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Organic Organic ChemistryChemistry

William H. BrownWilliam H. Brown

Christopher S. FooteChristopher S. Foote

Brent L. IversonBrent L. Iverson

William H. BrownWilliam H. Brown

Christopher S. FooteChristopher S. Foote

Brent L. IversonBrent L. Iverson

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StereoisomerismStereoisomerismand Chiralityand Chirality

Chapter 3Chapter 3

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IsomersIsomers Isomers:Isomers: different compounds with the same

molecular formula Constitutional isomers:Constitutional isomers: isomers with a different

connectivity Stereoisomers:Stereoisomers: isomers with the same

connectivity but a different orientation of their atoms in space

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ChiralityChirality Chiral:Chiral: from the Greek, cheir, hand• an object that is not superposable on its mirror image

Achiral:Achiral: an object that lacks chirality; one that lacks handedness• an achiral object has at least one element of symmetry• plane 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: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 SymmetryElements of Symmetry Symmetry in objectsSymmetry in objects

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Elements of SymmetryElements of Symmetry Plane of symmetry (cont’d)

HO OH

mirrorplane

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Chiral CenterChiral 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 centerchiral center• all chiral centers are stereocenters, but not all

stereocenters are chiral centers (see Figure 3.5)

Enantiomers:Enantiomers: stereoisomers that are nonsuperposable mirror images• refers to the relationship between pairs of objects

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EnantiomersEnantiomers 2-Butanol• has one chiral center• here are four different representations for one

enantiomer

• using (4) as a model, here are two different representations for the enantiomer of (4)

OH

CH3C CH2CH3

H

OH

CH3C CH2CH3

HH OH OH

(1) (2) (3) (4)

OH

(4)

OH OH

representations for theenantiomer of (4)

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EnantiomersEnantiomers The enantiomers of lactic acid• drawn in two different representations

C

C

HOCH3

H

OHO

C

C

OHCH3

H

O OH

OHOH

O

OHHO

O

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EnantiomersEnantiomers 2-Chlorobutane

CH3CHCH2CH3

Cl

ClH Cl H

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EnantiomersEnantiomers 3-Chlorocyclohexene

Cl Cl

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EnantiomersEnantiomers A nitrogen chiral center

N

CH2CH3H3C

N

CH3CH3CH2

A pair of enantiomers

++

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R,SR,S Convention Convention Priority rules

1. Each atom bonded to the chiral center is assigned a priority based on atomic number; the higher the atomic number, the higher the priority

2. If priority cannot be assigned per the atoms bonded to the chiral center, look to the next set of atoms; priority is assigned at the first point of difference

(53)(35)(17)(16)(8)(7)(6)(1)

Increasing priority

-H -CH3 -NH2 -OH -SH -Cl -Br -I

Increasing priority

(8)(7)(6)(1)-CH2-OH-CH2-NH2-CH2-CH3-CH2-H

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R,S ConventionR,S Convention

3. Atoms participating in a double or triple bond are considered to be bonded to an equivalent number of similar atoms by single bonds

-CH=CH2

O

-CH

C CH

O

H

C

C

O

C

-CH-CH2

C

C C HC

C

C

C

is treated as

is treated as

is treated as

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Naming Chiral CentersNaming Chiral Centers1. Locate the chiral center, identify its four substituents, and assign

priority from 1 (highest) to 4 (lowest) to each substituent

2. Orient the molecule so that the group of lowest priority (4) is directed away from you

3. Read the three groups projecting toward you in order from highest (1) to lowest priority (3)

4. If the groups are read clockwise, the configuration is RR; if they are read counterclockwise, the configuration is SS

(S)-2-Chlorobutane

ClH2 3

S1

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Naming Chiral CentersNaming Chiral Centers

