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2

IsomersIsomers: different compounds with the same molecular formulaConstitutional isomers: isomers with a different connectivityStereoisomers: 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

3

Isomerism → Constitutional Isomers and Stereoisomers

Stereoisomers are isomers with the same molecular formula and same connectivity of atoms but different arrangement of atoms in space

4

Stereochemistryis the chemistry of molecules in three dimension

5

HandednessStereochemistry of organic molecules can be understood, if we understand the meaning of handednessthe fundamental reason for this is that our hands are not identical, rather they are mirror images

6

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

7

• Although everything has a mirror image, mirror images may or may not be superimposable.

• Some molecules are like hands. Left and right hands are mirror images, but they are not identical, or superimposable → chiral (property of handedness)

The reason for Handedness→ chirality

8

Mirror Image

9

Chirality and Nonchirality

Mirror image: the reflection of an object in a mirrorObjects that are not superposable on their mirror images are said to be chiral, that is, they show handednessObjects 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

10

• Do these molecules contain a Plane of Symmetry (Mirror Plane)?

Achiral Molecules

11

• The molecule labeled A and its mirror image labeled B are not superimposable. No matter how you rotate A and B, all the atoms never align. Thus, CHBrClF is a chiral molecule, and A and B are different compounds.

• A and B are stereoisomers—specifically, they are enantiomers.

• A carbon atom with four different groups is a tetrahedral stereogenic center.

Chiral Molecules

12

• With one stereogenic center, a molecule will always be chiral.

• With two or more stereogenic centers, a molecule may or may not be chiral, e.g. Meso compound (contains a plane of symmetry or a mirror plane)

Chiral vs. Achiral

13

Chiral vs. AchiralChiral: from the Greek, cheir, hand

an object that is not superposable on its mirror image

Achiral: an object that lacks chirality; one that lacks handedness

an achiral object has at least one element of symmetryplane of symmetry: an imaginary plane passing through an object dividing it so that one half is the mirror image of the other halfcenter of symmetry: a point so situated that identical components are located on opposite sides and equidistant from that point along the axis passing through it

14

Elements of SymmetrySymmetry in objects

15

Plane of Symmetry or Mirror plane

Cl

ClBr

F F

Br

Cl Cl

plane ofsymmetry

TWO VIEWS OF THE PLANE OF SYMMETRY

side view

edgeview

FClBr

17

Plane of Symmetry

C

COOHHH

COOHC

CH3H

COOH

OH

Symmetry plane No symmetry plane

achiral chiral

18

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

19

Chiral Center

The most common (but not the only) cause of chirality in organic molecules is a tetrahedral atom, most commonly carbon, bonded to four different groups

A carbon with four different groups bonded to it is called a chiral center

all chiral centers are stereocenters, but not all stereocenters are chiral centers.

STEREOGENIC CARBON ATOMS

21

BrFH

Cl stereocenterThis is one type of ….

…. others are possible

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

Stereogenic Carbon Atoms

22

• To locate a stereogenic center, examine the four groups—not the four atoms—bonded to each tetrahedral carbon atom in a molecule.

• Omit from consideration all C atoms that cannot be tetrahedral stereogenic centers. These include

• Methylene and methyl units, i. e. CH2 and CH3 groups respectively.

• Any sp or sp2 hybridized Carbons, e.g. triple bonds, and double bonds in alkenes (C=C) and carbonyls (C=O).

Stereogenic Centers

23

Enantiomers

24

One of a pair of molecular species that are mirror images of each other and not superposable.

They are mirror-image stereoisomers.

Enantiomers

25

• To draw both enantiomers of a chiral compound such as 2-butanol, use the typical convention for depicting a tetrahedron: place two bonds in the plane, one in front of the plane on a wedge, and one behind the plane on a dash. Then, to form the first enantiomer, arbitrarily place the four groups—H, OH, CH3 and CH2CH3—on any bond to the stereogenic center. Then draw the mirror image.

