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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

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

is the chemistry of molecules in three dimension

Stereochemistry

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

Chirality

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 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)

Mirror Image

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

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

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 stereoisomersspecifically, they are enantiomers. A carbon atom with four different groups is a tetrahedral stereogenic center.

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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)

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Chiral: from the Greek, cheir, hand

Chiral vs. Achiral

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
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Elements of Symmetry
Symmetry in objects

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Plane of Symmetry or Mirror plane

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TWO VIEWS OF THE PLANE OF SYMMETRY


plane of symmetry

F Br Cl
F Cl Br

F Cl Br
edge view

Cl
side view

Cl

Plane of Symmetry
Symmetry plane COOH H C H COOH achiral No symmetry plane CH3 H C OH COOH chiral

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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 Cl Cl H Br ce nter of symmetry H

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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.

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STEREOGENIC CARBON ATOMS

Stereogenic Carbon Atoms

Cl H

This is one type of .

stereocenter

. others are possible

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

Stereogenic Centers
To locate a stereogenic center, examine the four groupsnot the four atomsbonded 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).

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Enantiomers

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Enantiomers
One of a pair of molecular species that are mirror images of each other and not superposable. They are mirror-image stereoisomers.

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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 groupsH, OH, CH3 and CH2CH3on any bond to the stereogenic center. Then draw the mirror image.

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Pairs of Enantiomers

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Enantiomers
Cl H
this molecule is chiral

Cl F Br

rotate

F Br
Cl H Br F

H
note that the fluorine and bromine have been interchanged in the enantiomer
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Enantiomers
Lactic acid
HO C C HO H CH3 H H3 C O O C C OH OH

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Enantiomers
3-Chlorocyclohexene
Cl Cl

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Enantiomers
OH

1,2-propanediol
OH H3 C C H CH2 OH HOH2 C C H

CH 3 CHCH 2 OH

OH CH3

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Enantiomers
A nitrogen chiral center
+
H3 C

N CH2 CH3

N CH3 CH2 CH3

A pair of enantiomers

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Enantiomers & Diastereomers


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Enantiomers & Diastereoisomer


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

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

entaiomers

Cl Br H3C H H CH3

entaiomers
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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

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Enantiomers & Diastereomers


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

CH2 OH

CH2 OH

CH2 OH

CH2 OH

A pair of e nantiomers (Eryth reos e)

A pair of e nantiomers (Threos e)

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

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Enantiomers & Diastereomers


2,3-Dihydroxybutanedioic acid (tartaric acid)
two chiral centers; 2n = 4, but only three stereoisomers exist
COOH H H C C OH HO OH HO COOH C C H H H HO COOH C C OH HO H H COOH C C H OH

COOH

COOH

COOH

COOH

A meso compound (plane of symme try)

A pair of enantiomers

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


2-Methylcyclopentanol
CH3 OH HO H3 C

H H H H cis- 2-Methylcyclope ntanol (a pair of enantiomers) CH3 H H H3 C

diastereomers

H OH H HO trans- 2-Methylcyclope ntanol (a pair of en antiomers)

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Enantiomers & Diastereomers


1,2-Cyclopentanediol
OH HO OH HO

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


H HO

diastereomers

OH

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

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Enantiomers & Diastereomers


cis-3-Methylcyclohexanol
H3 C OH HO CH3

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Enantiomers & Diastereomers


trans-3-Methylcyclohexanol
H3 C OH HO CH3

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Meso compounds
Meso compounds are achiral by virtue of a symmetry plane, but contain a stereogenic center.
plane of symmmetry

mirror

Cl Cl H3C H H CH3 H3C H

Cl Cl H CH3

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

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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.
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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 CH3 CH3


CH3

OH CH3

* C CH2 CH CH CH3 *

RR RS SR SS

22 = 4 stereoisomers RRR RRS RSR SRR RSS SRS SSR SSS

* *
CH3

OH CH3

CH

23 = 8 stereoisomers

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 C 4 4

clockwise

2 C

counter clockwise

3
view with substituent of lowest priority in back

(rectus)

(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).

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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.

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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:

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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:

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Examples Assigning Priorities

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

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R or S Enantiomers

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Positioning the Molecule for R/S Assignment

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R-enantiomer (Clockwise Rotation)

S-enantiomer (Counterclockwise Rotation)

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Manipulation of Chiral Molecules

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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

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

Increasing Priority
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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 CH2 H 6 CH2 CH3 7 CH2 NH2 8 CH2 OH

Increasing Priority
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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 -CH=CH2 O -CH is treated as is treated as C -CH-CH2 O C C H C CH is treated as C C C C H C C O

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Priorities
1. -OH
2. -COOH 3. -CH3 4. -H
HO H C COOH

CH3 (R)-(-)-lactic acid


H C

HOOC

OH

CH3 (S)-(+)-lactic acid


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Bromochlorofluoroiodomethane
1 1

I
4

I
4

F Cl

C Br
3

F Br
2

C Cl
3

R
Enantiomers

S
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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

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Stereoisomerism of Cyclic Compounds


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

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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

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Properties of Stereoisomers

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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)
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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
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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

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

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Optical Activity
observed rotation: the number of degrees, , 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 H H3 C OH (S)-(+)-Lactic acid [] D = +2.6
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COOH H C CH3 HO (R)-(-)-Lactatic acid [] D = -2.6


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Optical Purity
Optical purity: a way of describing the composition of a mixture of enantiomers
Percent optical purity =

[ ]s am p le []p u re en an tio mer

x 100

Enantiomeric excess: the difference between the percentage of two enantiomers in a mixture
[R] - [S] x 100 = %R - %S Enantiomeric excess (ee) = [R] + [S]

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


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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

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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.

