یئاضف یمیش : مشش لصف
هدیبطق رون
هدیبطق ریغ رون هدیبطق رون

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.

Na lamp
plane-polarized light sample cell a observed rotation a
0
0 polarizer plane is rotated analyzer chemist rotate to null

یئاضف یمیش : مشش لصف
CH
3
-CH
2
-CH
2
-CH
3
H
3
C CH
3
H
C C
H
CH
3
CH
3
-CH-CH
3
ینامتخاس یاهرموزیا
تسا توافتم اهمتا لاصتا هوحن
H
3
C H
H
C C یسدنه یاهرموزیا
CH
3
تسا توافتم اهمتا یسدنه عضو

Stereochemistry
 Some objects are not the same as their mirror images (they have no plane of symmetry)
 A right-hand glove is different than a left-hand glove
 The property is commonly called “handedness”
 Many organic molecules (including most biochemical compounds) have handedness that results from substitution patterns on sp 3 hybridized carbon
5

Louis Pasteur 1848
Sorbonne, Paris
HOOC CH CH COOH
OH OH tartaric acid
( found in wine must )
Na
+
OOC CH CH COO
OH OH
2-
NH
4
+ sodium ammonium tartrate
Pasteur crystallized this substance on a cold day.

Crystals of Sodium Ammonium Tartrate hemihedral faces
Pasteur found two different crystals.
mirror images
Biot’s results :
(+) (
)
Louis Pasteur separated these and gave them to Biot to measure.

non-superimposable mirror images
(also called optical isomers)
X
W
C
Z
Y
W
Y
Z
C
X
Pasteur decided that the molecules that made the crystals, just as the crystals themselves, must be mirror images.
Each crystal must contain a single type of enantiomer.

An object without symmetry is CHIRAL no symmetry
The mirror image of a chiral object is different and will not superimpose on the original object.
OBJECTS WHICH ARE CHIRAL
HAVE A SENSE OF “HANDEDNESS”
AND EXIST IN TWO FORMS

• The flask has a mirror plane, or plane of symmetry
• There is no mirror plane for a hand
10

One of the ways a molecule can be chiral is to have a stereocenter.
A stereocenter is an atom, or a group of atoms, that can potentially cause a molecule to be chiral.
stereocenters - can give rise to chirality

Enantiomers – Mirror Images
12

STEREOGENIC CARBONS
( called “chiral carbons” in older literature )
Cl stereocenter
H
Br
F
A stereogenic carbon is tetrahedral and has four different groups attached.
H
F
Cl
Br

plane of symmetry
Cl
Cl
Br side view
Cl
Cl
Cl
Br edge view
Cl

Chirality Centers



A point in a molecule where four different groups (or atoms) are attached to carbon is called a chirality center
There are two nonsuperimposable ways that
4 different groups (or atoms) can be attached to one carbon atom
A chiral molecule usually has at least one chirality center
15

Enantiomers and the Tetrahedral
Carbon

Enantiomers are molecules that are not the same as their mirror image

They are the “same” if the positions of the atoms can coincide on a one-to-one basis (we test if they are superimposable , which is imaginary)

This is illustrated by enantiomers of lactic acid
16

Mirror-image Forms of Lactic Acid

When H and OH substituents match up, COOH and CH
3 don’t
 when COOH and CH
3 coincide, H and OH don’t
17


Examples of Enantiomers
Molecules that have one carbon with 4 different substituents have a nonsuperimposable mirror image – enantiomer
18


Les énantiomères ont les mêmes propriétés physiques et chimiques, exceptées les réactions où la chiralité entre en jeu, ce qui est le cas dans les mécanismes biologiques. Un exemple tristement célèbre est celui de la thalidomide [1] , un sédatif utilisé dans les années 60. A cette époque, un laboratoire avait commercialisé une formulation où figurait un mélange des deux
énantiomères du principe actif (pour des questions de coût). Or si un des énantiomères était effectivement un sédatif, l'autre
était un tératogène. De nombreuses femmes enceintes ont fait les frais de cette découverte, et les industries pharmaceutiques prennent désormais de sérieuses précautions pour éviter de renouveler cette erreur, en cherchant systématiquement à comparer l'activité biologique de deux énantiomères
19

thalidomide

The Reason for Handedness:
Chirality



Molecules that are not superimposable with their mirror images are chiral (have handedness)
A plane of symmetry divides an entire molecule into two pieces that are exact mirror images
A molecule with a plane of symmetry is the same as its mirror image and is said to be achiral
21