• (R)-3-Chlorocyclohexene

• (R)-Mevalonic acid

Cl

H

2

3

R

1

23

41

HO OH

OHO CH3

23

1

R

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Enantiomers & DiastereomersEnantiomers & Diastereomers For a molecule with 1 chiral center, 21 = 2

stereoisomers are possible For a molecule with 2 chiral centers, a maximum

of 22 = 4 stereoisomers are possible For a molecule with n chiral centers, a maximum

of 2n stereoisomers are possible

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Enantiomers & DiastereomersEnantiomers & Diastereomers 2,3,4-Trihydroxybutanal• two chiral centers• 22 = 4 stereoisomers exist; two pairs of enantiomers

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

C

C

H OH

CHO

OH

CH2OH

H

C

C

HHO

CHO

HO

CH2OH

H

C

C

H OH

CHO

H

CH2OH

HO

C

C

HHO

CHO

H

CH2OH

OH

A pair of enantiomers(Erythreose)

A pair of enantiomers(Threose)

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Enantiomers & DiastereomersEnantiomers & Diastereomers 2,3-Dihydroxybutanedioic acid (tartaric acid)• two chiral centers; 2n = 4, but only three stereoisomers

exist

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

C

C

H OH

COOH

OH

COOH

H

C

C

HHO

COOH

HO

COOH

H

C

C

H OH

COOH

H

COOH

HO

C

C

HHO

COOH

H

COOH

OH

A pair of enantiomersA meso compound(plane of symmetry)

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Enantiomers & DiastereomersEnantiomers & Diastereomers 2-Methylcyclopentanol

H H

CH3 OH

H H

HO H3C

H OH

CH3 H

HO H

H H3C

cis-2-Methylcyclopentanol (a pair of enantiomers)

trans-2-Methylcyclopentanol (a pair of enantiomers)

diastereomers

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Enantiomers & DiastereomersEnantiomers & Diastereomers 1,2-Cyclopentanediol

H H

OH HO

H H

OH HO

H HO

OH H

OH H

H HO

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

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

diastereomers

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Enantiomers & DiastereomersEnantiomers & Diastereomers cis-3-Methylcyclohexanol

OHH3C HO CH3

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Enantiomers & DiastereomersEnantiomers & Diastereomers trans-3-Methylcyclohexanol

OH

H3C

HO

CH3

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IsomersIsomers

Compounds with thesame molecular formula

ConformationalIsomers

rotation aboutsingle bonds

with chiral centers

Stereoisomers

MesoCompounds

Enantiomers

ConstitutionalIsomers

Cis,Trans (E,Z) Isomers(can be calleddiastereomers)

Conformations

rotation restricted

differentconnectivity

Diastereomers

stereoisomersbut no chiral centers

Enantiomers

one chiral centerm ore than

one chiral center

chiralachiral

not mirror images

mirror images

Atropisomers

sameconnectivity

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Properties of StereoisomersProperties 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 LightPlane-Polarized Light Ordinary light:Ordinary light: light vibrating in all planes

perpendicular to its direction of propagation Plane-polarized light:Plane-polarized light: light vibrating only in

parallel planes Optically active:Optically active: refers to a compound that

rotates the plane of plane-polarized light

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Plane-Polarized LightPlane-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 LightPlane-Polarized Light Polarimeter:Polarimeter: a device for measuring the extent of

rotation of plane-polarized light

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Optical ActivityOptical Activity

• observed rotation:observed rotation: the number of degrees, , through which a compound rotates the plane of polarized light

• dextrorotatory (+):dextrorotatory (+): refers to a compound that rotates the plane of polarized light to the right

• levorotatory (-):levorotatory (-): refers to a compound that rotates of the plane of polarized light to the left

• specific rotation: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

DD

H3CC

OHH

COOH

CH3

C

HOH

COOH

[]21 = -2.6°= +2.6°21

[]

(R)-(-)-Lactatic acid(S)-(+)-Lactic acid

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Optical PurityOptical Purity Optical purity:Optical purity: a way of describing the

composition of a mixture of enantiomers

Enantiomeric excess:Enantiomeric excess: the difference between the percentage of two enantiomers in a mixture

