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 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
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
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
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
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
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
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.
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