Chirality Organic Chemistry CHE 275 Chapter 7 Stereochemistry

A molecule is chiral if its two mirror image forms are not superimposable upon one another. A molecule is achiral if its two mirror image forms are superimposable.

Bromochlorofluoromethane is Chiral
Br
It cannot be superimposed point for point on its mirror image.

Bromochlorofluoromethane is Chiral
Br Br

H F

Cl

H F

Cl

Cl F

To show nonsuperimposability, rotate this model 180 around a vertical axis.

Bromochlorofluoromethane is Chiral

Another Look

Br

Br

H F

Cl

H Cl

Enantiomers
nonsuperimposable mirror images are called enantiomers constitutional isomers and

Isomers

stereoisomers

enantiomers
are enantiomers with respect to each other

diastereomers

Chlorodifluoromethane is Achiral

Chlorodifluoromethane is Achiral

The two structures are mirror images, but are not enantiomers, because they can be superimposed on each other.

The Chirality Center

a carbon atom with four different groups attached to it y also called: chiral center asymmetric center stereocenter stereogenic center

Chirality and Chirality Centers

A molecule with a single chirality center is chiral. Bromochlorofluoromethane is an example. H Cl C Br F

w x C z

Chirality and Chirality Centers

A molecule with a single chirality center is chiral. 2-Butanol is another example. H CH3 C OH CH2CH3

One Chirality Center

CH3 CH3CH2CH2 C CH2CH2CH2CH3

CH2CH3

a chiral alkane

Interactive Question
Which one of the following is achiral? A) 2-chloropentane B) 3-chloropentane C) 1,2-dichloropentane D) 1,3-dichloropentane

One Chirality Center

OH

Linalool, a naturally occurring chiral alcohol

One Chirality Center

H2C O 1,2-Epoxypropane: a chirality center can be part of a ring
attached to the chirality center are: H CH3 OCH2 CH2O

One Chirality Center

CH3 Limonene: a chirality center can be part of a ring
attached to the chirality center are: H CH2CH2 CH2CH= C=

CHCH3

C CH3

CH2

One Chirality Center

H D C T CH3

A molecule with a single chirality center must be chiral.

But, a molecule with two or more chirality centers may be chiral or it may not (Sections 7.10-7.14).

Chiral as a result of isotopic substitution

A Plane of Symmetry
Symmetry tests for achiral structures
Any molecule with a plane of symmetry or a center of symmetry must be achiral.

A plane of symmetry bisects a molecule into two mirror image halves. Chlorodifluoromethane has a plane of symmetry.

Plane of Symmetry
The plane has the same thing on both sides for the flask There is no mirror plane for a hand We can apply this same analysis to molecules

A Plane of Symmetry

A plane of symmetry bisects a molecule into two mirror image halves. 1-Bromo-1-chloro-2-fluoroethene has a plane of symmetry.

A Center of Symmetry
A point in the center of the molecule is a center of symmetry if a line drawn from it to any element, when extended an equal distance in the opposite direction, encounters an identical element.

Interactive Question
Which one of the following compounds is chiral? A) 1-methylcyclohexanol B) cis-2-methylcyclohexanol C) trans-4-methylcyclohexanol D) cyclohexanol

Optical Activity
A substance is optically active if it rotates the plane of polarized light. In order for a substance to exhibit optical activity, it must be chiral and one enantiomer must be present in excess of the other.

Light

has wave properties periodic increase and decrease in amplitude of wave

Light

Polarized Light
ordinary (nonpolarized) light consists of many beams vibrating in different planes plane-polarized light consists of only those beams that vibrate in the same plane

optical activity is usually measured using light having a wavelength of 589 nm this is the wavelength of the yellow light from a sodium lamp and is called the D line of sodium

Polarization of Light

Rotation of Plane-Polarized Light

Nicol prism

Specific Rotation
observed rotation () depends on the number of molecules encountered and is proportional to: path length (l), and concentration (c) therefore, define specific rotation [] as:

Racemic Mixtures
a mixture containing equal quantities of enantiomers is called a racemic mixture a racemic mixture is optically inactive ( = 0) a sample that is optically inactive can be either an achiral substance or a racemic mixture

[] =

100 cl

concentration = g/100 mL length in decimeters

Optical Purity
an optically pure substance consists exclusively of a single enantiomer enantiomeric excess = % one enantiomer % other enantiomer % optical purity = enantiomeric excess

Interactive Question
Which of the molecules below is optically active?

