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CHAPTER 06 CHIRALITY: THE

HANDEDNESS OF MOLECULES

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Chem

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Mirror images

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Chem

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Mirror images

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Chem

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Mirror images

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Chem

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Mirror images

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Chem

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Mirror images

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Chem

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Mirror images

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Chem

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Mirror images

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Chem

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Mirror images

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Chem

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Mirror images

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Chem

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Mirror images

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Chem

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Mirror images

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Chem

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Mirror images

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Chem

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Mirror images

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Chem

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Mirror images

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Chem

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Mirror images

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Chem

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Mirror images

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Mirror images

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Chem

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Mirror images

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CHAPTER 06 CHIRALITY: THE

HANDEDNESS OF MOLECULES

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Stereoisomers

• Stereoisomers: Isomers (different compounds) that have all the same number and kind of atoms that are all connected the same, but differ in their arrangement in three dimensions.

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ISOMERS

17

ISOMERS(same number and kind of atoms, but are different molecules)

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ISOMERS

17

ISOMERS(same number and kind of atoms, but are different molecules)

Constitutional(bonded differently)

Stereoisomers(Only different in 3-dimensional arrangement)

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ISOMERS

17

ISOMERS(same number and kind of atoms, but are different molecules)

Constitutional(bonded differently)

Stereoisomers(Only different in 3-dimensional arrangement)

Enantiomers(mirror images)

Diastereomers(not mirror images)

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ISOMERS

17

ISOMERS(same number and kind of atoms, but are different molecules)

Constitutional(bonded differently)

Stereoisomers(Only different in 3-dimensional arrangement)

Enantiomers(mirror images)

Diastereomers(not mirror images)

Configurational cis/trans

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Symmetric Molecules

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Chirality - Stereoisomers

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Chem

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Chirality - Stereoisomers

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Chem

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Chirality - Stereoisomers

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Chirality - Stereoisomers

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Chirality

• Enantiomers - molecules that are not superimposable on their mirror image.

• Molecules that can exist as enantiomers are called Chiral Molecules.

• Molecules that have a plane of symmetry are not chiral (achiral).

• Stereogenic Carbons are those that have four different groups attached.

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Symmetry - Asymmetry

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Biomolecules are Chiral

• Carbohydrates / Sugars

• DNA

• Amino Acids / Proteins

22

OH

HO

H

HO

H

HOHH OH

OH

Glucose

H2NO

OHR

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Chirality in Smell and Taste

• Mirror image molecules (enantiomers) interact with chiral receptors in our nose differently.

23

O

(R)-(-)-Carvone (S)-(+)-Carvonespearmint oil caraway seed oil

O

(R)-(+)-Limonene (S)-(-)-Limoneneorange citrus turpentine/Lemon

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Chiral Molecules in Enzymes

24

O

ONH

N

O

O

NOH

H

Me

HO

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istry

Chiral Molecules in Enzymes

24

O

ONH

N

O

O

NOH

H

Me

HO

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istry

Chiral Molecules in Enzymes

24

O

ONH

N

O

O

NOH

H

Me

HO

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istry

The Case of Thalidomide

25

(R)-thalidomidebeneficial sedative

NH

O O

N

O

O

*

stereogeniccarbon

(S)-thalidomideteratogencauses birth defects

NH

OO

N

O

O

*

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istry

The Case of Thalidomide

25

(R)-thalidomidebeneficial sedative

NH

O O

N

O

O

*

stereogeniccarbon

(S)-thalidomideteratogencauses birth defects

NH

OO

N

O

O

*

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Optical Activity

• Enantiomers have identical physical properties

• mp, bp, spectroscopic, absorptions, etc.

• BUT they are different when interacting with plane-polarized light

• Christiaan Huygens - (1629-1695) Dutch astronomer, mathematician, andphysicist, discovers planepolarized light

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Optical Activity

• Jean-Baptiste Biot (1774-1862)

• In 1815 he discovers that certain natural organic compounds rotate plane polarized light.

27

Historical perspectiveJean Baptiste Biot (1774-1862)

In 1815, he notes that certain

natural organic compounds (liquids

or solutions) rotate plane polarized

light (Optical Activity).

plane

polarized

light

tube containing

a liquid organic

compound or

solution

plane

polarized

light

IN OUTmoleculemolecule

moleculemolecule

molecule

molecule

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Optical Activity

• Jean-Baptiste Biot (1774-1862)

• In 1815 he discovers that certain natural organic compounds rotate plane polarized light.

