1. WEL- COME

2. STEREOCHEMISTRY OF SOME ORGANIC COMPOUNDS
AND DRUG MOLECULES
Dr. A.G. Nikalje .

3. STEREOCHEMISTRY OF SOME ORGANIC COMPOUNDS

4. DEFINITION OF STEREOCHEMISTRY
Greek term stereos = solid.
Science of organic chemistry.
Deals with structure in three dimensions.
Based on the relationship between molecular structure and properties.
Contd.

5. Study of the static and dynamic aspects of the three dimensional shape of molecules.
Provides foundation for understanding structure and mechanism in organic chemistry.

6. ABOUT ORGANIC COMPOUNDS
Hydrocarbons
(H & C elements)
Aliphatic
Aromatic
Alkanes
Alkenes
Alkynes
Cyclic
aliphatic H H
Benzene H C C H C C H H C H H H
Acetylene H
Ethene
Methane
Cyclohexane

7. HISTORY Beginning of Organic Stereochemistry
n French Physicist Jean-Baptiste Biot
(1815)
n Found certain organic compounds /
molecules rotate the plane of the polarized
light in solution or in gas.
n This activity is called as Optical Activity.
Contd.

8. n Describe optical activity is due to the
Louis Pasteur (1848)
n Describe optical activity is due to the
presence of some dissymmetric grouping
of atoms in a molecule.
n Experiments made on tartaric acid.
n Confirmed asymmetric grouping (Chiral
carbon atom) is required for optical
activity.
Jacobus H. van’t Hoff and J.A. LeBel (1874)
n Laid foundation of stereochemistry
n Postulated asymmetric carbon model
(tetrahedral arrangement)
Contd.

9. n Concept of three dimensional structure
n Chemistry Nobel Prize 1901 (First
recipient of prize)
n Shape and size of Tetrahedral carbon
atom in methane
n Proposal of tetrahedral carbon base on
n Evidence of Isomer number (Greek:
isos = identical, meros = part)
n Only the tetrahedral structure
for methane agrees with the evidence
of isomer number.
Contd.

10. Tetrahedral carbon shape and size

11. CHIRAL CARBON ATOM Greek word cheir = hand
A chiral object is not superimposable on its mirror image.
Any object that cannot be superimposed on its mirror image is said to chiral i.e. it possesses the property of ‘handedness’ (our left hand is the mirror image of our right hand but the two hands are not superimposable) [to superimpose the two hands plane has to be changed].
Chiral objects – hand gloves, shoes.

12. CHIRALITY/ASYMMETRY Chirality or asymmetry
Chirality = handedness/phenomenon shown by chiral carbon atom.
Lactic acid

13. CHIRALITY/ASYMMETRY Lactic acid
Molecules that are not superimposable on their mirror images are chiral.
A carbon atom to which four different groups are attached is called chiral center/chiral carbon.

14. ISOMERS Greek word isos = identical, meros = part
Isomers are different compounds that have the same molecular formula.
Isomers are non-identical molecules with the same atomic composition.

15. Constitutional isomers Stereoisomers
Different functional group
Stuructural isomers
Positional isomers
isomers O H C H C H C H 3 C H 3 3 3 C O H C O CH H C CH 2 3 CH C H 2 3 Br OH CH
2-Methylpropane Br 3 (C H )
o-Hydroxybenzaldehyde 4 10
2-Bromotoluene
3-Bromotoluene
Benzoic acid
n-Butane (C H Br ) (C H O ) (C H Br ) (C H O ) 7 7 7 6 2 (C H ) 7 7 7 6 2 4 10

16. Isomers of Glyceraldehyde (C3H6O3)
ISOMERISM
ism suffix forming nouns – an action or its results
The phenomenon whereby a single molecular formula can represent more than one compound is called isomerism.
Isomers of Glyceraldehyde (C3H6O3)

17. STEREOISOMERS STEREOISOMERISM
Isomers studied with three dimensional aspects are called as stereoisomers.
STEREOISOMERISM
The phenomenon whereby a single molecular formula can represent more than one compound in three dimensions is called stereoisomerism.

