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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

2
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

3
Stereochemistry
is the chemistry of molecules in three dimension

4
Handedness
Stereochemistry of organic molecules can be
understood, if we understand the meaning of
handedness
the fundamental reason for this is that our
hands are not identical, rather they are mirror
images

5
Chirality

The mirror image Objects which are chiral have a


of a chiral object is sense of “handedness” and
different and will not exist in two forms.
superimpose on the
original object.
6
The reason for Handedness→ chirality
• 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)

7
Mirror Image

8
Chirality and Nonchirality
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

9
Achiral Molecules
• Do these molecules contain a Plane of Symmetry (Mirror Plane)?

10
Chiral Molecules
• 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.

11
Chiral vs. Achiral
• 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)

12
Chiral vs. Achiral
Chiral: 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
symmetry
plane of symmetry: an imaginary plane passing
through an object dividing it so that one half is the
mirror image of the other half
center 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

13
Elements of Symmetry
Symmetry in objects

14
Plane of Symmetry or Mirror plane

15
TWO VIEWS OF THE PLANE OF SYMMETRY

plane of
symmetry

F F

Cl Cl
Br Cl
Br
Cl
F side edge
Cl
Br view view
Plane of Symmetry

Symmetry plane No symmetry plane


COOH CH3
H C H H C OH
COOH COOH

achiral chiral

17
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

Br H

Cl
Cl

H center of
Br symmetry
18
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.

19
STEREOGENIC CARBON ATOMS
Stereogenic Carbon Atoms

Cl This is one type of ….


stereocenter
…. others are possible

H F
Br
A stereogenic carbon is tetrahedral and
has four different groups attached.
21
Stereogenic Centers
• 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).

22
Enantiomers

23
Enantiomers

One of a pair of molecular species that


are mirror images of each other and
not superposable.

They are mirror-image stereoisomers.

24
Drawing Enantiomers
• 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.

25
Pairs of Enantiomers

26
Enantiomers

Cl Cl rotate

H F F
Br Br H

this molecule Cl
is chiral note that the fluorine
and bromine have been
interchanged in the

H Br enantiomer

F 27
Enantiomers

HO O O OH
Lactic acid C C

C C
HO H H OH
CH 3 H3 C

28
Enantiomers
3-Chlorocyclohexene
Cl Cl

29
Enantiomers
OH
CH 3 CHCH 2 OH
1,2-propanediol
OH OH

H3 C C CH 2 OH HOH 2 C C CH 3

H H

30
Enantiomers
A nitrogen chiral center

+ +
N N
H3 C CH2 CH3 CH3 CH2 CH3
A pai r of enanti omers

31
Enantiomers &
Diastereomers
32
Enantiomers & Diastereoisomer
Enantiomers: opposite configurations at
all stereogenic centers.
Diastereomers: Stereoisomers that are
not mirror images of each other.
Different configuration at some
locations.

33
Two Stereocenters
Cl Br Br Cl
d
H3C CH3 H3C CH3 i
a
H H H H s
t
entaiomers e
r
Cl Br Br Cl o
m
e
r
H3C H H CH3 s

H CH3 H3C H

entaiomers
34
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

35
Enantiomers & Diastereomers
2,3,4-Trihydroxybutanal
two chiral centers
22 = 4 stereoisomers exist; two pairs of
enantiomers
CHO CHO CHO CHO
H C OH HO C H H C OH HO C H

H C OH HO C H HO C H H C OH

CH2 OH CH2 OH CH2 OH CH2 OH


A pai r of enanti omers A pai r of enanti omers
(Eryt hreose) (Threose)

Diastereomers:
stereoisomers that are not mirror images
refers to the relationship among two or more
objects 36
Enantiomers & Diastereomers
2,3-Dihydroxybutanedioic acid (tartaric acid)
two chiral centers; 2n = 4, but only three
stereoisomers exist

COOH COOH COOH COOH

H C OH HO C H H C OH HO C H

H C OH HO C H HO C H H C OH

COOH COOH COOH COOH


A meso compound A pair of enantiomers
(plane of symmetry)
Meso compound: an achiral compound
possessing two or more chiral centers that
also has chiral isomers
37
Enantiomers & Diastereomers
2-Methylcyclopentanol

CH3 OH HO H3 C

H H H H
ci s- 2-Methyl cycl opentanol
(a pai r of enanti omers) di astereomers

CH3 H H H3 C

H OH HO H
trans- 2-Methyl cycl opentanol
(a pai r of enanti omers)

