Chapter 5

Stereochemistry:
Arrangement of
Atoms in Space;
Stereochemistry of
Addition Reactions

enantiomers

9/06/07 update
1

Isomers
Isomers - compounds with the
same molecular formula but
different structures

Stereoisomers different 3D
structures
cis-trans are one example

stereo isomers = isomers which differ only in their 3D structures;

eg, cis & trans isomers, enantiomers and diastereomers

enantiomers = non-superimposable (different) mirror images;

majority of chemical and physical properties are identical

H OH

HO H
H3 C

HO2C

CO2H

CH3

(S)-(+)-lactic acid

(R)-(-)-lactic acid

enantiomers

can't
superimpose
rotate
180o

chiral = describes a molecule that is different from its mirror image;

enantiomers are chiral

achiral = describes a molecule that is the same as its mirror image

5.3 - Asymmetric Centers

Chiral molecules usually contain an asymmetric (chiral,
stereo, stereogenic) center
Asymmetric center - tetrahedral atom bonded to four
different groups - indicated with an asterisk (*)

achiral molecules have either one or both of the following

plane of symmetry
center of symmetry see next two slides
chiral molecule (R)-lactic acid (no symmetry)
achiral molecule water (plane of symmetry)

Cl
C C
H

Br

CH3
CH2CH3

mirror
planes of
symmetry

Br

H3C

CH2
HO

C
O

Cl

Cl H

Br
Br
H

H Cl

H
Br

H*

H
Br

Cl
* = center of symmetry in
geographical middle of the molecule

same

mirror

180

chiral center (stereo, stereogenic, asymmetric center)

an atom attached to 4 different atoms or groups

R3

chiral center

R4 C R
2
R1
most chiral molecules contain chiral centers
but a molecule can be chiral and not contain a chiral center
How about 2,3-hexadiene? chiral / achiralwhich??

CH3
C C
H

H
CH2CH3

Alsomolecule with
2 or more chiral
centers can be
achiral
9

Best descriptions of the cyclohexanes shown are

Br

CH3
1.
2.
3.

chiral
achiral
Impossible to describe

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

10

5.6 - Drawing Enantiomers

3D, prospective drawings

Br
CH3CH2

C
H

*Horizontal bonds are out of paper toward

viewer and
*Vertical bonds are into the paper away
from the viewer.

Br
CH3

CH3CH2

CH3
H

Fisher projection (short-hand)

]

11

5.8 - Optical Activity

What properties are the same with chiral compoundsenantiomers?
*Boiling point, melting point, solubility & cannot be easily separated (if at all)
What properties are different with chiral compounds?
*Interaction with plane-polarized light - light in which all the rays/waves oscillate
in a single plane (normal light has ray oscillations in all directions)

How do we get plane-polarized light? Passing normal light through a polarizer

12

Chiral compounds rotate ppl

polarimeter = instrument used to measure the amount (in )
by which materials rotate plane-polarized light
Schematic diagram of a polarimeter

optical activity = a substance that rotates plane polarized light is chiral

and said to be optically active
13

Specific rotation, [] = amount (degrees) that a substance rotates ppl

expressed in a standard form
It accounts for variables such as
(1) concentration (c)
(2) length (l) of the light path through the sample solution
(3) is the exptl (measured) rotation

exptl
rotation

temp

[]T

wavelength of
light; usually
sodium D line,
= 589 nm

c*l
conc of
sample
in g/mL

sample path length

in decimeters (dm)

14

Some molecules and

specific rotations

R1 O
heroin: R1 = R2 =
O

O
N

CH3

R2 O
morphine, R1 = R2 = H
[] = -132o

H3 C
codeine: R1 = CH3,
R2 = H

15

NH

C6H5O
O

HO
cholesterol
[] = -31.5o

penicillin V
[] = +223o

CO2H

OH
HO
O

HO
HO

glucose
[] = +53o

O
O
OH
HO

CH2OH
OH

sucrose
[] = +66.4o

fructose
[] = -92o
16

N
H

I
I

HO

NH3

N
N
nicotine

OH
OH
adrenaline

CO2

thyroxine (T4)

H
limonene
(lemon oil)

17

N
N

O
(R)-thalidomide
(antidepressant)

H
N

N
H

O
(S)-thalidomide
(mutagenic and
antiabortive)

The thalidomide story and tragedy..