A) 1 only B) 1 and 3 C) 1 and 2 D) 1, 2 and 3

Configuration
Relative configuration compares the arrangement of atoms in space of one compound with those of another. Absolute configuration is the precise arrangement of atoms in space.

Configuration
Relative configuration compares the arrangement of atoms in space of one compound with those of another. until the 1950s, all configurations were relative Absolute configuration is the precise arrangement of atoms in space. we can now determine the absolute configuration of almost any compound

Relative Configuration
Pd CH3CHCH OH [] + 33.2 CH2 CH3CHCH2CH3 OH [] + 13.5

Two Possibilities
H OH
Pd, H2

OH

No bonds are made or broken at the chirality center in this experiment. Therefore, when (+)-3-buten-2-ol and (+)-2-butanol have the same sign of rotation, the arrangement of atoms in space is analogous. The two have the same relative configuration.

HO

Pd, H2

HO

But in the absence of additional information, we can't tell which structure corresponds to (+)-3-buten-2-ol, and which one to ()-3-buten-2-ol.

Two Possibilities
H OH
Pd, H2

Absolute Configurations
OH

OH

Pd, H2

OH

[] = +13.5

[] = +33.2

HO

Pd, H2

HO

HO
Nor can we tell which structure corresponds to (+)-2-butanol, and which one to ()-2-butanol.

Pd, H2

HO

[] = -13.5

[] = -33.2

Relative Configuration
HBr CH3CH2CHCH2OH CH3 [] -5.8 CH3CH2CHCH2Br CH3 [] + 4.0

Two requirements for a system for specifying absolute configuration

1. need rules for ranking substituents at chirality center in order of decreasing precedence need convention for orienting molecule so that order of appearance of substituents can be compared with rank The system that is used was devised by R. S. Cahn, Sir Christopher Ingold, and V. Prelog.

2.

Not all compounds that have the same relative configuration have the same sign of rotation. No bonds are made or broken at the chirality center in the reaction shown, so the relative positions of the atoms are the same. Yet the sign of rotation changes.

Cahn-Ingold-Prelog Rules (Table 7.1)

Example

1. Rank the substituents at the chirality center according to same rules used in E-Z notation. 2. Orient the molecule so that lowest-ranked substituent points away from you.

Order of decreasing rank: 4>3>2 >1

The CIP Rules

1. Rank the substituents at the chirality center according to same rules used in E-Z notation. 2. Orient the molecule so that lowest-ranked substituent points away from you. 3. If the order of decreasing precedence traces a clockwise path, the absolute configuration is R. If the path is counterclockwise, the configuration is S.

Example

Order of decreasing rank: 432

clockwise R counterclockwise S

R-Configuration at Chiral
Interactive Question
Which one of the following groups has the highest ranking when precedence is assigned according to the Cahn-IngoldPrelog rules? A) -CH=CH2 B) -CH=O C) -CH2CH2Br D) -CH2F

Center

Lowest priority group is pointed away and direction of higher 3 is clockwise, or right turn

S-Configuration at Chiral
Center

Enantiomers of 2-Butanol
H CH3CH2 C H3C (S)-2-Butanol OH HO C CH3 (R)-2-Butanol H CH2CH3

Lowest priority group is pointed away and direction of higher 3 is counterclockwise, or left turn

Interactive Question
Determine the absolute configuration of the molecule shown. A) (S) B) (R) C) not optically active

Very important! Two different compounds with the same sign of rotation need not have the same configuration.

