1

Stereochemistry

2

Handedness Some things have a “handedness,”

that is look at your right and left hand. They look alike, but are not the same. They are mirror images.

3

Nobel Prize - 2001

Their research deals with the fact that many molecules appear in two forms that are mirror images of each other, just like the left and right hands.

4

The mirror imageof a chiral object isdifferent and will notsuperimpose on the original object.

Objects which are chiral have a sense of “handedness” and exist in two forms.

Chirality

5

Mirror Image

6

HCl

HCl Are these two

structures identical?

mirror

7

HCl

HCl

Stereoisomers

8

Stereoisomers

9

Stereoisomers

10

Stereoisomers

11

Stereoisomers

12

Stereoisomers

13

enantiomersenantiomers

Stereoisomers that are nonidentical mirror images are called enantiomers.enantiomers.

Stereoisomers

14

Visualize, visualize ….

C C

Br

F

H

Cl

BrH

CC

Br

F

H

Cl

BrH

CC

H

Br

F

Cl

BrH

15

Visualize, visualize …

C C

Br

F

H

Cl

BrH

CC

Br

F

H

Cl

BrH

Cl

HBr

F

H Br

Cl

BrH

F

Br H

16

C

CH3

BrF

H

C

CH3

FBr

H

enantiomer

1..3..5…etc interchanges = enantiomer

2..4..6...etc interchanges = original compound

ODD:

EVEN:

Visualize, visualize …

17

C C

CH3

BrF

H CH3

H

FBr

C C C C

CH3

BrF

H CH3

Br

FH CH3

H

BrF

H

CH3 BrF

ENANTIOMER ENANTIOMERSAME

12

3

YOU CAN USEINTERCHANGES

Are these identical or are they enantiomers?

18

Isomers Isomers: different compounds with the

same molecular formula Constitutional isomers: isomers with a

different connectivity Stereoisomers: isomers with the same

molecular formula, the same connectivity but a different orientation of their atoms in space that cannot be interconverted by rotation about a single bond

19

Chirality Mirror image: the reflection of an object in

a mirror Objects that are not superposable on their

mirror images are said to be chiral, that is, they show handedness

Objects that are superposable on their mirror images are said to be achiral, that is, they do not show handedness. An achiral object has at least one element of symmetry

20

Chirality A molecule

cannot be chiral if it has a plane of symmetry.

21

Chirality A plane of symmetry is a plane that

cuts through an object in such a way that one half of the object is an exact mirror image of the other half.

A molecule that has a plane of symmetry must be identical to its mirror image and therefore must be nonchiral, or achiral.

22

BrFH

Cl stereocenterThis is one type of ….

…. others are possible

A stereogenic carbon is tetrahedral and has four different groups attached.

Stereogenic Carbons

23ClClBr

F F

BrCl Cl

Elements of Symmetry Plane of symmetry: an imaginary

plane passing through an object dividing it such that one half is the mirror image of the other half

24

ClCl

Br

H

H

Br

center of symmetry

Elements of Symmetry Center of symmetry: a point so

situated that identical components of the object are located equidistant on opposite sides and equidistant from the point along any axis passing through the point

25

Two identical groups renders a tetrahedral carbon achiral.

F

BrClCl

ClClBr

FThe plane of the paper is a plane of symmetry

Achiral

26

Cl

ClBr

F F

Br

Cl Cl

plane ofsymmetry

side view edge view

Two Views of the Plane of Symmetry

27

Symmetry Plane

C

COOHHH

COOH

C

CH3

H

COOH

OH

Symmetry plane No symmetry plane

achiral chiral

28

CONSTITUTIONAL ISOMERS

Isomers with a differentorder of attachment ofthe atoms in their molecules

STEREOISOMERSIsomers with the same orderof attachment, but a differentconfiguration (3D arrangement)of groups on one or more of the atoms

ISOMERSDifferent compoundswith the same molecular formula

cis/trans ISOMERS

ENANTIOMERSStereoisomers whose molecules are non-superimposible mirrorimages of each other

DIASTEREOMERSStereoisomers whose molecules are not mirror images of each other

each isomer could

double bond or ring

both can apply

have stereoisomers

with a ring

TYPES OF ISOMERISMTYPES OF ISOMERISM(geometric)

