Name of the Course: BP401T Pharmaceutical Organic Chemistry-III

(S. Y. B. Pharm Semester-IV)

Unit-1 ( 10 Hours)
Stereo isomerism
Optical isomerism – Optical activity, enantiomerism, diastereoisomerism, meso compounds
Elements of symmetry, chiral and achiral molecules with more emphasis on Medicinal Chemistry.
DL system of nomenclature of optical isomers, sequence rules, RS
System of nomenclature of optical isomers
Reactions of chiral molecules
Racemic modification and resolution of racemic mixture. Asymmetric
Synthesis: partial and absolute

Prashant Kurkute, Ph.D.

Assistant Professor
( chemprashantkurkute@gmail.com )

School of Pharmacy and Technology Management, Mumbai

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 Reference books :

Stereochemistry of Carbon Compounds, TATA McGraw-Hill Ernst L Eliel

Stereochemistry of Organic Carbon Compounds, Principles and Applications, D. Nasipuri

Organic Chemistry, Seventh Edition, Morrison, Boyd, and Bhattacharjee.

Jerry March, Advanced Organic Chemistry, Reactions, Mechanism, and Structure

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 Homework
Try to draw and understand the different representations of the same molecules

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 Homework
Try to draw and understand the different representations of the same molecules

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 Reference books :

Stereochemistry of Carbon Compounds, TATA McGraw-Hill Ernst L Eliel

Stereochemistry of Organic Carbon Compounds, Principles and Applications, D. Nasipuri

Organic Chemistry, Seventh Edition, Morrison, Boyd, and Bhattacharjee.

Jerry March, Advanced Organic Chemistry, Reactions, Mechanism, and Structure

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 Drawing of molecules
(Fishers projections)

(They all have same geometry just different viewing angles)

Fisher’s projection formula:

1. The four substituents are drawn to the carbon atom with simple horizontal and vertical lines..

2. The horizontal substituents are protruding out of the plane of the paper.

3. The verticle substituents are protruding below the plane of the paper.

4. Structure cant be lifted out of the plane and rotated.

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 Drawing of molecules
(Fishers projections)

Enantiomer

One atom can hold and the other three atoms can rotate at a
time simultaneously without mixing in any direction.
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 Drawing of molecules
(Fishers projections)

Exchange of four atoms at a time without mixing them as shown in figure is allowed.
That is two operations.
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 Drawing of molecules
(Fishers projections)

Exchange of four atoms at a time without mixing them as shown in figure is

allowed.

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 Drawing of molecules
(Fishers projections)

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 D and L nomenclature
In 1890, Emil Fisher came up with the need to establish the relative configuration of different carbohydrates.

At this time, it was established that carbon with four different substituents rotates the plane of polarized light differently.
(Van’t Hoff and Le Bel)

Two enantiomers, (+) and (-), of Glyceraldehyde were isolated and purified.
There was no way to write the substituent in the right configuration (3D arrangement).

So he guessed and drew the structure (That is absolutely right as we know it now). They are called Fisher projections.

Don’t confuse the D and L to the dextro and levo-rotatory names. The D and L don’t tell about the rotation of the plane-
polarized light.

OH on the LEFT hand side OH on the RIGHT hand side

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 D and L nomenclature
To avoid ambiguity, Rosanoff (1906) suggested the following convention for Fishers representation.

1. The molecule is written with the longest carbon chain placed vertically
2. The most highly oxidized end of chain is placed at the top (As CHO in glucose)
3. If OH (Or any X group)at the bottom most chiral center (as C3 in Erythrose/Threose and C5 in glucose) is on right
hand side it is called D-configuration and f if it is on left side it is L-configuration.

Most of the natural sugars have D-configuration

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 Drawing of molecules
(DL nomenclature)
To avoid ambiguity, Rosanoff (1906) suggested the following convention for Fishers representation.

1. The molecule is written with longest carbon chain placed vertically

2. The most highly oxidized end of chain is placed at the top (As CHO in glucose)
3. If OH (Or any X group)at the bottom most chiral center (as C5 in glucose) is on right
hand side it is called D configuration and f if it is on left side it is L-configuration.

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 D and L nomenclature for amino acid
1. The molecule is written with longest carbon chain placed vertically
2. The most highly oxidized end of chain is placed at the top (As CHO in glucose)
3. If OH (Or any X group)at the bottom most chiral center (as C5 in glucose) is on right
hand side it is called D configuration and f if it is on left side it is L-configuration.

R= Substituents

In our body, proteins are made from L-amino acids.

The most natural amino acid has L-configuration.

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 R and S nomenclature
A self-consistent and unambiguous system was proposed by Cahn and Ingold in 1951 and elaborated by Cahn,
Ingold, and Prelog (CIP) (1955, 1966).
Like D and L, R and S are topographic descriptors. They don’t tell anything about signs of specific rotation.
(Latin word: Rectus: Right Sinister: Left)
Process to assign R and S :

1. The sequence rule arrange the four ligands at chirality center in priority order based on the molecular number.
a> b > c> d. (‘a’ having the highest priority and ‘d’ the lowest).

2. The chiral center is viewed from the side remote from the lowest ranking group.
(Molecule is seen as the lowest ranking group appearing away from the viewer side/ Look at the molecule
From the opposite side of the d atom).

3. Configuration is R if the arrangement appears clockwise (Right handed).

4. Configuration is S if the arrangement appears anti-clockwise (Left handed).

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 Sequence rules or standard subrules:

(0) Near end of axis or a plane precedes the farther end (proximity rule).

(1) Higher atomic number precedes lower eg. S> F> O> N> C> H.

(2) Higher atomic mass precedes the lower eg. T> D> H.

