Stereochemistry

Stereochemistry is the systematic presentation of a specific field of science and technology that traditionally requires a short preliminary excursion into history. Stereochemistry is the ‘chemistry of space ‘, that is stereochemistry deals with the spatial arrangements of atoms and groups in a molecule.

Stereochemistry can trace its roots to the year 1842 when the French chemist Louis Pasteur made an observation that the salts of tartaric acid collected from a wine production vessel have the ability to rotate plane-polarized light, whereas the same salts from different sources did not have this ability. This phenomenon is explained by optical isomerism.

1. Stereochemistry and Drug Action

2. Content Introduction Concept and classification of isomerism Molecular isomerism Chirality and molecular symmetry Group theoretical interpretation of chirality group Conformational analysis Practice problems Suggested Book : Ernest Ludwig Eliel; Samuel H. Wilen; Lewis N. Mander - Stereochemistry of organic compounds-Wiley-Interscience

3. Introduction Thalidomide (brand name Thalomid) is a sedative drug discovered in 1953 by Grünenthal GmbH and marketed in 1957 in West Germany. It was proclaimed a "wonder drug" for insomnia, coughs, colds and headache. The drug has been prescribed to many pregnant women in order to relieve pregnancy nausea. The total number of people affected by use during pregnancy is estimated at 10,000, of which about 40% died around the time of birth.

4. Significance of the knowledge of stereochemistry The drug was responsible for teratogenic deformities in children Thalidomide exists in two mirror-image forms: it is a racemic mixture of ( R )- and ( S )-enantiomers. The ( R )-enantiomer, shown in the figure, has sedative effects, whereas the ( S )-isomer is teratogenic. ( S )-(−)-thalidomide ( R )-(+)-thalidomide

5. Some other examples Drug R-enantiomer S-enantiomer Ibuprofen Slow acting Fast acting Prozac Anti-depressent Helps against migraine Naproxen Liver poison Arthritis treatment Methadone Opioid analgesic NMDA antagonist Dopa Biologically inactive Parkinson’s disease

6. Current scenario In pharmaceutical industries, 56% of the drugs currently in use are chiral products and 88% of the last ones are marketed as racemates consisting of an equimolar mixture of two enantiomers Chiral drug synthesis: 18 billion dollars annually (growing at rate of 9.04% per year) Prediction: 75% drugs will be sold as single enantiomer in coming years. Remdesivir

7. Purpose of the study New drug development Drug safety Pharmaceuticals Flavours Mimic nature

8. Concept of Isomerism Isomerism is a phenomenon in which certain compounds with the same molecular formula exist in different forms, as a result of their different organizations of atoms. The term isomer (from the Greek: “ isos ” meaning equal, same, and “ meros ” meaning part) describes the relationship between molecular arrangements that, although differing in chemical or physical properties, have a level of commonality (have the “same parts”). The concept of isomerism illustrates the fundamental importance of molecular structure and shape in organic chemistry.

9. Classification of Isomers

10. Constitutional (Structural) Isomers Constitutional (structural) isomers are isomers that differ in the sequence in which atoms are connected to one another, so they can contain different functional groups and/or bonding patterns (e.g., branching). There are five types of constitutional (structural) isomerism: chain isomerism positional isomerism functional isomerism metamerism tautomerism .

11. Chain (skeletal) isomers Chain (skeletal) isomers have the same molecular formula but differ in the order in which C-atoms are bonded to each other.

12. Position isomers Position isomers differ in the positions of some reference atom, group, or bond. Position isomerism in aromatic compounds occurs when the substituents are positioned on different parts of the benzene (or other aromatic) ring.

13. Functional isomers When substances have the same molecular formula (the same number of atoms of the same elements) but different functional groups.

