Dr. Nabila Al-Jaber

STEREOCHEMISTRY IS CHEMISTRY IN SPACE DESCRIBES CHEMISTRY AS A FUNCTION OF TIME

المركبات كيمياء من نوع هي الفراغية الكيمياءكدالة الكيمياء وتصف الفراغ في العضوية

معين تفاعل في كيميائية ظاهرة أي للزمن،الفراغية الكيمياء اساس على شرحها يمكن

CERTAIN MOLECULAR PHENOMENA WERE OBSERVED AND TO EXPLAIN THEM, THE PRINCIPLES OF STEREOCHEMISTRY WERE DEVELOPEDTHE TERM STEREOCHEMISTRY WAS FIRST COINED BY VICTOR MEYER

.

PLANE-POLARIZED LIGHT BEAM

unpolarizedbeam

wavelengthl

polarized beam

All sine waves (rays) in the beam aligned in same plane.

Sine wavesare not alignedin the sameplane.

NOT PLANE-POLARIZED

ENDVIEWSIDE

VIEW

singleray orphoton

A beam is a collectionof these rays.

الضوئي OpticallyالنشاطActive

Refers to molecules that interact with plane-polarized light

تداخل إلى للمركبات الضوئي النشاط يرجعالستقطب الضوء مستوى مع الجزيئات

Jean Baptiste Biot French Physicist - 1815

He discovered that some natural substances (glucose, nicotine, sucrose) rotate the plane of plane-polarized light and that others did not.

Optical Activity

incidentpolarizedlight

transmittedlight (rotated)

sample cell

angle ofrotation, a

(usually quartz)

a solution of the substance to beexamined is placed inside the cell

a

Dextrorotatory

Rotates the plane of plane-polarized lightto the right.

(+)- d-

Laevorotatory

Rotates the plane of plane-polarized lightto the left.

(-)- l-

TYPES OF OPTICAL ACTIVITYnew older

new older

[a]D = acl

Specific Rotation []D

a = observed rotation

c = concentration ( g/mL )

l = length of cell ( dm )

D = yellow light from sodium lamp

t = temperature ( Celsius )

t

Specific rotation calculated in this way is a physicalproperty of an optically active substance.

This equation correctsfor differences in celllength and concentration.

You always get the same

[a]D tvalue of

BIOT’S LAW

POLARIMETER

The instrument used to determine whether asubstance is optically active and to measure thedirection and degree of optical rotation is calleda polarimeter.

POLARIZED LIGHT

and the

Polaroid Film

THE POLAROID FILM WORKS LIKE A NICOL PRISM

polarized light

POLAROID SUNGLASSES

Each eye is polarized in a different plane toeliminate glare.

no lightcan pass

foldfold

Try this with a flexible pair ofclip-on sumglasses (polaroid).

AN EXPERIMENT YOU CAN DO

The Polarimeter

chemist

sample cell

polarizer

Na lamp

plane isrotated analyzer

aaplane-polarizedlight

observedrotation

00000

rotate to null

PASTEUR’S DISCOVERY

Louis Pasteur 1848 Sorbonne, Paris

HOOC CH CH COOH

OH OH

OOC CH CH COO

OH OH

NH4Na ++2-

tartaric acid sodium ammonium tartrate( found in wine must ) Pasteur crystallized this

substance on a cold day.

(+) (-)Louis Pasteur separated these and gave them to Biot to measure.

Biot’s results :

mirrorimages

Crystals of Sodium Ammonium Tartrate

hemihedral facesPasteur found twodifferent crystals.

THERE IS AN ELEMENT OF SERENDIPITY IN PASTEUR’S DISCOVERY. THE TWO TYPES OF CRYSTALS ARE FORMED ONLY AT THE CONDITIONS WHICH FAVOURED PASTEUR.

TARTARIC ACID IS ALSO KNOWN AS RACEMIC ACID. RACEMUS IN LATIN MEANS ‘ A BUNCH OF GRAPES’

HE MADE THIS DISCOVERY AT THE AGE OF 26.

(SEE REFLECTIONS ON MY LIFE)

Enantiomers

W

CX

ZY

W

CXY

Z

non-superimposable mirror images

Pasteur decided that the molecules that made the crystals,just as the crystals themselves, must be mirror images. Each crystal must contain a single type of enantiomer.

