Stereoisomerism

Stereoisomerism

Stereochemistry refers to the 3-dimensional properties and reactions of molecules. It has its own language and terms that need to be learned in order to fully communicate and understand the concepts.

 Chiral vs achiral molecule

A chiral molecule is a molecule that does not have a plane of symmetry or a center of symmetry. In other words, a chiral molecule cannot be superimposed on its mirror image. Chiral molecules have two non-superimposable mirror image forms, which are called enantiomers. Each enantiomer has the same physical and chemical properties, except for the direction in which it rotates the plane of polarized light.

For example, consider the molecule of limonene. Limonene is a naturally occurring compound found in citrus fruits such as oranges, lemons, and grapefruits. Limonene exists in two enantiomeric forms: (+)-limonene and (-)-limonene. The two enantiomers have the same chemical formula and molecular weight, but they have different three-dimensional arrangements of atoms, resulting in different physical and chemical properties. The (+)-limonene rotates the plane of polarized light to the right, while the (-)-limonene rotates it to the left.

On the other hand, an achiral molecule is a molecule that has a plane of symmetry or a center of symmetry. An achiral molecule can be superimposed on its mirror image. Achiral molecules have only one form, and it cannot rotate the plane of polarized light.

For example, consider the molecule of methane. Methane is an achiral molecule because it has a tetrahedral geometry with four identical carbon-hydrogen bonds, which are symmetrically arranged around the carbon atom. It does not have a plane of symmetry or a center of symmetry, but it can be superimposed on its mirror image. Methane does not rotate the plane of polarized light.

In summary, a chiral molecule is a molecule that cannot be superimposed on its mirror image, while an achiral molecule is a molecule that can be superimposed on its mirror image.

 Stereogenic center

A stereogenic center is an atom in a molecule that has four different substituents attached to it, creating a chiral center. This means that the molecule has a non-superimposable mirror image, and can exist in two forms that are mirror images of each other, called enantiomers. Stereogenic centers are commonly found in organic molecules and are important in pharmaceuticals, biological molecules, and materials science.

A molecule that does not have a stereogenic center is called achiral. Achiral molecules can have a plane of symmetry, which means that they are superimposable on their mirror image. Achiral molecules can also have multiple stereogenic centers, but if those centers are arranged in a way that the molecule has a plane of symmetry, the molecule is still achiral. An example of an achiral molecule is meso-tartaric acid, which has two stereogenic centers but also a plane of symmetry that makes the molecule superimposable on its mirror image.

 Stereoisomers

When isomerism is caused by the different arrangements of atoms or groups in space, the phenomenon is called Stereoisomerism (Greek, Stereos = occupying space). The stereoisomers have the same structural formulas but differ in the spatial arrangement of atoms or groups in the molecule. In other words, stereoisomerism is exhibited by such compounds which have identical molecular structures but different configurations. Stereoisomerism is of two types :

1.   Geometrical or cis-trans isomerism 

2.   Optical Isomerism.

 

Geometrical isomerism

Isomers which possess the same molecular and structural formula but differ in arrangement of atoms or groups in space around the double bonds, are known as geometrical isomers and the phenomenon is known as geometrical isomerism. Geometrical isomerism are show by the compounds having the structure.

 Cis – trans isomerism: When similar groups are on the same side it is cis and it same groups are on the opposite side it is trans isomerism. 



 Syn - anti isomerism :

Syn anti isomerism is not possible in ketoxime since only one from is possible two —CH3 groups are at one C.

In cyclic compounds

Physical properties of cis and trans isomers

Dipole moment: Usually dipole moment of cis is larger than the trans-isomer.

Melting point: The steric repulsion of the group (same) makes the cis isomer less stable than the trans isomers hence trans form has higher melting point than cis.

Different chemical properties: Syn-addition makes cis forms into meso and trans into d and l, anti addition makes cis into d – l and trans into meso

Optical isomerism

Any substance which rotates the plane polarised light (PPL) is said to be optically active. If a substance is optically active, it is non - superimposable on its mirror image. If a molecule of substance is superimposable on its mirror image, it cannot rotate PPL and hence optically inactive. The property of non-superimposability on mirror image is called chirality. The ultimate criterion for optical activity is chirality , i.e., non-superimposibility on its mirror image.

