Welcome to this course on Stereochemistry which is a basic subject branch of chemistry.

The course has been designed to primarily focus on the fundamental aspects.. Now stereochemistry

like any other branch of sub-disciplines has emerged from a historical perspective. The

subject area is fundamentally important and is applicable to not only to chemistry, but

also to various other branches of sciences like biology and medicine, in particular.

Why is the subject so important? That is because of many reasons. the primary reason is that

the world that we are living in today, is a chiral world. What does it mean? That means

it is made up of systems which have a handedness. Handedness lies in the nature of the two hands.

If I see the two hands, they look almost the same but they are not same. This is because

you cannot superimpose one hand on top of each other. (remember! Exactly similar objects

(clones of a particular object) are always superimposable).

The reason for the two hands not the same lies in their 3D-geometry that is the way

the fingers are aligned. Similar things happen in the molecular world. I have already said,

we live in a chiral world and that means that all the living systems that are there, they

are made up of molecules which exhibit this type of handedness. The stereochemistry is

a subject which deals with the property of the molecule that are controlled by the attached

functionalities in three-dimensional space. Chemistry as a subject developed on the basis

of function, reactivity and structure of molecules but purely looking them at a two-dimensional

platform. That means the chemistry what was known earlier was two-dimensional chemistry.

Basically we looked at molecules from a two-dimensional aspect.

Since this is the 1st class of stereochemistry so I thought that I will introduce the course

instructor which is myself, Professor Amit Basak and my teaching assistants, you can

see the names, Arundhati Mandal, Eshani Das, and Monisha Singha. They will help in answering

your queries and they will also upload the questions and the other teaching materials.They

will also try to dispel any doubt that you have while going through this course using

the forum available for this course. The problem of stereochemistry lies with the

visualization of molecules in three-dimensional space because you do not have the luxury of

having a molecular model in your hand when you see them in an examination hall. What

you have to do if you have a problem? You will need to visualize these in three-dimension

and then try to figure out that what would be the perfect geometry, how these interact

with other systems. This is the most difficult part of stereochemistry;

that is the visualization of molecules just by thought process in three-dimensional space.

Now, let me make little clearer. What is the problem between this two-dimensional chemistry

I was talking about.

Before I do that let me show you what are the different modules that are there in this

course. These are already put in the way when I think you can go through these 8 modules

that are orchestrated in such a fashion that slowly you would learn how to draw the three-dimensional

structure and then try to analyze their interrelationship and then finally we will come to the reactivity

of these molecules and the reactions involving with these molecules.

So basically this is a very fundamental undergraduate course at the BSc level and I do hope that

initially there may be some difficulties in visualization and conceptualization of this

3-D molecules but later on, I am confident that if you go through this course, you will

also feel confident like me in conceptualizing 3D structures, the reactivity

of molecules which can exhibit three-dimensional geometry.

Now, I again come back to the definition of stereochemistry. It is a function of, molecule

in three-dimensional space. I can clarify it little bit. If you take benzyle ehyde vs

ortho methoxy benzyledehyde, you know that the carbonyl group in benzaldehyde is more

susceptible to nucleophilic addition because of greater electrophilicity of the carbonyl

carbon. Both these two aldehydes react with a nucleophile,

like X- but their reactivity is little bit different; their rate of reaction will be

different because of the electronic effect of this methoxy group vs the hydrogen. What

are these electronic effects? That is the - I and + R. So here the reactivity difference

comes from the electronic effects.. I am saying is not that the methoxy is pointing

in this direction and that is the cause of difference in the activity of this carbonyl

vs the other carbonyl. While if you take the completely reduced system of these 2 molecules

especially the methoxy compound, If you reduce it, all the double bonds are reduced. you

get what is called a cyclohexyl system. And when you reduce, you have a a very interesting

situation and that this the aldehyde may be aligned on the same face as the methoxy group

or the aldehyde may be aligned in the opposite face of the methoxy group.

And because of this relationship, which is a geometrical relationship, the reactivity

of these carbonyls will be different. And this difference now comes as a result of the

different geometrical relationship between the methoxy and the aldehyde groups. In benzaldehyde

case, again I repeat, the methoxy is exerting electronic effects as compared to the hydrogen

and that is the reason for their difference in reactivity.