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

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Discovery of Enantiomers
There is no doubt that in dextro tartaric acid there exists an assymetric arrangement having a nonsuperimposible image.

COO Na H C OH HO C H COO Na
-

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OH OH HOOC H H

meso COOH

Tartaric Acid
OH OH OH OH H HOOC COOH H H COOH enantiomers

HOOC H

(+)-tartaric acid

(-)-tartaric acid

OH OH HOOC H H OH OH

meso COOH

ALSO FOUND
(as a minor component)

meso -tartaric acid

[]D = 0 more about this compound later

OH OH

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Diastereoisomer
Stereoisomers that are not mirror images of each other. Different configuration at some locations.
COOH NH2 H C H C OH CH3 COOH H 2N C H H C OH CH3

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

2R, 3R COOH H C NH2 HO H H 3C 2R, 3S C

2S, 3R
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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.

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Symmetry Plane
2R, 3S and 2S, 3R are identical Molecule has a plane of symmetry perpendicular to C-C and is therefore achira
COOH H C OH C HO H COOH 2R, 3R H COOH H HO C C OH COOH 2S, 3S

COOH H C OH H C OH COOH

COOH H HO C HO C H COOH 2S, 3R


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2R, 3S

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 H C OH C HO H COOH 2R, 3R H COOH H HO C C OH COOH 2S, 3S

COOH H C OH H C OH COOH

COOH Mirror H HO C image is C identical HO H COOH 2S, 3R


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2R, 3S

CH3CHCHCH3

2-Bromo-3-chlorobutane
Cl Br
S R
mirror

Cl Br

Br Cl
S R

CH3
diastereomers

H Cl Br

CH3

CH3

H Br Cl

CH3

enantiomers 1 S S

CH3

H CH3
enantiomers 2

H CH3

CH3

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CH3CHCHCH3

2,3-Dichlorobutane
Cl Cl
S R

Cl Cl

Cl Cl CH3
meso mirror image CH3 is identical CH3

CH3
diastereomers

H Cl Cl

Cl Cl
R R

CH3

H CH3
enantiomers

H CH3

CH3

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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 g


mp 140o d = 1.666 g/mL 0.94 mL H2O insoluble CHCl3
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Fischer Projections

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CH 3 H OH CH 2 CH 3

Fischer 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
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Fischer Projections

COOH

COOH

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

COOH C H H OH CH3

COOH OH CH3
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Fischer Projections

COOH H CH3 OH H

COOH OH CH3
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Fischer Projections
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
1.
OH H CH 3 CH 2 C CH 3 CH 2 CH 3 CH 2 CH 3 (S)-2-Butanol (Fischer projection)
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CH 3 (1) H C OH (2) H

CH 3 OH

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

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)

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Assigning R,S Configuration


4

H
2 3

H 3C OH 1

COOH
s-lactic acid
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Rules of Motion
Can rotate 180, but not 90 because 90 disobeys the Fischer projection.
Same groups go in and out of plane

COOH H OH CH3

COOH =H OH CH3 180 HO

CH3 H COOH =

CH3 HO H COOH

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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 H OH CH3 COOH =H OH CH3 90 H 3C OH (S)-lactic acid
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H COOH = H 3C

H COOH OH

(R)-lactic acid

Rules of Motion
One group can be held steady and the others rotated.
COOH H OH CH3 same as HO H COOH CH3

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Rules of Motion
To determine if two Fischer projections represent the same enantiomer carry out allowed motions.
H H 3C OH A C2H 5 HO C2H 5 H CH3 B H OH CH3 C 2H5 C
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H H 3C OH C2H 5 HO

C2H 5 H CH3 B H

OH CH3 C 2H5 C

Rules of Motion
A

By performing two allowed movements on B, we are able to generate projection A. Therefore, they are identical.
CH2CH3 HO H CH3 B CH3 HO H CH2CH3 CH3 CH3CH2 CH3 HO A
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H CH2CH3

H H 3C OH C2H 5 HO

C2H 5 H CH3 B H

OH CH3 C 2H5 C

Rules of Motion
A

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

OH H CH3 CH2CH3 C 180 H3C

CH2CH3 H OH OH 90 CH3

H OH
102 not A

CH2CH

Priorities
1. NH2
2. COOH 3. CH3 4. H
H HOOC NH 2 CH 3 S - stereochemistry HOOC H NH 2 CH 3
HOOC CH3 H2N H CH3 HOOC H NH2 CH3

HOOC H2N H CH3


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1-Bromo-2-chlorocyclohexane
Br Cl Cl Br

cis

diastereomers
Br Cl

enantiomers

Br Cl

trans

enantiomers
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1-Bromo-2-chlorocyclopropane
Br R
S

Cl

Cl R

Br

cis

diastereomers Br

enantiomers R R S S

Br

trans
Cl Cl

enantiomers
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1,2-Dibromocyclopropane
mirror image identical

Br

Br

Br

Br

cis
meso

diastereomers

Br Br Br

Br

trans

enantiomers

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Biological Significance of Stereoisomers


Structure
Stereochemistry causes

Properties
Biological effects

Example Pasteurs plant mold metabolized (+)-tartaric acid but not (-)-tartaric acid

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Biological Significance of Stereoisomers

Thalidomide

Marketed in 50 countries 1956-1962 Sedative for hysterical pregnant women Antiemetic to combat morning sickness Caused thousands of birth defects

N N 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

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Biological Significance of Stereoisomers

Another Biological Effect: Odor


O O

enantiomers

(R)-(-)-carvone smells like spearmint

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

Mirror image molecules do not have mirror image effects


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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

Enzymes and receptors are proteins; built from amino acids:

OH 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

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