Plane of symmetry
A plane of symmetry bisects a molecule into two mirror image halves. Chlorodifluoromethane has a plane of symmetry.
22

Plane of symmetry
A plane of symmetry bisects a molecule into two mirror image halves.
1-Bromo-1-chloro-2-fluoroethene has a plane of symmetry.
23



If two groups are the same, carbon is achiral.
A molecule with an internal mirror plane cannot be chiral.*
Caution! If there is no plane of symmetry, molecule may be chiral or achiral. See if mirror image can be superimposed.
24

H
H
Cl
Cl
H
H
Cl
Cl cis -1,2-dichlorocyclopentane
H
Cl
Cl
H
Cl
H
H
Cl trans 1,2-dichlorocyclopentane
25

26

maximum number of stereoisomers sometimes fewer than this number will exist
= 2 n , where n = number of stereocenters
(sterogenic carbons)

Chirality Centers in Chiral
Molecules

Groups are considered “different” if there is any structural variation (if the groups could not be superimposed if detached, they are different)

In cyclic molecules, we compare by following in each direction in a ring
28

CH
3
CH
3
CH
2
OH
C
CH
3
CH
2
OH
CH CH
*
CH
3
CH
3
R R
R S
S R
S S
2 2 = 4 stereoisomers
CH
3
*
*
*
OH
R R R
R R S
R S R
S R R
R S S
S R S
S S R
S S S
CH
CH
3
2 3 = 8 stereoisomers

30

31

Problem: Chirality Centers?
32

Center of symmetry
A point in the center of the molecule is a center of symmetry if a line drawn from it to any element, when extended an equal distance in the opposite direction, encounters an identical element.
33

The three dimensional arrangement of the groups attached to an atom
Stereoisomers differ in the configuration at one or more of their atoms.

R
S



Different molecules (enantiomers) must have different names.
Usually only one enantiomer will be biologically active.
O
OH
Configuration around the chiral carbon is specified with ( R ) and ( S ).
H
3
C
C
C
H
NH
2 natural alanine
35

Specific Rotation and Molecules


Characteristic property of a compound that is optically active – the compound must be chiral
The specific rotation of the enantiomer is equal in magnitude but opposite in sign (or direction).
36

Sequence Rules for Specification of
Configuration



The configuration is specified by the relative positions of all the groups with respect to each other at the chirality center
The groups are ranked in an established priority sequence (the same as the one used to determine E or Z) and compared.
The relationship of the groups in priority order in space determines the label applied to the configuration, according to a rule
37

R
S



Different molecules (enantiomers) must have different names.
Usually only one enantiomer will be biologically active.
O
OH
Configuration around the chiral carbon is specified with ( R ) and ( S ).
H
3
C
C
C
H
NH
2 natural alanine
38





Assign a priority number to each group attached to the chiral carbon.
Atom with highest atomic number assigned the highest priority #1.
In case of ties, look at the next atoms along the chain.
Double and triple bonds are treated like bonds to duplicate atoms.
39

یئاضف یمیش : مشش لصف
: یئاضف شیارآ نییعت یارب یلاوت دعاوق
.
دینک بترم یمتا نزو شهاک بسح رب ار دنتسه لصتم لاریاک زکرم هب امیقتسم هک یاهمتا .
1
متا نیمود زا تروص نیا رد دینک نییعت دیتسناوتن لوا هدعاق زا هدافتسا اب ار اههورگ مدقت و تیولوا رگا .
2
.
دینک نییعت ار اههورگ تیولوا و دینک هدافتسا اههورگ رد
رگید متا هب هداس یاه دنویپ اب هک متا دنچ ناونع هب دراد لاصتا رگید متا هب هناگ دنچ دنویپ اب هک یمتا .
3
.
دوش یم یقلت دراد لاصتا
H HO
COOH
H
C H
COOH
CH
OH
3
R
HOOC
H
3
S
H

