Chirality

Bettelheim, Brown, Campbell and Farrell

Chapter 15

Isomers• Types of chiral stereoisomers

– Enantiomers and diastereomers

sameconnectivity

Stereoisomers

Chiral

Enantiomers Diastereomers

Constitutional Isomers

Cis-Trans Isomers

withstereocenters

without stereocenters

Achiral

differentconnectivity

Isomers

Enantiomers• Enantiomers:Enantiomers: nonsuperimposable mirror

images– Example: 2-butanol

OH

CH3C CH2CH3

H

HO

CCH3

HCH3CH2

Original molecule Mirror image

Enantiomers

– See if the mirror image of 2-butanol is superimposable on the original by rotating the mirror image

Original molecule

OH

CH3C CH2CH3

H

OH

CCH3

HCH3CH2

OH

CH3C H

CH2CH3

Mirror image The mirror imagerotated by 180°

180° rotate by 180°about the

C-OH bond

Enantiomers– Then try to fit one molecule on top of the other so that

all groups and bonds match exactly

– If original and mirror image are not superimposable, they are different molecules

– Nonsuperimposable mirror images are enantiomersenantiomers

OH

CH3C CH2CH3

H

OH

CH3C H

CH2CH3

The original molecule

The mirror imageturned by 180°

Enantiomers

• Objects that are not superposable on their mirror images are chiralchiral (from the Greek: cheir, hand)– they show handedness

• The most common cause of enantiomerism in organic molecules is a carbon with four different groups bonded to it– a carbon with four different groups bonded to it is

called a stereocenter stereocenter also known as aalso known as a chiral chiral carboncarbon

Enantiomers• If an object and its mirror image are

superposable, they are identical and there is no possibility of enantiomerism– Identical molecules are achiralachiral (without chirality)

• Example of achiral molecule: 2-propanol– Notice that it has no stereocenter

Original molecule Mirror image

OH

CH3C CH3

H

OH

CCH3

HH3C

Enantiomers– To see the relationship between the original and its

mirror image, rotate the mirror image by 120°

– Can see that all atoms and bonds of the mirror image fit exactly on the original when it is rotated

– Thus, original and its mirror image are the same molecule

– Just viewed from different perspectives

Original molecule Mirror image

OH

CH3C CH3

H

OH

CCH3

HH3C

OH

CH3C CH3

H

The mirror imagerotated by 120°

120° rotate by 120°about the

C-OH bond

Enantiomers--Summary• Objects that are nonsuperposable on their mirror

images are chiralchiral (show handedness)– Chiral molecules have a carbon with four different

groups bonded to it– Carbon with four different groups bonded to it a

stereocenterstereocenter– Objects that are superposable on their mirror images

are achiralachiral (without chirality)– Nonsuperposable mirror images are called enantiomersenantiomers– Enantiomers always come in pairs

The R,S System– Enantiomers are different compounds and each

must have a different name– Example: Enantiomers of ibuprofen

– R,S system is a way to distinguish between enantiomers without having to draw them and point to one or the other

COOH

H CH3

HOOC

H3C H

The active enantiomerThe inactive enantiomerof ibuprofen

The R,S System

• The first step in assigning an R or S configuration to a stereocenter is to arrange the groups on the stereocenter in order of priority– Priority is based on atomic number– The higher the atomic number, the higher the

priority

.

-OH-NH2

-CHO

-CH2OH

-CH2CH3

-CH2H-H

-SH

-COHO

-CH2NH2

-CNH2

O

-I-Br

-Cl

Atom orGroup

oxygen (8)nitrogen (7)

carbon to oxygen, oxygen, then hydrogen (6 ->8, 8, 1)carbon to oxygen (6 -> 8)

carbon to carbon (6 -> 6)carbon to hydrogen (6 -> 1)hydrogen (1)

sulfur (16)

Reason for Priority: First Point of Difference(Atomic numbers)

carbon to oxygen, oxygen, then oxygen (6 ->8, 8, 8)

carbon to nitrogen (6 -> 7)

carbon to oxygen, oxygen, then nitrogen (6 ->8, 8, 7)

bromine (35)

chlorine (17)

iodine (53)

High priority

Low priority

.

The R,S System

– Example:Example: assign priorities to the groups in each set

-CH2OH -CH2CH2OH-CH2CH2OH -CH2NH2(a) (b)and and

-CH2OH -CH2CH2COH

O

-CH2NH2 -CH2COH

O

and(c) (d)and

The R,S System

– Example:Example: assign priorities to the groups in each set

-CH2OH -CH2CH2OH-CH2CH2OH -CH2NH2

-CH2OH -CH2CH2OH -CH2CH2OH -CH2NH2

(a) (b)and and

Higher priority Lower priority Higher priorityLower priority

-CH2OH -CH2CH2COH

O-CH2NH2 -CH2COH

O

-CH2OH -CH2CH2COH

O

-CH2NH2 -CH2COH

O

and(c) (d)and

Higher priority Lower priority Higher priority Lower priority

The R,S System• To assign an R or S configuration

1.assign a priority from 1 (highest) to 4 (lowest) to each group bonded to the stereocenter

2.orient the molecule in space so that the group of lowest priority (4) is directed away from you; the three groups of higher priority (1-3) then project toward you

3.read the three groups projecting toward you in order from highest (1) to lowest (3) priority

4. if reading the groups 1-2-3 is clockwise, the configuration is RR; if reading them is counterclockwise, the configuration is SS

.