27

light travels in waves but oscillates in all three dimensions along the path of travel

polarizing filter

Light is polarized and oscillates in a single dimension

chiralsample

when the polarized light passes through a chiral sample, it is bent out of the original plane

chiralsampleenantiomer

Note that the enantiomer will bend the light in the opposite direction

Historical perspectiveJean Baptiste Biot (1774-1862)

In 1815, he notes that certain

natural organic compounds (liquids

or solutions) rotate plane polarized

light (Optical Activity).

plane

polarized

light

tube containing

a liquid organic

compound or

solution

plane

polarized

light

IN OUTmoleculemolecule

moleculemolecule

molecule

molecule

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Tartaric Acid

• Carl Wilhelm Scheele (1742-1786)

• In 1769 he discovers Tartaric Acid fromtarter - the potassium salt of tartaric acidthat crystallizes out of wine.

28

Historical perspective

Carl Wilhelm Scheele (1742-1786)

“Oh, how happy I am! No care for eating or

drinking or dwelling, no care for my

pharmaceutical business, for this is mere play

to me. But to watch new phenomena this is all

my care, and how glad is the enquirer when

discovery rewards his diligence; then his heart

rejoices"

In 1769, he discovers Tartaric

Acid from tartar (the potassium

salt of tartaric acid, deposited

on barrels and corks during

fermentation of grape juice).

HO CO2H

CO2HHO

Tartaric Acid

6

*HO

O

OH

OHOH

O

*

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Tartaric Acid

• Louis Pasteur - (1822-1895)

• In1849 he separated mirror image crystals of sodium ammonium tartrate.

29

*O

O

OH

OHO

O

*Na NH4

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Louis Pasteur

30

“I found...that the tartrate was hemihedral..., but strange to say the paratartrate was hemihedral also. Only the hemihedral faces which in the tartrate were all turned the same way, were, in the paratartrates inclined sometimes to the right and sometimes to the left.... I carefully separated the crystals that were hemihedral to the right from those hemihedral to the left, and examined their solutions separately in the polarizing apparatus. I then saw with no less surprise than pleasure that the crystals hemihedral to the right deviated the plane of polarization to the right, and that those hemihedral to the left deviated it to theleft; and when I took an equal weightof each of the two kinds of crystals,the mixed solution was indifferenttowards the light in consequence of the neutralization of the two equal and opposite individual deviations.”

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Optical Activity

• Amount of rotation depends on how many molecules the light interacts with.

• Light at 589 nm (Sodium D line)

• Standardized for unit cell and concentration

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observed rotation (°)cell length (dm) x conc. (g/mL)[α]D =

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Racemates

• Racemic Mixture - 50/50 mixture of enantiomers. Shows NO optical activity.

32

“...when I took an equal weight of each of the two kinds of crystals, the mixed solution was indifferent towards the light in consequence of the neutralization of the two equal and opposite individual deviations.”

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Racemates

• Racemic Mixture - 50/50 mixture of enantiomers. Shows NO optical activity.

32

“...when I took an equal weight of each of the two kinds of crystals, the mixed solution was indifferent towards the light in consequence of the neutralization of the two equal and opposite individual deviations.”

light travels in waves but oscillates in all three dimensions along the path of travel

polarizing filter

Light is polarized and oscillates in a single dimension

chiralsample

when the polarized light passes through a chiral sample, it is bent out of the original plane

chiralsampleenantiomer

Note that the enantiomer will bend the light in the opposite direction

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istry

CIP Rules for R & S Configuration

• Rectus - Right, Sinister - Left

33

ClCl

(R)-2-chlorobutane(S)-2-chlorobutane

1

23

HH 41

2 3

4

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istry

CIP Rules for R & S Configuration

• Rectus - Right, Sinister - Left

33

ClCl

(R)-2-chlorobutane(S)-2-chlorobutane

1

23

HH 41

2 3

4

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istry

R & S Configuration

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HONH2

OH sphingosine

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R & S Configuration

34

HONH2

OH sphingosine

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R & S Configuration

34

HONH2

OH sphingosine

HO RNH2

OH

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istry

R & S Configuration

35

H2N

CH3

O

OHNH O

OH

alanine proline

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istry

R & S Configuration

36

glucoseO

HO

HO

OHOH

OH

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istry

R & S Configuration

36

glucoseO

HO

HO

OHOH

OH

SR

SR

S

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istry

Diastereomers

• Diastereomers - stereoisomers that are not mirror images

37

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istry

Diastereomers

• Diastereomers - stereoisomers that are not mirror images

37

STEREOISOMERS

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Diastereomers

• Diastereomers - stereoisomers that are not mirror images

37

STEREOISOMERS

ENANTIOMERS

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Diastereomers

• Diastereomers - stereoisomers that are not mirror images

37

STEREOISOMERS

DIASTEREOMERS ENANTIOMERS

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cis/trans Diastereomers

• Although not optically active (not chiral), cis/trans isomers are a form of diastereomer. They differ only in their arrangement in 3-dimensions but are not mirror images.

