chapter 7 stereochemistry copyright © the mcgraw-hill companies, inc. permission required for...

Chapter 7Chapter 7StereochemistryStereochemistry

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

The class of stereoisomers that is presented in Chapter 7 is different than the cis/trans (or E/G) geometric isomers.

These isomers are a result of a mirror image relationship between two compounds.

The term “chirality” applies to these isomers and is introduced here.

Stereochemistry

7.17.1Molecular Chirality: Molecular Chirality:

EnantiomersEnantiomers

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. An achiral molecule does not exhibit stereoisomerism.

Chirality

BrCl

H

F

Bromochlorofluoromethane is chiral

It is not superimposable point for point on its mirror image.

Note the four different attachments on C.

BrCl

H

F


H

ClBr

F

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

BrCl

H

F


H

ClBr

F

The structure on the right has been rotated.

Another look

These two structures are enantiomers.

Nonsuperimposable mirror images are called enantiomers, they occur in pairs.

Enantiomers

Classification of Isomers

stereoisomersconstitutionalisomers

diastereomersenantiomers(geometric)(geometric)

Includes E-Z isomersIncludes E-Z isomers

Isomers with Chiral Centers

diastereomersenantiomers

meso compounds

Chlorodifluoromethaneis achiral

Chlorodifluoromethaneis achiral

The two structures at the top are mirror images, but because they can be superimposed on each other they are identical and are not enantiomers.

7.27.2The Chirality CenterThe Chirality Center

A compound containing a carbon atom with four different groups attached to it.This means that this carbon must be sp3 and can not be sp2 or sp.

A Chiral Compound

w

x y

z

C

The carbon is called a(n):chirality or chiral centerasymmetric centerstereocenterstereogenic center

A molecule with a single chirality center is chiral. Enantiomeric structures are possible.

Bromochlorofluoromethane is an example.

Chirality and chirality centers

Cl F

Br

H

C

2-Butanol is another example.

Chirality and chirality centers

CH3

OH

H

C CH2CH3

Note that the CH2 and CH3's are not chiral.

Examples of molecules with 1 chirality center

CH3

C

CH2CH3

CH2CH2CH2CH3CH3CH2CH2

4-ethyl-4-methyloctane, a chiral alkane


3,7-dimethyl-1,6-octadien-3-ol,Linalool, a naturally occurring chiral alcohol

OH


1,2-Epoxypropane: one of the ring carbon atoms is is a chirality center.

O

H2C CHCH3

attached to this chirality center are:

—H

—CH3

—OCH2 or just —O

—CH2O or just —CH2


Limonene also has a chirality center as part of the ring.

CH3

H C

CH3

CH2

attached to thechirality center are:

—H

—CH2CH2

—CH2CH=

—C=


Chiral as a result of isotopic substitution

CH3CD

T

H

A molecule with a single chirality center must be chiral (enantiomeric structures are possible).

But, a molecule with two or more chirality centers may have structures that are chiral and others that are not (Sections 7.11-7.14).

Distinguish: enantiomers, diastereomers and meso compounds.

7.37.3Symmetry in Achiral Symmetry in Achiral

StructuresStructures

Symmetry tests for achiral structures

Any molecule with a plane of symmetryor 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

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

1-Bromo-1-chloro-2-fluoroethene has a planeof symmetry.

Plane of symmetry

A point in the center of themolecule 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.

Center of symmetry

7.47.4Optical ActivityOptical Activity

Optical activity is a property of some Optical activity is a property of some compounds containing chiral centers compounds containing chiral centers (enantiomers and diastereomers). (enantiomers and diastereomers).

A substance is optically active if it rotates the plane of polarized light.

In order for a substance to exhibit opticalactivity, it must contain a chiral carbon or carbons.

Two enantiomers have equal and opposite specific rotation values.

Optical Activity

Light

Light has wave properties, i.e. shows a periodic increase and decrease in amplitude of the electromagnetic wave.

Light

Optical activity is usually measured using light having a wavelength of 589 nm (monochromatic).

This is the wavelength of the yellow light from a sodium lamp and is called the D line of sodium.

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.

Nicol prismNicol prism

Polarization of light is accomplished using a Nicol prism or a polaroid lens.

Light that passes

through is in the

plane of the crystals

Rotation of Plane-polarized Light by a chiral compound

Observed rotation () depends on the number of molecules encountered and is proportional to:

path length (l), and concentration (c).

Therefore, specific rotation [] is defined as:

Specific Rotation

100

cl

c = concentration = g/100 mLl = length in decimetersobserved rotation

[] =

A mixture containing equal amounts of a pair of enantiomers is called a racemic mixture.

