11Fall, 2009Fall, 2009

Organic Chemistry IOrganic Chemistry IStereochemistryStereochemistry

Unit 9Unit 9

Dr. Ralph C. GatroneDr. Ralph C. GatroneDepartment of Chemistry and PhysicsDepartment of Chemistry and Physics

Virginia State UniversityVirginia State University

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Chapter ObjectivesChapter Objectives

• EnantiomersEnantiomers

• ChiralityChirality

• Optical ActivityOptical Activity

• Specifying ConfigurationSpecifying Configuration

• DiastereomersDiastereomers

• ResolutionResolution

• ProchiralityProchirality

• Chirality in NatureChirality in Nature

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StereochemistryStereochemistry• Consider your handsConsider your hands

– Right Hand mirror image of Left HandRight Hand mirror image of Left Hand– Non-superimposableNon-superimposable

• Consider molecules shown on leftConsider molecules shown on left– First and Second sets are superimposableFirst and Second sets are superimposable– Third set is non-superimposable with mirror imageThird set is non-superimposable with mirror image

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Plane of SymmetryPlane of Symmetry

• The plane has the The plane has the same thing on both same thing on both sides for the flasksides for the flask

• There is no mirror There is no mirror plane for a handplane for a hand

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StereochemistryStereochemistry

• Some objects are not the same as their mirror Some objects are not the same as their mirror images images

• no plane of symmetryno plane of symmetry– A right-hand glove is different than a left-hand A right-hand glove is different than a left-hand

gloveglove– The property is commonly called The property is commonly called

“handedness”“handedness”

• Organic molecules (including many drugs) Organic molecules (including many drugs) have handedness that results from have handedness that results from substitution patterns on substitution patterns on spsp33 hybridized carbon hybridized carbon

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Enantiomers – Mirror Enantiomers – Mirror ImagesImages• Molecules exist as three-dimensional objectsMolecules exist as three-dimensional objects

– Some molecules are the same as their mirror imageSome molecules are the same as their mirror image– Some molecules are different than their mirror image Some molecules are different than their mirror image

• Stereoisomers that are non-superimposable Stereoisomers that are non-superimposable with their mirror images are with their mirror images are – EnantiomersEnantiomers– Arises when we have 4 different groups on an spArises when we have 4 different groups on an sp33

Carbon atomCarbon atom

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Chirality and EnantiomersChirality and Enantiomers

• Chirality arisesChirality arises– spsp33 C atom has 4 different substituents C atom has 4 different substituents

• The C is referred to asThe C is referred to as– A chiral centerA chiral center– A stereogenic centerA stereogenic center– An asymmetric centerAn asymmetric center

• Chirality is a molecular propertyChirality is a molecular property– Due to presence of a chiral centerDue to presence of a chiral center

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Enantiomers and the Enantiomers and the Tetrahedral CarbonTetrahedral Carbon

• EnantiomersEnantiomers are molecules that are not are molecules that are not superimposable with their mirror imagesuperimposable with their mirror image

• Illustrated by enantiomers of lactic acidIllustrated by enantiomers of lactic acid

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Examples of EnantiomersExamples of Enantiomers

• Molecules that have one carbon with 4 Molecules that have one carbon with 4 different substituents have a different substituents have a nonsuperimposable mirror image – enantiomernonsuperimposable mirror image – enantiomer

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Chirality CentersChirality Centers

• A point in a molecule where four different groups (or atoms) are attached A point in a molecule where four different groups (or atoms) are attached to carbon is called a to carbon is called a chirality centerchirality center

• There are two nonsuperimposable ways that 4 different different groups There are two nonsuperimposable ways that 4 different different groups (or atoms) can be attached to one carbon atom(or atoms) can be attached to one carbon atom– If two groups are the same, then there is only one wayIf two groups are the same, then there is only one way

• A chiral molecule usually has at least one chirality center A chiral molecule usually has at least one chirality center

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Chirality Centers in Chiral Chirality Centers in Chiral MoleculesMolecules• Groups are considered “different” if there is any Groups are considered “different” if there is any

structural variation (if the groups could not be structural variation (if the groups could not be superimposed if detached, they are different)superimposed if detached, they are different)

• In cyclic molecules, we compare by following in In cyclic molecules, we compare by following in each direction in a ringeach direction in a ring

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LightLight

• As light travels it oscillates at right angles As light travels it oscillates at right angles to the forward directionto the forward direction

• If it passes through a thin slit, all light If it passes through a thin slit, all light except one plane (the slit) is toppedexcept one plane (the slit) is topped

• That single plane of light is known as That single plane of light is known as “Plane Polarized Light”“Plane Polarized Light”