38
Enantiomers & Diastereomers
1,2-Cyclopentanediol

OH HO OH HO

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

OH H H HO

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

39
Enantiomers & Diastereomers
cis-3-Methylcyclohexanol

H3 C OH HO CH 3

40
Enantiomers & Diastereomers
trans-3-Methylcyclohexanol

H3 C CH 3

OH HO

41
Meso compounds

Meso compounds are achiral by virtue of a


symmetry plane, but contain a stereogenic
center.

plane of symmmetry mirror

Cl Cl Cl Cl

H3C CH3 H3C CH3


H H H H

42
Meso compounds
Meso compound: achiral despite the
presence of stereogenic centers
Not optically active
Superposable on its mirror image
Has a plane of symmetry

43
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.
44
NUMBER OF
STEREOISOMERS POSSIBLE
How Many Stereoisomers
Are Possible?

maximum number of stereoisomers


sometimes fewer = 2n,
than this number
will exist

where n = number of stereocenters


(sterogenic carbons)
CH2OH OH RR
RS
CH3 *
C CH2 CH CH CH3 SR
* SS
CH3 CH3
22 = 4 stereoisomers
CH3
RRR RSS
* RRS SRS
RSR SSR
*
* OH SRR SSS

CH3 CH 23 = 8 stereoisomers
CH3
CONFIGURATION

ABSOLUTE CONFIGURATION ( R / S )
CONFIGURATION

The three dimensional arrangement of the


groups attached to an atom

Stereoisomers differ in the configuration at one or


more of their atoms.
CONFIGURATION
→ R,S convention

1 2
clockwise 2 1 counter
clockwise
C C
4 4
3 3
view with
substituent
of lowest
priority in
back
R (rectus) S (sinister)
Rules for Labeling Stereogenic Centers with R or S

• 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).

51
Priority Rules for Naming Enantiomers (R or S)

• 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.

52
Priority of Isotopes on a Stereogenic Center
• 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:

53
Priority Rules for Multiple Bonds in (R or S) Labeling
• 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.

• Other common multiple bonds are drawn below:

54
Examples Assigning Priorities

55
Cahn-Ingold-Prelog System for
Naming Enantiomers R or S

56
R or S Enantiomers

57
Positioning the Molecule for R/S Assignment

58
R-enantiomer (Clockwise Rotation)
S-enantiomer (Counterclockwise Rotation)

59
Manipulation of Chiral Molecules

60
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 R
If the groups descend in priority in
counterclockwise direction the enantiomer is S

61
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
1 6 7 8 16 17 35 53
H CH3 NH2 OH SH Cl Br I

Increasing Priority

62
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.

1 6 7 8
CH2 H CH2 CH3 CH2 NH2 CH2 OH

Increasing Priority

63
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 C
i s treated as
-CH=CH2 -CH-CH2

O O C
i s treated as
-CH C O
H
C C
i s treated as
C CH C C H
C C

64
Priorities
1. -OH H
HO COOH
2. -COOH C
3. -CH3 CH3

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

H
HOOC OH
C
CH3

(S)-(+)-lactic acid 65
Bromochlorofluoroiodomethane
1 1
I I
4 4
F C C
2 F
Cl Br Br Cl
3 3
2

R S
Enantiomers 66
R and S Assignments in Compounds
with Two or More Stereogenic Centers.
• When a compound has more than one stereogenic
center, the R and S configuration must be assigned to
each of them.

One stereoisomer of 2,3-dibromopentane


The complete name is (2S,3R)-2,3-dibromopentane

67
Stereoisomerism of Cyclic Compounds
1,4-dimethylcyclohexane
Neither the cis not trans isomers is optically active
Each has a plane of symmetry

68
1,3-dimethylcyclohexane
The trans and cis compounds each have two
stereogenic centers
The cis compound has a plane of symmetry
and is meso
The trans compound exists as a pair of
enantiomers

69
Properties of Stereoisomers

70
Properties of Stereoisomers
Enantiomers have identical physical and
chemical properties in achiral
environments
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 (see Table 3.1)

71
Plane-Polarized Light

Ordinary light: light vibrating in all


planes perpendicular to its direction of
propagation
Plane-polarized light: light vibrating only
in parallel planes
Optically active: refers to a compound
that rotates the plane of plane-polarized
light

72
Plane-Polarized Light
plane-polarized light is the vector sum of
left and right circularly polarized light
circularly polarized light reacts one way
with an R chiral center, and the opposite
way with its enantiomer
the result of interaction of plane-polarized
light with a chiral compound is rotation of
the plane of polarization