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

x 100[]sample

Percent optical purity =[]pure enantiomer

x 100[R] + [S][R] - [S]

Enantiomeric excess (ee) = = %R - %S

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Enantiomeric ExcessEnantiomeric Excess

Example:Example: a commercial synthesis of naproxen, a nonsteroidal anti-inflammatory drug (NSAID), gives the S enantiomer in 97% ee

Calculate the percentages of the R and S enantiomers in this mixture

H3CO

COOH

CH3

(S)-Naproxen

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ResolutionResolution Racemic mixture: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:Resolution: the separation of a racemic mixture into its enantiomers

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ResolutionResolution One means of resolution is to convert the pair of

enantiomers into two diastereomers • diastereomers are different compounds and have

different physical properties

A common reaction for chemical resolution is salt formation

• after separation of the diastereomers, the enantiomerically pure acids are recovered

RCOOH B RCOO-

HB+

(R,R)-Salt + (S,R)-Salt)(R)-Base(R,S)-Carboxylicacid

+ :

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ResolutionResolution

• racemic acids can be resolved using commercially available chiral bases such as 1-phenylethanamine

• racemic bases can be resolved using chiral acids such as

NH2 NH2

(S)-1-Phenylethanamine (R)-1-Phenylethanamine

H3C CH3COOHHOOCCH3

OHHO

O

OOH

OHOH

HO

O

O

OH(2R,3R)-(+)-Tartaric acid (S)-(-)-Malic acid (1S,3R)-(+)-Camphoric acid

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ResolutionResolution

Enzymes as resolving agents

H3CO

CH3

O OEt

OCH3

H3C

EtO O

NaOH, H2O2. HCl, H2O

H3CO

CH3

O OH

Ethyl ester of (S)-naproxen Ethyl ester of (R)-naproxen(not affected by the esterase)

+

1. esterase

(S)-Naproxen

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Amino AcidsAmino Acids

• the 20 most common amino acids have a central carbon, called an -carbon, bonded to an NH2 group and a COOH group

• in 19 of the 20, the -carbon is a chiral center • 18 of the 19 -carbons have the R configuration, one

has the S configuration• in the D,L system, all have the L configuration• at neutral pH, an amino acid exists as an internal salt• in this structural formula, the symbol RR = a side chain

O-

OH3N

R

side chain

Ionized or zwitterionform of an amino acid

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ProteinsProteins

• proteinsproteins are long chains of amino acids covalently bonded by amide bonds formed between the carboxyl group of one amino acid and the amino group of another amino acid

O

HN

NH

O R

HN

O-

OO

H3N

R R

Rn

for most proteins, n= 10-750

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Chirality in the Biological WorldChirality in the Biological World

Except for inorganic salts and a few low-molecular-weight organic substances, the molecules of living systems are chiral

Although these molecules can exist as a number of stereoisomers, generally only one is produced and used in a given biological system

It’s a chiral world!It’s a chiral world!

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Chirality in the Biological WorldChirality in the Biological World

Consider chymotrypsin, a protein-digesting enzyme in the digestive system of animals• chymotrypsin contains 251 chiral centers• the maximum number of stereoisomers possible is 2251

• there are only 238 stars in our galaxy!

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Chirality in the Biological WorldChirality in the Biological World

Enzymes are like hands in a handshake• the substrate fits into a binding site on the enzyme

surface• a left-handed molecule will only fit into a left-handed

binding site and• a right-handed molecule will only fit into a right-

handed binding site• enantiomers have different physiological properties

because of the handedness of their interactions with other chiral molecules in living systems

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Chirality in the Biological WorldChirality in the Biological World

• a schematic diagram of an enzyme surface capable of binding with (R)-glyceraldehyde but not with (S)-glyceraldehyde

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Stereoisomerism Stereoisomerism and Chiralityand Chirality

End Chapter 3End Chapter 3