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Optical ActivityOptical Activity• Biot in early 19Biot in early 19thth Century discovered Century discovered

– Plane-polarized light that passes through Plane-polarized light that passes through solutions of achiral compounds remains in that solutions of achiral compounds remains in that planeplane

– Solutions of chiral compounds rotate plane-Solutions of chiral compounds rotate plane-polarized light and the molecules are said to polarized light and the molecules are said to be be optically activeoptically active

• Some molecules caused plane polarized Some molecules caused plane polarized light to rotate to the right (dextrorotatory), light to rotate to the right (dextrorotatory), others to the left (levorotatory)others to the left (levorotatory)

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Optical ActivityOptical Activity

• Light passes through a plane polarizerLight passes through a plane polarizer

• Plane polarized light is rotated in solutions Plane polarized light is rotated in solutions of optically active compoundsof optically active compounds

• Measured with polarimeterMeasured with polarimeter

• Rotation, in degrees, is [Rotation, in degrees, is []]

• Clockwise rotation is called Clockwise rotation is called dextrorotatorydextrorotatory

• Counterclockwise is Counterclockwise is levorotatorylevorotatory

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Measurement of Optical Measurement of Optical RotationRotation• A A polarimeterpolarimeter measures the rotation of plane- measures the rotation of plane-

polarized that has passed through a solutionpolarized that has passed through a solution• The source passes through a The source passes through a polarizerpolarizer and and

then is detected at a second polarizerthen is detected at a second polarizer• The angle between the entrance and exit The angle between the entrance and exit

planes is the optical rotation.planes is the optical rotation.

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A Simple PolarimeterA Simple Polarimeter

• Measures extent of Measures extent of rotation of plane rotation of plane polarized lightpolarized light

• Operator lines up Operator lines up polarizing analyzer polarizing analyzer and measures angle and measures angle between incoming between incoming and outgoing lightand outgoing light

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Specific RotationSpecific Rotation

• Amount of rotation is dependent upon Amount of rotation is dependent upon number of molecules encounterednumber of molecules encountered

• Therefore define Therefore define specific rotation, [specific rotation, []]DD for for an optically active compoundan optically active compound

• [[]]DD = observed rotation/(pathlength x concentration) = observed rotation/(pathlength x concentration)

= = /(/(l l x C) = degrees/(dm x g/mL)x C) = degrees/(dm x g/mL)

• Specific rotation is that observed for 1 g/mL in Specific rotation is that observed for 1 g/mL in solution in cell with a 10 cm path using light solution in cell with a 10 cm path using light from sodium metal vapor (589 nanometers)from sodium metal vapor (589 nanometers)

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Discovery of EnantiomersDiscovery of Enantiomers• Louis Pasteur (1849) discovered that sodium Louis Pasteur (1849) discovered that sodium

ammonium salts of tartaric acid crystallize into right ammonium salts of tartaric acid crystallize into right handed and left handed formshanded and left handed forms

• The optical rotations of equal concentrations of these The optical rotations of equal concentrations of these forms have opposite optical rotationsforms have opposite optical rotations

• The solutions contain mirror image isomers, called The solutions contain mirror image isomers, called enantiomersenantiomers and they crystallized in distinctly and they crystallized in distinctly different shapes – such an event is raredifferent shapes – such an event is rare

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EnantiomersEnantiomers

• (+)-tartaric acid and (-) tartaric acid(+)-tartaric acid and (-) tartaric acid– Identical in every respectIdentical in every respect

•Chemical properties are identicalChemical properties are identical

•Spectroscopic properties are identicalSpectroscopic properties are identical

•Physical properties are identicalPhysical properties are identical

– ExceptExcept•Direction plane polarized light rotatesDirection plane polarized light rotates

•Biological propertiesBiological properties

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Enantiomers - DescriptionEnantiomers - Description

• How do we describe enantiomers?How do we describe enantiomers?

• Need a method to specify the Need a method to specify the arrangement of the groups on a arrangement of the groups on a chiral center.chiral center.