1959-62, prescribed as an analgesic for morning sickness
used extensively in Europe and Canada despite strong warnings that it not be
given to pregnant women.
FDA had not approved its use in U. S. at the time!
By 1961, it was recognized as the cause for numerous birth defects
(~7- 10,000 in 28 countries).
Presently being evaluated for the treatment of
AIDS CANCER LEPROSY ARTHRITIS
18

H3CO2C

CH3

O
H

H3C
H

CH3
O

H
CH3

CH2

Pyrethin IIfound in chrysanthemum familynatural insecticide

Identify the stereogenic centers

19

Question: You have a solution of a molecule that is suspected to

be chiral (should demonstrate optical activity) and find
that the experimental rotation () is exactly 0.
What could be done to demonstrate that the molecule actually is
chiral?
Highly improbable that the specific rotation of a chiral molecule
would be exactly 0.

What can you do?...

1.
2.
3.
4.

Try a different polarimeter

Increase the sample concentration
Come back after lunch and try again
Ask Raffaele or Rich for help
20

Absolute and relative configurations

absolute configuration = the precise (true) 3D arrangement of atoms in a molecule

same relative configuration

H3C

*
CH

CH

CH2

OH

H2

H3C

Pt

HO-H2C

CH2 CH3

CH3
[ = -5.8o

CH2 CH3

OH

o
[27
=
+33.2
D

*
CH

*
CH

o
[27
=
+13.5
D

HBr

Br-H2C

*
CH

CH2 CH3

CH3
[ = +4.0o

1951, first X-ray experiments were performed to allow the determination of the
absolute configuration of a molecule
21

5.7 - Naming enantiomers - R,S system (Cahn-Ingold-Prelog)

Enantiomers with one asymmetric center.one member has R configuration
the other has S configuration.
Visualize molecule in 3D and assign R/S priorities;
1->2->3 = R if clockwise, S = if counter clockwise

22

R/S notation = specifies absolute configuration of a chiral center;

there is no correspondence between R and + or S and

1 4
HO H
H3C
3

1
OH

H is
hidden

H3C
3

CO2H
2

(R)-(-)-lactic acid

CO2H
2

clockwise = R

m.i. = (S)-(+)-lactic acid

H2N
HO2C

CH3

3
CH3

H2N
1

CO2H
2

L-alanine
2-aminopropanoic acid

counter-clockwise = S

See: http://www.vanderbilt.edu/AnS/Chemistry/Rizzo/chem220a/absolute.pdf

23

Draw a 3D structure for

(R)-2-methyl-1-butanol

3
CH3
H3C

CH2 C
2
H4

1
CH2 OH

1
CH2OH
C
H3C
3

C2H5
2

HOH2C
tip
forward
slightly

H3C

C2H5
24

Fischer projections = short hand for displaying molecules

with stereogenic centers (sect 5.6)
*Horizontal bonds are out of paper toward viewer and
vertical bonds are into the paper away from the viewer.
Br
CH3CH2

C
H

Br
CH3

= CH3CH2

CH3
H

*90 rotation -> inverts the configuration (R -> S and vice versa).
*Can be rotated 180 about an axis perpendicular to the paper
without altering the configuration.
*If the projection is rotated in a way that lifts some groups
out of the paper, the absolute configuration will be reversed.
See: http://www.chem.uic.edu/web1/OCOL-II/WIN/STEREO/F12.HTM

25

CH2 CH3
H3C

CH

CH3

OH CH3
2,3-dimethyl-3-pentanol
CH3

H3 C
C
HO

Et
i-Pr

i-Pr

CH3
Et

i-Pr

Et
OH
(R)

OH
CH3
Et

interchange
i-Pr and Et

i-Pr

R -> S

OH
(S)
26

CH3

rotate 90
HO H
H3C

=
CO2H

OH
H3C

(R)-(-)-lactic acid

CO2H
H (R)

OH
CO2H (S)

rotate 180o
H

HO2C

OH
H3C

CH3
OH (R)

CO2H
H

Note: Interchange two of the groups attached to a chiral center,

the molecule mirror image.
Odd number of interchanges the mirror image.
Even number
absolute configuration unchanged.