So the activity of the reduced aldehyde, now is dependent on the steric disposition, that

means the three-dimensional disposition of the methoxy group in space, its relation to

the aldehyde. So that is a very simplified way of describing what is stereochemistry.

Now this subject did not evolve from a very rational approach like many other subjects.

Take for example, the discovery of medicines, Many of the medicines have discovered by chance

and then people know how these medicines worker and then developed newer medicines.

Similarly stereochemistry also developed by chance by trial and error, by serendipitous

discovery. And then people finally come out and explain what was happening. what was the

serendipitous observation, why was it happening.

I will tell you the historical perspective of the development of the subject. Now it

all started with the property of light which we know that it is electromagnetic it is an

electromagnetic wave. So there are 2 vectors, electrical vector, electrical waves and a

magnetic vector, a magnetic wave and both are perpendicular to each other. Now if you

consider only the electric vector, so what happens, in normal light the vibrations, the

electrical wave vibrations, are taking place in all directions, in all directions that

is possible around a point. That means if I take this, this is the light

passing from here to there. Then the wave actually is taking place in every possible

place in every possible direction. So basically it encompasses the whole 360 degree around

this axis of migration of the light. That is the normal light. Now in the 17th century,

the Dutch astronomer, Huygens, had discovered what is called plane polarised light.

This means what I was telling earlier that the wave was vibrating in all possible directions.

That is the normal light. But when it passes through a special type of glass which is made

up of some crystals, something else happens. It allows only the vibrations which are occurring

in a particular plane and then the light that comes out, all the vibrations are taking place

in a particular plane and that is what is called plane polarised light.

In this case because I am showing it is in the horizontal direction, so that will be

called horizontally polarised. But actually these are what are called either linearly

polarised light or for you as a beginner, you may just call it as plane polarised light.

And the plane in which the vibrations are taking place is called the plane of polarization.

This happens when light passes through a transparent plate made up of a special kind of a crystal.

For example, crystal of calcium carbonate which is known as calcite, they have this

special property. Not all crystals will do this. Now if you allow this plane polarised

light to travel through another crystal which can also produce plane polarised light thent

what happens? If you now have these crystals or this plate aligned in such a direction

thatl it will have the plane of polarisation perpendicular to the plane of polarisation

that the 2nd crystal is is generating. In that case, the question is what is the

outcome? This will completely block the propagation of the light on the right site. On the other

hand if you rotate this and ultimately by 90 degree, then what happens? The axis of

polarisation of both the plates will become aligned and then the light will come out.

So using these two plates, you can actually analyse whether if you put a compound in between

the plates, the light going from here to there or from left to right, then what happens?

Suppose the plane of polarisation is rotated while passing through the compound. Then the

light which comes out of the 2nd plate will be blocked. You will have to rotate the 2nd

plate in order to align with the plane of polarization . Then light will come out with

full intensity as before. .

And so it all started with the plane polarised light and its interaction with some special

types of molecules. People became interested to know how these molecules behave when plane

polarised light passes through these in solution or in liquid state. And very interestingly,

they found the following: . is the first crystalline plate by the way

is called polariser. So it will produce the plane polarised light and suppose the vibrations

are taking place in a vertical direction. When it goes through the solution, if the

solution does not change the plane of polarisation, the plane of polarisation remains vertical.

Now you put the other plate to view the light coming out of the solution The 2nd plate is

called an analyser (so called because you are analysing whether there is any perturbation

in the plane of polarisation of this light). So using this analyser, you can now check

whether there is any rotation in the plane of polarization while passing through the

solution of the sample. People started doing this sort of experiments using different types

of molecules. And what they found that there are some molecules which rotate this plane

of polarisation either clockwise or in anticlockwise fashion and there are some molecules which

do not. So if it rotates, suppose this is an example

where the plane of polarisation is getting rotated in a clockwise direction and how do

we know it? You rotate the analyser so that the axis becomes aligned to the rotated plane

of polarisation. Now you can see the light coming out from the analyser. So by the amount

of rotation that is needed to see the light coming out, that will be the amount of rotation

that has occurred while light is going through the solution .

