1. Lecture 10
Stereochemistry
Duncan Wardrop
November 26, 2012

2. Historical Importance of Stereochemisty
Once a molecule is asymmetric, its extension proceeds also in an asymmetrical sense. This concept completely eliminates the difference between natural and artificial synthesis. The advance of science has removed the last chemical hiding place for the once so highly esteemed vis vitalis.
Emil Fischer, 1894

3. different arrangement of atoms in space
Self Test Question
Which pair of molecules below are not stereoisomers?
geometrical
stereoisomers A B C D
conformational
stereoisomers
Stereoisomers:
same connectivity
different arrangement of atoms in space
identical
molecules
enantiomeric
stereoisomers

4. Self Test Question A B C D 1 2
Which structure cannot be moved in space (translation) or undergo rotation around single bonds to obtain a mirror image of the molecule (1) below? A B C D
identical to 1 1 2

5. Chirality 1 2 2
A molecule is chiral if its two mirror image forms are not superimposable on one another
Superimposable molecules can be laid on top of one another so that all equivalent atoms (points) line up

6. chiral: non-superimposable mirror images
Chiral Objects
chiral: non-superimposable mirror images
snail
mirror
image

7. chiral: non-superimposible mirror images
Chiral Objects
chiral: non-superimposible mirror images
milkyway
mirror image

8. chiral: non-superimposible mirror images
Chirality
chiral: non-superimposible mirror images
fingerprint
mirror image

9. chiral: non-superimposible mirror images
Chirality
chiral: non-superimposible mirror images
DNA double helix
mirror image

10. Chirality chiral: non-superimposable mirror images
cheir (Greek) = hand
chirality is synonymous with “handedness”

11. Molecules can Also Be Chiral
chiral: non-superimposible mirror images

12. Superimposibility
to check for superimposibility, rotate mirror image 180º along a plane perpendicular to the mirror plane
180º

13. chiral: non-superimposible mirror images
if the images are not identical, they are non superimposible; not all points (atoms) line up
chiral: non-superimposible mirror images

14. Not Everything is Chiral!
achiral: not chiral; mirror images are superimposible
basketball
mirror image

15. Not Everything is Chiral!
achiral: not chiral; mirror images are superimposible

16. Not Everything is Chiral!
achiral: not chiral; mirror images are superimposible

17. Symmetry Tests for Achiral Molecules
Any molecule with a plane of symmetry or a center of symmetry is achiral (not chiral)
A plane of symmetry bisects a molecule into two mirror image halves

18. Symmetry Tests for Achiral Molecules
Any molecule with a plane of symmetry or a center of symmetry is achiral (not chiral)
plane of symmetry
A plane of symmetry bisects a molecule into two mirror image halves

19. Symmetry Tests for Achiral Molecules
Any molecule with a plane of symmetry or a center of symmetry is achiral (not chiral) •
plane of symmetry •
A plane of symmetry bisects a molecule into two mirror image halves

20. Symmetry Tests for Achiral Molecules
Any molecule with a plane of symmetry or a center of symmetry is achiral (not chiral)
plane of symmetry
A plane of symmetry bisects a molecule into two mirror image halves

21. Symmetry Tests for Achiral Molecules
Any molecule with a plane of symmetry or a center of symmetry is achiral (not chiral)
center of symmetry: a line drawn from center of molecule to an element extends in opposite direction to an identical element

22. Symmetry Tests for Achiral Molecules
Any molecule with a plane of symmetry or a center of symmetry is achiral (not chiral)
center of symmetry: a line drawn from center of molecule to an element extends in opposite direction to an identical element

23. Self Test Question
Which molecule below is chiral? A B C D

24. Chirality Center
Chirality center: an atom bonded to ligands in a spatial arrangement which is not superimposable on its mirror image
Asymmetric carbon: a carbon atom bonded to four different atoms or groups (a type of chirality center)
other terminology
commonly used:
stereocenter
stereogenic center
avoid these terms; both have different meanings from chirality center

25. Chirality Center A molecule with a single chirality center is chiral
bromochlorofluoromethane is chiral

26. A molecule with a single chirality center is chiral
2-butanol is chiral
although two carbon atoms are bonded to the chirality center, they are part of different groups