Verify this statement by doing Problem 7.9 on page 289. All four compounds have positive rotations. What are their configurations according to the Cahn-Ingold-Prelog rules?

Chirality Center in a Ring

H3C H

Interactive Question
What is the absolute configuration of the molecule shown?

R H H CH2C=C > CH2CH2 > CH3 > H

A) (R) B) (S) C) not optically active

Fischer Projections

Rules for Fischer Projections

H Br Cl F

Purpose of Fischer projections is to show configuration at a chirality center without the necessity of drawing wedges and dashes or using models.

Arrange the molecule so that horizontal bonds at chirality center point toward you and vertical bonds point away from you.

Rules for Fischer Projections

H

Rules for Fischer Projections

H

Br

Cl

Br

Cl

F
Projection of molecule on page is a cross. When represented this way it is understood that horizontal bonds project outward, vertical bonds are back.

F Projection of molecule on page is a cross. When represented this way it is understood that horizontal bonds project outward, vertical bonds are back.

Physical Properties of Enantiomers

Same: melting point, boiling point, density, etc Different: properties that depend on shape of molecule (biological-physiological properties) can be different

Why is Chirality Important?

Chirality is important because of the structure of all of the proteins in your body Consider the above structure of myoglobin, a muscle protein found in sea mammals

Proteins Are Made Up of Amino Acids

Amino Acids Are Chiral

HO H H2N CH3 CO2H H H2N CO2H H H2 N CO2H

HN H H2N CO2H

Alanine

Phenylalanine

Serine

Tryptophan

All proteins are made up of the same 20 amino acids 19 of the 20 amino acids are chiral This means that all biological interactions are by definition chiral Enantiomers of the same molecule may have completely different biological properties

Chirality in Nature

Many Drugs Are Chiral

H N O OO N H H S CH3 CH3 CO2H H CO2H CH3

Penicillin V

(( S )S ) -Ibuprofen Ibuprofin

Stereoisomers are readily distinguished by chiral proteins (receptors) in nature Properties of drugs depend on stereochemistry Think of biological recognition as equivalent to 3-point interaction

When drugs are made and sold only one enantiomer is marketed This is because the other enantiomer sometimes has toxic properties An exception is Ibuprofen, which is sold as a racemate Only one enantiomer is active, but it racemizes in the body anyway

Odor
CH3 O O CH3

The Chirality Axis

A diverse group of molecules are chiral but do not contain a chirality center. Some of these contain a chirality axis-an axis about which groups are arranged so that the spatial arrangement is not superimposable on its mirror image. Examples include substituted biphenyls and allenes:

H3C

CH2

H3C

CH2

()-Carvone spearmint oil

(+)-Carvone caraway seed oil

B Y

In the appropriately substituted biphenyls, rotation around the bond joining the rings is slowed and the enantiomers can be isolated:
A X

Substituted 1,1-binaphthyl derivatives exhibit atropisomerism due to hindered rotation about the single bond that connects the two naphthalene rings.

P(C6H5)2 B Y P(C6H5)2

Conformational isomers that are stable, isolable compounds are called atropisomers.

Example: (S)-(-)-BINAP (discussed further next semester)

Chiral Reaction Products

If all of the components of the starting state (reactants, catalysts, solvents, etc.) are achiral, any chiral product will be formed as a racemic mixture. "Optically inactive starting materials can't give optically active products." Remember: In order for a substance to be optically active, it must be chiral and one enantiomer must be present in greater amounts than the other. CH3CH Achiral CH2

Example
O CH3COOH H3C H C O Chiral, but racemic CH2

Epoxidation from this direction gives R epoxide 50%

Example
R Br2, H2O CH3CH CH2 CH3CHCH2Br OH Achiral Chiral, but racemic

50%

Epoxidation from this direction gives S epoxide

Example

Mirror Image Transition States

Transition states are mirror images and product is racemic

HBr CH3CH2CH CH3 CH3CHCH2CH3 Br Achiral Chiral, but racemic

Many Reactions Convert Chiral Reactants to Chiral Products

However, if the reactant is racemic, the product will also be racemic. Remember: "Optically inactive starting materials can't give optically active products." CH3CHCH2CH3 OH

