Chapter 5 Stereoisomerism '13 BW

Background: Stereoisomers !
Chapter 5. Stereoisomerism! ! "

Junha Jeon !
Department of Chemistry ! University of Texas at Arlington ! Arlington, Texas 76019 ! " ! Chem 2321, Fall 13 !
the same connectivity between atoms ! but different 3-diemensional spatial arrangement of their atoms !
Talidomide!
(RS)-2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione! ignore!
5.1 Isomerism!
Nonidentical molecules that have the same formula!
Talidomide!
developed to treat morning sickness! found to be a cause of birth defects (10,000-20,000 victims in 46 countries)!!! !
1 !
Isomerism!
Nonidentical molecules that have the same formula!
cistrans Stereoisomerism: Ring System"
the same connectivity, but not identical" ! cis: two groups are on the same side.! ! trans: two groups are on opposite sides." More generally, ! cis-trans Isomerism: differ in the positions of atoms (or groups) relative to a reference plane
cistrans Stereoisomerism !
!"
cistrans Stereoisomerism: Double Bonds !!
To maintain orbital overlap in the pi bond, ! C=C double bonds cannot freely rotate.!
! cis: two groups are on the same side.! ! trans: two groups are on opposite sides." More generally, ! cis-trans Isomerism: differ in the positions of atoms (or groups) relative to a reference plane different compounds
2 !
5.2 Introduction to Stereoisomerism!

Many other important stereoisomers are available!!! So far,! 1. Stereoisomers, 2.Constitutional isomers!

Many other important stereoisomers are available!!! So far,! 1. Stereoisomers, 2.Constitutional isomers! a) Conformational isomers b) cis-trans isomers !

Many other important stereoisomers are available!!! So far,! 1. Stereoisomers, 2.Constitutional isomers! a) Conformational isomers b) cis-trans isomers ! and! c) Enantiomers d) Diastereomers!
Chirality!
! Two identical objects are superimposable on their mirror images.! !
Molecular Models are now useful!!"
3 !
Chirality!
! Two objects are nonsuperimposable on their mirror images not identical.! !
Chirality!
! Two objects are nonsuperimposable on their mirror images not identical.! ! Chiral molecules are nonsuperimposable on their mirror images and hold handedness. ! !
Chirality!
! Two objects are nonsuperimposable on their mirror images chiral.! ! Chiral molecules are nonsuperimposable on their mirror images and hold handedness. ! !
Chirality!
!" Two identical objects are superimposable on their mirror images achiral.!
Chirality Centers!
! Two objects are nonsuperimposable on their mirror images chiral.! ! Chiral molecules are nonsuperimposable on their mirror images and hold handedness. ! !
Chirality Centers!
! Chiral molecules are nonsuperimposable on their mirror images ! !and hold handedness. ! ! A central tetrahedral carbon atom bearing 4 different groups !
4 !
Chirality Centers!
! Chiral molecules are nonsuperimposable on their mirror images ! !and hold handedness. ! ! A central tetrahedral carbon atom bearing 4 different groups! : chirality center (a.k.a. stereogenic center, stereocenter )!
Chirality Centers!
! Chiral molecules are nonsuperimposable on their mirror images ! !and hold handedness. ! ! A central tetrahedral carbon atom bearing 4 different groups! : chirality center (a.k.a. stereogenic center, stereocenter )!
Enantiomers!
! When a compound is chiral, it should have one nonsuperimposable mirror image, called its enantiomer (opposite); a pair of enantiomers!
Enantiomers!
! When a compound is chiral, it should have one nonsuperimposable mirror image, called its enantiomer (opposite); a pair of enantiomers! ! In other words,! !Enantiomers: two molecules that are mirror images but are nonidentical and nonsuperimposible.! !
Conguration
!!
Designation Conguration: Need a Language !
X Y
X Y
X Y
X Y
! Conguration: the spatial arrangement of the atoms of a molecular entity the

three-dimensional orientation of substituents (cf. conformation: a variety of possible three-dimensional shapes)" ! draw!
5 !
Conguration: the Cahn-Ingold-Prelog System!

1. Using atomic numbers, prioritize the four groups attached to the chirality center.! 2. Arrange the molecule in space so the lowest priority group faces away from you (on a dash).! 3. Count the group priorities 123 to determine whether the order progresses in a clockwise or counterclockwise direction.! Descriptors: Clockwise = R and Counterclockwise = S! ! !