Biot, a French scientist who first discovered this phenomenon that there are some molecules

where if you pass the plane polarised light that undergoes rotation that means the plane

of polarization undergoes rotation and then you can find the amount of rotation and that

is characteristic of the sample. But as I told you, this does not happen with all compounds.

There are some particular compounds which have this typical property and he described

the phenomenona by saying that the molecules are showing optical activity and these molecules

he called optically active molecules. The reason for this rotation of plane of polarisation

was not known at that time. Then what happened?

After this event, Louis Pasteur, the famous French chemist came into the picture. So what

he did? At that time, known as tartaric acid was known. It was obtained from various sources

like it can be obtained from fermentation of grape juice. He isolated this tartaric

acid, and then did a crystallization experiment. This tartaric acid obtained from grape juice

fermentation was called Racemic acid. And this Racemic acid, he crystallised as the

sodium ammonium salt because it is a dicarboxylic acid. So one is sodium, one hydrogen is replaced

by sodium and the other one by ammonium. So it is a sodium ammonium salt. And then he

crystallised it and what he noticed that there are two kinds of crystals that were obtained.

And using using a microscope, he could separate these two kinds of crystals. And then he could

find that this one set of crystals is the perfect mirror image of the other crystal.

And then with the separated crystals, he analysed them. That means he wanted to know what is

the effect on the plane polarized light when it passes through these crystals but the crystals

are in solution now. So basically Racemic tartaric acid was divided

into two sets of crystals, these crystals were mirror images of each other and then

when light passes through these crystals, he found that one set of crystals is rotating

the light in a clockwise direction, the other set of crystals which are in solution, they

are rotating the light in the other, that is in the anticlockwise direction.

So the overall observation is that basically you have the same molecule, tartaric acid.

In two-dimensional chemistry, this looked to be only one compound but because they have

different rotating power,, they cannot be the same molecule. So the same, the molecule

which looks the same in two-dimensional geometry, Pasteur has shown that actually they can be

consisting of two different sets of molecules. So that actually is the beginning of the three-dimensional

chemistry which is now called stereochemistry. Thus Pasteur laid the foundation of stereochemistry.

But the question is why? How can you really explain this type of phenomena that where

you have the same molecular formula, same type of connectivity but you can have two

systems generated out of that? But before that, Pasteur actually did another experiment.

See, apart from Racemic acid which can be separated into two sets of crystals, he also

studied another form of tartaric acid. He found another form of tartaric acid, the

same molecule formula, same constitution. That means, same type of atoms attached to

similar type of atoms. And then he found that this tartaric acid which was called mesotartaric

acid, which he failed to separate it into two isomers unlike racemic acid and then he

found that this does not rotate the plane of plane polarised light. So this is again

different from the earlier Racemic acid that he obtained from the grapefruit juice.

Thus now we have 3 types of tartaric acid, one is this mesotartaric acid which cannot

be separated into two different crystalline forms, that means it is basically a single

compound,. And on the other hand, you have the tartaric acid which was obtained from

grapefruit juice, at that time it was called Racemic acid. It consists of two types of

tartaric acid, one was called dextro tartaric acid because it was rotating the plane of

polarized light in the clockwise direction, and the other one is the levo tartaric acid

because it was rotating the light in the other direction, that means counterclockwise or

anticlockwise direction.

However, Pasteur could not explain why this phenomena is happening. That means, the molecule

having the same molecular formula, same constitution but how can it exist in 3 different forms?

In 1874, Van’t Hoff and Le Bel, they proposed that this is because of the existence of carbon

in tartaric acid where the carbon is attached to 4 different groups.

Again I just go back to the previous experiment, if you consider the tartaric acid structure,

you see that there is a carbon. Usually we do not put the hydrogen which is attached

to the carbon. So that is why, the hydrogen is missing. So the carbon has a hydrogen,

has a carboxylic acid, has OH and this whole group. That means 4 different groups are attached

to this carbon and as these 4 different groups are attached to a carbon, according to Vant

Hoff and Le Bel, these groups will be tetrahedrally disposed.

And because of this tetrahedral arrangement, they said that if a carbon has this 4 different

groups attached to it, then you can generate 2 molecules out of it and one will be the

mirror image of the other. And they can exist as a pair of isomers. This is the breakthrough

concept. Remember, it is only 1874. At that time, the tetrahedral geometry of carbon by

sp3 hybridisation was not known. So it was a pure speculation or a brilliance

from these 2 scientists who could propose the tetrahedral geometry of carbon because

they knew that if the carbon is flat, square planar, then you cannot generate these type

of systems out of it. So just from geometric concept, they developed this tetrahedral geometry

of carbon.