Example
HBr CH3CHCH2CH3 Br Chiral, but racemic

Chiral, but racemic

Biochemical Reactions
Reactions in living systems are catalyzed by enzymes, which are enantiomerically homogeneous. The enzyme (catalyst) is part of the reacting system Such reactions don't violate the generalization that "Optically inactive starting materials can't give optically active products." HO2C C H C H

Example
H H2O fumarase CO2H HO2CCH2 (S)-()-Malic acid Single enantiomer HO2C C OH

Fumaric acid Achiral

Molecules with Two Chirality Centers

2,3-Hydroxybutanoic Acid
O
3 2

CH3CHCHCOH How many stereoisomers when a particular molecule contains two chirality centers? HO OH
What are all the possible R and S combinations of the two chirality centers in this molecule?

Carbon-2 R Carbon-3 R

R S

S R

S S

2,3-Hydroxybutanoic Acid
O
3 2

2,3-Hydroxybutanoic Acid
O
3 2

CH3CHCHCOH HO OH 4 Combinations = 4 Stereoisomers

CH3CHCHCOH HO OH 4 Combinations = 4 Stereoisomers What is the relationship between these stereoisomers?

Carbon-2 R Carbon-3 R

R S

S R

S S

Carbon-2 R Carbon-3 R

R S

S R

S S

2,3-Hydroxybutanoic Acid
HO

CO2H

[] = -9.5

[] = +9.5

CO2H

R
H H OH CH3 CO2H enantiomers HO H

S
OH H

O
3 2

S
CH3 CO2H

CH3CHCHCOH HO OH enantiomers: 2R,3R and 2S,3S 2R,3S and 2S,3R

HO

R
H H enantiomers H H

S
OH OH

Carbon-2 R Carbon-3 R

R S

S R

S S

HO

S
CH3 [] = +17.8 [] = -17.8

R
CH3

2,3-Dihydroxybutanoic Acid
O
3 2

Isomers

CH3CHCHCOH HO OH But not all relationships are enantiomeric Stereoisomers that are not enantiomers are diastereomers Carbon-2 R Carbon-3 R R S S R S S

constitutional isomers

stereoisomers

enantiomers

diastereomers

CO2H

[] = -9.5

[] = +9.5

CO2H

R
HO H H OH CH3 diastereomers CO2H enantiomers HO H

S
OH H

Fischer Projections
recall for Fischer projection: horizontal bonds point toward you; vertical bonds point away staggered conformation does not have correct orientation of bonds for Fischer projection

S
CH3 CO2H

CO2H

R
HO HO H H enantiomers H H

S
OH OH

CH3

S
CH3 [] = +17.8 [] = -17.8

R
CH3

Fischer Projections
transform molecule to eclipsed conformation in order to construct Fischer projection

Fischer Projections
CO2H H H CH3 OH OH

Erythro and Threo

stereochemical prefixes used to specify relative configuration in molecules with two chirality centers easiest to apply using Fischer projections H orientation: vertical carbon chain H 9.5 CH3 OH OH

Erythro
when carbon chain is vertical, same (or analogous) substituents on same side of Fischer projection CO2H HO HO CH3 CO2H H H +9.5

Threo
when carbon chain is vertical, same (or analogous) substituents on opposite sides of Fischer projection

Two Chirality Centers in a Ring

CO2H H HO +17.8 CH3 OH H HO H

CO2H H OH

trans-1-Bromo-1-chlorocyclopropane CH3 17.8 nonsuperimposable mirror images; enantiomers

Two Chirality Centers in a Ring

Two Chirality Centers in a Ring

cis-1-Bromo-1-chlorocyclopropane nonsuperimposable mirror images; enantiomers

cis-1-Bromo-1-chlorocyclopropane

trans-1-Bromo-1-chlorocyclopropane

stereoisomers that are not enantiomers; diastereomers

Achiral Molecules with Two Chirality Centers

It is possible for a molecule to have chirality centers yet be achiral.
2 3

3 Stereoisomers of 2,3Butanediol

CH3CHCHCH3 HO OH Consider a molecule with two equivalently substituted chirality centers such as 2,3butanediol.