A racemic mixture is optically inactive.( = 0)

A compound that is optically inactive can beeither an achiral substance, a racemic mixture or a meso compound.

Racemic Mixture

An optically pure substance consists exclusively of a single enantiomer. The excess of one enantiomer over another in a mixture is given by:

Enantiomeric excess = (R-S)/(R+S) by weight or% one enantiomer – % other enantiomer

Optical purity = []o / []p (observed/pure)

Optical purity = enantiomeric excess

Optical Purity

7.57.5Absolute and Relative Absolute and Relative

ConfigurationConfiguration

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.

Note: Absolute configuration and Specific rotation are not readily predicted from one another.

Configuration

No bonds are made or broken at the chirality center

in this experiment. In this case, 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.

CH3CHCH2CH3

OH

Pd

[] + 33.2° [] + 13.5°

Relative Configuration

CH3CHCH

OH

CH2

HHO

H OH H2, Pd

HHOH2, Pd

H OH

Two Possibilities

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.

HHO

H OH H2, Pd

HHOH2, Pd

H OH

Two Possibilities

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

HHO

H OH H2, Pd

HHOH2, Pd

H OH

[] +33.2°[] +13.5°

[] –13.5° [] –33.2°

Optical Rotations

enantiomers enantiomers

Relative configuration is independent of specific optical

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.

CH3CH2CHCH2Br

CH3

HBr

[] -5.8° [] + 4.0°

Relative Configuration

CH3CH2CHCH2OH

CH3

7.67.6The Cohn-Ingold-Prelog The Cohn-Ingold-Prelog R-S Notational SystemR-S Notational System

Designating Absolute Configuration Designating Absolute Configuration

1. Rules for ranking substituents at a chirality center are needed.

2. A convention for orienting a molecule so that order of appearance of substituents can be compared with rank.

The system used was devised by R. S. Cahn, Sir Christopher Ingold, and V. Prelog. This CIP ranking system is the same as was used for E-Z isomers.

Two Requirements for a Systemfor Specifying Absolute Configuration

43

2

1

Example

4 3

2

1

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

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.

The Cahn-Ingold-Prelog Rules(Table 7.1)

43

2

1

Example

4 3

2

1

clockwiseclockwise

RR

counterclockwisecounterclockwise

SS

Order of decreasing rank:

4 > 3 > 2 > 1

C OH

H3C

HCH3CH2

Enantiomers of 2-butanol CHO

CH3

HCH2CH3

(S)-2-Butanol (R)-2-Butanol

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?

HH3C

H

H

Chirality Center in a Ring

RR

—CH2C=C > —CH2CH2 > —CH3 > —H

7.77.7Fischer ProjectionsFischer Projections

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

Rules for Fischer Projections

Arrange the molecule so that at the chirality center, horizontal bonds point toward you and vertical bonds point away from you.This is important because the Fisher Projection is planar.

Br Cl

F

H

Rules for Fischer Projections

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

Br Cl

F

H

Br Cl

F

H

7.87.8Properties of EnantiomersProperties of Enantiomers

Same: melting point, boiling point, density, index of refraction, etc (all physical properties).

Different: properties that depend on shape of molecule

(biological-physiological properties) can bedifferent.

Physical Properties of Enantiomers

O O

CH3 CH3

H3C H3CCH2 CH2

Odor (–)-Carvonespearmint oil

(+)-Carvonecaraway seed oil

Ibuprofen is chiral, but normally sold asa racemic mixture. The S enantiomer is the one responsible for its analgesic and anti-inflammatory properties.

Chiral Drugs

CH2CH(CH3)2

HH3C

C

O

C

HO

7.97.9The Chirality AxisThe Chirality Axis

Compounds with no Chiral Center Compounds with no Chiral Center

The Chirality Axis

Some 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:

A

BY

X

C C C

A

B Y

X

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

A

BY

X B

AY

X

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

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

An example is (S)-(-)-BINAP shown below and discussed further in Chapter 14.

P(C6H5)2

P(C6H5)2

7.107.10Reactions that Create a Reactions that Create a

Chirality Center Chirality Center

Many Reactions Convert Achiral Reactants to Chiral Products

It is important to recognize, however, that 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.

This generalization can be more simply stated as "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.)

Example

CH3CH CH2

CH3COOH

O

H3C

O

CH2C

H

Chiral, but racemicAchiral

Epoxidation from this direction gives R epoxide.

R

Epoxidation from this direction gives S epoxide.

SS

50%

50%

Example

CH3CH CH2

Chiral, but racemic

Br2, H2O

CH3CHCH2Br

OH

Achiral

Example

CH3CH CHCH3

Chiral, but racemic

HBrCH3CHCH2CH3

Br

Achiral

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."

