1. Molecules in three dimensions
Stereochemistry
of organic compounds
Molecules in three dimensions

2. Staggered conformation Eclipsed conformation
Alkanes conformation
Stereochemistry concerned with the 3-D aspects of molecules
 bonds are cylindrically symmetrical
Rotation is possible around C-C bonds in chain molecules
Staggered conformation
Eclipsed conformation

3. Staggered conformation
Ethane
Conformation- Different arrangement of atoms resulting from rotation around σ bond
Conformations can be represented in 2 ways:
Staggered conformation

4. Torsional Strain We do not observe perfectly free rotation
There is a barrier to rotation, and some conformers are more stable than others
Staggered- most stable: all 6 C-H bonds are as far away as possible
Eclipsed- least stable: all 6 C-H bonds are as close as possible to each other

5. Conformers energy

6. Conformations of Other Alkanes
The eclipsed conformer of propane has 3 interactions: two ethane-type H-H interactions, and one H-CH3 interaction

7. Conformations of Other Alkanes
• Conformational situation is more complex for larger alkanes
• Not all staggered conformations has same energy, and not all
eclipsed conformations have same energy

8. Anti conformation- methyl groups are 180˚ apart
Gauche conformation- methyl groups are 60˚ apart
Which is the most energetically stable?

9. Steric Strain
Steric strain- repulsive interaction occurring between atoms that are forced closer together than their atomic radii allow

10. Energy cost for torsional and steric strain

11. Cycloalkanes conformation

12. Cycloalkanes conformation
Cycloalkanes are less flexible than chain alkanes
Much less conformational freedom in cycloalkanes

13. Stability of Cycloalkanes: Ring Strain
Rings larger than 3 atoms are not flat
Cyclic molecules adopt nonplanar conformations to minimize angle strain and torsional strain by ring-puckering
Larger rings have many more possible conformations than smaller rings and are more difficult to analyze

14. Stability of Cycloalkanes: The Baeyer Strain Theory
Baeyer (1885): since carbon prefers to have bond angles of approximately 109°, ring sizes other than five and six may be too strained to exist
Rings from 3 to 30 C’s do exist but are strained due to bond bending distortions and steric interactions

15. Types of Strain
Angle strain - expansion or compression of bond angles away from most stable (109º)
Torsional strain - eclipsing of bonds on neighboring atoms
Steric strain - repulsive interactions between nonbonded atoms in close proximity

16. Cyclopropane conformation
3-membered ring must have planar structure
Symmetrical with C–C–C bond angles of 60°
Requires that sp3 based bonds are bent (and weakened)
All C-H bonds are eclipsed

17. Bonds of cyclopropane are bent
In cyclopropane, the C-C bond is displaced outward from internuclear axis

18. Cyclobutane conformation
Cyclobutane has less angle strain than cyclopropane but more torsional strain because of its larger number of ring hydrogens
Cyclobutane is slightly bent out of plane - one carbon atom is about 25° above
The bend increases angle strain but decreases torsional strain

19. Cyclopentane conformation
Planar cyclopentane would have no angle strain but very high torsional strain
Actual conformations of cyclopentane are nonplanar, reducing torsional strain
Four carbon atoms are in a plane
The fifth carbon atom is above or below the plane – looks like an envelope

20. Conformations of Cyclohexane
Substituted cyclohexanes occur widely in nature
The cyclohexane ring is free of angle strain and torsional strain
The conformation has alternating atoms in a common plane and tetrahedral angles between all carbons
This is called a chair conformation

21. Conformations of Cyclohexane

22. How to Draw Cyclohexane

23. Axial and Equatorial Bonds in Cyclohexane
The chair conformation has two kinds of positions for substituents on the ring: axial positions and equatorial positions
Chair cyclohexane has six axial hydrogens perpendicular to the ring (parallel to the ring axis) and six equatorial hydrogens near the plane of the ring

24. Axial and Equatorial Bonds
Each carbon atom in cyclohexane has one axial and one equatorial hydrogen
Each face of the ring has three axial and three equatorial hydrogens in an alternating arrangement

25. Drawing the Axial and Equatorial Hydrogens

26. Conformational Mobility of Cyclohexane
Chair conformations readily interconvert, resulting in the exchange of axial and equatorial positions by a ring-flip

27. Cyclohexane Conformations
Chair conformation is the most stable
Boat is the least stable conformation (29 kJ/mol) because of steric and torsional strain

28. Conformations of Monosubstituted Cyclohexanes
Cyclohexane ring rapidly flips between chair conformations at room temp.
Two conformations of monosubstituted cyclohexane aren’t equally stable.
The equatorial conformer of methylcyclohexane is more stable than the axial by 7.6 kJ/mol

