33

3-1

Organic Organic Chemistry Chemistry

William H. Brown &William H. Brown &

Christopher S. FooteChristopher S. Foote

33

3-2

ChiralityChiralityChapter 3Chapter 3

33

3-3

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 molecular

formula and connectivity but a different orientation of their atoms in space

33

3-4

IsomersIsomersCompounds with the

same molecular formula

ConformationalIsomers

rotation abouta single bond

sameconnectivity

Stereoisomers

MesoCompounds

Chiral

Enantiomers Diastereomers

ConstitutionalIsomers

Cis,Trans (E,Z) Isomers

Achiral

Conformations

rotation restricted

with stereocenterswithout

stereocenters

Enantiomers

Chiral Achiral

differentconnectivity

33

3-5

ChiralityChirality Mirror image:Mirror image: the reflection of an object in a

mirror Chiral:Chiral: an object that is not superposable on its

mirror image; an object that shows handedness Achiral:Achiral: an object that lacks chirality; an object

that has no handedness • an achiral object has at least one element of symmetry

33

3-6

Elements of SymmetryElements 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

Br C Cl

H

H

33

3-7

Elements of SymmetryElements of Symmetry Plane of symmetry (contd.)

HO OH

mirrorplane

33

3-8

Elements of SymmetryElements of Symmetry Center of symmetry:Center of symmetry: a point so situated that

identical components of the object are located on opposite sides and equidistant from the point along any axis passing through it

ClCl

Br

H

H

Br

center of symmetry

33

3-9

StereocenterStereocenter 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 stereocenterstereocenter or, alternatively, a stereogenic centerstereogenic center

33

3-10

EnantiomersEnantiomers Enantiomers:Enantiomers: stereoisomers that are

nonsuperposable mirror images; refers to the relationship between pairs of objects

On the three following screens are examples chiral molecules. Each has one stereocenter and can exist as a pair of enantiomers.

33

3-11

EnantiomersEnantiomers Lactic acid

C

C

HOCH3

H

OHO

C

C

OHH3CH

O OH

33

3-12

EnantiomersEnantiomers 2-Chlorobutane

CH3CHCH2CH3

Cl

ClH Cl H

33

3-13

EnantiomersEnantiomers 3-Chlorocyclohexene

Cl

H

Cl

H

Cl

33

3-14

EnantiomersEnantiomers A nitrogen stereocenter

N

CH2CH3H3C

N

CH3CH3CH2

A pair of enantiomers

++

33

3-15

R,S ConventionR,S Convention Priority rules

1. Each atom bonded to the stereocenter 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 stereocenter, 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

33

3-16

R,S ConventionR,S Convention3. Atoms participating in a double or triple bond are

considered to be bonded to an equivalent number of similar atoms by single bonds

CC

O

-CH=CH2 -CH-CH2

-CH

O

H

C

C

O

is treated as

is treated as

33

3-17

Naming EnantiomersNaming Enantiomers1. Locate the stereocenter, 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 R; if they are read counterclockwise, the configuration is S

(S)-2-Chlorobutane

ClH2 3

S1

33

3-18

R,S ConfigurationR,S Configuration• (R)-3-Chlorocyclohexene

• (R)-Mevalonic acid

Cl

H 2

3

R

1

23

41

HO OH

OHO CH3

23

1

R

33

3-19

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

stereoisomers are possible For a molecule with 2 stereocenters, a maximum

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

of 2n stereoisomers are possible

33

3-20

Enantiomers & DiastereomersEnantiomers & Diastereomers 2,3,4-trihydroxybutanal

• two stereocenters; 22 = 4 stereoisomers exist

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)

33

3-21

Enantiomers & DiastereomersEnantiomers & Diastereomers 2,3-dihydroxybutanedioic acid (tartaric acid)

• two stereocenters; 2n = 4, but for this molecule, only three stereoisomers exist

Meso compound:Meso compound: an achiral compound possessing two or more stereocenters

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)

33

3-22

Enantiomers & DiastereomersEnantiomers & Diastereomers2-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

33

3-23

Enantiomers & DiastereomersEnantiomers & Diastereomers1,2-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

33

3-24

Enantiomers & DiastereomersEnantiomers & Diastereomers

cis-3-methylcyclohexanol

OHH3C HO CH3

33

3-25

Enantiomers & DiastereomersEnantiomers & Diastereomers

trans-3-methylcyclohexanol

OH

H3C

HO

CH3

33

3-26

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).