1. Using atomic numbers, prioritize the four groups attached to the chirality center.! 2. Arrange the molecule in space so the lowest priority group faces away from you (on a dash)! 3. Count the group priorities 123 to determine whether the order progresses in a clockwise or counterclockwise direction! Descriptors: Clockwise = R and Counterclockwise = S! ! !

1. Using atomic numbers, prioritize the four groups attached to the chirality center.! 2. Arrange the molecule in space so the lowest priority group faces away from you (on a dash).! 3. Count the group priorities 123 to determine whether the order progresses in a clockwise or counterclockwise direction! Descriptors: Clockwise = R and Counterclockwise = S! ! !

1. Using atomic numbers, prioritize the four groups attached to the chirality center.! 2. Arrange the molecule in space so the lowest priority group faces away from you (on a dash).! 3. Count the group priorities 123 to determine whether the order progresses in a clockwise or counterclockwise direction.! Descriptors (conguration of a chirality center): ! Clockwise = R" Counterclockwise = S! ! !


6 !
Assigning Priorities to All Four Groups!
Assigning Priorities to All Four Groups! 4! 2! 1! 3!
Then conguration?!
Assigning Priorities to All Four Groups! 4! 2! (R)! 1! 3!
7 !
Assigning Priorities to All Four Groups! 4! 2! 3! 1!
Assigning Priorities to All Four Groups! 4! 2! 3! (R)! 1!
Then conguration?!
1! 2! 3!
4!
Then conguration?!
Designating Congurations!
1! 2! (S)! 4!
Nomenclature for alcohols: put ol at the end of names!
3!
8 !
Question: How Many Chirality Centers?!
Question: How Many Chirality Centers?!
OH O O
OH
Ibuprofen Advil!
Ibuprofen Advil!
5.4 Optical Activity!

! Enantiomers: Identical physical properties (e.g. meting point, boiling point)! ! Why?!
Optical Activity!
! Enantiomers: Identical physical properties (e.g. meting point, boiling point)! ! Why? Intermolecular interactions should be identical.!
9 !
Optical Activity!
! Enantiomers: Identical physical properties (e.g. meting point, boiling point)! ! Why? Intermolecular interactions should be identical.! ! ! ! ! ! ! ! ! Are enantiomers distinguishable by any means?!
Optical Activity!
! Enantiomers: rotating in opposite directions upon exposure to plane-polarized light. ! ! Plane-polarized light: the orientation of the electric eld! ! ! ! ! ! !
Optical Activity!
! Enantiomers: rotating in opposite directions upon exposure to plane-polarized light. ! ! Plane-polarized light?! ! ! ! ! !
Optical Activity!
! Enantiomers: rotating in opposite directions upon exposure to plane-polarized light. ! ! Plane-polarization of light? the orientation of the electric eld! ! ! ! ! ! polarized light" unpolarized light"
Optical Activity!
! Enantiomers: rotating in opposite directions upon exposure to plane-polarized light. ! ! Plane-polarized light: only photons of a particular polarization (one directional light) passed through a polarizing lter! ! ! ! ! !
Polarimetry!
! When plane polarized light is directed through a sample of a chiral compound, the plane that the light travels on will rotate: optically active ! ! Optically inactive: the plane that the light travels on will not rotate.! ! ! ! ! !
10 !
Polarimetry!
! When plane polarized light is directed through a sample of a chiral compound, the plane that the light travels on will rotate: optically active ! ! Optically inactive! ! Polarimeter: The light source: a Na lamp (589 nm, i.e. the sodium D line)! ! ! ! ! !
Specic Rotation!
! Enantiomers: rotating in opposite directions upon exposure to plane-polarized light. ! !" Specic rotation [!]: the observed rotation, ! under the standard condition [a standard concentration (1 g/mL) and pathlength (1 dm)], but the temperature effect?!
Specic Rotation!
Specic Rotation!
l: levorotatory!
d: dextrorotatory!
()-2-Bromobutane!
(+)-2-Bromobutane!
Relationship Between R/S Conguration and Specic Rotation!

! R and S refer to the conguration of the chirality center:! independent of measurement conditions ! ! (+) and () signs refer to the direction that the plane of light is rotated:! dependent of measurement conditions (determined experimentally)! Therefore, no relationship between the R/S conguration and ! the direction of light rotation (+/)! !

! R and S refer to the conguration of the chirality center:! independent of measurement conditions ! ! (+) and () signs refer to the direction that the plane of light is rotated:! dependent of measurement conditions (determined experimentally)! Therefore, no relationship between the R/S conguration and ! the direction of light rotation (+/)! !
()-2-Bromobutane!
(+)-2-Bromobutane!
()-2-Bromobutane!
(+)-2-Bromobutane!
11 !