2R,3R chiral

2S,3S chiral

2R,3S achiral

3 Stereoisomers of 2,3Butanediol
CH3 HO H CH3 2R,3R chiral H OH H HO CH3 2S,3S chiral CH3 OH H H H CH3 2R,3S achiral CH3 OH OH

3 Stereoisomers of 2,3Butanediol

these two are enantiomers

2R,3R chiral

2S,3S chiral

3 Stereoisomers of 2,3Butanediol
CH3 HO H CH3 2R,3R chiral H OH H HO CH3 2S,3S chiral CH3 OH H these two are enantiomers

3 Stereoisomers of 2,3Butanediol

the third structure is superimposable on its mirror image

2R,3S achiral

3 Stereoisomers of 2,3Butanediol
therefore, this structure and its mirror image are the same

3 Stereoisomers of 2,3Butanediol
CH3 HO HO therefore, this structure and its mirror image H are the same H H CH3 H it is called a meso form a meso form is an achiral molecule that has chirality centers CH3 2R,3S achiral CH3 OH OH

it is called a meso form a meso form is an achiral molecule that has chirality centers

2R,3S achiral

3 Stereoisomers of 2,3Butanediol
meso forms have a plane of symmetry and/or a center of symmetry plane of symmetry is most common case top half of molecule is mirror image of bottom half

3 Stereoisomers of 2,3Butanediol
CH3 HO HO CH3 H H A line drawn the center of the Fischer projection of a meso form bisects it into two mirrorimage halves. CH3 H H CH3 2R,3S achiral OH OH

2R,3S achiral

Interactive Question
Determine the relationship between the compounds shown below.

Cyclic Compounds
meso chiral

S
A) identical B) enantiomers C) diastereomers D) meso

There are three stereoisomers of 1,2-dichlorocyclopropane; the achiral (meso) cis isomer and two enantiomers of the trans isomer.

Multiple Chirality Centers

Maximum number of stereoisomers = 2n

Example
O HOCH2CHCHCHCHCH

where n = number of structural units capable of stereochemical variation structural units include chirality centers and cis and/or trans double bonds number is reduced to less than 2n if meso forms are possible

OH OH OH
4 chirality centers 16 stereoisomers

OH

Cholic Acid (Figure 7.11) Interactive Question

How many chirality centers are in the molecule shown at the right? A) 1 B) 2 C) 3 D) 4 HO H CH3 H3C H HO H H H OH CH3 CH2CH2CO2H 11 chirality centers 211 = 2048 stereoisomers one is "natural" cholic acid a second is the enantiomer of natural cholic acid 2046 are diastereomers of cholic acid

Multiple Chirality Centers

Maximum number of stereoisomers = 2n where n = number of structural units capable of stereochemical variation structural units include chirality centers and cis and/or trans double bonds

How Many Stereoisomers?

3-Penten-2-ol

E H

S OH

HO H

Z number is reduced to less than 2n if meso forms are possible

R HO H

Z H

S OH

Interactive Question
(+)-Glucose has the Fischer projection shown. How many compounds are diastereomers of (+)-glucose? A) 8 B) 14 C) 15 D) 16

Reactions That Produce Diastereomers

C C + EY E C C Y

In order to know understand stereochemistry of product, you need to know two things:

(1) stereochemistry of alkene (cis or trans; Z or E) (2) stereochemistry of mechanism (syn or anti)

Bromine Addition to trans-2Butene

R S

Bromine Addition to trans-2Butene

S Br2 R S R

meso Anti addition to trans-2-butene gives meso diastereomer.

anti addition to trans-2-butene gives meso diastereomer

Bromine Addition to cis-2Butene

R S

Bromine Addition to cis-2Butene

R Br2 R + S S

50% Anti addition to cis-2-butene gives racemic mixture of chiral diastereomers.