Sequence Rules (IUPAC)



Assign each group priority according to the Cahn-
Ingold-Prelog scheme With the lowest priority group pointing away, look at remaining 3 groups in a plane
Clockwise is designated R (from “Rectus”
Latin for “right”)
Counterclockwise is designated S (from “Sinister”
Latin word for “left”)
41

R
S



Working in 3D, rotate molecule so that lowest priority group is in back.
Draw an arrow from highest to lowest priority group.
Clockwise = ( R ), Counterclockwise = ( S )
42

R-Configuration at Chirality Center

Lowest priority group is pointed away and direction of higher 3 is clockwise, or right turn
43

3
H
3
C
O
C
2
C
OH
H
1
NH
2
4 natural alanine
H
Cl
2
4
H
3
*
Cl
1
H
C
1
O
H
* C
3
CH
2
C
4
CH(CH
3
)
2
CH
2
OH expands to
2
C
C
H
C
CH
2
H
O
C
C
* C
CH(CH
3
)
2
CH
2
OH
O
44

Examples of Applying Sequence
Rules

If lowest priority is back, clockwise is R and counterclockwise is S
45

Practice Problem
46

Problem: Assign R or S
47

Problem: R or S?
48

Problem: Same structure or
Enantiomers?
49





Same boiling point, melting point, density
Same refractive index
Different direction of rotation in polarimeter
Different interaction with other chiral molecules


Enzymes
Taste buds, scent
50



Rotation of plane-polarized light
Enantiomers rotate light in opposite directions, but same number of degrees.
51
=>






Use monochromatic light, usually sodium D
Movable polarizing filter to measure angle
Clockwise = dextrorotatory = d or (+)
Counterclockwise = levorotatory = l or (-)
Not related to ( R ) and ( S )
52

Observed rotation depends on the length of the cell and concentration, as well as the strength of optical activity, temperature, and wavelength of light.
[ a
] = a
(observed) c
 l c is concentration in g/mL l is length of path in decimeters.
53

a
D

A 1.00-g sample is dissolved in 20.0 mL ethanol. 5.00 mL of this solution is placed in a 20.0-cm polarimeter tube at
25  C. The observed rotation is 1.25
 counterclockwise.
54

55





Equal quantities of d - and l - enantiomers.
Notation: ( d,l ) or (  )
No optical activity.
The mixture may have different b.p. and m.p. from the enantiomers!
56

If optically inactive reagents combine to form a chiral molecule, a racemic mixture of enantiomers is formed.
57




If equilibrium exists between two chiral conformers, molecule is not chiral.
Judge chirality by looking at the most symmetrical conformer.
Cyclohexane can be considered to be planar, on average.
58

H H
H
Br Br
H
Br Br
Nonsuperimposable mirror images, but equal energy and interconvertible .
H H
Br Br
Use planar approximation .
59

If the conformer is sterically hindered, it may exist as enantiomers.
60

یئاضف یمیش : مشش لصف
X
Y
C
*
X
C C
N
H
H
3
C
H
H
3
C
Y
N
X
Y
F
Et
F
Et
X
Y
F
Y
Et F
CO
2
H
C
CO
2
H
O
2
N
C
N
Cl
Y
N
*
H
NO
2
CH
3
2
*
C
H
CH
3
X
X
C
*
Y

Chirality at Atoms Other Than
Carbon
• Trivalent nitrogen is tetrahedral
• Does not form a stable chirality center since it rapidly inverts
62

• Chiral compounds with no chiral carbon
• Contains sp hybridized carbon with adjacent double bonds: -C=C=C-
• End carbons must have different groups.
This Allene is achiral.
63

