Organic Chemistry

William H. Brown Christopher S. Foote Brent L. Iverson

3-1

Stereoisomerism and Chirality

Chapter 3

3-2

Isomers
Isomers:

different compounds with the same molecular formula Constitutional isomers: isomers with a different connectivity Stereoisomers: isomers with the same connectivity but a different orientation of their atoms in space

3-3

Chirality
Chiral:

from the Greek, cheir, hand

an object that is not superposable on its mirror image

Achiral:

an object that lacks chirality; one that lacks handedness

an achiral object has at least one element 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: a point so situated that identical components are located on opposite sides and equidistant from that point along the axis passing through it
3-4

Elements of Symmetry
Symmetry

in objects

3-5

Elements of Symmetry
Plane

of symmetry (contd)
mirror plane

HO

OH

3-6

Chiral 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 center
all chiral centers are stereocenters, but not all stereocenters are chiral centers (see Figure 3.5)
Enantiomers:

stereoisomers that are nonsuperposable mirror images

refers to the relationship between pairs of objects
3-7

Enantiomers
2-Butanol

has one chiral center here are four different representations for one enantiomer
OH C H H3 C CH2 CH 3 (1) H H3 C C CH 2 CH3 (2) OH H OH (3) OH

(4)

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

representations for th e enan tiomer of (4)

3-8

Enantiomers
The

enantiomers of lactic acid

drawn in two different representations

O C C H CH3 OH HO OH HO C C H CH3 O

O OH OH HO

O OH

3-9

Enantiomers
2-Chlorobutane
Cl CH3 CHCH2 CH3
H Cl Cl H

3-10

Enantiomers
3-Chlorocyclohexene

Cl

Cl

3-11

Enantiomers
A

nitrogen chiral center

+
H3 C N CH2 CH3

N CH3 CH2 CH3

A pair of enantiomers

3-12

R,S 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
(1) (6) (7) (8) (16) (17) (35) (53)

-H

-CH 3

-N H 2

- OH

- SH

- Cl

- Br

-I

Increasing 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
(1) (6) (7) (8)

- CH 2 -H

- CH 2 -CH 3

- CH 2 -NH2

- CH 2 -OH

Increas ing priority

3-13

R,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
C -CH=CH2 O -CH is treated as is treated as C -CH-CH2 O C C H C CH is treated as C C C C H C C O

3-14

Naming Chiral Centers

1. 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 R; if they are read counterclockwise, the configuration is S
1

H Cl

(S)-2-Chlorobutane

3-15

Naming Chiral Centers

(R)-3-Chlorocyclohexene
Cl H
2 3 1

(R)-Mevalonic acid
1

1 4 HO CH3 O HO 3 2 OH
3

R 2

3-16

Enantiomers & Diastereomers

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
For

3-17

Enantiomers & Diastereomers

2,3,4-Trihydroxybutanal

two chiral centers 22 = 4 stereoisomers exist; two pairs of enantiomers

CHO H H C C OH HO OH HO CHO C C H H H HO CHO C C OH HO H H CHO C C H OH

CH2 OH

CH2 OH

CH2 OH

CH2 OH

A pair of e nantiomers (Eryth reos e)

A pair of e nantiomers (Threos e)

Diastereomers:

stereoisomers that are not mirror images refers to the relationship among two or more objects
3-18

Enantiomers & Diastereomers

2,3-Dihydroxybutanedioic

acid (tartaric acid)

two chiral centers; 2n = 4, but only three stereoisomers exist

COOH H H C C OH HO OH HO COOH C C H H H HO COOH C C OH HO H H COOH C C H OH

COOH

COOH

COOH

COOH

A meso compound (plane of symme try)

A pair of enantiomers

Meso

compound: an achiral compound possessing two or more chiral centers that also 3-19 has chiral isomers

Enantiomers & Diastereomers

2-Methylcyclopentanol
CH3 OH HO H3 C

H H H H cis- 2-Methylcyclope ntanol (a pair of enantiomers) CH3 H H H3 C

diastereomers

H OH H HO trans- 2-Methylcyclope ntanol (a pair of en antiomers)