How can you determine the absolute configuration from a Fischer projection??
27

Identify the absolute configurations of the

following
C2H5

Cl

CO2H
CH3CH2

H 3C H

41

42

43

44

61

62

63

64

1.
2.
3.
454. 46
65

66

CH3

E
Z
R
S47
67

48

49

50

51

52

53

54

55

56

57

58

59

60

68

69

70

71

72

73

74

75

76

77

78

79

80

28

A slightly expanded chart of isomers

same molecular formulas,
different structures

different 3D structure

H3C
H3C

CH2
O

Not
enantiomers

OH
CH3

R&S

2 or more chiral
centers

29

5.11 More than 1 Asymmetric Center

A compound can have a maximum of 2n stereoisomers,
where n = the number of asymmetric centers
3-bromo-2-butanol - 2 asymmetric centers = 4 stereoisomers:
A

Enantiomers = A/B and C/D.what are A/C, A/D, B/C, B/D?

30

CHO
* OH

* H
* OH

* OH

HO

# of chiral centers = 4
total # of stereoisomers =
24 = 16

CH2OH
(+)-glucose

31

Diastereomers = stereoisomers that are not enantiomers;

have different chemical and physical properties

CO2H
H
HO

OH

CO2H
enantiomers

CO2H
(2R,3R)-(+)tartaric acid

HO

H
OH
CO2H

diastereomers

(2S,3S)-(-)tartaric acid

CO2H
H

OH

OH
CO2H

(2R,3S)-tartaric acid (meso isomer)

32

CO2H
H

OH

OH
CO2H

(2R,3S)-tartaric acid (meso isomer)

meso isomer

= an achiral molecule with 2 or more chiral

centers + an internal plane of symmetry; the molecule is
achiral

*Note* absolute configurations of the two chiral

centers in meso-tartaric acid are opposite, R and S

33

Tartaric acid properties.

3 stereo isomers 4 crystal forms

(gm/ml)

H2O
solubility
(gm/100 ml)

+12

1.760

139

168-170

-12

1.760

139

meso

146-8

1.660

125

(+-)

206

1.788

20.6

Stereoisomer

Mp
(oC)

(+)

168-170

(-)

(o)

pKa # 1

pKa # 2

(+) or (-)

2.98

4.34

meso

3.23

4.82
34

*Chiral molecules with 2 stereogenic centers

diastereomers

CO2H
2
H
OH
3
H
OH
4CH
3

CO2H

CO2H

HO

HO

HO

CH3

(2S,3S)
(2R,3R)
(liquid)

OH
H

CO2H
HO
H

CH3

H
OH
CH3

(2R,3S)
(2S,3R)
(solid)

various 2,3-dihydroxybutanoic acids

35

*Achiral molecules with 2 stereogenic centers

CO2H
H
HO

OH
H

CO2H

CO2H
HO
H

CO2H

HO

OH

OH

HO

OH

CO2H

CO2H

CO2H

(2R,3R)

(2S,3S)

(2S,3R)

various tartaric acids

CO2H
(2R,3S)
identical

meso isomer

36

racemic mixture = 1:1 mixture of enantiomers;

has no optical activity
Louis Pasteur, ~1860 crystallized racemic mixture of sodium ammonium tartrate
mirror image crystals.

Citric acid most

common in fruits
37

Determine absolute configuration of citric acid

1.
2.
3.

S
Neither
R

Which of the following are chiral?

H CH3
HO
OH

OH
Br

H CH3

C
38

5.10 - Enantiomeric excess (optical purity)

Example[] of (+)-alanine from fossil sample = + 4.25o
[] of pure (+)-alanine = + 8.5o

EE = optical purity (%) = {[]observed / []pure}x100

SoEE = op = {4.25 / 8.5} x 100 = 50%
Interpretation50% of sample is pure (+), other 50% is racemic mixture
Each square represents 25% of the sample

(+)

(+)

(+)

(-)

50% is (+)

50% is racemic = 25% (+) + 25% (-)

total sample = 75% (+) and 25% (-)
39

5.16 - Separation of Enantiomers

How can enantiomers be separated?
Fractional recrystallization
(1) Reaction to convert enantiomers to diastereomers for separation
(disastereomers have different physical properties).
(2) Separate diastereomers convert back to enantiomers
Chromatography - passage of a solution of enantiomers through a column
packed with a chiral material - one enantiomer will have a greater affinity (like a
right hand prefers a right glove) and travel slower through the column.
Chiral probes - materials capable of distinguishing between enantiomers

40

Separation of a racemic aminoalkyne by fractional crystallization

H

H
C CH HC C

H3C

racemic amine
[] = 0o

CH3

NH2

NH2

R
CO2H
H
HO

H2O

OH (2R,3R)-(+)H

tartaric acid
(chiral acid)

CO2H
.................diastereomers.................
CO2

H
H3C

C CH
NH3

H
HO

OH
H
CO2H

CO2

H
+ HC C

CH3 H
HO
NH
3

..different solubilities..