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configurational Diastereomers

39

OH

OH

O

HO

O

HO

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istry

configurational Diastereomers

39

OH

OH

O

HO

O

HO

HO

HO

O

OH

O

OH

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istry

configurational Diastereomers

39

OH

OH

O

HO

O

HO

HO

HO

O

OH

O

OH

S R

S R

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istry

configurational Diastereomers

39

OH

OH

O

HO

O

HO

HO

HO

O

OH

O

OH

ENANTIOMERS

S R

S R

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istry

configurational Diastereomers

39

OH

OH

O

HO

O

HO

HO

HO

O

OH

O

OH

ENANTIOMERS

S R

S R

OH

OH

O

HO

O

HOS

R

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istry

configurational Diastereomers

39

OH

OH

O

HO

O

HO

HO

HO

O

OH

O

OH

ENANTIOMERS

S R

S R

DIASTEREOMERSDIASTEREOMERS

OH

OH

O

HO

O

HOS

R

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MESO compounds

• Meso Compounds are molecules that contain stereogenic carbons, but are not chiral. Their mirror images are identical. This occurs when there is a plane of symmetry in the molecule.

40

OH

OH

O

HO

O

HO

HO

HO

O

OH

O

OH

S R

SR

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MESO compounds

• Meso Compounds are molecules that contain stereogenic carbons, but are not chiral. Their mirror images are identical. This occurs when there is a plane of symmetry in the molecule.

40

OH

OH

O

HO

O

HO

HO

HO

O

OH

O

OH

S R

SR

IDENTICAL

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MESO compounds

• Meso Compounds are molecules that contain stereogenic carbons, but are not chiral. Their mirror images are identical. This occurs when there is a plane of symmetry in the molecule.

40

OH

OH

O

HO

O

HO

HO

HO

O

OH

O

OH

S R

SR

IDENTICAL

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Fischer Projections

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Fischer Projections

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Diasteromers

• Diastereomers have different physical properties

43

OH

OH

O

HO

O

HO

HO

HO

O

OH

O

OH

OH

OH

O

HO

O

HO

(S,S) +12° 168-170°C 1.7598

(R,R) -12° 168-170°C 1.7598

(S,R) meso 0 146-148°C 1.666

molecule configoptical

rotation densitymp

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ISOMERS

44

ISOMERS(same number and kind of atoms, but are different molecules)

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ISOMERS

44

ISOMERS(same number and kind of atoms, but are different molecules)

Constitutional(bonded differently)

Stereoisomers(Only different in 3-dimensional arrangement)

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ISOMERS

44

ISOMERS(same number and kind of atoms, but are different molecules)

Constitutional(bonded differently)

Stereoisomers(Only different in 3-dimensional arrangement)

Enantiomers(mirror images)

Diastereomers(not mirror images)

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ISOMERS

44

ISOMERS(same number and kind of atoms, but are different molecules)

Constitutional(bonded differently)

Stereoisomers(Only different in 3-dimensional arrangement)

Enantiomers(mirror images)

Diastereomers(not mirror images)

Configurational cis/trans

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Reactions can produce stereogenic centers

• Racemic mixtures will always result unless there is other chirality to influence a difference in the reaction path.

45

HBr Br

Br Br+

R S

50:50

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Chirality in Reactions

46

Br2

Br

BrBr

Br Br

Br

+

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istry

Chirality in Reactions

47

cis-2-butene

Br2

Br Br BrBr

+ enantiomersRS S R

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istry

Chirality in Reactions

47

cis-2-butene

Br2

Br Br BrBr

+ enantiomersRS S R

Br

Br

Br

BrS

SR

R

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Chirality in Reactions

48

trans-2-butene

Br2

Br Br BrBr

Br

Br

Br

Br

+ identical

MESO

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Diastereoselectivity

• An existing stereogenic center can influence the creation of another.

49

Br

Br

Br2

Br

BrBr

Br

H3C

H3C

H3C

Major Product

H3C

BrH3C

Major Product

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istry

Resolution of Enantiomers

• The separation of enantiomers from a racemic mixture is called a resolution.

50

*O

O

OH

OHO

O

*Na NH4

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istry

Chemical Resolution

• Enantiomers have identical physical properties, so we need to prepare diastereomers.

51

R

S

SO

OHOH

O

OHOH

+

NH2

racemicmixture

one enantiomer

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istry

Chemical Resolution

• Enantiomers have identical physical properties, so we need to prepare diastereomers.

51

R

S

SO

OHOH

O

OHOH

+

NH2

racemicmixture

one enantiomer

O

OOH NH3

+

O

OOH NH3

diastereomeric salts

R S

S S

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istry

Chemical Resolution

• We can also make covalent bonds.

52

O

Cl+

NH2

one enantiomer diastereomeric products

NH2

Racemic Mixture

HN

O

Ph

HN

O

PhR

S

S

S

S

S

R

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istry

Indication of mixed stereochemistry

53

NH2

Racemic Mixture