Stereochemistry and Chirality

OBJECTIVES


Give the operational definition of stereochemistry Describe tetrahedral carbon atoms and their mirrors images Compare and contrast chiral and achiral symmetry Determine chiral and achiral structure

OBJECTIVES
 

Draw chiral and achiral structure Compute for the specific rotation of a compound Relate the importance of chirality on human and nature Specify configuration of a compound

Sit comfortably. Fold the hands together.

What is the stereochemistry?

Stereochemistry refers to the 3-dimensional (3D) properties and reactions of molecules. molecules.

CWXYZ

2D vs 3D
X C Y Z

STEREOCHEMISTRY


branch of chemistry concerned with three-dimensional threestructures of molecules

Tetrahedral carbon atom and its mirror images

ENANTIOMER
  

not identical to its mirror image Enantio means opposite Enantiomer is related to each other as right hand is related to the left hand and result whenever a tetrahedral carbon atom is bonded to four different substituents ( one need not be H)

Lactic Acid: a molecule of general formula CHXYZ

Mirror

Chiral molecules that are not identical to their mirror images and thus exist in two enantiomeric forms

Stereochemistry has its own language and terms that need to be learned in order to fully communicate and understand the concepts. Chirality or Handedness
What is Chirality? Chiral comes from the Greek word cheir meaning HAND

Hands are non-superimposable mirror images nonthey are chiral

 The right-handed and left-handed forms of a chiral rightleftmolecule make up a pair of stereoisomers called enantiomers. enantiomers.

Anticlockwise configuration

(S) sinister LEFT isomer) (L-isomer)

(R) rectus RIGHT (D-isomer) isomer)

Clockwise configuration

Enantiomers (from Greek enantio, opposite and merso , part) have opposite configuration

How can you predict whether a given molecule is or is not chiral? chiral?  ANSWER:
A molecule that is not chiral if it contains a plane symmetry. Ex. Hand has no symmetry while flask has.

 Properties of ENANTIOMERS
Enantiomers-nonsuperimposable mirror images.

C C
Stereocenter Or Chiralcenter

Identical physical properties, so difficult to be separated

An equimolar (50/50) mixture of enantiomers known as RACEMIC MIXTURE or RACEMATE Drastically different behaviors in living systems.

Example ACHIRAL Propanoic acid

CHIRAL Lactic Acid

CH3 C H COOH

CH3 C OH H COOH
NOT Symmetry Plane

Symmetry Plane

ACHIRAL


A molecule that has a plane symmetry in any of its possible conformations must be identical to its mirror images and hence must be nonchiral

Is

33-methylhexane Chiral? Chiral? Is 2-methycyclohexanone 2Chiral? Chiral?

Which of the following molecules are chiral? chiral?

A. 3-bromopentane 3B. 1,3-Dibromopentane 1,3C. 3-Methyl-1-hexene 3-MethylD. Cis-1,4-Dimethylcyclohexane Cis-1,4-

 Enantiomers differ in the way they rotate isomers). plane polarised light (Optical isomers).

Ordinary (nonpolarized) light consists of many beams vibrating in different planes

PlanePlane-Polarized Light consists of only those beams that vibrate in the same plane

Rotation of plane-polarized light plane-

Dextrorotatory (+)

Levorotatory (-)

Enantiomers Have Equal And Opposite

Rotations

(+)-nno

(-)-nno

SPECIFIC ROTATION
1. Cholic acid, the major steroid found in bile, was found to have a rotation of +2.220 when a 3.00 g sample was dissolved in 5.00 mL of alcohol in a sample tube with a 1.00 cm path lenght. lenght. Calculate for specific rotation for cholic acid.

SPECIFIC ROTATION
2. Polarimeter are so sensitive that they can measure rotation to the thousandth of a degree, an important advantage when only small amounts of a sample are available. For example, when 7.00 mg of ecdysone, an insect hormone ecdysone, that control molting in the silkworm moth, was dissolved in 1.00 mL of chloroform in a cell with a 2.00 cm path length, an observed rotation of + 0.0870 was found. Calculate the specific rotation for ecdysone. ecdysone.

