1. Stereochemistry- Chapter 3
1. Stereoisomerism
2. Chirality
3. Naming stereocenters - R/S configuration
4. Acyclic Molecules with 2 or more stereocenters
5. Cyclic Molecules with 2 or more stereocenters
6. Properties of Stereocenters
7. Optical activity
8. Separation of Enantiomers, Resolution
9. Significance of Chirality in the biological world
Lect 6, Sept 17, 2002
Lecture 6, Feb 11, 2003
Lecture 7 Fall 03
February 6 04

2. Isomers - same molecular formula - different compounds
constitutional isomers - different connectivity
stereoisomers - same connectivity
- different orientation in space
(recall cis/trans)

3. Chirality handedness not superposable on its mirror image
symmetry = superposable
types:
plane imaginary plane through an object
one half is the mirror image of the other
center identical parts on an axis
equidistant from a point

4. If symmetry is present, the substance is achiral.
Elements of Symmetry
Conformations of 2,3-butanediol*
syn - plane of symmetry
anti - point of symmetry . .
If symmetry is present, the substance is achiral.
*meso or R,S (later)

5. Elements of Symmetry
Plane of symmetry
achiral

6. Chiral Center chiral center - carbon (atom) with 4 different groups
common source of chirality - tetrahedral (sp3) carbon (atom) - bonded to 4 different groups
chiral center - carbon (atom) with 4 different groups
Enantiomers: stereoisomers
nonsuperposable mirror images
All chiral centers are stereocenters
Not all stereocenters are chiral centers

7. Enantiomers representation of mirror image or enantiomer
2-Butanol - 1 chiral center
different representations for this enantiomer
representation of mirror image
or enantiomer

8. Enantiomers
3-Chlorocyclohexene

9. Enantiomers
A nitrogen chiral center

10. Enantiomers
2-Chlorobutane
How is handedness designated?

11. Enantiomers
Enantiomers of lactic acid
another representation

12. R,S Convention - Priority rules
Each atom bonded to the chiral center assigned a priority by atomic number
higher atomic number, higher the priority
increasing priority
Same atoms bonded to the chiral center
look to the next set of atoms
priority assigned to 1st point of difference
increasing priority

13. R,S Convention
double (triple) bond atoms viewed as bonded to an equivalent number of atoms by single bonds

14. Naming Chiral Centers
1. Locate the chiral center, prioritize four substituents
1 (highest) to 4 (lowest)
2. Orient molecule so that lowest priority (4) group is directed away ( behind )
3. Read three groups toward you (in front) (1) to (3)
Clockwise R configuration; counterclockwise S

15. Naming Chiral Centers
( )-3-Chlorocyclohexene R
( )-mevalonic acid R

16. Stereochemistry- Chapter 3
1. Stereoisomerism
2. Chirality
3. Naming stereocenters - R/S configuration
4. Acyclic Molecules with 2 or more stereocenters
5. Cyclic Molecules with 2 or more stereocenters
6. Properties of Stereocenters
7. Optical activity
8. Separation of Enantiomers, Resolution
9. Significance of Chirality in the biological world
Lect 6, Sept 17, 2002
Lecture 6, Feb 11, 2003
Lecture 7 Fall 03
February 6 04

17. Ibuprofen Naproxen S isomer
S isomer particularly active, but R slowly converted to S
Naproxen
S isomer

18. Assign R/S to stereogenic carbon in coniine
Assign R or S to carvone
S caraway/dill R
spearmint
Assign R/S to stereogenic carbon in coniine
Golden pitcher plant
R-(-)-coniine
poison hemlock

19. Enantiomers & Diastereomers
molecule with 1 chiral center:
21 = 2 stereoisomers are possible
molecule with 2 chiral centers:
a max of 22 = 4 stereoisomers “possible”
molecule with n chiral centers:
2n = maximum stereoisomers are possible

20. 2n
256 (ignore sugar)

21. Enantiomers & Diastereomers
2,3,4-trihydroxybutanal 2 chiral centers
22 = 4 stereoisomers “possible” & exist
2 pairs of enantiomer
(Erythrose)
Diastereomers: stereoisomers that are not mirror images

22. Enantiomers & Diastereomers
2,3-Dihydroxybutanedioic acid (tartaric acid)
2n = 4 “possible”
but only three stereoisomers exist
Meso compound: achiral but possessing 2 or more chiral centers
enantiomers
symmetry plane-superposable
(same compound)

23. Enantiomers & Diastereomers
2-Methylcyclopentanol
cis-2-Methylcyclopentanol
enantiomers left right
diastereomers
top
bottom
trans-2-Methylcyclopentanol

24. Enantiomers & Diastereomers
1,2-cyclopentanediol
diastereomers
trans-1,2-cyclopentanediol
(enantiomers)
cis-1,2-cyclopentanediol
(a meso compound)

25. Enantiomers & Diastereomers
cis-3-methylcyclohexanol
flip: axial-equatorial reverse
but still cis

26. Enantiomers & Diastereomers
trans-3-methylcyclohexanol
flip: axial-equatorial reverse
but still trans

27. Isomers

28. Properties of Stereoisomers
Enantiomers: identical physical and chemical properties in achiral environments
m. pt. 174o 174o pK
Diastereomers: different compounds different physical and chemical properties
m. pt. 146o 174o pK