18. STEREOISOMERISM
Stereoisomerism occurs in molecules with identical structures, by which is meant they have the same order of atoms but differ in their spatial arrangement (configuration) in relation with chiral carbon atom.

19. CLASSIFICATION OF STEREOISOMERS
Configurational
stereoisomers
Conformational
Enantiomers
Diastereomers
Geometric isomers
Relative isomers
Absolute configuration
Optical isomers
Meso structures
(mirror images)
(non superimposable)
(not mirror images)
Dextro ( d
) (+)
Levo l
)(-)
Racemic dl
) (±)
cis
trans Z E
Erythro
Threo D L R S

20. CONFIGURATION Configuration - manner of arrangement/ shape/outline.
Arrangement of atoms that characterises a particular stereoisomer is called configuration.
Probability.

21. CONFIGURATIONAL STEREOISOMERS
Configurational stereoisomers – manner of arrangement/shape/outline/attachment of atoms in three dimensions.
Configurational stereoisomers, interconverted by inversion (turning-inside-out) at a chiral center.

22. ENANTIOMERS 2,3-Dichloropentane
Enantiomers Greek word enantio = opposite
Isomers that are mirror image of each other are called enantiomers.
Two stereoisomers that are not superimposable mirror image of each other.
2,3-Dichloropentane

23. 1,2-Dichlorocyclopentane
Enantiomers have identical chemical properties except towards optically active reagents.
Have identical physical properties, except for the ‘chiral’ direction of rotation of the plane of polarised light.

24. ENANTIOMERISM
The phenomenon of formation of enantiomers is called enantiomerism.

25. OPTICAL ISOMERS Optical visual; of or according to optics.
Optic of eye or sight.
Some substances rotates the plane of polarization and such substances are called optically active.
If the rotation of plane is to the right (clockwise) the substance is dextrorotatory (Latin: dexter = right) denoted by (d) or (+).
If the rotation of plane is to be left (counter clockwise) the substance is levorotatory (Latin: laevus = left) denoted by (l) or (-).

26. OPTICAL ISOMERS The two forms are called optical isomers.
Mirror image non superimposable.
Optical isomers also called enantiomers.
(d) or (+) Lactic acid (l) or (-) Lactic acid
The phenomenon is called optical isomerism.

27. OPTICAL ISOMERS
(d) or (+) Glyceraldehyde (l) or (-) Glyceraldehyde

28. RACEMIC MODIFICATION
A mixture of enantiomers is called a racemic modification.
Racemic modification is optically inactive if the mixture is 50:50.
When enantiomers are mixed together, the rotation caused by a molecule of one isomer is exactly cancelled by an equal and opposite rotation caused by a molecule of its enantiomer.
(dl) or (±) – lactic acid.

29. DIASTEREOMERS Dia means two. For more than one chiral centers.
Stereoisomers that are not mirror images of each others are called diastereomers.
Diastereomers are stereoisomers but not enantiomers.

30. DIASTEREOMERS 2,3-Dichloropentane (not mirror image)
* chiral carbon atom

31. DIASTEREOMERS Diastereomers have different physical properties.
Chemical properties are not identical.
May be optically inactive.
The phenomenon of formation of diastereomers is called diastereoisomerism.

32. MESO STRUCTURES Molecules have symmetric end – the term Meso is used.
Meso means combining form middle, intermediate.
A Meso compound is one whose molecules are supeimposable on their mirror images even though they contain chiral centers.
A Meso compound is optically inactive.

33. MESO STRUCTURES 2,3-Dichlorobutane
Superimposable; turned end-for-end a Meso compound (in same plane).

34. MESO STRUCTURES
In meso structure one half of the molecule is the mirror image of the other half.
2,3-Dicholorobutane
In meso compounds two chiral centers have opposite configuration.

35. GEOMETRIC ISOMERS Science of properties and relations of lines (bond).
Not require chiral carbon atom.
The particular kind of diastereomers that owe their existence to hindered rotation about double bonds are called geometric isomers.