 If a molecule of organic compound contains 'one' chiral carbon, it must be chiral and hence optically active.

 

Chiral carbon: If all the four bonds of carbon are satisfied by four different atoms / groups, it is chiral. Here it should be noted that isotopes are regarded as different atoms / groups ) chiral carbon is designated by an asterisk(*).

 

Optical isomerism in bromochloroiodomethane: The structural formula of bromochloroiodomethane is 

The molecule has one chiral carbon as designated by star. So molecule is chiral. It is non - superimposable on its mirror image.

According to Van't Hoff rule,

Total number of optical isomers should be = 2n; when n is number of chiral centre

The Fischer projections of the two isomers are 

Stereoisomers which are mirror - image of each other are called enantiomers or enantiomorphs. (i) and (ii) are enantiomers. All the physical and chemical properties of enantiomers are same except two:

They rotate PPL to the same extent but in opposite direction. One which rotates PPL in clockwise direction is called dextro-rotatory (dextro is Latin word meaning thereby right) and is designated by d or (+). One which rotates PPL in anti-clockwise direction is called laevo rotatory (means towards left) and designated by l or (–).

They react with optically active compounds with different rates.

 Elements of Symmetry

If an organic molecule contains more than one chiral carbons then the molecule may be chiral or achiral depending whether it has element of symmetry or not.

If a molecule have either

a)   a plane of symmetry, and  / or

b)   centre of symmetry, and / or

c)   n-fold alternating axis of symmetry

If an object is superimposable on its mirror image; it cannot rotate PPL and hence optically inactive. If an object can be cut exactly into two equal halves so that half of its become mirror image of other half., it has plane of symmetry.

Centre of symmetry: It is a point inside a molecule from which on travelling equal distance in opposite directions one takes equal time

Thus, if an organic molecule contains more than one chiral carbons but also have any elements of symmetry, it is superimposable on its mirror - image, cannot rotate PPL and optically inactive. If the molecule have more than one chiral centres but not have any element of symmetry, it must be chiral.
 

Enantiomers

Stereoisomers which are related to each other as mirror images are called enantiomers. Enantiomers can contain any number of stereogenic centers, as long as each center is the exact mirror image of the corresponding center in the other molecule.

 

If one or more of these centers differs in configuration, the two molecules are no longer mirror images, but are totally different chemical compounds with differing physical and biological properties. Stereoisomers which are not enantiomers are called diastereomers.

For a molecule with multiple chiral centers, the number of possible diastereomers is given by Van't Hoff rule : x = 2n
Where x is the number of possible isomers and n is the number of stereogenic centers. Thus, for molecules with two stereogenic centers there are four possible stereoisomers. For cholesterol, with eight stereogenic centers, there are 256 possible stereoisomers, etc.
A third type of stereoisomer which must be considered is a meso compound. A meso compound contains at least two stereogenic centers, yet the molecule itself is not chiral. This is because meso compounds contain an internal plane of symmetry; the molecule can be split by an imaginary mirror so that all atoms on one side of the mirror are the exact reflection of the atoms on the other side. This can be seen below for cis-1,2-dimethylcyclopentane; there are two chiral centers in the molecule since the two carbons labeled with the red asterisk are each bonded to four different groups. A mirror placed through the molecule, along the plane indicated by the dashed line, will exactly bisect the molecule with all groups exactly reflected by their counterparts on the other side of the "mirror".
 

Stereoisomerism in 2,3-dibromopentane?

The structural formula of 2,3-dibromopentane is 

 

The molecule contains two chiral carbons and hence according to Van't Hoff rule the total number of optical isomers should be 2n = 22 = 4 and it is. The four optical isomers are.

 

I,II,III and IV are four stereoisomers of 2,3-dibromopentane.

I and III are enantiomers.

III and IV are also enantiomers

 

Diastereomers

Diastereomers are stereoisomers which are not mirror images of each other. For now, we will concentrate on understanding enantiomers, and come back to diastereomers later.

We defined a chiral center as a tetrahedral carbon with four different substituents.  If, instead, a tetrahedral carbon has two identical substituents (two black atoms in the cartoon figure below), then of course it still has a mirror image (everything has a mirror image, unless we are talking about a vampire!) However, it is superimposable on its mirror image, and has a plane of symmetry.