27. A molecule with a single chirality center is chiral
1,2-epoxypropane: a chirality center can be part of a ring
attached to the chirality center are: -H
-CH3
-CH2O
-OCH2

28. A molecule with a single chirality center is chiral
chiral as a result of isotopic substitution

29. 1 Chirality Center = Chiral
A molecule with a single chirality center must be chiral.
But a molecule with two or more chirality centers may be chiral or it may not be chiral (Sections )

30. Self Test Question
How many chirality centers in a molecule of codeine?
A. 7
B. 6
C. 5
D. 4
E. 3

31. Cahn–Ingold–Prelog (CIP)
Priority Rules
R-S Notation for
Chirality Centers

32. CIP R/S Notation
Step One: Locate chirality center
chirality center

33. CIP R/S Notation
Step Two: Orient molecule so that lowest ranked (CIP priority) atom or group points away from you
chirality center

34. CIP R/S Notation
Step Three: Number 3 highest priority groups in order of increasing priority (CIP sequence rules) 3
chirality center 2 1

35. counterclockwise (sinister) = S
CIP R/S Notation
Step Four: Determine rotation direction of groups in decreasing priority 3
chirality center 2 1
clockwise (rectus) = R
counterclockwise (sinister) = S
(R)-1-chloroethanol

36. Self Test Question
Which molecule has a chirality center with an absolute configuration of R? A B C D 2 3
clockwise = R 1

37. Enantiomers
molecules which are non-superimposible mirror images are called enantiomers;
enantiomer describes a relationship between two molecules (enantiomer: opposite handedness)
(S)-2-butanol
(R)-2-butanol
enantiomers have opposite configurations (R/S) at every chirality center

38. Enantiomers
molecules which are non-superimposible mirror images are called enantiomers;
enantiomer describes a relationship between two molecules (enantiomer: opposite handedness)
(S)-2-chloro-2-butanol
(R)-2-chloro-2-butanol
enantiomers have opposite configurations (R/S) at every chirality center

39. Isomers isomers constitutional (structural) no yes stereoisomers yes
Do the molecules have the same connectivity?
constitutional
(structural) no
yes
stereoisomers
Can the molecules be interconverted by rotation around single bonds?
yes no
conformational
configurational

40. configurational stereoisomers
Is the isomerism at a doulbe bond?
yes no
geometrical
optical
Are the compounds non-superimposible mirror images? no
yes
enantiomers
diastereomers

41. Self Test Question Which pair of molecules are enantiomers? A B C D
Remember: if a molecule has a plane or center of symmetry, it is not chiral and therefore has no enantiomers.

42. Self Test Question Which molecule is (R)-1-hexen-3-ol? A B C D E
clockwise = R 3 2

43. Self Test Question
The three asymmetric carbon atoms in penicillin G are labeled a-c. List the R/S configuration of each in order of a,b,c.
A. R,R,S
B. S,S,R
C. R,S,R
D. S,R,S
E. S,R,R a b c

44. Self Test Question
The three asymmetric carbon atoms in penicillin G are labeled a-c. List the R/S configuration of each in order of a,b,c.
A. R,R,S
B. S,S,R
C. R,S,R
D. S,R,S
E. S,R,R a
N(CCH)
S(SC)
C(OON)

45. Self Test Question
The three asymmetric carbon atoms in penicillin G are labeled a-c. List the R/S configuration of each in order of a,b,c.
A. R,R,S
B. S,S,R
C. R,S,R
D. S,R,S
E. S,R,R b

46. Self Test Question
The three asymmetric carbon atoms in penicillin G are labeled a-c. List the R/S configuration of each in order of a,b,c.
A. R,R,S
B. S,S,R
C. R,S,R
D. S,R,S
E. S,R,R
C(SCC) c
C(OOO)

47. Self Test Question
The three asymmetric carbon atoms in penicillin G are labeled a-c. List the R/S configuration of each in order of a,b,c.
A. R,R,S
B. S,S,R
C. R,S,R
D. S,R,S
E. S,R,R a b c

48. Self Test Question
List the R/S configuration of each asymmetric carbon in the enantiomer of penicillin G in the order a,b,c.
Remember: enantiomers have opposite configurations at every chirality center.
A. R,R,S
B. S,S,R
C. R,S,R
D. S,R,S
E. S,R,R
(R) b b a a
(R) c c
(S)