Drawing Enantiomers

26

Pairs of Enantiomers

27

BrFH

Cl Cl

HBrF

HFBr

Cl

rotate

this moleculeis chiral note that the fluorine

and bromine have beeninterchanged in theenantiomer

Enantiomers

28

Enantiomers

Lactic acidC

C

HOCH3

H

OHO

C

C

OHH3 CH

O OH

29

Enantiomers3-Chlorocyclohexene

Cl Cl

30

Enantiomers

1,2-propanediolCH3 CHCH 2 OH

OH

C

OH

H

CH2 OHH3 C C

OH

H

HOH2 C CH3

31

EnantiomersA nitrogen chiral center

N

CH2 CH3H3 C

N

CH3CH3 CH2

A pai r of enantiomers

++

32

Enantiomers & Diastereomers

33

Enantiomers & Diastereoisomer

Enantiomers: opposite configurations at all stereogenic centers.Diastereomers: Stereoisomers that are not mirror images of each other. Different configuration at somelocations.

34

Two Stereocenters

diasteromers

entaiomers

entaiomers

Br Cl

H3CH

HCH3

Cl Br

HH3C

CH3H

Cl Br

HH3C

HCH3

Br Cl

HH3C

HCH3

35

Enantiomers & Diastereomers

For a molecule with 1 stereocenter, 2 stereoisomers are possibleFor a molecule with 2 stereocenters, a maximum of 4 stereoisomers are possibleFor a molecule with n stereocenters, a maximum of 2n stereoisomers are possible 2n-1 pairs of enantiomers

36

Enantiomers & Diastereomers2,3,4-Trihydroxybutanal

two chiral centers22 = 4 stereoisomers exist; two pairs of enantiomers

Diastereomers:stereoisomers that are not mirror imagesrefers to the relationship among two or more objects

C

C

H OH

CHO

OH

CH2 OH

H

C

C

HHO

CHO

HO

CH2 OH

H

C

C

H OH

CHO

H

CH2 OH

HO

C

C

HHO

CHO

H

CH2 OH

OH

A pai r of enantiomers(Erythreose)

A pai r of enantiomers(Threose)

37

Enantiomers & Diastereomers2,3-Dihydroxybutanedioic acid (tartaric acid)

two chiral centers; 2n = 4, but only three stereoisomers exist

Meso compound: an achiral compound possessing two or more chiral centers that also has chiral isomers

C

C

H OH

COOH

OH

COOH

H

C

C

HHO

COOH

HO

COOH

H

C

C

H OH

COOH

H

COOH

HO

C

C

HHO

COOH

H

COOH

OH

A pair of enantiomersA meso compound(plane of symmetry)

38

Enantiomers & Diastereomers2-Methylcyclopentanol

H H

CH3 OH

H H

HO H3 C

H OH

CH3 H

HO H

H H3 C

cis- 2-Methyl cyclopentanol (a pai r of enantiomers)

trans- 2-Methyl cyclopentanol (a pai r of enantiomers)

diastereomers

39

Enantiomers & Diastereomers1,2-Cyclopentanediol

H H

OH HO

H H

OH HO

H HO

OH H

OH H

H HO

cis- 1,2-Cyclopentanediol(a meso compound)

trans- 1,2-Cyclopentanediol(a pair of enantiomers)

diastereomers

40

Enantiomers & Diastereomerscis-3-Methylcyclohexanol

OHH3 C HO CH3

41

Enantiomers & Diastereomerstrans-3-Methylcyclohexanol

OH

H3 C

HO

CH3

42

Meso compounds

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

43

Meso compound: achiral despite the presence of stereogenic centers

Not optically activeSuperposable on its mirror imageHas a plane of symmetry

Meso compounds

44

The Three Stereoisomers of 2,3-dibromobutane

• Because one stereoisomer of 2,3-dibromobutane is superimposable on its mirror image, there are only three stereoisomers, not four.

NUMBER OF STEREOISOMERS POSSIBLE

How Many Stereoisomers Are Possible?

maximum number of stereoisomers = 2n,

where n = number of stereocenters(sterogenic carbons)

sometimes fewerthan this numberwill exist

CH3 C

CH2OH

CH3

CH2 CH CH

CH3

CH3

OH*

*

22 = 4 stereoisomers

R RR SS RS S

CH3

OH

CHCH3 CH3

***

23 = 8 stereoisomers

R R RR R SR S RS R R

R S SS R SS S RS S S

CONFIGURATION

ABSOLUTE CONFIGURATION ( R / S )

CONFIGURATION

The three dimensional arrangement of the groups attached to an atom

Stereoisomers differ in the configuration at one ormore of their atoms.

2

CONFIGURATION → R,S convention

clockwise counterclockwise

(rectus) (sinister)

view with substituentof lowestpriority inback

1 2

4

3

C C

1

4

3

R S

51

• Since enantiomers are two different compounds, they need to be distinguished by name. This is done by adding the prefix R or S to the IUPAC name of the enantiomer.