 

This molecule is achiral (lacking chirality). Using the same reasoning, we can see that a trigonal planar (sp2-hybridized) carbon is also not a chiral center.

 

Notice that structure E can be superimposed on F, its mirror image – all you have to do is pick E up, flip it over, and it is the same as F.  This molecule has a plane of symmetry, and is achiral.

Let’s apply our general discussion to real molecules.  For now, we will limit our discussion to molecules with a single chiral center.  It turns out that tartaric acid, the subject of our chapter introduction, has two chiral centers, so we will come back to it later.

Consider 2-butanol, drawn in two dimensions below.

 

Carbon 2 is a chiral center: it is sp3-hybridized and tetrahedral (even though it is not drawn that way above), and the four things attached to is are different: a hydrogen, a methyl (-CH3) group, an ethyl (-CH2CH3) group, and a hydroxyl (OH) group.  Let’s draw the bonding at C2 in three dimensions, and call this structure A.  We will also draw the mirror image of A, and call this structure B.

 

When we try to superimpose A onto B, we find that we cannot do it.  A and B are both chiral molecules, and they are enantiomers of each other.

2-propanol, unlike 2-butanol, is not a chiral molecule.  Carbon #2 is bonded to two identical substituents (methyl groups), and so it is not a chiral center.

 

Notice that 2-propanol is superimposable on its own mirror image.

When we look at very simple molecules like 2-butanol, it is not difficult to draw out the mirror image and recognize that it is not superimposable.  However, with larger, more complex molecules, this can be a daunting challenge in terms of drawing and three-dimensional visualization.  The easy way to determine if a molecule is chiral is simply to look for the presence of one or more chiral centers: molecules with chiral centers will (almost always) be chiral.  We insert the ‘almost always’ caveat here because it is possible to come up with the exception to this rule.

Here’s another trick to make your stereochemical life easier: if you want to draw the enantiomer of a chiral molecule, it is not necessary to go to the trouble of drawing the point-for-point mirror image, as we have done up to now for purposes of illustration.  Instead, keep the carbon skeleton the same, and simply reverse the solid and dashed wedge bonds on the chiral carbon: that accomplishes the same thing.  You should use models to convince yourself that this is true, and also to convince yourself that swapping any two substituents about the chiral carbon will result in the formation of the enantiomer.

 

Here are four more examples of chiral biomolecules, each one shown as a pair of enantiomers, with chiral centers marked by red dots.

 

Here are some examples of achiral biomolecules – convince yourself that none of them contain a chiral center:

 

When looking for chiral centers, it is important to recognize that the question of whether or not the dashed/solid wedge drawing convention is used is irrelevant.  Chiral molecules are sometimes drawn without using wedges (although obviously this means that stereochemical information is being omitted). Conversely, wedges may be used on carbons that are not chiral centers – look, for example, at the drawings of glycine and citrate in the figure above.

Can a chiral center be something other than a tetrahedral carbon with four different substituents?  The answer to this question is ‘yes’ – however, these alternative chiral centers are less common, and outside the scope of our discussion here.

You may also have wondered about amines: shouldn’t we consider a secondary or tertiary amine to be a chiral center, as they are tetrahedral and attached to four different substituents, if the lone-pair electrons are counted as a ‘substituent’? Put another way, isn’t an amine non-superimposable on its mirror image?

The answer: yes it is, in the static picture, but in reality, the nitrogen of an amine is rapidly and reversibly inverting, or turning inside out, at room temperature.

 

If you have trouble picturing this, take an old tennis ball and cut it in half.   Then, take one of the concave halves and flip it inside out, then back again: this is what the amine is doing. The end result is that the two ‘enantiomers’ if the amine are actually two rapidly interconverting forms of the same molecule, and thus the amine itself is not a chiral center.  This inversion process does not take place on a tetrahedral carbon, which of course has no lone-pair electrons.

When we go to the third row in the periodic table, with elements such as sulfur and phosphorus, this process of flipping the lone pairs is much slower, so we can resolve enantiomers for compounds such as phosphines (the phosphorus analog of amines).

 

Optical activity

Optical activity is the ability of a chiral molecule to rotate the plane of plane-polairsed light, measured using a polarimeter.  A simple polarimeter consists of a light source, polarising lens, sample tube and analysing lens.