The R,S System

– example:example: assign an R or S configuration to each stereocenter

OH

CH3C CH2CH3

HH3C COOH

C

HH2N

(a) (b)

2-Butanol Alanine

The R,S System

– example:example: assign an R or S configuration to each stereocenter

OH

CH3C CH2CH3

H

R R

1

2

34

(R)-2-Butanol

(a)

H3C COOHC

HH2N R R

1

23

4

(R)-Alanine

(b)

The R,S System

– Look at enantiomers of ibuprofen

COOH

H CH3

HOOC

H3C H

R S

(S)-Ibuprofen(the active enentiomer)

(R)-Ibuprofen(the inactive enantiomer)

1 12 2

3 3 44

Two (or more) Stereocenters• For a molecule with nn stereocenters, the maximum

number of stereoisomers possible

is 22nn

– A molecule with one stereocenter has 21 = 2 stereoisomers (one pair of enantiomers) possible

– A molecule with two stereocenters has a maximum of 22 = 4 possible stereoisomers (two pairs of enantiomers)

– A molecule with three stereocenters has a maximum of 23 = 8 possible stereoisomers (four pairs of enantiomers)

– etc.

Two Stereocenters• 2,3,4-trihydroxybutanal

– two stereocenters; 22 = 4 stereoisomers exist

– diastereomers:diastereomers: stereoisomers that are not mirror images

– (a) and (c), for example, are diastereomers

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)

(a) (b) (c) (d)

Stereoisomers– Identify all stereocenters in each molecule – How many stereoisomers are possible for

each

CH3

CH3

OH

OH

CH2=CHCHCH2CH3

OH

NH2

OHHO

HO

COOH

NH2

OH

NH2

OH

O

(a) (b) (c)

(d) (e) (f)

Stereoisomers– Identify all stereocenters in each molecule – How many stereoisomers are possible for

each

CH3

CH3

OH

OH

CH2=CHCHCH2CH3

OH

NH2

OHHO

HO

COOH

NH2

OH

NH2

OH

O

(a) (b) (c)

(d) (e) (f)

21 = 2

22 = 4

22 = 4

21 = 2

21 = 2

22 = 4

** *

**

* *

*

*

Stereoisomers

• The 2n rule also applies to molecules with three or more stereocenters

HO

Cholesterol has 8 stereocenters;256 stereoisomers are possible

HO

H3C

H3C

This is the stereoisomer found in human metabolism

** * * *

*

H

H

H

*

H3CH

H

*H

Optical Activity• Ordinary light:Ordinary light: light waves vibrating in all

planes perpendicular to its direction of propagation

• Plane-polarized light:Plane-polarized light: light waves vibrating only in parallel planes

• Polarimeter:Polarimeter: an instrument for measuring the ability of a compound to rotate the plane of plane-polarized light

• Optically active:Optically active: showing that a compound rotates the plane of plane-polarized light

Polarimeter

Polarimeter

Light vibrates in many directions

Polarizer— only light in one plane allowed

Polarized light rotated by sample

Rotated beam

Polarized light vibrates in vertical plane

Optical Activity– Dextrorotatory:Dextrorotatory: clockwise rotation of the plane

of plane-polarized light– Levorotatory:Levorotatory: counterclockwise rotation of the

plane of plane-polarized light– Specific rotation:Specific rotation: the observed rotation of an

optically active substance at a concentration of 1 g/mL in a sample tube 10 cm long

DD

H3CC

OHH

COOH

CH3

C

HOH

COOH

[]21 = -2.6°= +2.6°21

[]

(R)-(-)-Lactatic acid(S)-(+)-Lactic acid

Chirality in Biomolecules

• Most molecules in living systems are chiral!!– Exceptions are inorganic salts and a few low-

molecular-weight organic substances– Generally, only one stereoisomer found in nature,

even though although a number of stereoisomers are possible

– Occasionally more than one stereoisomer is found in nature, but these rarely exist together in the same biological system

Chirality in Biomolecules• Enzymes (protein bio-catalysts) all have many

stereocenters– Chymotrypsin is an enzyme in the intestines of animals

that catalyzes the digestion of proteins– Chymotrypsin has 251 stereocenters– Maximum number of stereoisomers possible is 2251!– Only one of these stereoisomers is produced and used

by any given organism– Enzymes are VERY SPECIFIC– Enzymes either produce or react with only substances

that match their chiral requirements

Chirality in Biomolecules– An enzyme distinguishes between a molecule and

its enantiomer

Chirality in Biomolecules– Enantiomers elicit different physiological responses– (S)-ibuprofen is active as a pain and fever reliever,

while its R enantiomer is inactive– S enantiomer of naproxen active as pain reliever,

but R enantiomer is a liver toxin!

HOOC

H3C H

HOOC

H3C H

OCH3(S)-Ibuprofen (S)-Naproxen