14. Metamerism Metamerism is a type of structural isomerism in which molecular structures differ by the attachment of different groups to the same atom

15. T automerism Tautomerism is an ability of certain chemical compounds to exist as a mixture of two interconvertible isomers in dynamic equilibrium

16. Stereochemistry Stereochemistry is a study concerned with the spatial arrangements (three- dimensional configuration) of atoms and groups in molecules, and the effect of these arrangements on the molecules’ physical, chemical, and pharmacological behavior, as well as the direction and reaction rates. The prefix “stereo-”, borrowed from the Greek ( stereos ), means “solid and is used with reference to hardness, solidity, and “three-dimensionality” (3D). Isomers that differ in the relative atom or group arrangement in the space around one or more (e.g., carbon) atoms are known as stereoisomers.

17. History of Stereochemistry Christian Hyugens discover plane polarized light in 16 th century 1815 Biot discover that certain compounds rotate the plane of the plane polarized light 1847, Louis Pasteur discovered that two forms of Tartaric acid gives two opposite optical rotation 1874, Van’t Hoff and LeBel proposed that carbon with 4 attachments are tetrahedral 1894, Emil Fisher introduced the concept of asymmetric induction 1912, G. Bredig and P.S. Fisk first report the quinine mediated enantioselective reaction of benzaldehyde and hydrogen cyanide with 10% ee.

18. Classification of stereoisomers Conformational configurational isomers enantiomers and diastereomers Conformational isomers Configurational isomers (Differ by rotation around single bond) (Differ by their configuration)

19. Nature of Configurational isomers Configurational isomers are stereoisomers that do not readily interconvert under normal conditions and thus can be separated and isolated. Interconversion in these stereoisomers usually involves a bond breaking process. Configurational isomerism can exist as a result of either rigidity in a molecule (geometrical isomers) or right- or left- handed arrangement of atoms around the carbon atom (optical isomers).

20. Enantiomers and diastereomers Enantiomers (Non-superimposable mirror image) Diastereomers (Non-superimposable non-mirror image)

21. Geometrical Isomerism Geometrical isomerism is a form of stereoisomerism describing the orientation of functional groups within a molecule that occurred as a result of restricted rotation, and different configurations can be interconverted only by breaking and reforming covalent bonds. A large variety of geometric isomers may be broadly classified as follows: Compounds having double bonds Cyclic compounds (including homocyclic, heterocyclic, and fused ring systems) Compounds with restricted rotation about a single bond

22. Compounds having double bonds Cis/trans or E/Z isomers Geometric (E/Z or cis/trans) Isomers Resulting from Double Bonds “E ” and “Z ” come from the German terms “ entgege n” and “ zusammen ”, meaning “apart” and “together,” respectively. If the higher priority groups are on the opposite sides of the double bond (or cyclic structure), the isomer is denoted by the descriptor, E (or trans-isomer). Otherwise if higher-ranking substituents are on the same side of the double bond (or cyclic), the Z descriptor must be used

23. Geometric ( cis/trans ) Isomers of Monocyclic Systems Geometrical isomerism is observed also in certain bis-substituted (and higher substituted) homocyclic and heterocyclic compounds as well as in fused ring systems. In general, if any two sp3 carbons in a ring have two different substituent groups (not counting other ring atoms), then stereoisomerism is possible. Bis- substituted cycloalkane stereoisomers, for example, may be designated by nomenclature prefixes such as cis and trans , which describe the relative orientation of substituents attached to two different members of the cycle.

24. The Effect of Geometric (cis/trans) Isomerism on Physical Properties Can have very different physical properties, such as different boiling and melting points

25. Geometric (cis/trans) Isomerism of Fused Systems Fused rings share two adjacent carbon atoms and the bond between them. two cyclohexane rings fused together giving a bicyclic system decalin The skeleton of steroids consists of three fused cyclohexane rings and one cyclopentane ring

26. Stereochemistry of steroids trans-trans-trans (most natural and synthetic steroids have this skeleton, e.g., 5α-dihydrotestosterone) cis-trans-trans (some natural steroids have this skeleton, e.g., cholic acids) cis-trans-cis (few natural steroids have this skeleton, like cardiac glycosides) 5α-dihydrotestosterone an endogenous androgen sex steroid and hormone Cholic acid Cholic acid (KOE lik AS id) is used to treat bile acid synthesis disorders Cardiac glycosides a class of organic compounds that increase the output force of the heart and decrease its rate of contractions by acting on the cellular sodium- potassium ATPase pump