29. 1,3-Diaxial Interactions
Difference between axial and equatorial conformers is due to steric strain caused by 1,3-diaxial interactions
Hydrogen atoms of the axial methyl group on C1 are too close to the axial hydrogens three carbons away on C3 and C5, resulting in 7.6 kJ/mol of steric strain

30. Relationship to Gauche Butane Interactions
Gauche butane is less stable than anti butane by 3.8 kJ/mol because of steric interference between hydrogen atoms on the two methyl groups
The four-carbon fragment of axial methylcyclohexane and gauche butane have the same steric interaction
In general, equatorial positions give more stable isomer

31. Geometry of C=C bond Carbon atoms in a double bond are sp2-hybridized
Three equivalent orbitals at 120º in plane
Fourth orbital is atomic p orbital
Combination of electrons in two sp2 orbitals of two atoms forms  bond between them
Additive interaction of p orbitals creates a  bonding orbital
Occupied  orbital prevents rotation about -bond
Rotation prevented by  bond - high barrier, about 268 kJ/mole in ethylene

32. Rotation of  Bond Is Prohibitive
This prevents rotation about a carbon-carbon double bond (unlike a carbon-carbon single bond).
Creates possible alternative structures for substituted C=C bonds

33. Cis-trans Isomerism in Alkenes
The presence of a carbon-carbon double bond can create two possible structures – 2 stereoisomers
cis isomer - two groups on same side of the double bond
trans isomer - two groups on opposite sides

34. What molecules can exist as cis-trans stereoisomers
Are these molecules
cis-trans isomers?
And what about
these molecules?

35. Explain when C=C double bond exist in 2 forms: cis and trans

36. Assigning double bond configuration
Neither compound is clearly “cis” or “trans”
Substituents on C1 are different than those on C2
We need to define “similarity” in a precise way to distinguish the two stereoisomers
Cis, trans nomenclature only works for disubstituted double bonds
E/Z Nomenclature for 2, 3 or 4 substituted double bond

37. E, Z Stereochemical Nomenclature
High(C1)-Low(C1)-Hi(C2)-Low(C2)

38. E,Z Stereochemical Nomenclature
Priority rules of Cahn, Ingold, and Prelog (CIP rules) are used for assigning Higher and Lower substituents
Compare where higher priority groups are with respect to bond and designate as prefix
E -entgegen, opposite sides
Z - zusammen, together on the same side

39. Ranking Priorities: Cahn-Ingold-Prelog Rules
Must rank atoms that are connected at comparison point
Higher atomic number gets higher priority
I > Br > Cl > S > P > F > O > N > C > H

40. RULE 2
If atomic numbers are the same, compare at next connection point at same distance
Compare until something has higher atomic number
Do not combine – always compare

41. RULE 3
Substituent is drawn with connections shown and no double or triple bonds
Added atoms are valued with 0 ligands themselves

42. Assigning double bond configuration Cl > CH3 CH2OH > CH2CH3
(Z)-3-chloro-2-ethyl-2-buten-1-ol
21 March 2018
(E)-3-chloro-2-ethyl-2-buten-1-ol

43. Cis-trans isomerism in cycloalkanes
For cycloalkanes with 2 substituents at different carbons
– 2 orientations of substituents with respect to ring plane
are possible
They are also cis-trans (E, Z) stereoisomers

44. Chirality

45. What is chirality?
Some objects are not the same as their mirror images (technically, they have no plane of symmetry)
A right-hand glove is different than a left-hand glove. The property is commonly called “handedness”
Some organic molecules have handedness that results from substitution patterns on sp3 hybridized carbon

46. Molecules that have one carbon with 4 different substituents have a non-superimposable mirror image (these molecules are chiral)
Enantiomers = non-superimposable mirror image stereoisomers

47. Enantiomers of lactic acid Trying to superimpose these molecules

48. If an object has a plane of symmetry it’s the same as its mirror image
A plane of symmetry divides an entire molecule into two pieces that are exact mirror images
Achiral means that the object has a plane of symmetry
Molecules that are not superimposable with their mirror images are chiral (have handedness)
Hands, gloves are prime examples of chiral object
They have a “left” and a “right” version
Organic molecules can be Chiral or Achiral

49. Chiral and Achiral molecules

50. Chiral Centers
A point in a molecule where four different groups (or atoms) are attached to carbon is called a chiral center (or stereogenic center)
There are two ways that 4 different groups (or atoms) can be attached to one carbon atom
If two groups are the same, then there is only one way
A chiral molecule usually has at least one chiral center

51. Chiral Centers in Cyclic Molecules
Groups are considered “different” if there is any structural variation (if the groups could not be superimposed if detached, they are different)
In cyclic molecules, we compare by following in each direction in a ring