Example

Chiral, but racemic

HBrCH3CHCH2CH3

OH

CH3CHCH2CH3

Br

Chiral, but racemic

Many Biochemical Reactions Convertan Achiral Reactant to a SingleEnantiomer of a Chiral Product

Reactions in living systems may be catalyzed by enzymes, which are enantiomerically homogeneous.

The enzyme (catalyst) is part of the reacting system, so such reactions don't violate the generalization that "Optically inactive starting materials can't give optically active products."

Example

fumarase

H2O

C C

HO2C H

CO2HH

C OH

HHO2C

HO2CCH2

Fumaric acid (S)-(–)-Malic acid

Achiral Single enantiomer

7.117.11Chiral Molecules with Two Chiral Molecules with Two

Chirality Centers Chirality Centers

How many stereoisomers are How many stereoisomers are possible when a molecule possible when a molecule contains two chirality centers?contains two chirality centers?

2,3-Dihydroxybutanoic Acid

What are all the possible R and S combinations of the two chirality centers in this molecule ?

4 Combinations = 4 Stereoisomers

O

CH3CHCHCOH

HO OH

23

Carbon-2 R R S SCarbon-3 R S R S


23


What is the relationship between these stereoisomers ?enantiomers: 2R,3R and 2S,3S

2R,3S and 2S,3R

O

CH3CHCHCOH

HO OH

HO

CO2H

CH3

H

OHHR

R

CO2H

CH3

H

HHO

OH

S

S

CO2H

H

CH3

HO

HHO

R

S

CO2H

CH3

H OH

OHHR

S

enantiomersenantiomers


[] = -9.5° [] = +9.5°

[] = -17.8°[] = +17.8°


23


But not all relationships are enantiomeric.Stereoisomers that are not enantiomers are diastereomers.

O

CH3CHCHCOH

HO OH

HO

CO2H

CH3

H

OHHR

R

CO2H

CH3

H

HHO

OH

S

S

CO2H

H

CH3

HO

HHO

R

S

CO2H

CH3

H OH

OHHR

S



[] = -9.5° [] = +9.5°

[] = -17.8°[] = +17.8°

diastereomersdiastereomersdiastereomersdiastereomers

CO2H

CH3

Fischer Projections

For Fischer projection: horizontal bonds point toward you; vertical bonds point away.

A staggered conformation does not have the correct orientation of bonds for Fischer projection.

Fischer Projections

Transform molecule to eclipsed conformation in order to construct Fischer projection.

CO2H

CH3

OH

OH

H

H

Erythro and Threo

Stereochemical prefixes used to specify relative configuration in molecules with two chirality centers

Easiest to apply using Fischer projections

Orientation: vertical carbon chain

When the carbon chain is vertical and the same (or analogous) substituents are on the same side of the Fischer projection, this is the erythro form.

CO2H

CH3

OH

OH

H

H

–9.5° +9.5°

CO2H

CH3

H

H

HO

HO

Erythro

When the carbon chain is vertical and the same (or analogous) substituents are on opposite sides of the Fischer projection, this is the threo form.

+17.8° –17.8°

OH

CO2H

CH3

H

H

HO

CO2H

CH3

OHH

HHO

Threo

S SR R

Two Chirality Centers in a Ring

nonsuperimposable mirror images; enantiomers

trans-1-Bromo-1-chlorocyclopropane

S RS R


nonsuperimposable mirror images; enantiomers

cis-1-Bromo-1-chlorocyclopropane

S RS R


Stereoisomers that are not enantiomers are diastereomers (these are not mirror images).

cis-1-Bromo-1-chloro-cyclopropane trans-1-Bromo-1-chloro-

cyclopropane

7.127.12Achiral Molecules with Two Achiral Molecules with Two


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

2,3-Butanediol

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

CH3CHCHCH3

HO OH

32

Three Stereoisomers of 2,3-Butanediol

2R,3R 2S,3S

chiral chiral

2R,3S

achiral


2R,3R 2S,3S 2R,3S

chiral chiral achiral

CH3

CH3

OHH

HHOH OH

CH3

CH3

HHO H

CH3

CH3

OH

OHH


2R,3R 2S,3S

chiral chiral

These two areenantiomers.


2R,3R 2S,3S

chiral chiral

These two areenantiomers.

CH3

CH3

OHH

HHOH OH

CH3

CH3

HHO


2R,3S

achiral

• The third structure is superposable on its

• mirror image.

Therefore, this structure and its mirror imageare the same.

It is called a meso form.

A meso form is an achiral molecule that has chirality centers.


2R,3Sachiral

HHO

CH3

CH3

HHO

Fischer projections of the meso form.