OH
H
CO2H

41

CO2

H
H3 C

C CH
NH3
(S)

OH

HO

H
CO2H
(R,R)

tartrate salt of the

S-amine [S,R,R]
[] = -24.4o

CO2

H
+ HC C

CH3 H
HO
NH

OH
H

(R)

CO2H

(R,R)

tartrate salt of the

R-amine [R,R,R]
[] = +24.1o

careful fractional crystallization

S,R,R-diastereomer
crystallizes --> solid

R,R,R-diastereomer
remains in solution
K2CO3, H2O
(weak base)
42

NH3+ + CO3-2

NH2 + HCO3H

H
H3C

C CH
NH2

(S) [] = -52.7o,
bp 82-4o

HC C

CH3
NH2

(R) [] = +53.2o,
bp 82-4o

Why arent the []s exactly the same magnitudewhat should they be?
43

5.14 - Reactions involving chiral molecules

(no change in chiral center, but R/S can change)

44

5.19 - Electrophilic Addition Reactions

Reactions that form products with asymmetric centers

achiral
Br
Et
H

Br
C2H5
H

H
H

Br

Et
H
Br

Et
H

achiral

CH3

(R)

CH3
Et
H

CH3

Br
(S)

CH3
racemic
mixture

45

OH
HCl
Et
i-Pr

CH3

racemic mixture

(R)
Cl

2 steps (what's # 1?)

Et
i-Pr
Et
i-Pr

Et
i-Pr
CH3

Cl-

CH3
+

Et
i-Pr
CH3

(R)

achiral

CH3

(S)

Cl

46

Reactant has a chiral center & reaction makes a new one

H
H3C

Cl
CH=CH2

HBr

H3 C

Cl

H3 C

Br
H

H3C

Cl

Br

CH3
H
47

Product with two chiral centers

C2H5 CH3
C
C

+ HCl

C2H5 CH3

*
*

*
*

*
48

Stereochemistry of H2 addition is syn.

CH3
CH3

H2
Pt/C

85% cis <- major

15% trans

Describe the trans-product

CH3 H
2
CH3

Pd/C

CH3
H 15%
CH3
H
H

1.
2.
3.
4.

Meso
Racemic mixture
Achiral
Mixture of diastereomers
49

Peroxyacid reaction syn-addition

Question: What is/are the product/s of the reaction of cis-2-butene

and a peroxyacid?
50

Describe the product

H3C

1.
2.
3.
4.

CH3CO3H

H3C
O

Racemic mixture
Mixture of disastereomers
Meso
None of these apply

51

Hydroboration-Oxidationsyn, anti-Markovnikov hydration

Concerted reaction - bond-breaking/making processes occur in the same step
The boron and hydride ion add to the two sp2 carbons at the same time addition must be syn

Replacement of C-B bond with O-H

52

Hydroboration-Oxidation.syn-addition of HOH

Brominationanti-addition of Br-Br

53

Is the product chiral?

H
H

Br2

Br
H

H
Br

1.

Yes, has 2 stereocenters

2.
3.

No, it is a meso compound

There is no plane of symmetry,
so yes it is chiral.

54

5.21 - Biological Molecules

Enzymes are chiral reagents because their binding site is chiral

55

Receptors - protein that binds a particular molecule

Also are chiral - allow selective binding of enantiomers
Example - receptors in the nose are able to distinguish between 10,000
different smells - each enantiomer fits into a different receptor

The nose knows!

56

Many drug molecules are synthesized as racemates..either both molecules have

comparable activity or one is inactive.

R = bronchodilator (albuterol)
S = antagonist

19 of 20 essential amino acids are chiral.

O

H2N

OH
O

H2N H
Bitter

H2N

OH
O

Asparagine

H NH2
Sweet

57

Other stereogenic centers

Me
Et N:
Pr

Me Et
N

Me
:N Et

Pr

Pr

this umbrella inversion also takes

place in phosphines

rapid equilibration

O
with sulfur the rate of
inversion is slow....
enantiomers can be isolated

R1
R2
58

Broccoli contains sulforaphane

Increases the activity of certain enzymes capable of degrading
toxic/carcinogenic compounds.

O
H3C

Only (R)-stereoisomer is active and found in plants.

59