29

Enantiomers Enantiomers: stereoisomers that

are nonsuperposable mirror images; refers to the relationship between pairs of objects

30

BrFH

Cl Cl

HBrF

HFBr

Cl

rotate

this moleculeis chiral

note that the fluorineand bromine have beeninterchanged in theenantiomer

do interchanges in class

Enantiomers

31

Enantiomers Lactic acid

C

C

HOCH3

H

OHO

C

C

OHH3CH

O OH

32

Enantiomers 1,2-propanediol

CH3CHCH2OH

OH

C

OH

H

CH2OHH3C C

OH

H

HOH2C CH3

33

Enantiomers 3-Chlorocyclohexene

Cl

H

Cl

H

Cl

34

CH3CH2CH2CH2CH2 C CH2CH2CH2CH3

Br

H

35

HO CH3

CH3

CH3

H

H

36

CH3

O

O

carvone nootkatonespearment oil grapefruit oil

37

CH3

O

HCH3C

CH2

CH3

O

HCH3C

CH2

(R)-carvonecaraway and dill seed oils

(S)-carvonespearmint oil

Carvone

38

LimoneneCH3

HCH3C

CH2

CH3

HCH3C

CH2

(R)-limoneneodor of oranges

(S)-limoneneodor of lemons

39

Chiral Drugs Most pharmaceutical drugs are

chiral thalidomide

N

N

O

O O

O

H

H

N

N

O

O O

O

HH

40

Optically Active Refers to molecules that interact

with plane-polarized light

Jean Baptiste Biot French Physicist - 1815

He discovered that some natural substances (glucose, nicotine, sucrose) rotate the plane of plane-polarized light and that others did not.

41

Optical Activity

incidentpolarizedlight

transmittedlight (rotated)

sample cell

angle ofrotation,

(usually quartz)

a solution of the substance to beexamined is placed inside the cell

42

Plane Polarized Light Ordinary light: consists of waves vibrating

in all planes perpendicular to its direction of propagation

Plane polarized light: consists of waves vibrating only in one plane

Plane polarized light is an equal mixture of left and right-circularly polarized light. These two forms are nonsuperposable mirror images and, therefore, enantiomers.

43

Plane-Polarized Light Beam

.

unpolarizedbeam

wavelength

=c

frequency ( n )

c = speed of light

polarized beam

Sine wavesare not alignedin the sameplane.

NOT PLANE-POLARIZED

ENDVIEWSIDE

VIEW

44

Plane Polarized Light Because of its handedness, circularly

polarized light reacts one way with a stereocenter with R-handedness, and differently with its enantiomer

The net effect of the interaction of plane polarized light with a chiral compound is that the plane of polarization is rotated

Polarimeter: a device for measuring the extent of rotation of plane polarized light

45

Optical Activity optical activity - ability of certain molecules

to rotate plane polarized light

detected using a polarimeter

46

Polarimeter

47

l(dam)

sample cell

Na vapor lamp

polarizer analyzer

Polarimeter

48

Optical Activity Observed rotation: the number of

degrees, , through which a compound rotates the plane of polarized light

Dextrorotatory (+): rotation of the plane of polarized light to the right

Levorotatory (-): rotation of the plane of polarized light to the left

49

Optical Activity Specific rotation:

Observed rotation of the plane of polarized light when a sample is placed in a tube 1.0 dam in length and at a concentration of 1g/mL.

= observed rotation

c = concentration ( g/mL )

l = length of cell ( dm )

D = yellow light from sodium lamp

T = temperature ( Celsius )

cl

TD

50

Optical Activity For a pair of enantiomers, the

value of the specific rotation of each is the same, but opposite in sign

[]25D

-13.52 +13.52D25

[]

(R)-(-)-2-Butanol(S)-(+)-2-Butanol

C

OH

CH3CH3CH2

HC

HO

H3C CH2CH3

H

51

Discovery of EnantiomersLouis Pasteur Recrystallized

tartaric acid Two different kinds

of crystals that were mirror images.

Each type of crystal rotated light in opposite directions.

52

Discovery of Enantiomers

“There is no doubt that in dextro tartaric acid there exists an assymetric arrangement having a nonsuperimposible image.”