36. GEOMETRIC ISOMERS The configurations of the isomeric 2-butenes
cis-2-Butene trans-2-Butene
(not mirror image)
cis – (Latin: on this side or same side or identical groups)
trans – (Latin: across or opposite)

37. GEOMETRIC ISOMERISM
The phenomenon of forming geometric isomers is called geometric isomerism.
A pair of geometric isomers, are, then diastereomers, as they are not mirror images.
Geometric isomers, interconverted – in principle – by rotation about a double bond.
Geometric isomers have different physical and frequently different chemical reactivities.

38. GEOMETRIC ISOMERS CYCLIC COMPOUNDS
cis-Decalin cis-Decalin
trans-Decalin trans-Decalin

39. GEOMETRIC ISOMERS Z AND E Z German : Zusammen = together, same side
E German : entgegen = opposite, opposite side
(Z)-1-Bromo- (E)-1-Bromo-
1-chloropropene 1-chloropropene
Priority
CH3 > H
Br > Cl

40. RELATIVE CONFIGURATION
Erythro and Threo isomers
Used for molecules having non-symmetric ends.
Generally used in Fischer projection.
Not mirror images.
Resembles with diastereomers.

41. Erythro and Threo isomers
Two like functional groups
Same side Opposite side
(Erythro) (Threo)
Erythrose Threose

42. RELATIVE CONFIGURATION D and L isomers
Used for molecules having non symmetric ends.
Orientation of –H and –OH on chiral carbon which is farther most from the primary chiral carbon.
Generally used in Fischer projection.

43. D and L isomers
D-Glucose L-Glucose

44. ABSOLUTE CONFIGURATION
R and S isomers
Suggested by Cahn, Ingold and Prelog (CIP).
R Latin : rectus = right
S Latin : sinister = left
R.S. Cahn (The Chemical Society, London)
Sir Christopher Ingold (University College, London)

45. R and S isomers
V. Prelog (Eidgenossiche Technische Hochschule, Zurich)
CIP system most frequently used for designating absolute configurations of chiral compounds.

46. R and S isomers
Sequence rules
1) Arrange the ligands associated with an element of chirality into order of priority.
Priority Rules
Higher atomic number is given higher priority.
Higher atomic mass is given higher priority.

47. [(R, R)] or (S, S)] > [(R, S) or (S, S)].
R and S isomers
cis > trans
[(R, R)] or (S, S)] > [(R, S) or (S, S)].
I > Br > Cl
2) View the molecule with the lowest priority group pointing away from the viewer.
3) Count the remaining ligands in order of decreasing priority.

48. Bromochloroiodomethane
R and S isomers
If the path traced is clockwise, the (R) absolute configuration is assigned.
If the path traced is counterclockwise, the (S) absolute configuration is assigned.
R S
Bromochloroiodomethane
Priority
I > Br > Cl > H

49. R S Atoms priority I > Br > Cl > H At. No. 53 35 17 1 At. Wt.
R and S isomers
R S
Priority
I > Br > Cl > H
Atoms priority
I > Br > Cl > H
At. No. 53 35 17 1
At. Wt.
126.91
79.91
35.06
1.008

50. (-)-2-Butanol (+)-2-Butanol Relative configuration
R and S isomers
(-)-2-Butanol (+)-2-Butanol
Relative configuration
(R)-2-Butanol (S)-2-Butanol
Absolute configuration
Priority
HO > CH3CH2 > CH3

51. Forms of representing organic compounds
Cyclic
Noncyclic
compounds
compounds
Ethane
Empirical
Molecular
Structural
formula
formula
formula CH 3 C H 2 6
(C:H; 1:3)
Contd.

52. Ethane Structural Newman Chain formula projection (normal chain)
Fischer formula
Andiron formula
(Sawhorse drawing)
Ball & Stick
formula
Dimensional formula
(Wedge-and-dash
drawing)
Newman
projection
Electronic H C
Ethane Structural 3

53. Cyclic compounds Cyclohexane Emperical formula Molecular Structural CH2 C 6 H 1
Contd.

54. Cyclohexane structural formula Chain formula Haworth projection
Wedge-and-
dash drawing
Ball and
Stick formula
Newman
Chair
formula
Polygon H

55. Conformational
Stereoisomers
Eclipsed
Staggered
Skew
Anti
Gauche
Chair
Boat
Twist boat
Half chair

56. Eclipsed conformation ethane
CONFORMATIONS
Different arrangements of atoms that can be converted into one another by rotation about single bonds are called conformations.
Eclipsed conformation ethane

57. Staggered conformation Ethane
CONFORMATIONS
Staggered conformation Ethane
The infinity of intermediate conformations are called skew conformations.