McMurry Organic Chemistry 6th edition Ch 9 (c) 2003

“Sawhorse” Projection
CHO
HOCH
2
H
OH
EVOLUTION OF THE
FISCHER PROJECTION
Orient the main chain vertically with the most oxidized group at the top.
CHO
H OH
CH
2
OH
Substituents will stick out toward you like prongs
Fischer Projection
H
CHO
OH
CH
2
OH
Main chain bends away from you






Carbon chain is on the vertical line.
Highest oxidized carbon at top.
Rotation of 180  in plane doesn’t change molecule.
Do not rotate 90  !
Do not turn over out of plane!
66

HOOC
H
OH
H
CH
3
OH
CH
3
HO C
H
COOH
CH
3
یئاضف یمیش : مشش لصف
: رشیف یاهحرط
H
3
C
H
C
COOH
OH
90 o
HOOC
R S
OH
180 o
CH
3
C H
HO
COOH
C
H
R
CH
3

INCREASING OXIDATION STATE
C=O on carbon-2 increases the priority of C-OH
CH
3
CH
2
OH CH
C O
OH CHO
O
C
H increasing oxidation state
COOH
C
O
OH
In the Fisher projection the main chain is oriented with the most highly oxidized group at the top.

PLACE THE PRIORITY=4 GROUP IN ONE OF THE VERTICAL
POSITIONS, THEN LOOK AT THE OTHER THREE
2
CHO
OH
1
4 H
CH
2
OH
3 alternatively:
4 H
2
CHO
OH
1
CH
2
OH
3
H
4
#4 at top position
OHC
2
3
R
HOCH
2
OH
1
CH
2
OH
R
3
1
BOTH IN BACK
SAME RESULT
OH
2
CHO
4
H
#4 at bottom position



Easy to draw, easy to find enantiomers, easy to find internal mirror planes.
Examples:
H
Cl
CH
3
Cl
CH
3
H
Cl
H
CH
3
H
CH
3
Cl
H
H
CH
3
Cl
CH
3
Cl
 a
An achiral compound with chirality centers is called meso compound – it has a plane of symmetry
71

R
S



Lowest priority (usually H) comes forward, so assignment rules are backwards!
Clockwise 1-2-3 is (
1-2-3 is ( R ).
S ) and counterclockwise
Example:
( S )
CH
3
H Cl
Cl
CH
3
H
( S)
72


50:50 تبسن هب رمویتنانا ود زا یطولخم : کیمسار طولخم
شخر چ رظن زا طقف و دنتسه ناسکی یکیزیف صاوخ یاراد اه رم ویتنانا
.
تسا لکشم مه زه اهنآ یزاسادج لیلد نیمه هب .
دنتسه توافتم هدیبطق رون
2 زا شیب ای 2 اب ییاه لوکلوم ( دنتسه ییاضف یاه رموزیا اهرم وئرتساید
تواف تم یکیزیف صاوخ و دنتسین مه یا هنیآ ریواصت هک ) لاریاک زکرم
) توافتم شوجو بوذ هطقن ( .
دنراد
.
دریگیم تروص یتحار هب اهنا یزاسادج
دنتسهرم وئرتساید یعون زین سنارت و سیس یسدنه یاهرموزیا

Physical Properties of Stereoisomers
74

Cis-trans isomers are not mirror images, so these are diastereomers.
H H
C C
H
3
C CH
3
cis-2-butene
H CH
3
C C
H
3
C H
trans-2-butene
75

H
COOH
NH
3
HO
CH
3
2R, 3S
H
H
H
COOH
NH
3
*
*
OH
CH
3
2R, 3R
رموئرتساید
2 n = اه رموزیا دادعت
رمویتنانا
رمویتنانا
H
2
N
COOH
H
HO
CH
3
2S, 3S
H
: اه رموئرتساید
H
2
N
H
CH
3
2S, 3R
OH
رموئرتساید
COOH
H

H
H
COOH
OH
*
*
OH
COOH
2R, 3S
180 o
HO HO H H H
: وزم تابیکرت
COOH
OH
H HO OH H HO
2S, 3S 2S, 3R
H
COOH
2R, 3R
وزم