50%

anti addition to cis-2-butene gives racemic mixture of chiral diastereomers

Epoxidation of trans-2Butene
R RCO3H R S + S

Epoxidation of cis-2-Butene
R

S RCO3H R

50%

50%

syn addition to trans-2-butene gives a racemic mixture of chiral diastereomers

meso syn addition to cis-2-butene gives the meso diastereomer

Stereospecific Reaction
of two stereoisomers of a particular starting material, each one gives different stereoisomeric forms of the product related to mechanism: terms such as syn addition and anti addition refer to stereospecificity

cis-2-butene

bromination .

anti

2R,3R + 2S,3S

trans-2-butene bromination

anti

meso

Stereospecific reaction

cis-2-butene

epoxidation

syn syn

meso 2R,3R + 2S,3S

trans-2-butene epoxidation

Stereoselective Reaction
a single starting material can give two or more stereoisomeric products, but gives one of them in greater amounts than any other

Interactive Question
Which compound gives only a single stereoisomer of 1,3-dimethylcyclopentane on catalytic hydrogenation?

H CH3 CH2 H2 Pt

H CH3 + CH3 H 68%

H CH3 H CH3 32% C) D) both A and B A) B)

Resolution of Enantiomers
enantiomers separation of a racemic mixture into its two enantiomeric forms C(+) C(-)

Strategy
C(+) P(+) C(+)P(+) C(-)P(+) C(+)P(+) C(-)P(+) C(-) P(+)

2P(+)

diastereomers

Resolution of Enantiomers

Resolution of Enantiomers

Amine salts are often used for resolution of carboxylic acids

Use of a chiral amine leads to diastereotopic salts Diastereomers have different physical properties and can then be separated

Stereoregular Polymers

Atactic Polypropylene

atactic isotactic syndiotactic

random stereochemistry of methyl groups attached to main chain (stereorandom) properties not very useful for fibers etc. formed by free-radical polymerization

Isotactic Polypropylene

Syndiotactic Polypropylene

stereoregular polymer; all methyl groups on same side of main chain useful properties prepared by coordination polymerization under Ziegler-Natta conditions

stereoregular polymer; methyl groups alternate side-to-side on main chain useful properties prepared by coordination polymerization under Ziegler-Natta conditions

Chirality Centers on Other Atoms: Silicon

b a Si c d d Si c b a

Nitrogen Chirality Centers

b a N c : very fast : N c b a

silicon, like carbon, forms four bonds in its stable compounds and many chiral silicon compounds have been resolved

pyramidal geometry at nitrogen can produce a chiral structure, but enantiomers equilibrate too rapidly to be resolved

Phosphorus
b a P c : slow : P c b a a

Sulfur in Sulfoxides
b slow +S O_ : : S+ O_ b a

pyramidal geometry at phosphorus can produce a chiral structure; pyramidal inversion slower than for amines and compounds of the type shown have been resolved

pyramidal geometry at sulfur can produce a chiral structure; pyramidal inversion is slow and compounds of the type shown have been resolved

Summary: Chapter 7
Summary: Chapter 7 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 Molecular Chirality: Enantiomers The Chirality Center Symmetry in Achiral Structures Optical Activity Absolute and Relative Configuration Cahn-Ingold-Prelog Notation Fischer Projections Properties of Enantiomers The Chirality Axis 7.10 7.11 7.12 7.13 7.14 7.15 7.16 7.17

Summary: Chapter 7
Summary: Chapter 7 Reactions that Create a Chirality Center Chiral Molecules with 2 Chirality Centers Achiral Molecules with 2 Chirality Centers Molecules with Multiple Chirality Centers Diastereomers Resolution of Enantiomers Stereoregular Polymers Chirality Centers other than Carbon