! R and S refer to the conguration of the chirality center:! independent of measurement conditions ! ! (+) and () signs refer to the direction that the plane of light is rotated:! dependent of measurement conditions (determined experimentally)! Therefore, NO relationship between the R/S conguration and ! the direction of light rotation (+/)! !
Enantiomeric Excess!
! Enantiomerically pure (enantiopure, optically pure): only a single enantiomer! ! Racemic mixture (optically inactive): equal amounts of both enantiomers! !" Scalemic mixture (optically active): unequal amounts of both enantiomers (nonracemic chiral compound) enantioenriched! !" Enantiomeric excess (ee): % ee"
()-2-Bromobutane!
(+)-2-Bromobutane!
! Enantiomerically pure (enantiopure, optically pure): only a single enantiomer! ! Racemic mixture (optically inactive): equal amounts of both enantiomers! ! Scalemic mixture (optically active): unequal amounts of both enantiomers (nonracemic chiral compound) enantioenriched! !" Enantiomeric excess (ee): % ee"
Enantiomeric Excess: Practice II!

!" Enantiomeric excess (ee): % ee" Problem 1: enantiomeric excess of a solution (R)-2-bromobutane where the observed specic rotation was found to be 10?! !! ! ! ! ! ! ()-2-Bromobutane! (+)-2-Bromobutane! ! !
12 !
Enantiomeric Excess: Practice II!

!" Enantiomeric excess (ee): % ee" Problem 1: enantiomeric excess of a solution (R)-2-bromobutane where the observed specic rotation was found to be 10.2?! !! ! ! ! ! ! ()-2-Bromobutane! (+)-2-Bromobutane! ! ! " % ee = (10.2)/(23.1) ! = 44.2% ee"
Enantiomeric Excess: Practice I!

!" Enantiomeric excess (ee): % ee" Problem 2: enantiomeric excess of a solution containing 70% (R)-2-bromobutane and 30% (S)-2-bromobutane?! !! ! ! ! ! ! ()-2-Bromobutane! (+)-2-Bromobutane! ! !

!" Enantiomeric excess (ee): % ee" Problem 2: enantiomeric excess of a solution containing 70% (R)-2-bromobutane and 30% (S)-2-bromobutane?! !! ! ! ! ! ! ()-2-Bromobutane! (+)-2-Bromobutane! ! !
% ee = (R) enantiomer + (S) enantiomer (R) enantiomer (S) enantiomer
X

!" Enantiomeric excess (ee): % ee" Problem 2: enantiomeric excess of a solution containing 70% (R)-2-bromobutane and 30% (S)-2-bromobutane?! !! ! ! ! ! ! ()-2-Bromobutane! (+)-2-Bromobutane! !
100% (R) enantiomer (S) enantiomer % ee = (R) enantiomer + (S) enantiomer
X
" 40% ee (40% excess of the ! R stereoisomer)"
100%
Stereoisomeric Relationships!
Diastereomers: stereoisomers that are not mirror images of one another. !(e.g. cistrans isomers) ! ! ! ! ! ! ! !
Diastereomers: stereoisomers that are not mirror images of one another. !(e.g. cistrans isomers) ! ! ! ! ! ! ! !
13 !
Diastereomers: stereoisomers that are not mirror images of one another. !(e.g. cistrans isomers)! ! Lets consider compounds containing more than ! one chirality center.! ! How many chirality centers? And how many possible! stereoisomers?! !
Diastereomeric Relationships!
Diastereomers: stereoisomers that are not mirror images of one another. !(e.g. cistrans isomers)! ! Lets consider compounds containing more than ! one chirality center.! ! How many chirality centers? And how many possible! stereoisomers? 22 = 4! !
! Lets consider compounds containing three chirality centers. And how many possible stereoisomers?! !
14 !
! Lets consider compounds containing three chirality centers. And how many possible stereoisomers? 23 = 8 (4 pairs of enantiomers) ! ! !
Symmetry and Chirality!

! Compounds containing more than one chirality will be chiral: not always true!!! ! Are they chiral?! !
chiral!
achiral!


chiral!
achiral!
chiral!
achiral!
Rotational and Reectional Symmetry!

! Rotational symmetry: an axis of symmetry (Cn) ! (e.g. trans-1,2-dimethylcyclohexane) ; for 90 = C2! ! Reectional symmetry: a plane of symmetry (#) ! (e.g. cis-1,2-dimethylcyclohexane)! !