H

CH3

CH3

OH

OHH


2R,3S

achiral

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.


2R,3S

achiral

A line drawnthe center ofthe Fischer projection of ameso formbisects it intotwo mirror-image halves.

HHO

CH3

CH3

HHO H

CH3

CH3

OH

OHH

S R RRRR

chiralmeso

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

Cyclic Compounds

7.137.13Molecules with Multiple Molecules with Multiple


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.

Number is reduced to less than 2n if meso forms are possible.

How Many Stereoisomers?

Example

4 chirality centers

16 stereoisomers

O

HOCH2CH—CH—CH—CHCH

OH OH OH OH

HO OH

H

H

HO

H3C

H

HCH2CH2CO2H

CH3

H

CH3

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.

Cholic Acid (Figure 7.11)

3-Penten-2-ol

HO H

E R

H OH

E S

HHO

Z R

H OH

S

How Many Stereoisomers? Z

7.147.14Reactions that Produce Diastereomers Reactions that Produce Diastereomers

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)

Stereochemistry of Addition to Alkenes

C C + E—Y C CE Y

R

S

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

Bromine Addition to trans-2-ButeneFig. 7.12

Bromine Addition to cis-2-ButeneFig. 7.12

Anti addition to cis-2-butene gives racemic mixture of chiral diastereomer.

RCO3H

R

R S

S

Syn addition to trans-2-butene gives racemic mixture of chiral diastereomer.

Epoxidation of trans-2-ButeneProblem 7.26

50% 50%

+

R

S R

S

Epoxidation of cis-2-ButeneProblem 7.26

syn addition to cis-2-butene gives meso diastereomer

RCO3H

meso

Of two stereoisomers of a particular starting material, each one gives differentstereoisomeric forms of the product.

Related to mechanism: terms such assyn addition and anti addition refer tostereospecificity.

Stereospecific Reaction

.

transtrans-2-butene-2-butene

ciscis-2-butene-2-butene

transtrans-2-butene-2-butene

ciscis-2-butene-2-butene brominationbromination antianti 22RR,3,3RR + 2 + 2SS,3,3SS

brominationbromination

epoxidationepoxidation

epoxidationepoxidation

antianti

synsyn

synsyn

mesomeso

mesomeso

22RR,3,3RR + 2 + 2SS,3,3SS

Stereospecific reactions

Compound Reaction Attack Product(s)

A single starting material can give two or morestereoisomeric products, but gives one of themin greater amounts than any other.

+

CH3

H

CH3

H

68% 32%

Stereoselective reaction

CH3

CH2

H CH3

H

CH3

H

H2

Pt

7.157.15Resolution of Enantiomers Resolution of Enantiomers

separation of a racemic mixture into its two separation of a racemic mixture into its two enantiomeric formsenantiomeric forms

Enantiomers, racemic

C(+)C(+)C(+)C(+) C(-)C(-)C(-)C(-)

2P(+)2P(+)

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

Separate diastereomers

C(+)C(+)P(+)C(+)C(+)P(+)

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

P(+)P(+)

P(+)P(+)

C(+)C(+)C(+)C(+)

C(-)C(-)C(-)C(-)

Strategy

pure

pure

Add pureenantiomer

7.167.16Stereoregular Polymers Stereoregular Polymers

atacticatactic

isotacticisotactic

syndiotacticsyndiotactic

Atactic Polypropylene

Random stereochemistry of sidechains (methyl groups here) attached to main chain = stereorandom polymer (atactic).Properties not very useful for fibers etc.Formed by free-radical polymerization.

Isotactic Polypropylene

All sidechains (methyl groups here) onsame side of main chain = stereoregular polymer (isotactic).Useful properties.Prepared by coordination polymerization under Ziegler-Natta conditions.

Syndiotactic Polypropylene

Sidechains (methyl groups here) alternate from one side to the other on main chain = stereoregular polymer (syndiotactic).Useful properties.Prepared by coordination polymerization under Ziegler-Natta conditions.

7.177.17Chirality Centers Other than CarbonChirality Centers Other than Carbon

Silicon

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

Si Sid d

ab

c

ab

c

Nitrogen in Amines

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

N N: :

ab

c

ab

c

very fast

Phosphorus in Phosphines

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

P P: :

ab

c

ab

c

slow

Sulfur in Sulfoxides

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

S S: :

ab

O_

ab

O_

slow

+ +

End of Chapter 7End of Chapter 7StereochemistryStereochemistry

chapter 7 stereochemistry copyright © the mcgraw-hill companies, inc. permission required for...

Documents

chirality centerchiral

chirality centersnote

molecular chirality

chirality centerlimonene

chirality center3

chirality center1

term chirality

single chirality center