73
Plane-Polarized Light

Polarimeter: a device for measuring the


extent of rotation of plane-polarized
light

74
Optical Activity
observed rotation: the number of degrees, α, through
which a compound rotates the plane of polarized
light
dextrorotatory (+): refers to a compound that
rotates the plane of polarized light to the right
levorotatory (-): refers to a compound that rotates of
the plane of polarized light to the left
specific 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
COOH COOH
C H H C
H3 C OH CH3
HO
(S)-(+)-Lacti c aci d (R)-(-)-L actati c aci d
21 21
[ α] D = +2.6° [ α] D = -2.6°

75
Optical Purity
Optical purity: a way of describing the
composition of a mixture of enantiomers

[α ]sam p l e
Percent opti cal puri ty = x 100
[α ]p u re en an ti o mer
Enantiomeric excess: the difference between
the percentage of two enantiomers in a
mixture
[R] - [S]
Enan ti omeri c excess (ee) = x 100 = %R - %S
[R] + [S]

optical purity is numerically equal to enantiomeric


excess, but is experimentally determined

76
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

77
Racemates
• 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.

78
Specific Rotation
• 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).

79
Discovery of Enantiomers

“There is no doubt
that in dextro - +
tartaric acid there
COO Na
exists an H C OH
assymetric
arrangement HO C H
having a
nonsuperimposible - +
COO Na
image.”

80
Tartaric Acid
OH OH OH OH
HOOC H H COOH
H COOH HOOC H

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

OH OH meso ALSO FOUND


(as a minor component)
HOOC COOH
H H [α]D = 0
more about this
meso -tartaric acid compound later
81
Diastereoisomer
Stereoisomers
that are not
mirror images of H
COOH
NH2
COOH
each other. C H 2N C H

Different C C
H OH H OH
configuration at CH3 CH3
some locations.

82
Diastereomers
Threonine: 2 pairs H
COOH
NH2 COOH
H 2N H
of enantiomers C C
C C
H OH HO H
CH3 H 3C
2R,3R 2S,3S 2R,3S & 2S,3R 2R, 3R 2S, 3S
2S,3S 2R,3R 2R,3S & 2S,3R COOH COOH
2R,3S 2S,3R 2R,3R & 2S,3S H C NH2 H 2N C H
2S,3R 2R,3S 2R,3R & 2S,3S C C
HO H H OH
H 3C CH3

2R, 3S 2S, 3R

83
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.

84
Symmetry Plane
2R, 3S and 2S, 3R COOH COOH
HO H
are identical H C OH C

Molecule has a plane


C C
HO H H OH
COOH
of symmetry
COOH
2R, 3R 2S, 3S
perpendicular to C-C COOH COOH
and is therefore H C OH HO
C
H

achira C C
H OH HO H
COOH COOH

2R, 3S 2S, 3R

85
Symmetry Plane
2R, 3S and 2S, 3R COOH COOH
are identical H C OH HO
C
H

Molecule has a plane HO


C
H H
C
OH
of symmetry COOH COOH
perpendicular to C-C 2R, 3R 2S, 3S

and is therefore COOH


Mirror
COOH
achira H C OH HO H
Cimage is
One meso H
C
OH HO
Cidentical
H
compound and a COOH COOH
pair of enantiomers 2R, 3S 2S, 3R

86
2-Bromo-3-chlorobutane
mirror
Cl Br Br Cl
S R S R
CH3 CH3 CH3 CH3
H H H H
enantiomers 1
diastereomers
Cl Br Br Cl
S S R R
CH3 H H CH3
H CH3 CH3 H
enantiomers 2

87
2,3-Dichlorobutane
Cl Cl Cl Cl
S R mirror image
CH3 CH3 CH3 is identical CH3
H H H H
meso
diastereomers
Cl Cl Cl Cl
S S R R
CH3 H H CH3
H CH3 CH3 H
enantiomers

88
Tartaric Acid
(-) - tartaric acid (+) - tartaric acid
[α]D = -12.0o [α]D = +12.0o
mp 168 - 170o mp 168 - 170o
solubility of 1 g solubility of 1 g
0.75 mL H2O 0.75 mL H2O
1.7 mL methanol 1.7 mL methanol
250 mL ether 250 mL ether
insoluble CHCl3 insoluble CHCl3
d = 1.758 g/mL d = 1.758 g/mL

meso - tartaric acid


[α ]D = 0 o solubility of 1 g
mp 140o 0.94 mL H2O
d = 1.666 g/mL insoluble CHCl3
89
Fischer Projections