• Comparative Method Comparative Method

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Relative 3-Dimensionl Relative 3-Dimensionl StructureStructure• a correlation system a correlation system

classifying related classifying related molecules into molecules into “families” focused on “families” focused on carbohydratescarbohydrates– Correlate to D- and L-Correlate to D- and L-

glyceraldehydeglyceraldehyde– D-erythrose is the mirror D-erythrose is the mirror

image of L-erythroseimage of L-erythrose

• Does not apply in Does not apply in generalgeneral

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Sequence Rules for Sequence Rules for Specification of ConfigurationSpecification of Configuration• A general method applies to the configuration at each A general method applies to the configuration at each

chirality center (instead of to the the whole molecule)chirality center (instead of to the the whole molecule)• The configuration is specified by the relative positions The configuration is specified by the relative positions

of all the groups with respect to each other at the of all the groups with respect to each other at the chiral centerchiral center

• The groups are ranked in an established priority The groups are ranked in an established priority sequence and comparedsequence and compared

• The relationship of the groups in priority order in The relationship of the groups in priority order in space determines the label applied to the space determines the label applied to the configuration, according to a ruleconfiguration, according to a rule

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Sequence RulesSequence Rules

H

CO2H

OHCH3

Assign priorities to each group on chiral carbon using Cahn-Ingold-Prelog Rules

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Sequence RulesSequence Rules

OHCH3

H

CO2H

1

4

3

2

Priorities are based on atomic number

O: AN = 8 priority = 1

H: AN = 1, priority = 4

C = C = 6, tie, use next atom, CO2H is O while CH3 is H

CO2H priority = 2 and CH3 priority is 3

Rewrite structure just using numbers – no atoms

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Sequence RulesSequence Rules

1

4

3

2

Must have the priority 4 group on upper dashed line

Ignore the group

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Sequence RulesSequence Rules13

2

If rotation is clockwise the configuration of the C is R

If the rotation is counterclockwise the configuration is S

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Sequence RulesSequence Rules

• What if 4 isn’t in upper dashed position?What if 4 isn’t in upper dashed position?

1

3

2

4

Switch the 4 with the number that is in the upper dashed position.

If you do this switch, you MUST switch the other positions also.

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Sequence RulesSequence Rules

1

3

2

4

1

3 4

2

becomes

3

2 1

4

1

3

2

ignore

counterclockwise

assigned S

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What if the structure is written What if the structure is written differently?differently?

CH3

HOHCO2H

H

CH3

OH

HO2C

H

CH3

OHHO2CH

CH3

CO2HOH

thumb

fingers

arm

Left Hand Right Hand

thumb

fingers

arm

rotate

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Fischer ProjectionsFischer Projections

• Developed by Emil Fischer for Developed by Emil Fischer for carbohydratescarbohydrates

• Demonstrating projections on flat surfaceDemonstrating projections on flat surface

CH3 OH

H

CO2H

CH3

H

OH

CO2H

=

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Fischer ProjectionsFischer Projections

• Useful for molecules with Useful for molecules with more than one chiral more than one chiral centercenter

=

important point (structure is eclipsed)

=

bond is down, eclipsing front bond that is also down

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Two Chiral CentersTwo Chiral Centers

• Molecules with more Molecules with more than one chirality than one chirality center have mirror center have mirror image stereoisomers image stereoisomers that are enantiomersthat are enantiomers

• In addition they can In addition they can have stereoisomeric have stereoisomeric forms that are not forms that are not mirror images, called mirror images, called diastereomersdiastereomers

2R,3S 2S,3R

2R,3R 2S,3S

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DiastereomersDiastereomers

• Cis and trans alkenes are diastereomersCis and trans alkenes are diastereomers• Molecules have different chemical and physical Molecules have different chemical and physical

propertiesproperties

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Tartaric AcidTartaric Acid• Tartaric acid has two chiral centers and two diastereomeric Tartaric acid has two chiral centers and two diastereomeric

formsforms• One form is chiral and the other is achiral, but both have two One form is chiral and the other is achiral, but both have two

chiral centerschiral centers• An achiral compound with chirality centers is called a An achiral compound with chirality centers is called a mesomeso

compound – it has a plane of symmetrycompound – it has a plane of symmetry• The two structures on the right in the figure are identical so The two structures on the right in the figure are identical so

the compound (the compound (2R, 3S2R, 3S) ) is achiral is achiral

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Physical Properties of Physical Properties of StereoisomersStereoisomers

• Enantiomeric molecules differ in the direction in Enantiomeric molecules differ in the direction in which they rotate plane polarized but their which they rotate plane polarized but their other common physical properties are the sameother common physical properties are the same

• Diastereomers have a complete set of different Diastereomers have a complete set of different common physical propertiescommon physical properties

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Molecules with More Than Molecules with More Than Two Chirality CentersTwo Chirality Centers• Molecules can have very many chirality centersMolecules can have very many chirality centers• Each point has two possible permanent Each point has two possible permanent

arrangements arrangements ((R R or or SS)),, generating two possible generating two possible stereoisomersstereoisomers

• So the number of possible stereoisomers with n So the number of possible stereoisomers with n chirality centers is 2chirality centers is 2nn