 

When light passes through a sample that can rotate plane polarised light, the light appears to dim because it no longer passes straight through the polarising filters.  The amount of rotation is quantified as the number of degrees that the analysing lens must be rotated by so that it appears as if no dimming of the light has occurred.
 

Measuring Optical Activity

When rotation is quantified using a polarimeter it is known as an observed rotation, because rotation is affected by path length (l, the time the light travels through a sample) and concentration (c, how much of the sample is present that will rotate the light).  When these effects are eliminated a standard for comparison of all molecules is obtained, the specific rotation, [a].

[a] = 100a / cl    when concentration is expressed as g sample /100ml solution

Specific rotation is a physical property like the boiling point of a sample and can be looked up in reference texts.    Take a look at a problem.

Enantiomers will rotate the plane of polarisation in exactly equal amounts (same magnitude) but in opposite directions.

Dextrorotary designated as or (+), clockwise rotation (to the right)
Levorotary designated as l or (-), anti-clockwise rotation (to the left)

If only one enantiomer is present a sample is considered to be optically pure.  When a sample consists of a mixture of enantiomers, the effect of each enantiomer cancels out, molecule for molecule.

For example, a 50:50 mixture of two enantiomers or a racemic mixture will not rotate plane polarised light and is optically inactive.  A mixture that contains one enantiomer excess, however, will display a net plane of polarisation in the direction characteristic of the enantiomer that is in excess.

Determining Optical Purity

The optical purity or the enantiomeric excess (ee%) of a sample can be determined as follows:

Optical purity = % enantiomeric excess = % enantiomer1 - % enantiomer2
                     = 100 [a]mixture / [a]pure sample

ee%  =  100 ([major enantiomer] - [minor enantiomer]) / ([major enantiomer] + [minor enantiomer])

where [major enantiomer] = concentration of the major enantiomer
          [minor enantiomer] = concentration of the minor enantiomer

 

Meso compounds

In the simplest case, a compound with two chirality centers where there is the same set of four groups at each chirality center, the combination where the four groups are arranged such that the centers are mirror images of each other (i.e. where the molecule has an internal mirror plane) is a meso compound.

 

For example, consider 2,3-dichlorobutane.  There are two chirality centers (C2 and C3), each with -H, -Cl, -CH3 and the other -CHClCH3 groups attached. Since there are two chirality centers, then, at least in principle, there are 4 possible permutations of the stereocenters : (R,R), (R,S), (S,R) and (S,S)

 

The (R,R) and (S,S) structures are non-superimposable mirror images, so they are a pair of enantiomers.
If we look at the (R,S) and (S,R) as drawn above, it should be reasonably easy to recognise that these two structures are actually the same thing because they are superimposable, i.e. (R,S) º (S,R). This structure is the meso isomer. To verify this, rotate one of the models 180 degrees about the vertical axis to make it look the same as the other structure. In the conformations of the (R,S) shown above, the mirror plane should be obvious (vertical plane bisecting the middle of the central C-C bond).

     

 


(R,S)-2,3-dichlorobutane


(S,R)-2,3-dichlorobutane

However, let's look at the other important conformation of the meso isomer and make sure we can recognise it is the meso isomer.

The relationship of A to B is not immediately obvious. However, once the right hand end has been rotated about the central C-C bond by 180 degrees, A can been seen to be the mirror image of B .  A quick way of recognising whether a molecule is achiral is to look for a plane of symmetry.

 

E-Z configuration

Isomerism:

  • “The phenomenon of the existence of two or more compounds possessing the same molecular formula but different properties is known as isomerism.”
  • Such compounds are called isomers.

E-Z isomerism:

  • It is a type of stereoisomerism.
  • It applies to alkene which contains C=C double bond and two different groups on both end.

Rules for E-Z system:

  • The atoms or groups attached to each olefinic carbon are given priority as per the sequence rule.
  • If the higher priority groups are present on same sides across the double bond, the geometrical isomer is said to have Z-configuration or 'cis'.
  • If the higher priority groups are present on opposite sides across the double bond, the geometrical isomer is said to have E-configuration or 'trans'.
  • For example:

 

 

R-S configuration

The R-S configuration, also known as the Cahn-Ingold-Prelog (CIP) system, is used to describe the absolute configuration of chiral centers in molecules.