(also called optical isomers)

Pasteur’s hypothesis eventually led to the discoverythat tetravalent carbon atoms are tetrahedral.

Only tetrahedral geometry can lead to mirror imagemolecules:

Square planar, square pyrimidal or trigonal pyramidwill not work:

C

C C

tetrahedralcarbon

C C C

Van’t Hoff andLeBel (1874)

ENANTIOMERS HAVE EQUAL AND OPPOSITE ROTATIONS

W

CX

ZY

W

CXY

Z

(+)-nno (-)-nno

dextrorotatory laevorotatory

Enantiomers

ALL OTHER PHYSICAL PROPERTIES ARE THE SAME

H COOHH

OH OH

HOOCHOOC H

H COOH

OH OH

H HCOOH

OH OH

HOOC

meso

enantiomers

(as a minor component)

ALSO FOUND

H COOHH

OH OH

HOOCHOOC H

H COOH

OH OH

H HCOOH

OH OH

HOOC

meso

enantiomers

(+)-tartaric acid (-)-tartaric acid

TARTARIC ACIDfrom fermentation of wine

[a]D = 0

meso -tartaric acid

Enantiomers

IF A COMPOUND WITH TWO CHIRALITY CENTRES HAS THE SAME FOUR GROUPS BONDED TO EACH OF THE CHIRALITY CENTRES, ONE OF ITS STEREOISOMERS WILL BE A MESO COMPOUND

THE NEXT IMPORTANT DEVELOPMENT IN STEREOCHEMISTRY WAS THE CONCEPT OF CONFORMATIONAL ANALYSIS (1950).

THEN 3D STEREOCHEMISTRY BECAME TIME DEPENDENT

(TEMPORAL) AND MARKED THE ADVENT OF DYNAMIC STEREOCHEMISTRY

MOLECULAR SYMMETRY AND CHIRALITY

STEREOCHEMISTRY IS PRIMARILY CONCERNED WITH MOLECULAR GEOMETRY AND MOLECULAR GEOMETRY IS BEST EXPLAINED IN TERMS OF SYMMETRY

SYMMETRY OPERATION AND ELEMENTS OF SYMMETRY

• AXIS OF SYMMETRY,

• PLANE OF SYMMETRY (σv, σh & σd)

• CENTRE OF SYMMETRY

plane ofsymmetry

A SYMMETRIC OBJECT HAS A PLANE OF SYMMETRY - ALSO CALLED A MIRROR PLANE

Mirror Plane

no symmetry

CHIRALAn object without symmetry is

The mirror imageof a chiral object isdifferent and will notsuperimpose on the original object.

OBJECTS WHICH ARE CHIRALHAVE A SENSE OF “HANDEDNESS”AND EXIST IN TWO FORMS

STEREOCENTERS

One of the ways a molecule can be chiral is to have astereocenter.

A stereocenter is an atom, or a group of atoms, that can potentially cause a molecule to be chiral.

stereocenters - cangive rise to chirality

BrFH

Cl

STEREOGENIC CARBONS

A stereogenic carbon is tetrahedral and has four different groups attached.

stereocenter

( called “chiral carbons” in older literature )

HFClBr

Cl

ClBrBr

Cl Cl

plane ofsymmetry

side view edge view

Cl Cl

PRESENT ACHIRAL

MOLECULES Sn AXIS

ABSENT CHIRAL, DISSYMMETRIC

NO Cn

ASYMMETRIC

CONFIGURATION

ABSOLUTE CONFIGURATION ( R / S )

CONFIGURATION

The three dimensional arrangement of the groups attached to an atom

المركزية بالذرة المرتبطة المجموعات أو للذرات األبعاد ثالثي الترتيب

Stereoisomers differ in the configuration at one ormore of their atoms.

مجموعة أو ذرة في اختالفها عند الفراغية هيئتها في المركبات تختلف

2

CONFIGURATION - relates to the three dimensionalsense of attachment for groups attached to a chiralatom or group of atoms (i.e., attached to a stereocenter).

clockwise counterclockwise

(rectus) (sinister)

view with substituentof lowestpriority inback

1 2

4

3

C C

1

4

3

R S

Enantiomers are assigned a CONFIGURATIONusing the same priority rules we developed for E/Z stereoisomers.

1. Higher atomic number has higher priority.

2. If priority cannot be decided based on the first atom attached move to the next atom, following the path having the highest prioity atom.