• Naming enantiomers with the prefixes R or S is called the Cahn-Ingold-Prelog system.

• To designate enantiomers as R or S, priorities must be assigned to each group bonded to the stereogenic center, in order of decreasing atomic number. The atom of highest atomic number gets the highest priority (1).

Rules for Labeling Stereogenic Centers with R or S

52

• If two atoms on a stereogenic center are the same, assign priority based on the atomic number of the atoms bonded to these atoms. One atom of higher priority determines the higher priority.

Priority Rules for Naming Enantiomers (R or S)

53

• If two isotopes are bonded to the stereogenic center, assign priorities in order of decreasing mass number. Thus, in comparing the three isotopes of hydrogen, the order of priorities is:

Priority of Isotopes on a Stereogenic Center

54

• To assign a priority to an atom that is part of a multiple bond, treat a multiply bonded atom as an equivalent number of singly bonded atoms. For example, the C of a C=O is considered to be bonded to two O atoms.

Priority Rules for Multiple Bonds in (R or S) Labeling

• Other common multiple bonds are drawn below:

55

Examples Assigning Priorities

56

Cahn-Ingold-Prelog System for Naming Enantiomers R or S

57

R or S Enantiomers

58

Positioning the Molecule for R/S Assignment

59

R-enantiomer (Clockwise Rotation)

S-enantiomer (Counterclockwise Rotation)

60

Manipulation of Chiral Molecules

61

The molecule is rotated to put the lowest priority group back

If the groups descend in priority (a,b then c) in clockwise direction the enantiomer is RIf the groups descend in priority in counterclockwise direction the enantiomer is S

62

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 I1 6 7 8 16 17 35 53

63

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

64

R,S ConventionAtoms participating in a double or triple bond are considered to be bonded to an equivalent number of similar atoms by single bonds

-CH=CH2

O

-CH

C CH

O

H

CCO

C

-CH-CH2

C

C C HC

C

C

C

is treated as

is treated as

is treated as

65

Priorities

1. -OH2. -COOH3. -CH3

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

C

HHO COOH

CH3

C

H

CH3

HOOC OH

(S)-(+)-lactic acid

66

I

CBrCl

F

I

CClBr

F

1

2

3

4

R S

1

32

4

Enantiomers

Bromochlorofluoroiodomethane

67

• When a compound has more than one stereogenic center, the R and S configuration must be assigned to each of them.

R and S Assignments in Compounds with Two or More Stereogenic Centers.

One stereoisomer of 2,3-dibromopentaneThe complete name is (2S,3R)-2,3-dibromopentane

68

Stereoisomerism of Cyclic Compounds1,4-dimethylcyclohexane

Neither the cis not trans isomers is optically activeEach has a plane of symmetry

69

1,3-dimethylcyclohexaneThe trans and cis compounds each have two stereogenic centersThe cis compound has a plane of symmetry and is mesoThe trans compound exists as a pair of enantiomers

70

Properties of Stereoisomers

71

Properties of Stereoisomers

Enantiomers have identical physical and chemical properties in achiral environmentsDiastereomers are different compounds and have different physical and chemical properties

meso tartaric acid, for example, has different physical and chemical properties from its enantiomers (see Table 3.1)

72

Plane-Polarized Light

Ordinary light: light vibrating in all planes perpendicular to its direction of propagationPlane-polarized light: light vibrating only in parallel planesOptically active: refers to a compound that rotates the plane of plane-polarized light

73

Plane-Polarized Lightplane-polarized light is the vector sum of left and right circularly polarized lightcircularly polarized light reacts one way with an R chiral center, and the opposite way with its enantiomerthe result of interaction of plane-polarized light with a chiral compound is rotation of the plane of polarization

74

Plane-Polarized Light

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

75

Optical Activityobserved rotation: the number of degrees, α, through which a compound rotates the plane of polarized lightdextrorotatory (+): refers to a compound that rotates the plane of polarized light to the rightlevorotatory (-): refers to a compound that rotates of the plane of polarized light to the leftspecific rotation: observed rotation when a pure sample is placed in a tube 1.0 dm in length and concentration in g/mL (density); for a solution, concentration is expressed in g/ 100 mL

DD

H3 CC

OHH

COOH

CH3

CHOH

COOH

[α]21 = -2.6°= +2.6°21

[α]