C

C

COO-Na+

COO-Na+

H

HO H

OH

53

H COOHH

OHOH

HOOCHOOC HH COOH

OHOH

H HCOOH

OHOH

HOOC

meso

enantiomers

(as a minor component)ALSO FOUND

more about thiscompound later

H COOHH

OHOH

HOOCHOOC HH COOH

OHOH

H HCOOH

OHOH

HOOC

meso

enantiomers(+)-tartaric acid (-)-tartaric acid

[]D = 0

meso -tartaric acid

Tartaric Acid

54

R,S Convention Priority rules (Cahn, Ingold, Prelog)

Each atom bonded to the stereocenter is assigned a priority, based on atomic number. The higher the atomic number, the higher the priority

Increasing Priority

H CH3 NH2 OH SH Cl Br I

1 6 7 8 16 17 35 53

55

R,S Convention If priority cannot be assigned on the

basis of the atoms bonded to the stereocenter, look to the next set of atoms. Priority is assigned at the first point of difference.

CH2 H CH2 CH3 CH2 NH2 CH2 OH1 6 7 8

Increasing Priority

56

R,S Convention Atoms participating in a double or

triple bond are considered to be bonded to an equivalent number of similar atoms by single bonds

C

H

O C

H

O

O

C

57

Naming Enantiomers

1. Locate the stereocenter2. Assign a priority to each

substituent from 1 (highest) to 4 (lowest)

3. Orient the molecule so that the group of lowest priority (4) is directed away from you

58

Naming Enantiomers

4. Read the three groups projecting toward you in order from highest (1) to lowest priority (3)

5. If reading is clockwise, configuration is R (from the Latin rectus). If it is counterclockwise, configuration is S (from the Latin sinister).

59

2clockwise counterclockwise

(rectus) (sinister)

view with substituentof lowestpriority inback

1 2

4

3

C C

1

4

3

R S

R, S Convention

60

I

C

BrCl

F

I

C

ClBrF

1

2

3

4

RR SS

1

32

4

Enantiomers

Bromochlorofluoroiodomethane

61

Priorities

1. -OH2. -COOH3. -CH3

4. -H (R)-(-)-lactic acid

C

HHO COOH

CH3

C

H

CH3

HOOC OH

(S)-(+)-lactic acid

62

You try it!

1. Br2. COOH3. CH3

4. H

CH3

Br

H

COOH

HH3C

Br

COOH

63

Diastereoisomer Enantiomers: opposite

configurations at all stereogenic centers.

Diastereomers: Stereoisomers that are not mirror images of each other. Different configuration at some locations.

64

Diastereoisomer Stereoisomers

that are not mirror images of each other. Different configuration at some locations.

COOH

C

C

H

HCH3

NH2

OH

COOH

C

C

H

H OHCH3

H2N

65

Two Stereocenters

diasteromers

entaiomers

entaiomers

Br Cl

H3CH

HCH3

Cl Br

HH3C

CH3

H

Cl Br

HH3C

HCH3

Br Cl

HH3C

HCH3

66

Diastereomers Threonine: 2 pairs

of enantiomers

COOH

C

C

H

H OHCH3

H2N

COOH

C

C

H

HCH3

NH2

OH

2R, 3S 2S, 3R

2R, 3R 2S, 3S

COOH

C

C

H

HHOH3C

NH2

COOH

C

C

H

HH3C

H2N

HO

2R,3R 2S,3S 2R,3S & 2S,3R2S,3S 2R,3R 2R,3S & 2S,3R2R,3S 2S,3R 2R,3R & 2S,3S2S,3R 2R,3S 2R,3R & 2S,3S

67

Enantiomers & Diastereomers For a molecule with 1 stereocenter,

2 stereoisomers are possible For a molecule with 2 stereocenters,

a maximum of 4 stereoisomers are possible

For a molecule with n stereocenters, a maximum of 2n stereoisomers are possible

2n-1 pairs of enantiomers

68

Enantiomers & Diastereomers For tartaric acid, the three possible

stereoisomers are one meso compound and a pair of enantiomers.

Meso compound: an achiral compound possessing two or more stereocenters.