33

3-27

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• plane polarized light is the vector sum of left and right

circularly polarized light; these two forms of light are enantiomers

• because of their handedness, each component of circularly polarized light interacts in an opposite way with a chiral molecule.

33

3-28

Plane-Polarized LightPlane-Polarized Light

QuickTime™ and aPhoto - JPEG decompressor

are needed to see this picture.

33

3-29

Plane-Polarized LightPlane-Polarized Light• because of its handedness, circularly polarized light

reacts one way with an R stereocenter, and in an opposite with its enantiomer

• the net effect of the interaction of plane polarized light with a chiral compound is that the plane of polarization is rotated

Polarimeter:Polarimeter: a device for measuring the extent of rotation of plane polarized light

33

3-30

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

33

3-31

Optical ActivityOptical Activity Specific rotation:Specific rotation: observed rotation of the plane

of polarized light when a sample is placed in a tube 1.0 dm in length and at a concentration of 1g/mL

length (dm) x concentration (g/mL)

observed rotation (degrees)=λ

T[] =Specific rotation

33

3-32

Optical ActivityOptical Activity For a pair of enantiomers, the value of the

specific rotation of each is the same, but opposite in sign

[]25D

-13.52 +13.52D25

[α]

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

C

OH

CH3CH3CH2

HC

HO

H3C CH2CH3

H

33

3-33

Enantiomeric ExcessEnantiomeric Excess When dealing with a mixture of enantiomers, it

is essential to describe the composition of the mixture and the degree to which one enantiomer is in excess

The most common designation is enantiomeric excess (ee)

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

ee = = %R - %S

33

3-34

Enantiomeric ExcessEnantiomeric Excess Example: a commercial synthesis of naproxen, a

nonsteroidal antiinflammatory drug (NSAID), gives this enantiomer in 97% ee. Assign an R or S configuration to its stereocenter, and calculate the % R and S enantiomers in the mixture.

H3CO

CCOOH

H CH3

Naproxen

33

3-35

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 activity is zero.

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

33

3-36

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+

(RR')-Salt + (SR')-Salt)(R')-Base(R,S)-Carboxylicacid

+ :

33

3-37

ResolutionResolution Examples of enantiomerically pure bases

DD = -16525

[]

(-)-Quinine

= +22823[ ]

(+)-Cinchonine

H

N

N

H

H

HO HHO

N

CH3 O

H H

H

H

N

33

3-38

QuickTime™ and aPhoto - JPEG decompressor

are needed to see this picture.

33

3-39

ResolutionResolution Enzymes as resolving agents

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

+

NaOH, H2O1. esterase

(S)-Naproxen

2. HCl, H2O

H3COCH3

CO

H

OCH2CH3

H3COCH3

CO

H

OH

OCH3

H3C

CO

H

CH3CH2O

33

3-40

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!

33

3-41

Chirality in the Biological WorldChirality in the Biological World Consider chymotrypsin, a protein-digesting

enzyme in the digestive system of animals• chymotrypsin contains 251 stereocenters• the maximum number of stereoisomers possible is 2251

• there are only 238 stars in our galaxy!

33

3-42

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

33

3-43

Chirality in the Biological WorldChirality in the Biological World

QuickTime™ and aPhoto - JPEG decompressor

are needed to see this picture.

33

3-44

Prob 3.15Prob 3.15Draw mirror images for each molecule.

(d)

(c)(b)(a)

O OH

H

C

OH

COOHH

H3CC

CHO

CH2OH

OHH CH2N H

CH3

COOH

(h)(g)

(e) (f)

OH

CH3

CH3

H OH

OH

CH3

H

H

OH

OH

CH3

33

3-45

Prob 3.16Prob 3.16Which are identical with (a) and which are mirror images of (a)?