3-20

Enantiomers & Diastereomers

1,2-Cyclopentanediol

OH HO

OH HO

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

H HO

diastereomers

OH

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

3-21

Enantiomers & Diastereomers

cis-3-Methylcyclohexanol

H3 C

OH HO

CH3

3-22

Enantiomers & Diastereomers

trans-3-Methylcyclohexanol

H3 C OH HO

CH3

3-23

Isomers
Compoun ds w ith the same molecu lar formula same conn ectivity Stereoisomers s tereoisomers bu t no ch iral centers Cis,Trans (E,Z ) Isomers (can b e called diastereomers) d ifferen t conn ectivity Constitu tion al Isomers rotation ab ou t sin gle b on ds Con formations rotation restricted Conformation al Isomers Atropisomers m ore than on e chiral cen ter ach iral Meso Comp ou nds ch iral mirror images En antiomers one ch iral center

w ith ch iral centers

not mirror images

D iastereomers

En antiomers

3-24

Properties 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)

3-25

Plane-Polarized Light
Ordinary

light: light vibrating in all planes perpendicular to its direction of propagation Plane-polarized light: light vibrating only in parallel planes Optically active: refers to a compound that rotates the plane of plane-polarized light

3-26

Plane-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

3-27

Plane-Polarized Light
Polarimeter:

a device for measuring the extent of rotation of plane-polarized light

3-28

Optical Activity
observed rotation: the number of degrees, , through which a compound rotates the plane of polarized light dextrorotatory (+): refers to a compound that rotates the plane of polarized light to the right levorotatory (-): refers to a compound that rotates of the plane of polarized light to the left 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
COOH H H3 C OH (S)-(+)-Lactic acid [ ] D = +2.6
21

COOH H C CH3 HO (R)-(-)-Lactatic acid [ ] D = -2.6

21

3-29

Optical Purity
Optical

purity: a way of describing the composition of a mixture of enantiomers

Percent optical purity =

[ ]s am p le []p u re en an tio mer

x 100

Enantiomeric

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

[R] - [S] x 100 = %R - %S Enantiomeric excess (ee) = [R] + [S]

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

3-30

Enantiomeric Excess
Example: a commercial synthesis of naproxen, a nonsteroidal anti-inflammatory drug (NSAID), gives the S enantiomer in 97% ee
CH3 COOH H3 CO (S)-N ap roxen

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

3-31

Resolution
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:

the separation of a racemic mixture into its enantiomers

3-32

Resolution
One

means of resolution is to convert the pair of enantiomers into two diastereomers

diastereomers are different compounds and have different physical properties

common reaction for chemical resolution is salt formation

+ :B RCOOH (R,S)-Carboxylic (R)-Bas e acid

RCOO HB (R,R)-Salt + (S,R)-Salt)

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

3-33

Resolution
racemic acids can be resolved using commercially available chiral bases such as 1-phenylethanamine
NH2 NH2

(S)-1-Ph enylethan amin e

(R)-1-Phenylethan amin e

racemic bases can be resolved using chiral acids such as

OH O HO O OH HO O OH HOOC H3 C CH3 COOH CH3 (1S,3R)-(+)-Camphoric acid
3-34

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

3-35

Resolution
Enzymes

as resolving agents
O OEt CH3 EtO H3 C OCH3 Ethyl ester of (R )-nap roxen (n ot affected b y th e esterase) O

H3 CO Ethyl ester of (S)-nap roxen 1. esterase NaOH, H2 O 2 . HCl, H2 O O OH CH3 H3 CO (S)-N ap roxen

3-36

Amino 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 R = a side chain
sid e chain O H3 N O-

R Ionized or zw itterion form of an amino acid

3-37

Proteins
proteins 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
R H3 N O H N R O N H R H N n O O R
-

for mos t protein s, n= 10-750

3-38

Chirality in the Biological World

Except

for inorganic salts and a few lowmolecular-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 Its a chiral world!

3-39

Chirality 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!

3-40

Chirality 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 righthanded binding site enantiomers have different physiological properties because of the handedness of their interactions with other chiral molecules in living systems

3-41

Chirality in the Biological World

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

3-42

Stereoisomerism and Chirality

End Chapter 3
3-43