(3) Z precedes over E

(4) Like pair precedes unlike pair. Like R,R and S,S precedes over unlike pair R,S and S,R

(1) R precedes S

For majority of compounds subrules 1, and 2 are sufficient.

Subrule(0) is applicable for axial and planner chirality.

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 (1) Higher atomic number precedes lower eg.
S > I > Br > C l> S > P > F > O > N > C > H.

Atoms directly attached to the chiral carbon must be sequenced for priority. If the decision
remains undecided, then pass to the next carbon atom until the decision is reached as per
subrule 1.
Procedure:

1. Examine the atoms directly attached to the stereocenter of the compound and decide propriety on the atomic number.

2. If priority still remains undecided, see the immediate attach atoms to determine priority. The carbon attached with a
high atomic number substituent gets priority.

Home work
(S) (S) (R)

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 (S) (S) (R)

(A) (B) (C)

(A): The immediate attach group to chiral carbon are , F, Cl, Br, H. Give the propriety on the molecular number. Br, Cl,
F, H.

(B): The immediate attach group to chiral carbon as per priority order are: Br, O, C, H. Every atom attached to chiral
atom has different atomic number. Therefore Br> O>C>H.
The Iodine is not directly attached to the chiral atom.

(C): The immediate group to chiral carbon are Br, C, C, H. In this case Br get highest priority, H get lowest priority, and
two carbon atoms are in the tie-up. Therefore in this case of carbon, we see the immediate attach group the carbon
atoms. The immediate group to carbon atoms are H, H, O and H , H, I. As Iodine has a higher molecular number, the
carbon attached to it gets the highest priority.

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 (1) Higher atomic number precedes lower eg. I>Br>Cl>S>P>F> O> N> C> H.

Atoms directly attached to the chiral carbon must be sequenced for priority. If the decision
remains undecided, then pass to the next carbon atom until the decision is reached as per
subrule 1.

R S

R
S

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In branching chains, the earliest atom with highest priority is chosen despite the length of the chain and other substituents.

(R)

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(2) Higher atomic mass precedes the lower eg. T> D> H.
D and T are isotopes of H having same atomic numbers but different
mass number like 2 and 3 respectively

This rule must be used when the first rule is completely exhausted.

Sequence rule 2 must to be applied only after sequence rule 1.

Therefore:

(R)
(S)

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 Double bond in R and S system
The carbon atom must have 4 atoms attached to decide the priority.
In the case of a double bond or triple bond, they are converted to a single bond by attaching the equivalent atoms,
called phantom atoms.

Phantom atoms are written in paratheses. The phantom atoms are treated equally as the real atom. Phantom atoms
cant bind to any other atoms.

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 :NOTE:
Instead of visualizing the lowest propriety atom from the backside, you can visualize it from the nearest side also.
In this case, use the opposite configuration.

R
R

R configuration because the lowest priority

1. The lowest H atom is away from the observer. group is towards the viewer.

2. Therefore the observed conformation If you observe the lowest priority atom close to the observer.
is the right conformation
1. Draw the circle as per the priority of other
substitutes

2. Assign the opposite conformation than observed

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 R and S system for lone pairs
Amine has a pyramidal shape, but if we consider the lone pair
it has tetrahedral geometry.
Generally, because of the low energy barrier, they have two
conformations in the solution.

If we fix the nitrogen and prevent the inversion,

the two isomers can be separated.

Lone pair get the lowest priority

(4)

(2) (2) (2)

(1) (1) (1)

(3) (3) (3)

R S
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 R and S system

(4)
Quaternary ammonium compounds
are locked in only one conformation.
(2)
(1)

(3)

R
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 R and S system
Phosphine compounds are locked in only one conformation because of
sufficient energy barrier.

S R

Lone pair get lowest priority always

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 R and S nomenclature using Fisher’s projections
Draw the fisher projection of molecule.
1. if the lowest priority group (4, d) is on the vertical line (Top or bottom), then see the priority group
orientation. It gives the correct configuration.
2. If the lowest priority group (4, d) is on the horizontal line, then see the priority group orientation.
Use the opposite configuration than observed

Homework to
students to
Convert this to a Homework to students to
flying wedge complete another half

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 R and S nomenclature For Amino acids
Glycine plane of symmetry

Except for Glycine, all amino acids are chiral in nature. Glycine

Human proteins are made of L-amino acids.

All L-amino acids have S configuration except for cysteine And

Selenocysteine which possess R configuration because of Priority rule:
S and Se > O

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 (2)

(1) (4)

(3)

As the lowest priority group is on the horizontal line,

it gets the opposite configuration than observed.

Therefore molecule has S configuration.

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 Drawing of molecules
(DL nomenclature)

Dr. Prashant Kurkute, L-amino acids are present in humans.

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 Meso compound
Meso compounds are
optically inactive
although they contain
chiral carbon.

The one part of molecule

cancel the effect of other
part of molecule.

Although meso
compounds possess
chiral centers they are
symmetric.

Therefore we can conclude that Plane of plane of symmetry is essential for optical activity

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 Meso compound

Meso compounds also possess

a center of Inversion.
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 Diastereomers

A is diastereomer of C and D, B is diastereomers with C and D, C is diastereomer with A and B, and

D is diastereomer with A and B.

Diastereomers are the molecules that have same molecular formula but are not superimposable mirror
images of each other. (Di = Two, Stereo: Stereocenter, mers: Isomers).
In other words, they are stereoisomers but not enantiomers.
Diastereomers has more than two stereocenter. Total number of Diastereomers may be 2n where n is
number of stereocenter.
Diastereomers
Dr. have different chemical and physical properties.
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 Diastereomers

Diastereomers are called Epimers in carbohydrates.

Glucose and galactose epimers that have an identical

configuration in all the positions except at position C-4.

Therefore D-glucose and D-galactose are C-4 epimers.

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