15 !


! Compounds containing more than one chirality will be chiral: not always true!!! !
Why???!
!
chiral!
achiral!

! Rotational symmetry: an axis of symmetry! Chirality is not dependent in any way on rotational symmetry.! ! Reectional symmetry: a plane of symmetry! Any compound that possesses a plane of symmetry in any conformation will be achiral.! ! ! vs.!

! Rotational symmetry: an axis of symmetry! Chirality is not dependent in any way on rotational symmetry.! ! Reectional symmetry: a plane of symmetry! Any compound that possesses a plane of symmetry in any conformation will be achiral.! ! ! vs.!
identical"

Bonus Additional Reectional Symmetry: A Center of Inversion!

! Reectional symmetry! a plane of symmetry (#) ! a center of symmetry or inversion center (i)! ! Is this compound chiral?!
O N
chiral! achiral!
N O
16 !

! Reectional symmetry! a plane of symmetry (#) ! a center of symmetry or inversion center (i)! ! Is this compound chiral?!

! Reectional symmetry! a plane of symmetry (#) ! a center of symmetry or inversion center (i)! ! Is this compound chiral? ! In fact, no plane of symmetry exists. Then chiral?!
O N
N O
O N
N O

! Reectional symmetry! a plane of symmetry (#) ! a center of symmetry or inversion center (i)! ! Is this compound chiral? But, a center of symmetry (inversion center, one type of reectional symmetry) exists. Therefore, achiral!
Meso Compounds!
Meso compounds: possessing reectional symmetry (a plane of symmetry)! achiral.! ! How many stereoisomers?!
OH OH
O N
N O
Meso Compounds!
Meso compounds: possessing reectional symmetry (a plane of symmetry)! achiral.! ! How many stereoisomers? 22 = 4 ??!
Meso Compounds!
Meso compounds: possessing reectional symmetry (a plane of symmetry)! achiral.! ! How many stereoisomers? 22 = 4 ??! !
OH OH
17 !
Meso Compounds!
Meso Compounds!
meso compound"
5.7 Fischer Projections!
Fischer Projections!
Conguration ? ! Useful for a stereochemistry in sugars ! ! !
Fischer Projections!
5.8 Conformationally Mobile Acyclic System!

! Two conformations (butane) are nonsuperimposible mirror images: Enantiomers! ! Butane in two conformations is not enantiomers!!!! constantly interconverting via single-bond rotation (which occurs with a very low energy barrier)! ! If the fast conformational interconversion can be prevented, two conformational isomers can be enantiomeric. How? extremely low temperature! !
18 !
Conformationally Mobile Acyclic System!

! Two conformations (butane) are nonsuperimposible mirror images: Enantiomers! ! Butane in two conformations is not enantiomers!!! (no chiral compounds, i.e. optically inactive) constantly interconverting via single-bond rotation (which occurs with a very low energy barrier)! ! If the fast conformational interconversion can be prevented, two conformational isomers can be enantiomeric. How? extremely low temperature! !

! Two conformations (butane) are nonsuperimposible mirror images: Enantiomers! ! Butane in two conformations is not enantiomers!!! (no chiral compounds, i.e. optically inactive) constantly interconverting via single-bond rotation (which occurs with a very low energy barrier)! ! If the fast conformational interconversion can be prevented, two conformational isomers can be enantiomeric. Any idea? !

! Two conformations (butane) are nonsuperimposible mirror images: Enantiomers! ! Butane in two conformations is not enantiomers!!! (no chiral compounds, i.e. optically inactive) constantly interconverting via single-bond rotation (which occurs with a very low energy barrier)! ! If the fast conformational interconversion can be prevented, two conformational isomers can be enantiomeric. Any idea? at extremely low temperature!
Conformationally Mobile Cyclic System!

cis-1,2-Dimethylcyclohexane! ! Nonsuperimposible mirror image: enantiomeric?! ! This compound is, however, optically inactive, because the conformations rapidly interconvert at room temperature.! ! !


19 !

cis-1,2-Dimethylcyclohexane! ! Nonsuperimposible mirror image: enantiomeric?! ! This compound is, however, optically inactive, because the conformations rapidly interconvert at room temperature.! ! Meso compound! ! !
5.9 Resolution of Enantiomers!

Enantiomers: Identical physical properties (e.g. meting point, boiling point)! How can we separate them?! ! !
Resolution of Enantiomers: Crystallization!

