case of trans-1,2-dimethylcyclopropane:
H H
Me H H Me
Nonsuperimposable
trans-1,2-dimethylcyclopropane with the molecular
H H configuration (X) is optically active
H Me Me H
(X) (Y)
mirror mirror image
Optical activity?
Plane of symmetry
cis-3,6-dimethyl-piperazine-2,5-dione
Vs
trans-3,6-dimethyl-piperazine-2,5-dione.
trans isomer: center of symmetry cis isomer: no element of Symmetry except
C2
Thus optically active/ Dissymmetric
Two stereoisomers possible for :
cis-3,6-dimethyl-piperazine-2,5-dione
a b
one is mirror image of other
Enantiomer
STEREOCHEMISTRY
ISOMERS
Do molecules have same molecular formulae?
No Yes
Not isomers Isomers
Do they have
same connectivity
No Yes
Constitutional isomers Stereoisomers
STEREOCHEMISTRY
Stereoisomers
Can they be interconverted by rotation about a
single bond?
No Yes
Configurational isomers Conformational isomers
Is isomerism due to restricted rotation?
Yes No
Geometrical isomers Optical isomers
STEREOCHEMISTRY
Optical Isomers
Are the compounds nonsuperimposable mirror
images?
No Yes
Diastereomers Enantiomers
Glossary
Symmetry
Chirality Asymmetric molecules
Dissymetric molecules Enantiomers
Diastereomers
SOURCE OF CHIRALITY
Chiral Centre Chiral Axis
Chiral Plane
Helicity
Chiral Centre
PROJECTION STRUCTURE OF STEREOISOMRS
How to represent 3-dimentional structure in 2-dimention?
Fischer
CHOProjections Sawhorse Projections
CH2OH
H
OH H OH
PROJECTION STRUCTURE OF STEREOISOMRS
How to represent 3-dimentional structure in 2-dimention?
Newman Projections Flying wedge Projections
Zigzag Projections
STEREOCHEMICAL NOMENCLATURE
D, L-System
STEREOCHEMICAL NOMENCLATURE
D, L-System
No correlation between configuration and the sign of rotation.
STEREOCHEMICAL NOMENCLATURE
D, L-System: Amino acids
STEREOCHEMICAL NOMENCLATURE
The Cahn-lngold-Prelog R/S convention R – Rectus-right
S – Sinister - left
Sequence Rule and the Chirality Rule
A
Assign priority to the atoms or Visualize the molecules from the
groups connected to chiral centre opposite side of the lowest
D priority group
C B
A → B → C arranged in clockwise orientation: R configuration
A → B → C arranged in anticlockwise orientation: S configuration
CIP RULES
Higher atomic number takes precedence
Each atom is assigned a priority based on atomic number I
H3C
̶ H, ̶ CH3, ̶ NH2, ̶ OH, ̶ SH, ̶ Cl, ̶ Br, ̶I Cl
H
Increasing priority
Higher atomic mass number takes precedence
CH3
D
̶ H, ̶D ̶ Cl35, ̶ Cl37
OH
H
Increasing priority
• Atom directly linked to the central chiral atom must be considered first
• If priority remain undecided for some ligands, passover to the next atom
in the ligand. Priority is assigned at the first point of difference
̶ CH2 ̶ H ̶ CH2 ̶ CH3 ̶ CH2 ̶ NH2 ̶ CH2 ̶ OH ̶ CH2 ̶ Cl
Increasing priority
Multiple bonds- Break and duplicate
Assign Priority
-COOH and –C(OH)3 –CH(CH3)2 and -CH=CH2
-C≡CH and –C(CH3)3 –CH2-N(CH3)2 and -C≡N
o cis precede trans b
c
D
H a
o R precede S.
COOH
R
H OH
A A A
H D
r D C D C R
D
B
H OH B B C
S
COOH
To assign the configuration when the lowest priority group is not away from the
viewer
To assign the configuration when the lowest priority group is not away from the
viewer
1. Swap the groups
2. Assign configuration
R/S
Exchanging a pair of groups about a chiral centre generates the opposite isomer
3. Configuration after swapping the group S, then original configuration is R and vice versa
Warning: Do not forget the step 3 if you follow this method
1 4
2
4 3 2
R 3
R
2 4 S
4
3 3
2
1
C C C
B
HC HC C A
CH2
C CH CH CH2 C
C C
C D
CH3 C C
H3C-H2C C CH3
H2C
CH3
Single exchange changes the configuration:
Double Exchanges does not change the Configuration:
R S
Single exchange of ligands 180o rotation along C1and C2
COOH
HO
Me
H
Assign the configuration and draw the enantiomer of each of the following
molecules.