58. Anti conformation n-Butane
CONFORMATIONS
Anti conformation n-Butane

59. Gauche conformation n-Butane
CONFORMATIONS
Gauche conformation n-Butane
Van der Waals forces
Repulsive (Steric repulsion)
Strain (Steric strain)
Strain (Torsional strain)
Shielding / Crowding of CH3 groups.
Mirror images (Conformational) enantiomers
Anti and Gauche are not mirror images (conformational) diastereomers

60. CONFORMATIONAL ISOMERS / CONFORMERS
Different conformations corresponding to energy minima are called conformational isomers or conformers.
Conformational isomers are interconvertable by rapid rotations about one or more single bonds (C-C).

61. Potential energy changes during rotation about the carbon-carbon single bond of ethane.

62. Potential energy changes during rotation about the C(2)-C(3) bond of n-butane.

63. Potential energy relationships among conformations of cyclohexane.

64. CONFORMATIONS OF CYCLOHEXANE
Chair Boat
Twist-boat Half-chair

65. CHAIR CONFORMER OF CYCLOHEXANE

66. CHAIR FORM MOST STABLE CONFORMATION
Symmetrical
Compact
Completely free of strain-angle/torsional/ Van der Waals forces (strain/torsion/repulsion).
Every angle is the tetrahedral angle.
Every C-C bond precise staggering.
Energy minima
No crowding of hydrogen atoms.

67. Chair Conformation of Cyclohexane

68. Boat conformation of Cyclohexane

69. Sawhorse projection formula: Ethane

70. Newman projection formula: Ethane(Staggered)
Anti conformation; 180 o tortional angle

71. Sawhorse &Newman projection formula: Ethane

73. Conformational Isomerism in Cyclohexane:
Cyclohexane exists in two puckered conformations, the boat and chair forms, that have tetrahedral bond angles. The boat form is less stable and
not preferred because of interactions between the two end or flagpole
carbons and because the hydrogens on the other adjacent carbons are
eclipsed. In the preferred chair form, atoms on adjacent carbons are
staggered and there are no flagpole type interactions. There are two
orientations of hydrogens in the chair conformation. Axial hydrogens are
oriented directly above or below the "plane" of the ring in an alternating
arrangement. Equatorial hydrogens protrude out along the perimeter of the ring.

75. CHAIR FORM MOST STABLE CONFORMATION
Everything just fits (geometrical demands).
Architectural perfection.
Cyclohexane chairs in the structure of diamond.
Diamond most stable form of carbon and the hardest substance known.
Replacing one methylene group with oxygen make up the most abundant building block of the organic world, D-glucose.

76. CHAIR FORM MOST STABLE CONFORMATION
Appearance of chair form in diamond

77. CHAIR FORM MOST STABLE CONFORMATION
a-D-(+)-Glucopyranose
Appearance of chair form in

78. GLUCOSE NOMENCLATURE
FISCHER PROJECTION

79. FISCHER PROJECTION

80. HAWORTH CHAIR
PROJECTION CONFORMER

81. HAWORTH CHAIR
PROJECTION CONFORMER

82. HAWORTH CHAIR
PROJECTION CONFORMER

83. HAWORTH CHAIR
PROJECTION
CONFORMER

84. Ethane
Make a model of ethane, C2H6. Rotate the two carbons relative to each other around the carbon-carbon bond. Make the staggered and eclipsed conformations.

85. Bromoethane

89. Geometrical isomerism in oximes

90. STEREO CHEMISTRY OF SOME DRUG MOLECULES

91. CONFUSING ‘C’ Chemistry Carbon Compounds Configurations Chirality
Conformations

92. THANK YOU