49. Stereoisomers with >1 Chirality Center
(2S,3R)-3-chloro-2-hexanol or (2S,3R)-3-chlorohexan-2-ol
Number longest chain so that highest priority group has lowest locant.
List locants of asymmetric carbons in increasing order within parentheses at the beginning of name.
List stereodescriptor (R/S) after each asymmetric locant.
R & S are italicized when typed
a comma separates each steredescriptor (no spaces)
stereodescriptors are not considered when alphabetizing subgroups
asymmetric locants are not written if their exclusion is unambiguous ( ) -
chiral
locant
R/S ,
chiral
locant
R/S
parent
class suffix

50. Drawing Fisher Projections
Step One: Draw (imagine) totally eclipsed conformation

51. Drawing Fisher Projections
Step Two: Imagine that the carbon skeleton atoms form a “C” and you are looking at the back of the C.

52. Drawing Fisher Projections
Step Three: Flatten out the “C” so vertical bonds point away from you and horizontal toward you.

53. Self Test Question Which Fisher project is (2R,3R)-2,3-pentandiol? A CB D

54. Properties of Enantiomers
boiling point = 231 ºC
density = 0.96
1H-NMR δs = same as (S)
13C-NMR δs = same as (S)
IR spectrum ῡs = same as (S)
optical rotation = –61º
smell = earthy
(R)-(-)-carvone
boiling point = 231 ºC
density = 0.96
1H-NMR δs = same as (R)
13C-NMR δs = same as (R)
IR spectrum ῡs = same as (R)
optical rotation = +61º
smell = spearmint
(S)-(+)-carvone

55. Properties of Enantiomers
(S)-(+)-Carvone
(S)-carvone is the enantiomer of (R)-carvone
Enantiomers have the same physical properities including IR vibrational frequencies, mp, bp, Rf, etc.
(R)-(-)-Carvone
IR spectra for both enantiomers of carvone--and for any two enantiomeric compounds--are identical.

56. Optical Rotation (–) = counterclockwise = levorotary
(+) = clockwise = dextrorotary
enantiomers rotate plane polarized light an equal magnitude, but in opposite directions

57. Optical Rotation (100)(α) [α] = (c)(l)
degree of optical rotation depends on concentration of a solution containing the chiral compound
[α]: specific optical rotation; determined in specified concenetration and path length units for universal comparison
(100)(α)
[α] = 25 D
(c)(l)
α = degree of rotation determined by polarimeter
c = concentration (g/dL); 10 dL = 1 L
l = path length (cm)

58. enantiomeric excess (ee)
Optical Rotation
racemic mixture = contains equal quantities of both enantiomers (1:1, 50/50, etc); [α] = 0º
enantiomeric excess (ee) = |% A enantiomer - % B enantiomer|
% A enantiomer
% B enantiomer
enantiomeric excess (ee)
100 75 25 50
racemic mixture

59. R/S versus (+)/(-)
Enantiomers have equal magnitudes, but opposite signs of specific rotation
Caution: the sign of rotation (+/-) cannot be determined from R/S configuration!

60. Diastereomers:Chiral Molecules with >1 Chirality Center
stereoisomers that are not mirror images
stereoisomers with ≥ 2 chirality centers that are not all opposite
diastereomers may have different physical properties!

61. Meso Forms meso forms = achiral molecules with chirality centers
meso forms are optically inactive (0º optical rotation) R S R S R S R S
Two tests for meso:
plane or center of symmetry
two chirality centers with same groups, but opposite configurations
meso
meso

62. Determining the Number of Stereoisomers
2n = maximum number of stereoisomers
n = chirality centers
2n = 24 = 16 stereoisomers

63. Determining the Number of Stereoisomers
2n = maximum number of stereoisomers
n = chirality centers
alkenes that have geometrical isomers are also a type of chirality center!
2n = 22 = 4 stereoisomers

64. Determining the Number of Stereoisomers
2n = maximum number of stereoisomers
n = chirality centers
2n = 23 = 8 stereoisomers

65. Self-Test Question 2 4 8 16 32 TRH
Thyrotropin releasing hormone (TRH) stimulates the anterior pituitary to release thyroid stimulating hormone (TSH); the thyroid gland regulates metabolism. How many stereoisomers are possible in TRH? 2 4 8 16 32
TRH