The R and S designations are assigned based on the priority of the four different substituents attached to a chiral carbon atom. The priority is assigned based on the atomic number of the atom attached to the chiral center. The higher the atomic number, the higher the priority. If two or more atoms have the same atomic number, the priority is determined based on the next atom in the chain.

Once the priorities are assigned, the molecule is oriented so that the lowest priority group is facing away from the viewer. Then, the remaining three groups are viewed in order of decreasing priority. If the groups are arranged in a clockwise direction, it is assigned an R configuration. If the groups are arranged in a counterclockwise direction, it is assigned an S configuration.

For example, in the molecule 2-chlorobutane, the chiral center is the second carbon atom (from the left) which is attached to a chlorine atom, a methyl group, an ethyl group, and a hydrogen atom. The priorities of these groups, based on atomic number, are: chlorine > ethyl > methyl > hydrogen. If we arrange the groups in decreasing order of priority, we get: chlorine > ethyl > methyl. Therefore, the configuration of this chiral center is R.

The R-S configuration system is widely used in organic chemistry to describe the stereochemistry of chiral compounds.

 

some explanations for the examples of R and S configurations:

1.     (R)-2-chlorobutane: In this molecule, the highest priority group is the chlorine atom, which is attached to the second carbon atom in the chain. The second highest priority group is the methyl group, followed by the ethyl group and the hydrogen atom. To determine the R or S configuration, we need to imagine the molecule in 3D space, with the lowest priority group (hydrogen atom) pointing away from us. Then we trace a path from the highest priority group to the next three groups in a counterclockwise direction. In this case, the path from chlorine to methyl to ethyl is counterclockwise, which gives the molecule an R configuration.

2.     (S)-3-methylhexane: In this molecule, the highest priority group is the methyl group attached to the third carbon atom in the chain. The second highest priority group is the ethyl group, followed by two more methyl groups and a hydrogen atom. Again, we imagine the molecule in 3D space, with the hydrogen atom pointing away from us. We trace a path from the highest priority group to the next three groups in a counterclockwise direction, which in this case is from methyl to ethyl to one of the methyl groups. This gives the molecule an S configuration.

3.     (R)-2-bromobutane: In this molecule, the highest priority group is the bromine atom attached to the second carbon atom in the chain. The second highest priority group is the ethyl group, followed by two methyl groups and a hydrogen atom. We again imagine the molecule in 3D space, with the hydrogen atom pointing away from us, and trace a path from bromine to ethyl to one of the methyl groups in a counterclockwise direction. This gives the molecule an R configuration.

 

 Erythro and thero configuration

 

Erythro and threo configurations are stereoisomers that differ in the relative orientation of two identical substituents on a molecule.

In the erythro configuration, the two identical substituents are on the same side of the molecule. The name "erythro" comes from the Greek word "erythros" meaning "red," because erythro is often used to describe pairs of stereoisomers that can be separated and distinguished by chromatography, where one is red and the other is not.

In the threo configuration, the two identical substituents are on opposite sides of the molecule. The name "threo" comes from the Greek word "threō" meaning "I run," because threo is often used to describe pairs of stereoisomers that migrate together during chromatography.

Erythro and threo configurations can be observed in molecules with two chiral centers, where the two substituents on each chiral center are the same. In such cases, the erythro and threo configurations can be designated as erythro-erythro, erythro-threo, threo-erythro, and threo-threo, depending on the relative orientations of the substituents on each chiral center.

 

1.     Erythro-2,3-dibromobutane: This molecule has two bromine atoms attached to a four-carbon chain. In the erythro isomer, the two bromine atoms are on the same side of the chain, while in the threo isomer, they are on opposite sides.

2.     Threo-2,3-dichlorobutane: Similar to the previous example, this molecule has two chlorine atoms attached to a four-carbon chain. In the threo isomer, the two chlorine atoms are on the same side of the chain, while in the erythro isomer, they are on opposite sides.

3.     Erythro-1,2-diaminocyclohexane: This molecule has two amino groups attached to a cyclohexane ring. In the erythro isomer, the two amino groups are on the same side of the ring, while in the threo isomer, they are on opposite sides.

4.     Threo-1,2-dibromo-1,2-diphenylethane: This molecule has two bromine atoms and two phenyl groups attached to a two-carbon chain. In the threo isomer, the two bromine atoms and two phenyl groups are on opposite sides of the chain, while in the erythro isomer, they are on the same side.