3. Expand multiple bonds by replicating the atoms attached to each end of the bond.

SPECIFICATION OF CONFIGURATION

SEQUENCE RULE

CAHN-INGOLD-PRELOG

I

C

BrCl

F

I

C

ClBrF

1

2

3

4

R S

Bromochlorofluoroiodomethane

1

32

4

Enantiomers

How Many Stereoisomers Are Possible?

maximum number of stereoisomers

= 2n,

where n = number of stereocenters

(sterogenic carbons)

sometimes fewerthan this numberwill exist

CH3 C

CH2OH

CH3

CH2 CH CH

CH3

CH3

OH*

*

22 = 4 stereoisomers

R RR SS RS S

CH3

OH

CHCH3 CH3

***

23 = 8 stereoisomers

R R RR R SR S RS R R

R S SS R SS S RS S S

CONSTITUTIONAL ISOMERS

Isomers with a differentorder of attachment ofthe atoms in their molecules

STEREOISOMERSIsomers with the same orderof attachment, but a differentconfiguration (3D arrangement)of groups on one or more of the atoms

ISOMERSDifferent compoundswith the same molecular formula

cis/trans ISOMERS

ENANTIOMERSStereoisomers whose molecules are non-superimposible mirrorimages of each other

DIASTEREOMERSStereoisomers whose molecules are not mirror images of each other

each isomer could

double bond or ring

both can apply

have stereoisomers

with a ring

TYPES OF ISOMERISM(geometric)

IMPORTANCE OF STEREOCHEMISTRY

AN ACHIRAL REAGENT REACTS IDENTICALLY WITH BOTH ENANTIOMERS.

AN ACHIRAL SOCK FITS ON EITHER FOOT

A CHIRAL REAGENT REACTS DIFFERENTLY WITH EACH ENANTIOMERS

A CHIRAL SHOE FITS ON ONLY ONE FOOT

RECEPTORS ARE PROTEINS THAT BIND PARTICULAR MOLECULES

BECAUSE A RECEPTOR WILL RECOGNISE ONLY ONE OF A PAIR OF ENANTIOMERS, ENANTIOMERS CAN HAVE DIFFERENT PHYSIOLOGICAL PROPERTIES.

RECEPTORS LOCATED ON THE EXTERIOR OF NERVE CELLS IN THE NOSE ARE ABLE TO PERCIEVE AND DIFFERENTIATE THE ESTIMATED 10000 SMELLS TO WHICH THEY ARE EXPOSED.

(R)-(-)-CARVONE IS FOUND IN SPEARMINT OIL AND (S)-(+)- CARVONE IS FOUND IN CARAWAY SEED OIL. EACH HAS A DIFFERENT SMELL AS IT FITS INTO DIFFERENT RECEPTORS.

CH3O

C

CH2H3C

(R)-(-) CARVONE

CH3O

C

CH2H3C

(S)-(+) CARVONE

ABOUT HALF THE COMMERCIALLY AVAILABLE DRUGS HAVE ONE OR MORE CHIRALITY CENTRES.

SYNTHETIC DRUGS ARE RACEMIC MIXTURES.

THEY ARE MARKETED AS SUCH BECAUSE OF THE HIGH COST OF SEPARATION.

DRUGS FROM NATURAL SOURCES ARE SINGLE ENANTIOMERS.

ONE ENANTIOMER MAY BE MORE POTENT AND THE OTHER MAY HAVE SIDE EFFECTS.

SOMETIMES SEPARATION IS NOT DONE TO AVOID OVERDOSAGE.

(S)-(-)-KETAMINE IS FOUR TIMES MORE POTENT THAN (R)-(-)-KETAMINE AND HAS LESS SIDE EFFECTS.

THE ACTIVE INGREDIENT OF IBUPROFEN IS THE (S)-(+)-ISOMER.

OCONHCH3

THE STEREOCHEMISTRY OF REACTIONS ARE VERY IMPORTANT.

A REGIOSELECTIVE REACTION FORMS MORE OF ONE CONSTITUTIONAL ISOMER THAN THE OTHER.

A B + C MORE ‘B’ IS FORMED THAN ‘C’, WHERE B AND C ARE CONSTITUTIONAL ISOMERS.

A STEREOSELECTIVE REACTION FORMS MORE OF ONE STEREOISOMER THAN THE OTHER.