27. Geometrical isomerism in Bridge system Bridged rings (or bridged systems) share two nonadjacent carbon atoms (so-called “bridgehead carbons”) and one or more carbon atoms between them. If a substituent is placed on one of these atoms of a bridged ring system, a special type of isomerism occurs: endo-exo isomerism The prefix endo- is reserved for the isomer in which a substituent is attached to the highest numbered bridge and is orientated toward the lowest numbered bridge (a substituent is located closest or “syn-” to the longest bridge). The prefix exo- is given for the isomer in which a substituent is orientated away from the lowest numbered bridge (a substituent is located farthest or “anti-” to the longest bridge)

28. Bridged ring and fused ring natural products Strychnos family of Corynanthe alkaloids Neurotoxines a component of many essential oils

29. Significance of Cis-trans isomerism in biological system Chemistry of Vision Interconversion of 11-cis- and 11- trans-retinal isomers This process gives out a signal to nerve cells and hence to the brain Role of cis/trans isomerism in vision

30. Stereochemistry and Drug Action

31. Stereochemistry Stereochemistry is a study concerned with the spatial arrangements (three- dimensional configuration) of atoms and groups in molecules, and the effect of these arrangements on the molecules’ physical, chemical, and pharmacological behavior, as well as the direction and reaction rates. The prefix “stereo-”, borrowed from the Greek ( stereos ), means “solid and is used with reference to hardness, solidity, and “three-dimensionality” (3D). Isomers that differ in the relative atom or group arrangement in the space around one or more (e.g., carbon) atoms are known as stereoisomers.

32. Concept of Chirality and Optical Isomerism Chirality is defined as the geometric property of a rigid object (e.g., a molecule or drug) that is not superimposable with its mirror image. Chirality is a property of matter found throughout biological systems, from the basic building blocks of life such as amino acids, carbohydrates, and nucleotides to the layout of the human body, and it is often illustrated with the idea of left- and right-handedness. Chirality in drugs and natural products most often originates from a carbon atom attached to four different substituents (known also as a chiral center or stereogenic center) Other structural (stereogenic) features can give rise to chirality, including quadrivalent chiral atoms, tervalent chiral atoms, restricted rotation, and helical shape

33. Plane-Polarized light

34. Plane-Polarized lights through certain compounds

35. Plane-Polarized lights through certain compounds

36. Plane-Polarized lights through certain compounds

37. Enantiomers (Optical Isomers) Two isomers are called enantiomers or optical isomers if they are mirror images of each other, have the same chemical and physical properties, and differ in their behavior toward the plane polarized light. Such a phenomenon is known as enantiomerism or optical isomerism Enantiomers have exactly the same energy; solubility in typical achiral solvents; identical physical constants, such as melting points and boiling points; as well as nuclear magnetic resonance (NMR), infrared (IR) spectra, and so on. Their chemical properties, including both the qualitative reaction rates and the quantitative reaction rates are identical when reacting with achiral chemical species. Enantiomers are extremely important especially in biological and medicinal chemistry. For example, the pain reliever ibuprofen exists as two enantiomers, but only one of them is effective (the S-isomer) in treating pain

38. Optical Activity and Optical Purity Substances that rotates the plane of a plane polarized light is called an optically active compound, and the property by virtue of which it rotates the plane polarized light is called optical activity. The amount (in degrees) that a chiral material will rotate light is called the optical rotation. A substance can rotate light either in the clockwise direction (known as the dextrorotary or (+)- form) or in the opposite (anti-clockwise) direction (known as the levorotatory or (-)-form). The specific rotation of a compound is measured by a polarimeter consisting of a source of light, Nicol prism (polarizer), a polarimeter tube containing the solution of the chiral compound, and another Nicol prism (analyzer).