So what is the ultimate? At first, it was the development of plane polarised light.

Then the observation that some molecules rotate the plane of plane polarised light. The 3rd

is discovery of tartaric acid. So it all started with tartaric acid. And the tartaric acid

exists in in 3 different forms And finally Van’t Hoff and Le Bel’s proposition, They

postulated that this is because of the existence of a carbon with 4 different groups and you

can generate 2 different molecules out of this. So that takes care of the slides. Now

I will show you, I will start from Van’t Hoff and Le Bel, what they said I will show

you in a model.

See, if you look at this, this system, that there is a carbon, there is a green atom,

there is a blue atom, there is a white atom and a red atom. So this is a tetrahedral carbon

with 4 different groups and if you take a mirror image of this and I can take a mirror

image of this, I can build up this molecule. They you can see that they are mirror images

of each other. But if you would now want to see whether they

are identical or not, you try to what is called the principle of superposition. So you want

to put one on top of each other and then see whether they are superimposable, that means

all the green atoms or blue atoms or red atoms or the white atoms, they match or they fall

on top of one another or not. So that is what is called superimposition.

So you apply that superimposition principle. Now whatever you do, if you try to match the

green and the blue, you see there is a mismatch between the red and the white. Here also,

there is a mismatch between the red and the white. If you want to match the red ones and

the green ones, now what happens, you see there is a mismatch between the blue and the

between the blue and the white. So basically you cannot superimpose these

2 molecules. So they are mirror images, they are different. So that is the starting point

as I said. So they are now isomers because you know what are isomers? Isomers are molecules

with the same molecular formula but having different properties. That means a different

molecule with same molecular formula are called isomers, .

So let us start with the isomerism which is a very important concept in, not only in stereochemistry

but also in two-dimensional chemistry we know. And we can now subdivide this isomerism into

2 classes, one was based on two-dimensional chemistry and that is the kind of isomerism

you are exposed to, and is called constitutional isomerism.

Now what is meant by constitution? Constitution is nothing but what is called the connectivity.

That means if I have a 3 carbon system and then if I have OH at C1 positio. In another

molecule, suppose the OH is attached at the C2, . Now what is the difference between these

2 molecules? The difference is in the connectivity. Here,

the terminal carbon is connected to OH, here the middle carbon is connected to OH. So that

is what, that means they have different constitution. Constitution means the connectivity. So this

is also isomerism but that will be called constitutional isomerism. So you have a set

of constitutional isomerism. Similar is, in constitutional isomerism, you

have different branches, you have different subdivisions. These are all known. Like one

is called chain isomerism where the carbon chain is different. So if you have 4 carbon

system, you can grow this 4 carbon system in this fashion also. So again the Constitution

is different. This is N butane and this is 2 methyl butane.

They are different molecules because their Constitution is different. So but that is

called chain isomerism. Then you have you have positional isomerism like this example,

positional isomerism, the hydroxy group changes position from here to there. So that is called

positional isomerism. And another class of constitutional isomerism is what is called

functional group isomerism. I am not again putting the hydrogens. So this

is the ether molecule. So you this is ethyl methyl ether. You can draw another molecule

with the same molecular formula but that will be called propanol, one propanol. So that

is what is called functional group isomerism. So you have 3 types, chain isomerism, then

positional isomerism and you have functional group isomerism.

But this is two-dimensional chemistry, again I repeat. The more important one which is

relevant to our subject is this, is the other part where the Constitution is same. But the

molecules are different and that is called stereo isomerism. So is the Constitution is

different, that means connectivity, atom connectivity is different. Then if they fall into the class

of constitutional isomerism. If the connectivity is same but the molecules

are still different like tartaric acid as I showed where where the connectivities are

all same but you have 3 different types of tartaric acid. So then the concept of stereo

isomerism comes. So what are stereo isomers then? Molecules with same molecular formula,

with same functional groups, with same Constitution, so what the difference?