These are just a few examples, there are many other molecules that exhibit erythro and threo isomerism.

 

Conformational isomers

Conformational isomers are different arrangements of atoms in a molecule that arise from free rotation about single bonds. They have the same molecular formula, same connectivity of atoms, but differ only in the orientation of groups in space. The different conformations of a molecule can be interconverted by rotation about single bonds, without breaking any covalent bonds.

The most common example of conformational isomers is ethane. In the staggered conformation, the two carbon atoms are as far apart as possible, resulting in minimum energy and maximum stability. In the eclipsed conformation, the two carbon atoms are as close together as possible, leading to higher energy and less stability. Other examples of conformational isomers include cyclohexane, which can adopt both a chair and a boat conformation, and butane, which can have both an anti and a gauche conformation.

The different conformations of a molecule can have different physical and chemical properties, such as melting and boiling points, reactivity, and biological activity. The study of conformational isomers is important in understanding the behavior of molecules in various fields of chemistry, including organic chemistry, biochemistry, and medicinal chemistry.

 Types of conformational isomers

1.     Eclipse Conformation

The carbon atoms are arranged in such a way that the hydrogen atoms are parallel to one another. It acts as a steric barrier between them. In the eclipsed conformation, the hydrogen atoms connected to the two carbon atoms are as near to each other as feasible. Because of the proximity of hydrogen atoms, it is said to be a little unstable.

Eclipse Conformation

2.     Staggered Conformation

The hydrogen atoms connected to the two carbon atoms are as far apart as possible in this configuration. The atoms in the staggered conformation are evenly spaced from one another, and these conformations are more stable and preferred than the eclipsed conformation. Because the hydrogen atoms are separated by a large distance, it is more stable. Between the electron clouds of C-H bonds, the distance generates the least repulsive force and the least energy.

 

Conformational Isomers of Ethane

 

At room temperature, ethane, an organic molecule, is a colorless and odorless gas. There are seven sigma bonds and six carbon-hydrogen bonds in this molecule. Two carbons protrude at 120° angles from the six carbon-hydrogen linkages. The staggered conformation is the one with the lowest energy. All of the C-H bonds on the front carbon are positioned at 60° relative to the C-H bonds on the back carbon in this conformation. The space between bonds is likewise maximized, in addition to the 60° placement.


Conformational Isomers of Ethane

Furthermore, the molecules now have the maximum energy conformation of ethane, which is the 'eclipsed' conformation, after rotating the front CH3 group 60 degrees clockwise. The hydrogens on the front carbon are as close as feasible to the hydrogens on the back carbon in this configuration. When compared to the staggered conformation, the eclipsed conformation produces 3 kcal/mol more energy.

Conformational Isomers of Butane

 

Butane is an alkane with C-C bonds. It differs from that of ethane in a few ways. Different conformational isomerism is achieved in butane when the molecule is rotated around the C-C bond axis. The methyl group connected to the two end carbon atoms gives butane two substituents. The methyl group has a larger surface area than hydrogen atoms. The gauche or staggered shape of butane is obtained by rotating the front methyl group by 60 degrees. The gauche becomes the eclipsed conformation of butane when the methyl group is rotated by 120 degrees.


Conformational Isomers of Butane

 Resolution of racemic mixture

A racemic mixture is a mixture of equal amounts of two enantiomers of a chiral molecule, which have the same physical and chemical properties but rotate plane-polarized light in opposite directions. Since they have the same properties, they cannot be separated by traditional methods such as distillation or crystallization.

The process of separating enantiomers from a racemic mixture is called resolution. There are several methods for resolution of racemic mixtures, including:

1.     Enzymatic resolution: In this method, enzymes are used to selectively react with one of the enantiomers, leaving the other one untouched. For example, chiral enzymes like lipases can be used to selectively hydrolyze one of the enantiomers of a racemic mixture of esters.

2.     Chemical resolution: This method relies on the chemical properties of the enantiomers to be separated. For example, if one enantiomer is more soluble in a particular solvent than the other, the racemic mixture can be treated with that solvent to selectively dissolve one of the enantiomers.

