SEMINAR ON STEREOCHEMISTRY

DELIVERED BY:VIJAY M. BHOSALE

GUIDED BY:M.A BOMBAYALA

CONTENT: INTRODUCTION

HISTORY

ISOMERS CLASSIFICATION

DISCRIPTION OF ISOMRISMS

CONFIGURATIONAL ISOMERIMS

CONFORMATIONAL ISOMERISM

CHEMICAL ISOSTRIMMERISM

BIOISOSTERISM

Stereochemistry:An introduction

Stereochemistry of Tetrahedral Carbons We need :one Carbon sp3-hybridized, at least to represent molecules as 3D objects

For example:H H

H c Cl H c Cl 2D DRAWING Not for stereochem

Br Br

3 D DRAWINGH H Appropriate for stereochem

H C Cl Cl C H

Br Br

A

Thus, we can define……

Stereoisomer's: isomers that have same formula and connectivity but differ in the position of the atomin space

Stereochemistry: chemistry that studies the properties of stereoisomers .

Historicalperspective

Christian Huygens:

(1629-1695). Dutch astronomer,mathematician, and physicist.He discovers plane polarized light :

Historical perspectiveCarl Wilhelm Scheele: (1742-1786)

“Oh, how happy I am! No care for eating ordrinking or dwelling, no care for mypharmaceutical business, for this is mere playto me. But watch new phenomena this is allmy care, and how glad is the enquirer whendiscovery rewards his diligence; then his heartRejoices”

In 1769, he discovers TartaricAcid from tartar (the potassiumsalt of tartaric acid, depositedon barrelsand corks duringfermentation of grape juice )

OH CO2H

OH CO2H

Historical perspective

Jean Baptiste Biot (1774-1862)In 1815, he notes that certainnatural organic compounds (liquidsor solutions) rotate plane polarizedlight (Optical Activity).

MO

LE

CU

LE

planepolarizedlight

tube containinga liquid organiccompound orsolution

planepolarizedlight

IN OUT

Definitions

Optically Active: the ability of some Compounds to rotate plane polarized ligtht.

Dextrorotatory (+): an optically activecompound that rotates plane polarized

light in a clockwise direction .

Levorotatory (-): an optically activecompound that rotates plane polarizedlight in a counterclockwise

Historical perspectiveIn 1819 , Racemic Acid wasdiscovered. Later shown to havethe same formula as Tartaric Acid.Historical perspective

In 1838, Biot notes that RacemicAcid does not rotate planepolarized light:

OH CO2H

OH CO2H

planepolarizedlight

IN OUT

tube containingsolution ofRacemic Acid(RA)

plane polarized light,unchanged

RA is not opticallyactive

Historical perspective

In 1847, he repeats earlier work onRacemic Acid. Crystallization ofsodium ammonium salt gives mirrorimage crystals that he separated byhand. Equimolar solutions of separatedcrystals have equal but opposite opticalactivity:

Louis Pasteur (1822-1895)

[α]D

STRUCTURAL ISOMERISM

Because of difference in the arrangement of atom in the molecule within space .

Having same molecular formula and different structure.

TYPE OF STRUCTURAL ISOMERISM

CHAIN/NUCLEAR ISOMERISM

POSITION ISOMERISM

FUNCTIONAL ISOMERISM

METAMERISM

TAUTOMERISM

CHAIN ISOMERISM

e.g. CH3CH2CH2CH3

n- BUTANE

CH3CH2CH-CH3

CH3

ISOPANTANE

POSITION ISOMERISM

CH3CH2CH2-IN-PROPYL IODIDE

CH3CHCH3

IISOPRPYL IODIDE

FUNCTIONAL ISOMERISM

CH3CH2OHETHYL ALCOHOL

CH3OCH3DIMETHYL ETHER

METAMERISM

C2H5 OC2H5

DIETHYL ETHERCH3OCH2CH2CH3

METHYL n-PROPYL ETHER

TAUTOMERISM

In which one isomer get constantly changing into other

H-C= NHYDROCYNIC ACID

H-N= CISOHYDROCYNIC

ACID

STEREOISOMERISM

Isomerism having same molecular and structural formula but different spatial arrangement of atom or group

3-D STRUCTURE OF LACTIC ACID

TYPE OF STEREOISOMERISM

GEOMETRICAL ISOMERISM

OPTICAL ISOMERISM

GEOMETRICAL ISOMERIMSM

Cis –Trans isomerism e.g. 2 -Butene

CH3- C - H

=

H - C - CH3

TRANS

CH3 –C – H

=

CH3 – C - H

CIS

PROPERTIES OF ISOMER

Trans isomer are more stable than cis isomers.

Different physical and chemical properties.

Geometrical isomerism also possible in cyclic compound w/o any rotation of bond .

OPTICAL ISOMERISM Rotate the P.P.L Compound having chiral center

Are of two type Laevo-RotatoryDextro-Rotatory

• Equimolecular mixture of different isomer are the RACEMIC MIXTURE

Enantiomer : Having non-super imposible mirror image

Diastereomers : Having non super imposable non mirror image.

CONFIGURATION:ARRANGEMENT OF ATOMS THAT CHARECTORIZES

A PARTICULAR STEREOISOMERS CALLED

COFIGURATION.