90
CH 3

H OH

Fischer Projections CH 2 CH 3

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

91
Fischer Projections

COOH COOH
C H OH
H
OH CH3 CH3
How?
(R)-lactic acid
92
Fischer Projections

COOH COOH

H C H OH
OH CH3 CH3

93
Fischer Projections

COOH COOH
H OH H OH
CH3 CH3
94
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
OH CH3 CH 3

C (1) H C OH (2) H OH
H
CH 3
CH3 CH 2
CH 2 CH 3 CH 2 CH 3
(S)-2-Butanol (S)-2-Butanol
(3-D formula) (Fischer projection)
95
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)

96
Assigning R,S Configuration
4

H
2

3 H 3C COOH
OH
1 s-lactic acid
97
Rules of Motion
 Can rotate 180°, but not 90° because
90° disobeys the Fischer projection.
Same groups go in and out of plane

COOH COOH CH3


CH3
H OH 180 HO H
=H OH HO H =
CH3 CH3 COOH COOH

98
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
COOH COOH H
H
H OH 90 H 3C COOH
=H OH H 3C COOH =
CH3 CH3 OH OH

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

99
Rules of Motion
 One group can be held steady and the
others rotated.

COOH COOH
H OH same as HO CH3
CH3 H

100
Rules of Motion
To determine if two Fischer projections
represent the same enantiomer carry
out allowed motions.
H C 2H 5 OH
H 3C C 2H 5 HO H H CH3
OH CH3 C 2H 5

A B C
101
H C 2H 5 OH
H 3C C 2H 5 HO H H CH3
OH CH3 C 2H 5

Rules of Motion A B C

By performing two allowed movements


on B, we are able to generate
projection A. Therefore, they are
identical.
CH2CH3 HO H
CH3 CH3CH2
HO H H CH2CH3 CH3 CH2CH3
CH3 CH3 HO

B A

102
H C 2H 5 OH
H 3C C 2H 5 HO H H CH3
OH CH3 C 2H 5

Rules of Motion A B C

Perform one of the two allowed motions


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

OH CH2CH3 H
H CH 3 180 H OH CH3
H 3C CH2CH
90
CH2CH3 OH OH

103
C not A
Priorities
HOOC
1. NH2 CH3
H

2. COOH H 2N H HOOC NH2


CH3 CH3
3. CH3
4. H
H H HOOC
HOOC NH2 HOOC NH2
CH3 CH3 H 2N H
CH3
S - stereochemistry 104
1-Bromo-2-chlorocyclohexane
Br Cl Cl Br cis

enantiomers
diastereomers

Br Br trans

Cl Cl
enantiomers
105
1-Bromo-2-chlorocyclopropane

Br R Cl Cl R Br
S S
cis

enantiomers
diastereomers
Br R Br
R S S
trans
Cl Cl

enantiomers
106
1,2-Dibromocyclopropane
mirror image identical

Br Br Br Br
cis

meso
diastereomers

Br Br
trans
Br Br

enantiomers 107
Biological Significance of Stereoisomers

Structure causes Properties

Stereochemistry Biological effects

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

108
Biological Significance of Stereoisomers
Thalidomide
O
•Marketed in 50 countries 1956-1962
Sedative for “hysterical” pregnant women
N O
Antiemetic to combat morning sickness
N
•Caused thousands of birth defects
O O H

Teratogen: causes fetal abnormalities


One stereocenter

•Sold as racemic mixture: 1:1 mixture of enantiomers


R enantiomer = antiemetic (not teratogenic)
S enantiomer = teratogenic (not antiemetic)
•Single-enantiomer drug not useful: quickly racemizes in body

109
Biological Significance of Stereoisomers
Another Biological Effect: Odor
O O
enantiomers

H H

(R)-(-)-carvone (S)-(+)-carvone
smells like spearmint smells like caraway

Mirror image molecules do not have “mirror image effects”


110
Biological Significance of Stereoisomers
Of 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
R H

OH
•Enzymes and receptors are proteins; built from amino acids: H2N

O
•Most amino acids are chiral, so protein cavity is also chiral
•Metaphor: Stereoisomer = left hand or right hand
Protein hole = left glove or right glove
Left hand fits left glove but not right glove
Left hand triggers “left protein” but not “right protein”
•(R)-carvone triggers spearmint smell receptor but not caraway smell receptor

111
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