3.     Chromatographic resolution: This method involves separating the enantiomers on a stationary phase based on their differential interactions with the stationary phase. For example, chiral chromatography using a chiral stationary phase can be used to separate enantiomers based on their different affinities for the stationary phase.

4.     Diastereomeric salt formation: In this method, the racemic mixture is treated with a chiral resolving agent to form a diastereomeric salt, which can then be separated by traditional methods such as filtration or recrystallization.

Resolution of racemic mixtures is an important process in the production of drugs and other chiral compounds, as only one enantiomer may have the desired pharmacological activity, while the other may have harmful side effects.

 Racemization

In organic chemistry, one special type of molecular structure is referred to as a chiral center. Chiral centers are formed when a carbon center has four different substituents. Depending on the arrangement of the substituents about the central carbon, the molecule can either be described as having either a relative or absolute configuration.

Relative configuration uses the notion D- and L- when naming enantiomers of sugars or amino acids. Enantiomers are pairs of molecules that are non-superimposable mirror images of one another. Figure  shows an example of the two enantiomers of trans-cyclohexane. D stands for dextrorotatory, or right-sided, while L is in reference to levorotatory, or left-sided. This means that the priority group that helps to define the molecule is located on either the right or left sides of the structure.


Figure . An example of enantiomers for trans-cyclohexane.


In sugars, the hydroxyl group  of the last carbon is located on the right for D sugars and on the left for L sugars. In much the same manner, in amino acids, the amino group (NH2) is found to the right in D amino acids and on the left in L amino acids.

The other method for naming enantiomers uses the R, and S designations. The R and S configurations are used to identify the two enantiomers of a chiral center, or stereocenter. The R designation refers to right-handedness and reflects the clockwise orientation of the substituents in order of decreasing priority (from 1 to 4). By contrast, S stands for "sinister," of left-handedness, which is the counterclockwise orientation of the substituents in order of decreasing priority (from 1 to 4). Priority is determined by the atomic number, with "1" representing the highest priority and "4" the lowest priority.

The R and S enantiomers of a chiral center each rotate light in opposing directions. This rotation can be observed in purified samples containing either the R or S enantiomer of a compound. However, there are many instances in both nature and in the laboratory when equal mixtures of the two enantiomers exist. This is referred to as racemization.

What is racemization in organic chemistry? The racemization definition must include each of the following characteristics:

  • It is an equimolar mixture, meaning that there are equal amounts of two substances.
  • Two enantiomers in the R and S configurations are present in the mixture.
  • The mixture is optically inactive.

The optical inactivity of a racemic mixture is due to the presence of equal amounts of the R and S enantiomers in the mixture. Because each enantiomer reflects light in an opposing manner, the two enantiomers will cancel each other in terms of their optical rotation. Thus, the mixture is optically inactive.

The formation of racemic modification, another name for racemization, occurs when a racemic mixture is produced. There are two main methods responsible for the production of racemates, as racemic mixtures are sometimes called:

1.     First, an equal amount of the two enantiomers for a compound can be mixed together.

2.     Second, reactions can result in the creation of chiral centers, such as an SN1 reaction

Examples of Racemization

There are numerous examples of racemization both in nature and under laboratory conditions. For example, in nature, there is a preference towards the use of L-amino acids and D-sugars. However, when amino acids are exposed to strong acidic or basic environments, a racemic mixture of L- and D-amino acids can form.

Some other examples of racemization in chemistry include:

  • The addition of R-3-phenyl-2-butanone to a solution of aqueous ethanol containing NaOH or HCl will produce a racemic mixture including the R and L configurations of 3-phenyl-2-butanone.
  • The addition of HBr to 1-butene will produce a racemic mixture of the enantiomers of 2-bromobutane.
  • The hydrogenation of certain alkenes (compounds with carbon-carbon double bonds) will produce new chiral centers that result in racemic mixtures. For example, 3-methyl-3-heptene will produce a racemic mixture of (R)- and (S)-3-methylheptane.

Racemization Mechanism

As mentioned earlier in this lesson, one common racemization mechanism is the SN1 substitution reaction. SN1 reactions in involve two main components: a nucleophile and a leaving group. A nucleophile refers to any molecule that is able to donate electrons to electron-poor sites. A leaving group is able to maintain its stability when leaving a larger molecule. This is due to the fact that leaving groups will take electrons with them when departing from a molecule.