Enantiomers: Identical physical properties (e.g. meting point, boiling point)! How can we separate them?! 1. Resolution via Crystallization! Pasteur: understood two distinct shapes of crystals (e.g., a racemic mixture of tartrate: not general)! ! !
Resolution of Enantiomers: Resolution!

Enantiomers: Identical physical properties (e.g. meting point, boiling point)! How can we separate them?! 1. Resolution via Crystallization! 2. Resolution: A simple idea is that diastereomers have different physical properties: temporarily generating diastereomers from enantiomers using a resolving agent! !
Resolution of Enantiomers: Resolution!

Enantiomers: Identical physical properties (e.g. meting point, boiling point)! How can we separate them?! 2. Resolution: A simple idea is that diastereomers have different physical properties: temporarily generating diastereomers from enantiomers using a resolving agent! !
Resolution of Enantiomers: Chiral Column Chromatography!

Enantiomers: Identical physical properties (e.g. meting point, boiling point)! How can we separate them?! 1. Resolution via Crystallization! 2. Resolution: A simple idea is that diastereomers have different physical properties: temporarily generating diastereomers from enantiomers using a resolving agent! 3. Chiral column Chromatography: using a chiral absorbent that interacts with each enantiomers differently! !
20 !

Chapter 5 Stereoisomerism '13 BW

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Background: Stereoisomers !

Chapter 5. Stereoisomerism! ! "

cistrans Stereoisomerism: Ring System"

cistrans Stereoisomerism: Double Bonds !!

cistrans Stereoisomerism: Double Bonds !!

cistrans Stereoisomerism: Double Bonds !!

cistrans Stereoisomerism: Double Bonds !!

5.2 Introduction to Stereoisomerism!

5.2 Introduction to Stereoisomerism!

5.2 Introduction to Stereoisomerism!

Molecular Models are now useful!!"

Designation Conguration: Need a Language !

! Conguration: the spatial arrangement of the atoms of a molecular entity the

Conguration: the Cahn-Ingold-Prelog System!

Conguration: the Cahn-Ingold-Prelog System!

Conguration: the Cahn-Ingold-Prelog System!

Conguration: the Cahn-Ingold-Prelog System!

Conguration: the Cahn-Ingold-Prelog System!

Conguration: the Cahn-Ingold-Prelog System!

Assigning Priorities to All Four Groups!

Assigning Priorities to All Four Groups!

Assigning Priorities to All Four Groups!

Assigning Priorities to All Four Groups! 4! 2! 1! 3!

Assigning Priorities to All Four Groups! 4! 2! (R)! 1! 3!

Assigning Priorities to All Four Groups!

Assigning Priorities to All Four Groups! 4! 2! 3! 1!

Assigning Priorities to All Four Groups! 4! 2! 3! (R)! 1!

Assigning Priorities to All Four Groups!

Assigning Priorities to All Four Groups!

Assigning Priorities to All Four Groups!

Nomenclature for alcohols: put ol at the end of names!

Nomenclature for alcohols: put ol at the end of names!

Question: How Many Chirality Centers?!

Question: How Many Chirality Centers?!

5.4 Optical Activity!

Relationship Between R/S Conguration and Specic Rotation!

Relationship Between R/S Conguration and Specic Rotation!

Relationship Between R/S Conguration and Specic Rotation!

Enantiomeric Excess: Practice II!

Enantiomeric Excess: Practice II!

Enantiomeric Excess: Practice I!

Enantiomeric Excess: Practice I!

Enantiomeric Excess: Practice I!

" 40% ee (40% excess of the ! R stereoisomer)"

Symmetry and Chirality!

Symmetry and Chirality!

Symmetry and Chirality!

Rotational and Reectional Symmetry!

Rotational and Reectional Symmetry!

Rotational and Reectional Symmetry!

Symmetry and Chirality!

Rotational and Reectional Symmetry!

Rotational and Reectional Symmetry!

Rotational and Reectional Symmetry!

Bonus Additional Reectional Symmetry: A Center of Inversion!

Bonus Additional Reectional Symmetry: A Center of Inversion!

Bonus Additional Reectional Symmetry: A Center of Inversion!

Bonus Additional Reectional Symmetry: A Center of Inversion!

5.7 Fischer Projections!

Conguration ? ! Useful for a stereochemistry in sugars ! ! !

5.8 Conformationally Mobile Acyclic System!

Conformationally Mobile Acyclic System!

Conformationally Mobile Acyclic System!