The difference is the arrangement of the groups in the three-dimensional space such that is,

they are the stereoisomers. Now in stereo isomerism you have again two different types

of stereo isomerism, one is called Enantiomerism and the other is called Diastereo isomerism.

Okay? We will discuss, we will start from this stereo isomerism, Enantio and Diastereo

from now on, okay. Enantiomers are molecules which are mirror

images, non-superimposable mirror images of each other. Like what I showed about the Racemic

tartaric acid which was resolved into 2 sets of crystals, one crystal was mirror image

of the other crystal but they are not superimposable. They are different.

Similarly molecules, if you look at the molecular level, molecules which are stereoisomers and

mirror images, non-superimposable mirror images of each other, they are called Enantiomers

whereas molecules which have same Constitution, same functional groups, same connectivity,

but they are not mirror images of each other and they are called diastereomers or you can

say the molecules are exhibiting Diastereo isomerism okay?

Okay, let us wipe this out now. Let us concentrate on the 1st on the Enantiomerism. So Enantiomers

are what? Enantiomers again I repeat, are molecules which are non-superimposable, are

stereo isomers which are non-superimposable on each other, which are non-superimposable

mirror images of each other. They are called Enantiomers and they have the typical property

of rotating the plane of plane polarised light. So Enantiomer is always a pair, Enantiomeric

pair. So one is the mirror image of the other. So if I have a A, I have a mirror image of

A. If this has got a + rotation, so I can have a mirror image which will have a - rotation.

So they are a pair of Enantiomers okay. So Enantiomerism is directly connected to optical

activity. So if you take just one Enantiomer and pass the light, this light will be rotated

clockwise or anticlockwise direction. One thing one should remember that this rotation

when we tell, we have to view the rotation from against the propagation of the light.

So if light moves from here to there, the Observer is here, the Observer I should be

here and then he will see whether it is rotating clockwise or anticlockwise. This is very important

because if you look from this side then the clockwise becomes anticlockwise and the anticlockwise

becomes clockwise. So basically what when the chemists measure

the optical rotation of a molecule, what is the optical rotation? That means the degree

of rotation that what the molecule does onto the plane of plane polarised light. So we

have to view against the propagation of the light. Then you can say that whether it is

clockwise rotation or it is anticlockwise rotation.

Now by the way, clockwise rotation is also called dextro as I already mentioned, dextro

rotate any molecule, if the molecule rotates the plane of the plane polarised light in

the clockwise direction, that is called dextro rotatory molecule and the other one, will

be called liver rotatory molecule means liver rotatory molecule. Rotate the plane of plane

polarised light into the left side. The question is, we know that they form superimposable

mirror image, a non-superimposable mirror images sorry, they form a non-superimposable

mirror image system. But what makes it what is the cause of this rotation? What is the

genesis of this optical activity? Okay? Now by the way, another terminology is there that

molecules which can rotate the plane of plane polarised light, they are, earlier I said,

they are optically active compounds, they are also called chiral molecules okay?

Chiral molecules, like the two hands, one hand is the mirror image of the other. But

they are not superimposable as I said and this is hand. So if I consider this as a molecule,

so if light passes through this, the light will suffer rotation. If light passes through

this, that will also suffer rotation but the 2 rotations will be just opposite to each

other okay? This is earlier it used to be called handedness but the same thing is, the

modern day we call it chirality. So now we can summarise little better that

what we have learnt is that there are molecules which have the same molecule formula, same

connectivity, same functional group but they can be different. They are called stereo isomerism

and that stereo isomerism is arising because of the disposition, different disposition

of groups in the three-dimensional space. Then we have seen that there are 2 sets of

stereo isomers, one is called Enantiomers and the other set is called Diastereomers.

Enantiomers have non-superimposable mirror images and Diastereomers are, they are not

mirror images of each other but they are stereoisomers okay?

Then Enantiomers have the property of rotating the plane of plane polarised light. I have

not concentrate in we will back to the Diastereomers later on but let us 1st concentrate on the

Enantiomers. Because they are chiral, they have the capability of rotating the plane

of plane polarised light. Now comes the bigger issue that why this molecules which have non-resolvable

or which have non-superimposable mirror images, why do they rotate the plane of plane polarised

light, okay? So that will be the next half an hour we will discuss the genesis of this

optical activity.