(R)-(-)-Lactatic acid(S)-(+)-Lactic acid

76

Optical PurityOptical purity: a way of describing the composition of a mixture of enantiomers

Enantiomeric excess: the difference between the percentage of two enantiomers in a mixture

optical purity is numerically equal to enantiomeric excess, but is experimentally determined

x 100[α]sam plePercent optical puri ty =

[α]pure enantiomer

x 100[R] + [S][R] - [S]

Enantiomeric excess (ee) = = %R - %S

77

Resolution

Racemic mixture: an equimolar mixture of two enantiomers

because a racemic mixture contains equal numbers of dextrorotatory and levorotatory molecules, its specific rotation is zero

Resolution: the separation of a racemic mixture into its enantiomers

78

• An equal amount of two enantiomers is called a racemate or a racemic mixture. A racemic mixture is optically inactive. Because two enantiomers rotate plane-polarized light to an equal extent but in opposite directions, the rotations cancel, and no rotation is observed.

Racemates

79

• Specific rotation is a standardized physical constant for the amount that a chiral compound rotates plane-polarized light. Specific rotation is denoted by the symbol [α] and defined using a specific sample tube length (l, in dm), concentration (c in g/mL), temperature (25 0C) and wavelength (589 nm).

Specific Rotation

80

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

81

H HCOOH

OH OH

HOOC

meso(as a minor component)

ALSO FOUND

more about thiscompound later

H COOHH

OH OH

HOOCHOOC H

H COOH

OH OH

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

[α]D = 0

meso -tartaric acid

Tartaric Acid

82

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

COOHCC

H

HCH3

NH2

OH

COOHCC

H

H OHCH3

H2N

83

DiastereomersThreonine: 2 pairs of enantiomers

COOHCC

H

H OHCH3

H2N

COOHCC

H

HCH3

NH2

OH

2R, 3S 2S, 3R

2R, 3R 2S, 3S

COOHCC

H

HHOH3C

NH2

COOHCC

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

84

Enantiomers & DiastereomersFor 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.

85

Symmetry Plane2R, 3S and 2S, 3R are identicalMolecule has a plane of symmetry perpendicular to C-C and is therefore achira

COOHCC

H

HO HCOOH

OH

2R, 3S 2S, 3R

2R, 3R 2S, 3S

COOHCC

H

OHHCOOH

OHCOOHCC

H

HO HCOOH

HO

COOHCC

H

OHCOOH

HO

H

86

Symmetry Plane2R, 3S and 2S, 3R are identicalMolecule has a plane of symmetry perpendicular to C-C and is therefore achiraOne meso compound and a pair of enantiomers

COOHCC

H

HO HCOOH

OH

2R, 3S 2S, 3R

2R, 3R 2S, 3S

COOHCC

H

OHHCOOH

OHCOOHCC

H

HO HCOOH

HO

COOHCC

H

OHCOOH

HO

H

Mirror image is identical

87

H CH3CH3 H

Cl Br

CH3 HH CH3

Br Cl

H HCH3 CH3

Br Cl

H HCH3 CH3

Cl Br

enantiomers 1

enantiomers 2

diastereomers

S R RS

S S R R

mirror

2-Bromo-3-chlorobutane

88

H HCH3 CH3

Cl Cl

H HCH3 CH3

Cl Cl

CH3 HH CH3

Cl Cl

H CH3CH3 H

Cl Clmeso

enantiomers

diastereomers

S R

S S R R

mirror imageis identical

2,3-Dichlorobutane

89

Tartaric Acid(-) - tartaric acid

[α]D = -12.0o

mp 168 - 170o

solubility of 1 g0.75 mL H2O

1.7 mL methanol250 mL ether

insoluble CHCl3d = 1.758 g/mL

(+) - tartaric acid[α]D = +12.0o

mp 168 - 170o

solubility of 1 g0.75 mL H2O

1.7 mL methanol250 mL ether

insoluble CHCl3d = 1.758 g/mL

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

90

Fischer Projections

91

H OH

CH3

CH2 CH3Fischer ProjectionsFischer projection: a two-dimensional representation showing the configuration of a stereocenter

horizontal lines represent bonds projecting forward vertical lines represent bonds projecting to the rearthe only atom in the plane of the paper is the stereocenter

92

Fischer Projections

(R)-lactic acid

C

COOH

HOH CH3

COOH

CH3

H OH

How?