(d)(c)

(b)(a) CH

H3COH

COOH

C

CH3

HHOOCHO

CHO

HCH3

COOH

C

CH3

COOHHOH

33

3-46

Prob 3.17Prob 3.17Mark all stereocenters in each molecule.

(d)

(c)(b)(a)CH3CCH=CH2 HCOH CH3CHCHCOOH

CH3CCH2 CH3

OH

CH3

CH3

COOH CH3

NH2

(g)

(f)(e)HCOH

HOCCOOH

CH3CH2 CHCH=CH2

OH

CH2OH

CH2OH

CH2COOH

CH2COOH

O

33

3-47

Prob 3.20Prob 3.20 Assign an R or S configuration to the stereocenter in

each enantiomer.

(+)-Carvone20

[] +62.5°-62.5°[]20(-)-Carvone

Spearmint oil Caraway and dill seed oil

CH3O

H C CH2CH3

H

CH3

O

CCH3

H2C

DD

33

3-48

Prob 3.21Prob 3.21 Assign an R or S configuration to this enantiomer of 2-

butanol. Also draw a Newman production viewed along the bond between carbons 2 and 3.

H3C

CH3

HOH

HH

33

3-49

Prob 3.22Prob 3.22 Assign an R or S configuration to each stereocenter in

this enantiomer of ephedrine.

D

C C

CH3HO

H

HNHCH3

Ephedrine[]21 -41°

33

3-50

Prob 3.23Prob 3.23 Assign an R or S configuration to this

enantiomer of carbon-14 labeled citric acid.

C-COOH

CH2COOH

O

Oxaloacetic acid

+ CH3CSCoA14

CH2COOH

C

CH2COOH

HOOC OH

citrate synthase

14

Acetyl-CoA

[2-14C]Citric acid

O

33

3-51

Prob 3.24Prob 3.24 Draw all stereoisomers possible for this compound. Label

which are meso and which are pairs of enantiomers.

COOHHOOC

H3C CH3

33

3-52

Prob 3.25Prob 3.25 Mark are stereocenters in each molecule. How many

stereoisomers are possible for each molecule?

(d)

(a) (b) (c)CH-COOHCH2-COOH OH

CH3CHCHCOOH

CH-COOHHO OH HO

(f)

(g) (h)

(e)OH

O

O OH

OHO

COOH

33

3-53

Prob 3.26Prob 3.26 Label the eight stereocenters in cholesterol.

HO

33

3-54

Prob 3.27Prob 3.27 Label the four stereocenters in amoxicillin.

N

S

CH3

CH3

C OHO

O

HNCH-C

NH2

O

HO

33

3-55

Prob 3.29Prob 3.29 Are the formulas in each set identical, enantiomers, or

diastereomers?Cl

H

H

OH

Cl

H

H

HO

(a) and

Cl

OH

H

H

(b)

HO

H

H

Cl

and

(c)

Cl

H

H

HO

HO

Cl

H

H

and

33

3-56

Prob 3.30Prob 3.30 Which are meso compounds?

C C

Br Br

HCH3

HCH3

C

Br

H

C

CH3

H

CH3Br

OH

CH3OH(a) (b) (c)

OHCH3OH

OHCH3

OH

CH2OH

OHH

CH2OH

OHH(d) (e) (f)

CHO

OHHCH2OH

OHH(g) (h) (i)

CH2OH

OHHCH2OH

HHOCH2OH

OHHCH2OH

OHH

33

3-57

Prob 3.31Prob 3.31 Oxidation of this bicyclic alkene gives a dicarboxylic

acid. Is the product of this oxidation one enantiomer, a racemic mixture, or a meso compound?

COOHHOOCvigorousoxidation

33

3-58

Prob 3.35Prob 3.35 Verify that although, this molecule has no stereocenter, it

is chiral.

O O

33

3-59

Prob 3.36Prob 3.36 Verify that, although this substituted allene has no

stereocenter, it is chiral.

C C C

H

(CH3)3CC(CH3)3

H

[]D

25-314

33

3-60

ChiralityChirality

End of Chapter 3End of Chapter 3