A B + C MORE ‘B’ IS FORMED THAN ‘C’, WHERE B AND C ARE STEREOISOMERS.

IN A STEREOSPECIFIC REACTION, EACH STEREOISOMERIC REACTANT FORMS A DIFFERENT STEREOISOMERIC PRODUCT OR A DIFFERENT SET OF STEREOISOMERIC PRODUCTS.

A B

C D

‘A’ AND ‘C’ ARE STEREOISOMERS

‘B’ AND ‘D’ ARE STEREOISOMERS

A STEREOSPECIFIC REACTION IS ALSO STEREOSELECTIVE. A STEREOSELECTIVE REACTION IS NOT NECESSARILY STEREOSPECIFIC

ALL THE REACTIONS THAT OCCUR IN BIOLOGICAL SYSTEMS ARE CATALYSED BY ENZYMES.

AN ENZYME CATALYSED REACTION FORMS ONLY ONE STEREOISOMER BECAUSE AN ENZYME POSSESSES A CHIRAL BINDING SITE.

THEY ARE COMPLETELY STEREOSELECTIVE.

THE ENZYME FUMARASE, WHICH CATALYSES THE ADDITION OF WATER TO FUMARATE, FORMS ONLY (S)-MALATE. COO-

-OOCH2COH

HC C

H

-OOC

COO-

H

+ H2Ofumarase

fumarate (S)-malate

ENZYME CATALYSIS IS STEREOSPECIFIC. AN ENZYME CATALYSES THE REACTION OF ONLY ONE STEREOISOMER.

FUMARASE CATALYSE THE ADDITION OF WATER TO FUMARATE BUT NOT TO MALEATE

C C

-OOC

H

COO-

H

+ H2Ofumarase

maleate

no reaction

AN ENZYME CAN DIFFERENTIATE STEREOISOMERS BECAUSE OF THE CHIRAL BINDING SITE

FISCHER PROJECTIONS

CHO

HOCH2 HOH

OHH

CHO

CH2OHH

CH2OH

CHO

OH

EVOLUTION OF THEFISCHER PROJECTION

Substituents willstick out towardyou like prongs

Fischer Projection

Main chain bendsaway from you

“Sawhorse” Projection

Orient themain chainvertically withthe mostoxidized groupat the top.

ORIENTATION OFTHE MAIN CHAINAND THE SUBSTITUENTSIN A FISCHERPROJECTION

continuation of the main chain

CH3

OHH

OHH

OHH

CH3

OH

OH

OH

H

H

H

CH3 CH2OH CH

C

OH

O

CHO COOH

CO

HC

O

OH

INCREASING OXIDATION STATE

increasing oxidation state

In the Fisher projection the main chain is orientedwith the most highly oxidized group at the top.

C=O on carbon-2 increasesthe priority of C-OH

H HCH3 CH3

Cl Br

CH3

CH3

H

H

Cl

Br

Cl

CH3

Br

CH3

main chain in red

orient main chain vertically

convert toFischerProjection

rotate 90o

Br

Cl

CH3

H

H

DETERMINATION OF R / S CONFIGURATIONIN FISCHER PROJECTIONS

H

CH2OH

CHO

OH

PLACE THE PRIORITY=4 GROUP IN ONE OF THE VERTICALPOSITIONS, THEN LOOK AT THE OTHER THREE

H

OH

OHC CH2OH1

2

3

4

1

2 3

4

R

alternatively:

H

CH2OH

CHO

OH1

2

3

4 HOCH2 CHO

OH2

1

4

3

H

R

#4 at top position

#4 at bottom position

BOTH IN BACKSAME RESULT

H

CH2OH

CHO

OH 1

2

3

4

FOR THE MENTALLY AGILEWHY BOTHER INTERCHANGING? JUST REVERSE YOUR RESULT!

H comingtoward you

Same moleculeas on previousslide. S reverse R

Same resultas before.

THE SIMPLEST WAY OF ASSIGNING (R S) CONFIGURATION WAS GIVEN BY EPLING (1982)

1. FIX THE PRIORITY

2. TRACE A SEMICIRCLE JOINING a b c IGNORING d.

3. CLOCKWISE IS ‘R’ AND ANTICLOCKWISE ‘S’ IF ‘d’ IS VERTICAL (TOP OR BOTTOM)

4. IF ‘d’ IS ON THE HORIZONTAL LINE REVERSE THE NOTATION.