Meso compounds have internal mirror plane.
رمویتنانا

H
HO
COOH
OH
H
COOH
(2R,3R)-tartaric acid
HO
H
COOH
H
OH
COOH
(2S,3S)-tartaric acid
H
H
COOH
OH
OH
COOH
(2R,3S)-tartaric acid
78

79

یئاضف یمیش : مشش لصف
: اهرمویتنانا یزاسادج
Et
H
H
3
C
C
S
NH
2
H
2
N
Et
C B
H
CH
+
3
R
S
H
H
3
B C
R
OH
OH
C
A
S
COOH
H
H
3
C
C
OH
H
H
3
C
C
رمویتنانا
AB
H
H
3
C
R S
Et
C
Et
NH
3
+
AB
3
N
C
H
CH
3
B
S
NaOH
B
R
رموئرتساید
Et
H
H
3
C
C
NH
2
S
Et
H
2
N
C
H
CH
3
R

React a racemic mixture with a chiral compound to form diastereomers, which can be separated .
=>
81

82

=>
83

Problem: Assign configurations
84

Problem: R or S?
85

Problem: Assign R or S
86

Another example of a meso compound
87

A Brief Review of Isomerism
88

Constitutional Isomers

Different order of connections gives different carbon backbone and/or different functional groups
89

Stereoisomers

Same connections, different spatial arrangement of atoms

Enantiomers (nonsuperimposable mirror images)

Diastereomers (all other stereoisomers)

Includes cis, trans and configurational
90

Stereochemistry of Reactions:
Addition of HBr to Alkenes



Many reactions can produce new chirality centers from compounds without them
What is the stereochemistry of the chiral product?
What relative amounts of stereoisomers form?
91

CH
3
CH
2
CH CH
2
Br
_
CH
3
CH
2
CH CH
2
HBr
H
+
یئاضف یمیش : مشش لصف
: اه نکلآ هب HBr شیازفا
Br
CH
3
CH
2
CH
2
CH
3
کیمسار طولخم
+
CH
3
CH
2
CH
2
CH
3
H
3
CH
2
C
+
C
H
CH
3
Br
_
Br
H
3
CH
2
C
C
H
CH
3
S
H
3
CH
2
C
C
H
CH
3
R
Br

H
H
3
C
C C
H
CH
3
Br
2
H
H
3
C
C C
H
CH
3
Br
2
Br
+
H
H
3
C
C
Br
_
C
H
CH
3
Br
+
H
H
3
C
C
Br
_
C
H
CH
3
یئاضف یمیش : مشش لصف
H
H
3
C
Br
C C
: اه نکلآ هب Br
2
شیازفا
Br Br
CH
3
H
2R, 3S
Br
H
H
3
C CH
H
3
H
3
C
H
C
Br
C
Br
2S, 3R
H
CH
3
Br Br
H
3
C
H
Br
H
CH
3
Br Br
H
H
3
C
C C
H
CH
3
2R, 3R
Br
H
H
3
C H
CH
3
Br
H
3
C
H
C
Br Br
C
H
CH
3
2S, 3S
Br H
3
C
H CH
H
3

Stereochemistry of Reactions:
Addition of HBr to a Chiral Alkene

Gives diastereomers in unequal amounts.

Facial approaches are different in energy
94

Prilosec (omeprazole): Chiral Sulfur
Racemic (at sulfur); the S enantiomer is physiologically active
95

Pure (S) enantiomer
96

Chirality in Nature

Stereoisomers are readily distinguished by chiral receptors in nature

Properties of drugs depend on stereochemistry

Think of biological recognition as equivalent to 3-point interaction
97

98

The Importance of Stereochemistry
CHIRALITY       ACTIVITY
( orange odor )
R configuration
Limonene
S
( lemon odor )
( extremely toxic )
( contraceptive )
H
3
C CH
3
COOH
HS
NH
2
CH
3
O N
H
CH
3
OH
Penicillamine
Propranolol
HOOC
H
3
C CH
3
NH
2
H
3
C
CH
3
N
H
HO
O
SH
( antiarthritic )
(

-bloker )
Chiralica Merck