How many chiral carbons are there in reserpine? (an antipsychotic
drug)
Fischer Projection
Fischer Projection
• Intersection of vertical and horizontal lines represent a chiral centre
• Horizontal lines represent bonds directed towards the reader
• Vertical lines represent bonds directed away from the reader
• Carbon chain is drawn along vertical line with most highly
oxidized end carbon at the top
Determining configuration in Fischer projections
• Assign priorities
• Lowest priority group on the back side
(should be on the vertical line)
Determining configuration in Fischer projections
Examples
R R R
1
Working with Fischer projections
2 4
• May be rotated in the plane of paper through 180 degree 3
3
1
Rotate through 180°
4 2
2 4
1
3
R
R
1
Working with Fischer projections
2 4
• Should not be rotated through 90 degree 3
4
1
Rotate through 90°
1 3
2 4
2
3
s
R
Enantiomer
1
Working with Fischer projections
2 4
• To draw the enantiomer of a molecule in Fischer Projection 3
1
1
Exchange groups on horizontal line
4 2
2 4
3
3
s
R
Enantiomer
Interconversion between Fischer projection and flying wedge
representation
a a
Tilt towards left
C =d c
c
b d b
COOH COOH COOH Me COOH
H2N H H2N H H
Me H2N H
Me Me NH2
Fischer projection Alanine
Interconversion between Fischer projection and flying wedge
representation
Molecules with more than one chiral centre
Molecules with one chiral centre Molecules with two chiral centres
Two enantiomers
4 stereoisomers
Molecules with more than one chiral centre
Molecules with three chiral centres
8 stereoisomers
Molecules with n chiral centre 2n stereoisomers
Molecules with more than one chiral centre
Molecules with more than one chiral centre
1R,2R 1S,2S
1S,2R 1R,2S
If all of the chiral centers are of opposite R/S configuration between two
stereoisomers, they are enantiomers.
If at least one, but not all of the chiral centers are opposite between two stereoisomers,
they are diastereomers.
Enantiomers
❖ Identical physical properties such as melting point, boiling point, infrared
absorptions and NMR spectra.
❖ Different chiroptical properties such as optical rotation
❖ Behave differently in chiral environment
Enantiomers
Fisher projection loses its meaning when rotated out of the plane by 180°
Diastereomers
Epimers: diastereomers which differ at only a single chiral center
Diastereomers
• Different physical properties such as melting points, boiling points, densities,
solubilities, refractive indices, dielectric constants and specific rotations.
• Can be separated from one another through techniques like fractional
crystallization, fractional distillation, chromatography etc.
• Show similar, but not identical chemical properties.
Erythro and Threo Nomenclature
For naming of molecules having two chiral centers
Erythro and Threo Nomenclature
How to draw all the stereoisomers
Meso Configuration
Molecule with two stereocentres and
Molecule with two stereocentres each centre has the same substituents
How many stereoisomers are possible? How many stereoisomers are possible?
Enantiomers
Meso
Meso Configuration How to recognize a meso compound
Contains a plane of symmetry.
Two stereocentres
Meso?
Meso Configuration
Does meso has an enantiomer?
Features of meso compounds
Meso compounds are achiral
Meso compounds cannot have enantiomers
Features of meso compounds
Interconversion between Fischer projection and flying wedge
representation
Courtesy: [Link]
Fischer projection to flying wedge (more than one chiral centre)
Method 1
Courtesy: [Link]
Fischer projection to flying wedge (more than one chiral centre)
Courtesy: [Link]
Fischer projection to flying wedge (more than one chiral centre)
Method 2
Courtesy: [Link]
Flying wedge to Fischer (more than one chiral centre)
In Fischer projection bonds are eclipsed
In Flying wedge the bonds are staggered
Courtesy: [Link]
Flying wedge to Newman (more than one chiral centre)
Courtesy: [Link]
Flying wedge to Newman (more than one chiral centre)
Courtesy: [Link]
Newman to Flying wedge (more than one chiral centre)
Courtesy: [Link]
Newman to Flying wedge (more than one chiral centre)
Courtesy: [Link]
Newman to Flying wedge (more than one chiral centre)
Courtesy: [Link]
Geometrical isomers
Geometrical isomers
E Z
Cahn-Ingold-Prelog (CIP) convention
Geometrical isomers
(Z)-3-chloropenta- 1,3-diene
Conformation of conjugated system: s-cis/s-trans conformation
Dynamic
Draw the structure of (2E,4E)-hepta-2,4-diene(s-cis)
3 5
2 4
× (2E,4E)-hepta-2,4-diene(s-trans)
(2E,4E)-hepta-2,4-diene(s-cis)