52. Drawing Chiral Centers H.E. Fischer (Nobel Prize 1902)
Chiral carbon in the plane
Carbon chain - vertical, bonds behind the plane
Substituents - horizontal, bonds above the plane
Fischer’s projection or
Fischer’s cross

53. Drawing Chiral Centers (Fischer convention)
mirror plane
(-) or l-glyceraldehyde (+) or d-glyceraldehyde
L (relative configuration) D (relative configuration)
(S) (absolute configuration) (R) (absolute configuration)

54. Drawing Chiral Centers
L-Glyceraldehyde
3 equivalent structures of the same enantiomer
(the same configuration of chiral carbon)

55. Optical Activity
Light restricted to pass through a plane is plane-polarized
A polarimeter measures the rotation of plane-polarized light that has passed through a solution of optically active molecule

56. Optical Activity Rotation, in degrees, is []
Clockwise (+) = dextrorotatory;
Anti-clockwise (-) = levorotatory
Plane-polarized light that passes through solutions
of achiral compounds remains in that plane
([α] = 0, optically inactive)
Solutions of chiral compounds rotate plane-polarized light and the molecules are said to be optically active

57. Measurement of Optical Rotation
Specific rotation is that observed for 1 g/mL in solution
in a cell with a 10 cm path using light from sodium metal vapor (589 nm)
The specific rotation of enantiomers is equal in magnitude
but opposite in sign:
(+)-lactic acid = +3.82; (-)-lactic acid = -3.82

58. Specific Rotation of Some Organic Compounds
Specific rotation depends on:
Wavelength of polarized light
Solvent used for dissolving sample

59. Specification of Absolute Configuration
Method
• Assign each group priority 1-4 according to Cahn-Ingold- Prelog rules
• Rotate the assigned molecule until the lowest priority group (4) is in the back, look at remaining 3 groups in a plane
• Clockwise movement is designated R (from Latin word Rectus for “right”)
• Counterclockwise is designated S (from Latin word Sinister for “left”)

60. Specification of Absolute Configuration

61. Specification of Absolute Configuration OH > COOH > CH3 > H

62. Conformation and configuration
Structures that can be interconverted simply by rotation about single bonds are conformations of the same molecule
Structures that can be interconverted only by breaking one or more bonds have different configurations, and are stereoisomers

63. Conformation and configuration

64. Conformation and configuration

65. Diastereomers
Molecules with more than one chiral center have mirror image stereoisomers that are enantiomers
In addition they can have stereoisomeric forms that are not mirror images, called diastereomers

66. All Stereoisomers of threonine

67. Diastereomers are similar, but they are not mirror images
Enantiomers have opposite configurations at all chiral centers
Diastereomers are opposite at some, but not all chiral centers
Enantiomers have the same physical properties (except specific rotation)
Diastereomers have different physical properties

68. Achiral Molecules with Chiral Carbons
Tartaric acid has two chiral centers and two diastereomeric forms
One form is chiral and one is achiral, but both have two chiral centers
An achiral compound with chiral centers is called a meso compound – it has a plane of symmetry

69. Meso Compounds

70. Meso Compounds Chiral molecule Achiral molecule Plane of symmetry
Mirror plane

71. Chiral Molecules without Chiral Carbons
Substituted allenes:
Substituted spiranes

72. Chiral Molecules without Chiral Carbons
Ortho-substituted biphenyl compounds

73. Racemic Mixtures and The Resolution of Enantiomers
A 50:50 mixture of two enantiomers does not rotate light – called a racemic mixture
The single enantiomers need to be separated or resolved from the mixture (called a racemate)

74. Pasteur’s Resolution of Enantiomers
From the solution containing both enantiomers they crystallized in distinctly different shapes – such an event is rare
A (50:50) racemic mixture of both crystal types dissolved together was not optically active
The optical rotations of equal concentrations of these forms have opposite optical rotations

75. Racemate Resolution via Diastereomers
Diastereomers have different physical properties

76. Racemate Resolution by Enzymes Lipase = enzyme = biocatalyst
racemic alcohol – identical physical properties mixture of two different compounds:
of enantiomers –separation by physical methods alcohol and its acetate –different
impossible physical properties –easy separation

77. Chirality in Nature

78. Biological properties of enantiomers
In caraway seeds in spearmint oil

79. Biological properties of enantiomers
D-Dopa L-Dopa
(R)-enantiomer (S)-enantiomer
No biological effect anti-Parkinsonian agent

80. Chiral recognition of enantiomers

81. Cholesterol * * * * * * * *
8 chiral carbons – how many stereoisomers possible?
Only one is synthesized in living organisms

82. The same molecular formula
Summary of Isomerism
The same molecular formula

83. Constitutional Isomers
C4H10
C2H6O
C2H9N

84. Stereoisomers

85. Stereoisomers