Cholesterol has eight chiral centers and 28 possible isomers

OH

CH3 H

CH3

HH

H

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Racemic MixturesRacemic Mixtures• A 50:50 mixture of a pair of enantiomers A 50:50 mixture of a pair of enantiomers

does not rotate lightdoes not rotate light• called a called a racemic mixtureracemic mixture• Separation of a racemic mixture into Separation of a racemic mixture into

individual enantiomers is resolutionindividual enantiomers is resolution• ImportantImportant

– Albuterol – enantiomeric pairAlbuterol – enantiomeric pair• One causes bronchial passages to expandOne causes bronchial passages to expand• Other causes bronchial passages to contractOther causes bronchial passages to contract

– IbuprofenIbuprofen• R analgesicR analgesic• S no biological activityS no biological activity

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A Brief Review of IsomerismA Brief Review of Isomerism• The flowchart summarizes the types of isomers we The flowchart summarizes the types of isomers we

have seen have seen

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Constitutional IsomersConstitutional Isomers• Different order of connections gives Different order of connections gives

different carbon backbone and/or different different carbon backbone and/or different functional groupsfunctional groups

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StereoisomersStereoisomers• Same connections, different spatial arrangement of atomsSame connections, different spatial arrangement of atoms

– Enantiomers (nonsuperimposable mirror images)Enantiomers (nonsuperimposable mirror images)– Diastereomers (all other stereoisomers)Diastereomers (all other stereoisomers)

• Includes cis, trans and configurationalIncludes cis, trans and configurational

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Stereochemistry and Stereochemistry and ReactionsReactions• Most reactions generate a chiral centerMost reactions generate a chiral center

OHH1. Hg(OAc)2

2. NaBH4

chiral carbon

• Alcohol is prepared as a racemic mixtureAlcohol is prepared as a racemic mixture

• Why?Why?

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Racemic Mixture FormsRacemic Mixture Forms

• Addition of Hg(II) Addition of Hg(II) gives rise to two gives rise to two cationscations

• Addition of water Addition of water gives rise to both gives rise to both enantiomersenantiomers

H

HH Hg+

H

HH

Hg+

OH H

OH H

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Biological ChemistryBiological Chemistry

• Enzymes yield a single enantiomerEnzymes yield a single enantiomer

• Enzymes are chiral and induce Enzymes are chiral and induce chiralitychirality

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Reactions with Chiral Reactions with Chiral SubstratesSubstrates

• Reaction goes through chiral carbocationReaction goes through chiral carbocation

• Provides some stereochemical preferenceProvides some stereochemical preference

• Do not observe a 50:50 mixtureDo not observe a 50:50 mixture

• Products are diastereomericProducts are diastereomeric

CH3H CH3

HH

OH

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General RuleGeneral Rule

• Reactions of chiral substrates with:Reactions of chiral substrates with:• An achiral reactant gives unequal An achiral reactant gives unequal

amounts of diastereomersamounts of diastereomers• A chiral reactant gives a chiral productA chiral reactant gives a chiral product

• Reactions of achiral substrates withReactions of achiral substrates with• An achiral reactant gives an achiral An achiral reactant gives an achiral

productproduct

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ProchiralityProchirality

• a molecule is prochiral if it can a molecule is prochiral if it can become chiral in a single chemical become chiral in a single chemical stepstep

• spsp22 carbons are designated carbons are designated

• Re (similar to R) or Si (similar to S)Re (similar to R) or Si (similar to S)

• Consider the following:Consider the following:

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spsp3 3 hybridized carbon atomshybridized carbon atoms

• Prochiral centerProchiral center

• Becomes chiral by changing one Becomes chiral by changing one attached groupattached group

• Consider the following:Consider the following:

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DesignationDesignation

• pro-R: replaced atom leads to R pro-R: replaced atom leads to R configurationconfiguration

• pro-S: replaced atom leads to S pro-S: replaced atom leads to S configurationconfiguration

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Biological ChemistryBiological Chemistry

• Many biological reactions involve Many biological reactions involve prochiral centersprochiral centers

• Chiral centers are extremely Chiral centers are extremely important in biological processes and important in biological processes and drug developmentdrug development

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Chiral DrugsChiral Drugs

N

N

H

O OO

O

OH

OH

N

HOH

NOH

COOH

OH

thalidomide

enantiomer: treatment for morning sicknessenantiomer: teratogenic

alburerol

D-enantiomer: restricts airwayL-enantiomer: opens airway

allgegra

enantiomer: treatment for allergiesenatiomer: fatal heart arrhythmias