69

Symmetry Plane 2R, 3S and 2S, 3R

are identical Molecule has a

plane of symmetry perpendicular to C-C and is therefore achira

COOH

C

C

H

HO HCOOH

OH

2R, 3S 2S, 3R

2R, 3R 2S, 3S

COOH

C

C

H

OHHCOOH

OHCOOH

C

C

H

HO HCOOH

HO

COOH

C

C

H

OHCOOH

HO

H

70

Symmetry Plane 2R, 3S and 2S, 3R

are identical Molecule has a

plane of symmetry perpendicular to C-C and is therefore achira

One meso compound and a pair of enantiomers

COOH

C

C

H

HO HCOOH

OH

2R, 3S 2S, 3R

2R, 3R 2S, 3S

COOH

C

C

H

OHHCOOH

OHCOOH

C

C

H

HO HCOOH

HO

COOH

C

C

H

OHCOOH

HO

H

Mirror image is identical

71

H CH3

CH3 H

Cl Br

CH3 HH CH3

Br Cl

H HCH3 CH3

Br Cl

CH3CHCHCH3

Cl Br

H HCH3 CH3

Cl Br

enantiomers 1

enantiomers 2

diastereomers

S R RS

S S R R

mirror

2-Bromo-3-chlorobutane

72

H HCH3 CH3

Cl Cl

CH3CHCHCH3

Cl Cl

H HCH3 CH3

Cl Cl

CH3 HH CH3

Cl Cl

H CH3

CH3 H

Cl Cl

meso

enantiomers

diastereomers

S R

S S R R

mirror image is identical

2,3-Dichlorobutane

73

Meso Meso compounds are achiral by virtue

of a symmetry plane, but contain a stereogenic center.

Cl Cl

HH3C

HCH3

Cl Cl

HH3C

HCH3

plane of symmmetry mirror

74

Racemic Mixture Racemic mixture (d,l;): an

equimolar mixture (50:50) of two enantiomers because a racemic mixture contains

equal numbers of dextrorotatory and levorotatory molecules, its specific activity is zero.

75

Properties of Stereoisomers Enantiomers have identical

physical (except for ) and chemical properties.

Diastereomers are different compounds and have different physical and chemical properties

Meso-tartaric acid, for example, has different physical and chemical properties from its enantiomers

76

Tartaric Acid(-) - tartaric acid

[]D = -12.0o

mp 168 - 170o

solubility of 1 g 0.75 mL H2O

1.7 mL methanol 250 mL ether

insoluble CHCl3 d = 1.758 g/mL

(+) - tartaric acid[]D = +12.0o

mp 168 - 170o

solubility of 1 g 0.75 mL H2O

1.7 mL methanol 250 mL ether

insoluble CHCl3 d = 1.758 g/mL

meso - tartaric acid[]D = 0o solubility of 1 gmp 140o 0.94 mL H2Od = 1.666 g/mL insoluble CHCl3

77

H OH

CH3

CH2CH3Fischer Projections Fischer projection: a two-

dimensional representation showing the configuration of a stereocenter horizontal lines represent bonds

projecting forward vertical lines represent bonds

projecting to the rear the only atom in the plane of the paper

is the stereocenter

78

Fischer Projections

(R)-lactic acid

C

COOH

HOH CH3

COOH

CH3

H OH

How?

79

Fischer Projections

C

COOH

HOH CH3

COOH

CH3

H OH

80

Fischer Projections

COOH

CH3

H OH

COOH

CH3

H OH

81

Fischer Projections

1. Orient the stereocenter so that bonds projecting away from you are vertical and bonds projecting toward you are horizontal

2. Flatten it to two dimensions

(S)-2-Butanol (3-D formula)

(1) (2)

(S)-2-Butanol (Fischer projection)

CH3CH2

HCH3

OH

C

CH3

CH2CH3

OHH HC OH

CH3

CH2CH3

82

Assigning R,S Configuration Lowest priority group goes to the

top. View rest of projection. A curved arrow from highest to

lowest priority groups. Clockwise - R (rectus) Counterclockwise - S (sinister)

83

Assigning R,S Configuration

1

2

3

4

H

OH

H3C COOH

s-lactic acid

84

Rules of Motion

Can rotate 180°, but not 90° because 90° disobeys the Fischer projection. Same groups go in and out of plane

CH3

HO H

COOH

CH3

COOH

HO H180

COOH

H OH

CH3

COOH

CH3

H OH= =

85

Rules of Motion

Can rotate 180°, but not 90° because 90° disobeys the Fischer projection. Different groups go in and out of

plane This generates an enantiomeric

structure

H

H3C COOH

OH

H

OH

H3C COOH90

COOH

H OH

CH3

COOH

CH3

H OH= =

(R)-lactic acid (S)-lactic acid

86

Rules of Motion

One group can be held steady and the others rotated.