Br

I – C – Cl

H

Br

Cl – C – I

H

R and SConfiguration

Priority is given A/C to atm. No. e.g. I > Br > Cl > H

Conformational isomers / Conformers &

Conformational analysis :-Different arrangement of aloms that can be

converted into one another by rotation abbot a single

bond aue called as conformers or C.I. & conformational

analysis in the study of energy changes that accuse in

molecule when groups rotate about single bond or the

study of physical / Chemical properties of molecule

related to prgfered conformation is called as

conformational analysis.

Ex. :- Ethane, as posseesser C-C – bond thus gives

diff conformations by rotation about signle bond

Acc. To sawhorse formula :

Eclipsed Skew

Staggered

When aloms (intumediate form Whin

Placed

Are exactly that exists bein side

ways to

Opp. Each other Eclipse & staggered form each other

Acc. To Newman Projections.

Eclipsed Skew

Staggered

Less

More

Stable

Stabble

More P.E. Less

P.E.

Al

All conformers tilies to Maintain the most stable form & P.E

. is at MinM for staggered conformation

Eng barrier is 3 Kcal / Mor & rego for conv from one

another

Reason : in staggered : Aloms are far apart

So lers interoclion or

Sleric repulsion

So most stable form

Req. lens Eng.

In Eclipsed forms :- Aloms being exactly

apposile, closer to each other

More steric repulsion

due to bully grps logethr

So least stable

Req. more P.E.

Eng. Diagram

Ex. 2) A butane :-

Conformations abscrved are

Eclipsed Gauch Staggered

(Cisoid form) (As Skew Previously) (Transolid Anti form)

Exists as :

Thus as bulhy gps are far : staggered to be most stable form.

To change from the fully

Eclipsed Staggered

Form form

Eng req :- 3 K cal/mol,

Which can be atlained evnn at room temp by troction of collisions. & this

eng req. o rolate the molecule abou C.C. bond is called as lorioneal

energy.

As eng requirement :- or stability is more of staggered or Gauch

form, they are more preffered and exists as at the lower level in the eng.

Profile diagram

So least stable

Req. more P.E.

Eng. Diagram :-

Ex 2) n butane :-

Conformations absurved are

Eclipsed Gauch Staggered

(Cisoid form) (As skew previously) (Transolid Anti

form)

Exists as :-

Anti (Gauch)

(Gauch)

(Staggered) (I) (II)

(More stabble)

Faclors offecting confarmational Analysis

1) Vander Wool forces :-

In ex of n. butane ; staggered (Anti) form is most

stable while the cisoid (Eclipsed) form is least stable the

reason behind it is Vander- Wools repulsion is steric

repulsion ie.

As bulky e donaling gp ie. CH3 are closest to each

other & thus repelis & thus unstablizes the conformation

& for staggered

Far . apart

Less repulsion

More stable

1) Improve biological activity

2) Improve duration action of drug

3) To gain selectivity for determined receptor or enzyme

4) Reduce adverse effect ( side effect )

5) Optimize pharmacokinetic lead compound might present .

CLASSIFICATION OF BIOISOSTERISMALFRED BURGER (1970 )

TWO TYPE OF BIOISOSTERISM

1) 1)CLASSIC BIOISOSTERS

2)NON CLASSIC BIOISOSTERS

CLASSIC BIOISOSTERSThe isosters as atoms , ions , functional

group or mollecular sub units obeyessterice and electronic limitation

Dipole Dipole interaction :-equal & opp charges. Sepurates

mol. Is polar. (Diff e. vity)

exists betn 2 diff molecules

is betn H-E but not in H-H

So Dipole Moment should be minimum for maximum

stability.

In slaggered form it is zero but in lemp, causes the

molecule to

absorb eng. & conv to eclipsed

form & thus dipole moment. : stability & this is due to the dipole

– dipole

repulsire forces betn the two bulhy gps

& thus mahing the conformation unstable.

Anti / Transoid Cisoid(Staggered) (fully

eclipsed)(More stable) (Least

stable)

Gy drogen bouding :-As Hydrogen bonding increases stability ; As we know Anti / staggere are more stable in some cases

Ex. Etiylene glycol : Skew is more stable Then staggered form

Informoleuslar H-bonding more in skew this bonding stabilized skewform & so is most stable other conformations in cyclo alkanescylic compounds

(Chair form) (Boat form)

More stable Least stable

CLASSIC BIOISOSTERS GROUPS & ATOM

APPLICATIONS MONOVALENT : URACIL → 5 FLUORO URACIL

DIVALENT : Eg- ANTIHISTAMINIC AGENT

R>

NONCLASSIC BIOISOSTERS They do not have same no. Of atoms & do not set steric

and electronic rules of classical isoster but they can produce a similarity in biological activity.

NON- CLASSIC BIOISOSTERS

BIOISOSTERISM AS A STATERGY OF MOLECULAR MODIFICATION the correct use of bioisosterism demands physical ,

chemical , electronic & conformational parameter s involve in plane bioisosteric substitution , carefully analyze so as to predict , theoretically , any elemental attraction in term of pharmacodynemic & pharmacokinetic properties with new bioisosteric substance present.

THE FOLLOWING PARAMITER :

1) molecular size

2) sterice shape

3) electronic distribution

4) lipid solubility

5) pH partition coefficient

6) chemical reactivity

ISOTERIC REPLACEMENT

Eg – Fluorine Replacement Of Hydrogen In Uracile

Replacement of ester function of procaine with amide group gives procainamide

Replacement Of carbonyl oxygen in hypoxanthine to give 6 - mercaptopurine