29. Plane-Polarized Light
optical activity
Light vibrating in all planes  to direction of propagation
Plane-polarized light: light vibrating only in parallel planes
Plane-polarized light the vector sum of left and right circularly polarized light

30. Optically Activity Enantiomers (chiral) interact with circularly polarized light
rotating the plane one way with R center
and opposite way with S
result: rotation of plane-polarized light clockwise (+)
or counterclockwise (-)

31. Plane-Polarized Light (polarimeter)
Change in the polarized plane?
achiral
sample
no change in the plane

32. Plane-Polarized Light (polarimeter)
Change in the polarized plane? 
CHIRAL
rotates the plane

33. Stereochemistry- Chapter 3
1. Stereoisomerism
2. Chirality
3. Naming stereocenters - R/S configuration
4. Acyclic Molecules with 2 or more stereocenters
5. Cyclic Molecules with 2 or more stereocenters
6. Properties of Stereocenters
7. Optical activity
8. Separation of Enantiomers, Resolution
9. Significance of Chirality in the biological world
Lect 6, Sept 17, 2002
Lecture 6, Feb 11, 2003
Lecture 7 Fall 03
February 6 04

34. Optical Activity ( )-(+)-lactic acid ( )-(-)-lactic acid
observed rotation: , degrees a compound rotates polarized light - dextrorotatory (+) right
- levorotatory (-) left T
specific rotation []D =
( )-(+)-lactic acid ( )-(-)-lactic acid S R

35. R-enantiomer is (-); R or S above?
Example: 0.5g (-)-epinephrine-HCl in 10mL H2O measured in 20 cm cell (25o/D) obs = -5.0o, []D =?
25o
R-enantiomer is (-); R or S above?
[a] = deg (cm2g-1 )

36. Optical Activity
Racemic mixture: equal amounts of (+) and (-) enantiomers - rotation is 0o
For a 50/50 mixture of S and R,  = ? 0o

37. optical purity = 40% (S)-(+)-2-bromobutane, []D=+23.1o
But from the obs, []D= +9.2?
21o
It’s not pure; possibly some R present!
If some R, what percent?
Mix is between 100% S and /50 (S/R)
+23.1o > o < 0o
optical purity
= 40%
40% excess = 40%S
+ (60%S/R mixture)
40% excess = 40%S + (30%S + 30%R)
 the sample has 70%S and 30%R

38. Optical Purity: composition of a mixture of enantiomers
enantiomeric excess (ee): difference between the percent of 2 enantiomers in a mixture
ee = optical purity

39. e.g. 6g of (+)-2-butanol plus 4g of (-)-2-butanol, ee = ?
ee = x100%
6 - 4
6 + 4
= 20%
[]D of (+)-2-butanol = +13.5o; obs sample = ? rt
opt pure = = ee
obs
pure
20% =
obs
+13.5pure
obs = (.20)(+13.5%) = +2.7o

40. Enantiomeric Excess 100% sample = 97%S + (3%S and R)
Example: A commercial synthesis of naproxen (Aleve) gives the S enantiomer in 97% ee.
What are the percentages of the R & S in this mixture?
100% sample =
97%S + (3%S and R)
97%S + (1.5%S+1.5%R)
98.5%S + 1.5%R

41. Resolution - separation of enantiomers
One strategy: convert enantiomeric pair into 2 diastereomers
diastereomers - different compounds
different physical properties
Common - reaction forming salt
separate diastereomers
remove :B
leaves pure enantiomers 4

42. Resolution
racemic acids - resolved w/ available chiral bases, e.g. (S)- and (R)-1-phenylethanamine

43. Resolution by acid-base reactions
Pure-Sb
----resolved----
racemic
mix

44. Resolution Examples of enantiomerically pure bases   CH =CH H CH =CH2
=CH H CH 2
=CH H H H H HO H N N H HO H
CH3O N N
(+)-Cinchonine
(-)-Quinine 23 [  ]
= +228 D 25 [  ]
= -165 D

45. racemic bases with chiral acids like:
[]D = -127o HCCl3 from Strycnos seeds (S nux-vomica)
brucine
Strychnine no methoxy groups
racemic bases with chiral acids like:

46. Resolution [] = 0 enantiomeric mixture pure enantiomer + R S S R S S

47. Resolution [] = 0 enantiomeric mixture []25 = -8.2 pure enantiomerD
[] = 0
pure
enantiomer R S
Resolution S
[]25 = +8.2 D

48. lipase
>69%ee
50/50 mix
R-Enzyme

49. lipase >69%ee R-Enzyme A 50/50 enantiomeric mixture of esters
forms R-acid and recover S-ester.
R-Enzyme

50. Enzymes as resolving agents
racemic mix ethyl ester of (S)- and (R)-naproxin
(R)-ester - no effect
(S)-now acid
different functional gp.

51. CHEMICAL & ENGINEERING NEWS Oct 23, 2000, pg 55
Chiral Drugs Sales top $100 Billion
carbohydrates
deoxynucleic acid
amino acids

52. Proteins
proteins are long chains of amino acids covalently bonded by amide bonds formed between the carboxyl group of one amino acid and the amino group of another amino acid
Chapter 5