H

COOH

HO CH3same as

CH3

COOH

H OH

87

Rules of Motion To determine if two Fischer

projections represent the same enantiomer carry out allowed motions. C2H5

CH3

HO H

OH

C2H5

H CH3

H

OH

H3C C2H5

A B C

88

Rules of Motion By performing two allowed

movements on B, we are able to generate projection A. Therefore, they are identical.

H

CH3

HO

CH2CH3

CH2CH3

HHO

CH3

HO

H

CH3

CH2CH3

CH3

B A

CH3CH2

C2H5

CH3

HO H

OH

C2H5

H CH3

H

OH

H3C C2H5

A B C

89

Rules of Motion Perform one of the two allowed

motions to place the group with lowest priority at the top of the Fischer projection.

180

H

CH3

OH

CH2CH3

C not A

CH3H

OH

CH2CH3

CH2CH3

HH3C

OH

OH90

C2H5

CH3

HO H

OH

C2H5

H CH3

H

OH

H3C C2H5

A B C

90

Priorities

1. NH2

2. COOH3. CH3

4. H

S - stereochemistry

CH3

H

HOOC NH2

H

CH3

HOOC NH2

CH3

H2N H

HOOC

CH3

H2N H

HOOC

CH3

HOOC NH2

HCH3

91

Stereochemistry of Reactions

CH3CH2CH CH2ether

CH3CH2CHCH3

Br

achiral chiral

H Br

92

Addition of HBr

Br-

Br-

CCH3CH2

Br

HCH3

CCH3CH2

Br

HCH3

CH3CH2 C

CH3

H

CH3CH2CH CH2ether

H Br

CH3CH2 C

CH3

H

93

Addition of Br2

Cis

Racemic mixture Achiral bromonium ion

C CH H

CH3 CH3Br

Br

C CH H

CH3 CH3

Br2C C

H H

CH3 CH3

Br

Br-

aC C

H H

CH3 CH3Br

Br

ab

ba

b

94

Addition of Br2

Trans

Symmetry plane, therefore meso Models are superimposible

C C

Br

Br

H

H3C

CH3

H

ba

C C

BrH

H3C

CH3

HBr

a

Br-

C CH

CH3

Br

H

CH3Br2

C CH

CH3 H

CH3

b

a b

95

Addition of Br2

C C

Br

Br

H

H3C

CH3

H

C C

BrH

H3C

CH3

HBr

C C

BrH3C

H

CH3

H

Br

96

Addition of HBr to a Chiral Alkene

CH3 HHBr

C CH3

CH3 H HBr

-

CH3

CH3 H Br H

CH3

CH3 H BrH

2S,4R 2R,4R

97

Addition of HBr to a Chiral Alkene Chiral intermediate is not attacked

equally from top and bottom because of steric reasons. Therefore, a mixture of product is formed in unequal amounts.

98

Chirality in Substituted Cyclohexanes Symmetry plane No stereogenic centers 1,4-disubstituted Only cis & trans diastereomers

CH3

CH3

99

1,3-disubstituted Cis Symmetry plane Meso compound

CH3

CH3

CH3

CH3

100

1,3-disubstituted Trans No symmetry plane Therefore enantiomers

CH3

CH3

CH3

CH3

101

1,2-disubstituted Trans Enantiomers

CH3

CH3

CH3

CH3

102

1,2-disubstituted Cis Meso

CH3

CH3

CH3

CH3

103

Br Cl BrCl

Cl

Br Br

Cl

enantiomers

enantiomersdiastereomers

cis

trans

1-Bromo-2-chlorocyclohexane

104

ClBr BrCl

Cl

Br Br

Cl

enantiomers

enantiomers

cis

trans

diastereomers

R S SR

R R S S

1-Bromo-2-chlorocyclopropane

105

BrBr BrBr

Br

Br Br

Br

mirror image identical

meso

enantiomers

diastereomers

cis

trans

1,2-Dibromocyclopropane

106

(S)-ibuprofen

C

H

CH3

COOH