39. Some examples Naturally occurring alkaloid nicotine that constitutes approximately 0.6–3.0% of the dry weight of tobacco is levorotatory [(-)-nicotine] with a specific rotation of [α]D ¼ -166.4 o . Made in small amounts by the human body alpha-lipoic acid (thioctic acid), known as a superior antioxidant, which converts glucose (blood sugar) into energy, is R-dextro or (+)-form with a specific rotation of [α]D ¼ +120 o . Orally active penicillin antibiotic phenoxymethylpenicillin (penicillin V) with a strong antimicrobial activity occurs in nature in its (+)-form having a specific rotation of [α]D ¼ +223 o S-(+)-Carvone with a specific rotation of [α]D = +62.5 o is most abundant in the oils from dill seed oil (from Anethum graveolens ) and the seeds of caraway ( Carum carvi ); therefore, it smells like caraway. Spearmint oil (Mentha spicata) is a major source of naturally produced R-(-)-carvone that smells therefore like spearmint, and it rotates the plane polarized light to the same extent as S-(+)-carvone but in the opposite direction [α]D = -62.5 o .

40. Chiral molecules

41. Chiral molecules

42. Optically inactive

43. Symmetry and Group Theory The symmetry properties of molecules and how they can be used to predict vibrational spectra, hybridization, optical activity, etc.

44. Symmetry Elements Symmetry elements are mirror planes, axis of rotation, centers of inversion, etc. A molecule has a given symmetry element if the operation leaves the molecule appearing as if nothing has changed (even though atoms and bonds may have been moved.)

45. Symmetry Elements Element Symmetry Operation Symbol Identity E n -fold axis Rotation by 2π/ n C n Mirror plane Reflection σ Center of in- Inversion i version n -fold axis of Rotation by 2π/ n improper rotation followed by reflection perpendicular to the axis of rotation S n

46. Identity, E All molecules have Identity. This operation leaves the entire molecule unchanged. A highly asymmetric molecule such as a tetrahedral carbon with 4 different groups attached has only identity, and no other symmetry elements.

47. n -fold Rotation Water has a 2-fold axis of rotation. When rotated by 180 o , the hydrogen atoms trade places, but the molecule will look exactly the same.

48. n -fold Axis of Rotation Ammonia has a C 3 axis. Note that there are two operations associated with the C 3 axis. Rotation by 120 o in a clockwise or a counterclockwise direction provide two different orientations of the molecule.

49. Mirror Planes The reflection of the water molecule in either of its two mirror planes results in a molecule that looks unchanged.

50. Mirror Planes The subscript “v” in σ v , indicates a vertical plane of symmetry. This indicates that the mirror plane includes the principal axis of rotation (C 2 ).

51. Mirror Planes The benzene ring has a C 6 axis as its principal axis of rotation. The molecular plane is perpendicular to the C 6 axis, and is designated as a horizontal plane, σ h . 6 C .

52. Mirror Planes The vertical planes, σ v , go through the carbon atoms, and include the C 6 axis. The planes that bisect the bonds are called dihedral planes, σ d . C 6 .

53. I n v e r sion The inversion operation projects each atom through the center of inversion, and across to the other side of the molecule.

54. Improper Rotation An improper rotation is rotation, followed by reflection in the plane perpendicular to the axis of rotation.

55. Improper Rotation The staggered conformation of ethane has an S 6 axis that goes through both carbon atoms.

56. Improper Rotation Note that an S 1 axis doesn’t exist; it is same as a mirror plane.

57. Improper Rotation Likewise, an S 2 axis is a center of inversion.

58. Point Groups Molecules are classified and grouped based on their symmetry. A point group contains all objects that have the same symmetry elements .

59. Point group: C 2v

60. Point group: D 2h

61. Staggered ethane

62. Eclipsed ethane

63. Applications of Group Theory Predicting polarity of molecules. A molecule cannot have a permanent dipole moment if it has a center of inversion belongs to any of the D point groups belongs to the cubic groups T or O Predicting chirality of molecules. Chiral molecules lack an improper axis of rotation ( S n ), a center of symmetry ( i ) or a mirror plane ( σ ). Predicting the orbitals used in σ bonds. Group theory can be used to predict which orbitals on a central atom can be mixed to create hybrid orbitals.