Stereochemical Aspects on Drug Effects

Riyadh, November 22, 2006

Significance of Stereochemistry on Drug Effects

Drug molecules must generally interact with biomolecules (e.g. Receptors and Enzymes) in a very specific way to elicit a pharmacological response. The lock-and-key concept lock-andReceptor = lock Drug = key

Why do we care about this subtle form of stereoisomerism?

Biomolecules (sugars, amino acids, DNA, proteins, steroids) are chiral

COO

Proteins are built from L-amino Lacids, which implies that enzymes the catalysts of nature - are chiral

Also, receptors (drug, taste, biopharmaceuticals, agrochemicals) are chiral and the natural ligand to a receptor is often only one specific enantiomer
W
Enantiomers

This is why mirror image molecules can have radically different activities (effectivity, toxicity, taste) in the body. body.

Life is Chiral

W C

C X Z Y Y Z

Right-handed and left-handed molecules interact with living systems in very different ways and results for example in: Different smell
CH3 O CH3 O

(R)

(S)

H2C

H CH3

H H3C

CH2

( )

r i t il

(S)

il

Mirror plane

Olfactory sensors are chiral

 Different taste
Aspartame
O H O H 3N O H H N O CH3 H 3N O H O O H N O CH3 O H O

(S,S)

(R,R)

160 Times Sweeter than Sugar

Bitter!!

Taste buds are chiral

 Different drug effects Biomolecules, thus, can discriminate between enantiomers (isomers) of a given drug molecule.

The net result is same or different pharmacologic/ pharmacokinetic/ toxicologic activities

THALIDOMIDE: DISASTROUS BIOLOGICAL ACTIVITY OF THE WRONG ENANTIOMER WRONG

O O N N H O H H N O O O O

(R)-isomer

(S)-isomer

In the 1960s thalidomide was given as racemic mixture (RS) to pregnant women to reduce the effects of morning sickness. This led to many disabilities in babies and early deaths in many cases.

The photographs are both from Molecule of the Month at Bristol University: http://www.chm.bris.ac.uk/motm/thalidomide/start.html

*
H

 Later found that only the R-isomer can be used safely R In 1998 thalidomide has been approved by the Food and Drug Administration (FDA) to reduce the immune systems inflammatory response in a host of illnesses, including arthritis, lupus, cancer, leprosy, and AIDs.

O H CF3

NHCH 3

CH 3NH

O H CF 3

(S)-Fluoxetine

(R)-Fluoxetine the

The pure S enantiomer prevents migraines. A racemic mixture of fluoxetine (sold as antidepressant Prozac) doesnt prevent migraines.
( ) ( )

C
H2N H OH HO H

C
Copyright 1999, Michael J. Wovkulich. All rights reserved.

L-Dopa Anti-Parkinsons disease drug

D-Dopa Biologically inactive

has serious side effects

HOOC

OH

HO

COOH

NH2

Ketoprofen
Is a racemic molecule composed by
O OH
( )

O HO
( )

S(+) ketoprofen
powerful analgesic with anti-inflammatory activity with reduced toxicity

R(-) ketoprofen
devoid of pharmacological activity not biologically inert: toxic, increases risk of gastric disease

Stereoselectivity of action
R Levo (-) S Dextro (+)

R(-) ketoprofen

S(+) ketoprofen

Dexketoprofen
The Dextrorotatory (+) anticlockwise (S) enantiomer of Ketoprofen

powerful analgesic with antiinflammatory activity reduced toxicity compared to racemic formulation fewer gastrointestinal adverse events than racemic formulation

Therapeutic Armamentarium
NonNon-optically active Drugs (40%)

Optically active drugs (60%)

In 2000, 40% of drugs on sale in the US were single enantiomer-based. In 2004, about 80% of drugs entering market are single enantiomer variants FDA now requires information about the structure and activity of each isomer present in a racemic mixture of a new medication.