93

Fischer Projections

C

COOH

HOH CH3

COOH

CH3

H OH

94

Fischer Projections

COOH

CH3

H OH

COOH

CH3

H OH

95

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)

CH3 CH2

HCH3

OH

C

CH3

CH2 CH3

OHH HC OH

CH3

CH2 CH3

96

Assigning R,S ConfigurationLowest 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)

97

Assigning R,S Configuration

1

2

3

4

H

OHH3C COOH

s-lactic acid

98

Rules of Motion Can rotate 180°, but not 90° because

90° disobeys the Fischer projection.Same groups go in and out of plane

CH3HO H

COOH

CH3

COOHHO H

180COOH

H OH

CH3

COOH

CH3

H OH= =

99

Rules of Motion Can rotate 180°, but not 90° because

90° disobeys the Fischer projection.Different groups go in and out of planeThis generates an enantiomeric structure

HH3C COOH

OH

H

OHH3C COOH

90COOH

H OH

CH3

COOH

CH3

H OH= =

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

100

Rules of Motion One group can be held steady and the

others rotated.

H

COOH

HO CH3same asCH3

COOH

H OH

101

Rules of MotionTo determine if two Fischer projections represent the same enantiomer carry out allowed motions.

C2H5

CH3

HO HOH

C2H5

H CH3

H

OHH3C C2H5

A B C

102

Rules of MotionBy performing two allowed movements on B, we are able to generate projection A. Therefore, they are identical.

HCH3

HOCH2CH3

CH2CH3

HHOCH3

HOH

CH3

CH2CH3CH3

B A

CH3CH2

C2H5

CH3

HO HOH

C2H5

H CH3

H

OHH3C C2H5

A B C

103

Rules of MotionPerform one of the two allowed motions to place the group with lowest priority at the top of the Fischer projection.

180H

CH3

OHCH2CH

C not A

CH3HOH

CH2CH3

CH2CH3

HH3COH

OH90

C2H5

CH3

HO HOH

C2H5

H CH3

H

OHH3C C2H5

A B C

104

Priorities1. NH2

2. COOH3. CH3

4. H

S - stereochemistry

CH3

HHOOC NH2

H

CH3

HOOC NH2

CH3

H2N H

HOOC

CH3

H2N H

HOOC

CH3

HOOC NH2

HCH3

105

Br Cl BrCl

Cl

Br Br

Cl

enantiomers

enantiomersdiastereomers

cis

trans

1-Bromo-2-chlorocyclohexane

106

ClBr BrCl

Cl

Br Br

Cl

enantiomers

enantiomers

cis

trans

diastereomers

R S SR

R R S S

1-Bromo-2-chlorocyclopropane

107

BrBr BrBr

Br

Br Br

Br

mirror image identical

meso

enantiomers

diastereomers

cis

trans

1,2-Dibromocyclopropane

108

Biological Significance of Stereoisomers

Structure Properties

Stereochemistry Biological effects

causes

Example•Pasteur’s plant mold metabolized (+)-tartaric acid but not (-)-tartaric acid

109

Biological Significance of StereoisomersThalidomide

•Marketed in 50 countries 1956-1962Sedative for “hysterical” pregnant womenAntiemetic to combat morning sickness

•Caused thousands of birth defects

N

N

O

O O H

O

•Sold as racemic mixture: 1:1 mixture of enantiomersR enantiomer = antiemetic (not teratogenic)S enantiomer = teratogenic (not antiemetic)

•Single-enantiomer drug not useful: quickly racemizes in body

One stereocenter

Teratogen: causes fetal abnormalities

110

Biological Significance of StereoisomersAnother Biological Effect: Odor

Mirror image molecules do not have “mirror image effects”

enantiomers

(S)-(+)-carvone

O

H

(R)-(-)-carvone

O

H

smells like spearmint smells like caraway

111

Biological Significance of StereoisomersOf Hands, Gloves, and Biology

Why do stereoisomers have different biological properties?•Many biological effects involve interaction with a cavity in enzyme or receptor•Good fit to cavity (i.e., strong binding) triggers enzyme or receptor

•Most amino acids are chiral, so protein cavity is also chiral•Metaphor: Stereoisomer = left hand or right hand

Protein hole = left glove or right gloveLeft hand fits left glove but not right gloveLeft hand triggers “left protein” but not “right protein”

•(R)-carvone triggers spearmint smell receptor but not caraway smell receptor

H2N

O

HR

OH•Enzymes and receptors are proteins; built from amino acids:

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