64. Applications of Group Theory Predicting the orbitals used in molecular orbitals . Molecular orbitals result from the combining or overlap of atomic orbitals, and they encompass the entire molecule. Determining the symmetry properties of all molecular motion (rotations, translations and vibrations). Group theory can be used to predict which molecular vibrations will be seen in the infrared or Raman spectra.

65. Practice problems

66. Stereochemical Representations

67. Wedge-Hatched Bond Structure

68. Wedge-Hatched Bond Structure

69. Fischer Projection

70. Fischer Projection

71. Sawhorse Projection

72. Sawhorse Projection

73. Newman Projection

74. The Cahn-Ingold-Prelog (CIP) System The system used was devised by R. S. Cahn Sir Christopher Ingold Vladimir Prelog The CIP system provides a set of rules which allows us to define a set of stereochemical configurations of any stereocenters using the designations

75. R/S Nomenclature

76. Rule -1

77. Ru l e - 2

78. Ru l e - 3

79. Nomenclature in Fischer Projection

80. Assign the absolute configuration of the stereogenic centers of the following molecules 1’ 2’ 4’

81. Assign the absolute configuration of the stereogenic centers of the following molecules

82. Assign the absolute configuration of the stereogenic centers of the following molecules

83. Assign the absolute configuration of the stereogenic centers of the following molecules

84. Stereochemistry and Drug Action

85. Assign the absolute configuration of the stereogenic centers of the following molecules

86. Assign the absolute configuration of the stereogenic centers of the following molecules

87. Fischer Proj e ction to Sawh o rse Projection

88. Sawh o rse Projection to Fis c her Projection

89. Sawhor s e P r ojection to Newman Projection And then Fischer Projection

90. Fischer P r ojection to Newman Pro j ection and then Sawhorse Projection

91. Fischer P r ojection to Flying Wedge Projection

92. Flying Wedge P r ojection to Fischer Projection CH3 CH3 H OH Br H S R S R Identify the vertical line Identify the other groups whether in the left-side of the vertical line or right side If left side: below the plane groups will be in the left side If right side of the vertical line: below the lane group will be in the right side

93. Conformational analysis of cycloalkanes Steric strain Torsional strain Angle strain

94. Conformational analysis of cyclopropane Bond angle = 60 o Expected angle = 109 o 28’ Angle strain = Bond angle as per the hybridization – actual bond angle 2 6 H-H eclipsing interaction

95. Conformational analysis of cyclopropane Large angle strains is compensated slightly through bent bonds

96. Conformational analysis of cyclobutane cyclobutane Eight torsional strains Reduces some eclipsing strains by folding which causes additional angle strains Bond angle = 90 o

97. Conformational analysis of cyclopentane Cyclopentane Bond angle 108 o Angle strain very low 10 eclipsing strain or torsional strain which is very high (10 Kcal/mol) E n v elope Twist (Half-Chair) 6 Kcal/mol 4 C atoms in plane 3 C atoms in plane

98. Conformational analysis of cyclohexane 12 H-H eclipsing strains Ring strain = 20 Kcal/mol Cyclohexane avoids torsional interactions by adopting non-planar conformations, which reduces the bond angle to that of a perfect tetrahedron (~109 o 28’)

99. Different conformations of cyclohexane 1. Chair conformation Most stable conformation as it has no tortional strain as all H’s are staggered to each other

100. Different conformations of cyclohexane 2. Boat form Minimum angle strain Ring strain = 7 Kcal/mol 3. Half chair form Ring strain = 10.8 Kcal/mol Some angle strain Some tortional strain

101. Different conformations of cyclohexane 4. Twist-boat form Ring strain = 5.5 Kcal/mol minimum angle strain Vander walls strain is lowered by twisting