A-level Chemistry/WJEC/Module 4/Stereoisomerism

Stereochemistry is the 3-dimensional arrangement of atoms in space. Stereoisomers are isomers that are different only because of their stereochemistry. There are two different types of stereoisomers.

We already met one example of stereoisomer - E-Z isomers - in Topic 2.5.2 Alkenes

A Brief Reminder about Isomers

Molecules that are isomers have the same molecular formula but their structures are different from each other. There are two main categories of isomers: structural isomers and stereoisomers.

Structural Isomers

Structural isomers (more correctly known as constitutional isomers) are molecules that have the same molecular formula but their connectivities are different. Structural isomers usually have very different physical and chemical properties.

Stereoisomers

Although most people are accustomed to thinking of chemistry as two-dimensional drawings and structures, this "paper chemistry" is not really how these molecules act in real life. Of course, these molecules are really three-dimensional shapes, and not just 2D drawings. Stereochemistry aims to explain the natural phenomena of spatial arrangements of these molecules.

Stereoisomers are isomers of molecules with the same formula and connectivity (the same "constitution"), but with different arrangements of their atoms in space. Two stereoisomers have atoms linked together in the same order, but the two molecules do not have the same three-dimensional shapes.

Stereoisomers can be divided into two sub-categories: enantiomers and diastereomers. These molecules have the same connectivity but differ in their 3D arrangement.

Enantiomers

Enantiomers are molecules that are mirror images of one another and are not superimposable. Enantiomers have identical physical and chemical properties, apart from:

Enantiomers rotate the plane of polarised light in opposite directions. One isomer rotates light clockwise, the other anti-clockwise.

Enantiomers react in exactly the same way except when they react with other enantiomers. Many biological molecules such as enzymes and receptors are enantiomers, so enzymes and receptors can react differently with enantiomers.

Stereocenter: Any atom in a molecule that is attached to 4 different atoms. Such atoms are also known as chiral centers and are marked with an asterisk (*). A chiral molecule is special in that it is not identical to its mirror image, or in other words, the only criterion for chirality is that the object and its mirror image must be non-superimposable.^[1] For example, methane (CH₄) is identical to its mirror image; therefore, this molecule is not chiral. It is possible for a molecule to be chiral without having a chiral center, but this is beyond A-level chemistry.

Enantiomers are structures that are mirror images of one another that are non-superimposable. Non-superimposable means that no matter what way you rotate it, you will not be able to place it directly on top of the other facing the same way. You can easily demonstrate this with your hands because your hands are also non-superimposable, as you cannot place your hands on top of one another with your thumbs facing in the same direction, while your palms face the same way. Enantiomers have almost identical physical and chemical properties.

This is a depiction of both R and S enantiomers.

Enantiomers are generally classified with either an R or S configuration. Identifying R or S configurations is not a requirement of this course, but the system is similar to that used for E and Z isomers:

One must first rank its four substituents by atomic number. The highest priority substituent (rank 1) will be the substituent atom with the largest atomic number; conversely, the lowest priority substituent (rank 4) will be the substituent atom with the lowest atomic number. For this reason, a hydrogen substituent is always given the lowest priority. There are further rules to prioritise chains of atoms, if the first atoms in two chains is the same element, and to prioritise double and triple bonds, isotopes, etc.

Once the four substituents have been ranked by priority, a series of rules can be followed to determine the configuration.

As you can tell from the drawing, on the left, the methyl group is pointing out at us, while the hydroxyl group is pointing back. On the molecule in the right, this order is reversed. This is a prime example of enantiomers.

Confusion about enantiomers

One might think that you can simply just rotate the molecule and they would be exactly the same, but this is not the case. If you rotated the molecule above, the hydroxyl and methyl will be imposed on one another, however, the fluorine and hydrogen will now be on opposite sides. This is what it means to be non-superimposable

Optical Activity

If two enantiomers of a chiral molecule were isolated into two different containers in pure form, it would be extremely difficult to distinguish the two based on just their physical properties such as boiling points, melting points, and densities. Because only certain enantiomers of certain drugs are effective while the other enantiomers are ineffective or even detrimental to the body, it is very important to be able to distinguish enantiomers.

Enantiomers are optically active, meaning they have the ability to rotate plane-polarised light. A dextrorotatory (+) molecule rotates plane-polarised light in a clockwise direction, while a laevorotatory (-) molecule rotates plane-polarised light in a counterclockwise direction. If the R isomer is (+) then the S isomer will be (-). However, it is not possible to find the (+) or (-) rotation from the R or S designation. In other molecules, the R isomer may be (-) and the S isomer would then be (+).

Fortunately chiral molecules possess a unique property that rotates light waves in a particular direction when light is passed through a sample containing the enantiomers. This unique reaction that chiral molecules have with light is called optical activity and results in enantiomers often being referred to as optical isomers. The rotation of light as seen from the perspective of the viewer facing the light source can either be clockwise, dextrorotatory ("dexter" is Latin for "right"), or counterclockwise, laevorotatory ("laevus" is Latin for "left"). Molecules that rotate light clockwise are referred to as (+) enantiomers while molecules that rotate light counterclockwise are referred to as (-) enantiomers. The enantiomer of a chiral molecule will cause an equal and opposite direction of rotation.

Plane-polarised light results from passing a beam of ordinary light through a special material called a polariser. A polariser serves as a filter for the light waves that pass through it and filters out all but one light wave, the plane-polarised light wave. Once the light has been filtered to just the plane-polarised light, the light wave travels through the chiral molecules. The electric field of the light wave interacts with the chiral molecules and causes the light wave to rotate at a particular direction; this rotation is called optical rotation. If the sample causes optical rotation, then the sample is referred to as optically active. Optical rotation can be measured precisely with a polarimeter.

Oftentimes reactions that yield chiral molecules are not stereospecific which may lead to products that have a 1:1 mixture of enantiomers. This reaction mixture is referred to as a racemic mixture because when a plane-polarised light passes through this sample, half of the chiral molecules would rotate the light wave clockwise while the other half would rotate the light counterclockwise. This results in a sample with no net optical activity. However, when the ratio of enantiomers is not 1:1, then there will be optical activity. One of the major goals of pharmaceutical companies is to perform reactions that yield optically pure products because this saves them very much time from the purification process of optically impure samples, not to mention money on the reactants used during production.

Polarimetry

Optical activity is directly proportional to the ratio of the two enantiomers of a compound. When an equal ratio of the two enantiomers of a compound are present, the sample is considered optically inactive or racemic. If only one of the enantiomers is present, then the sample is considered optically pure. To describe a mixture that falls in-between these two extremes, one can use the enantiomer excess (ee) relation. This is used for when one enantiomer is in excess of the other enantiomer in a mixture.^[1] The enantiomer excess equation is:

Enantiomer excess (ee) = % of major enantiomer - % of minor enantiomer

The enantiomer excess equation tells us how much of one enantiomer is in excess of a racemic solution (since in a racemate the ratio of enantiomers is 1:1). The enantiomer excess is also known as optical purity and can be found by the relation:

Enantiomer excess (ee) = optical purity = ([a]_Mixture/[a]_{Pure enantiomer}) X 100%

Example

A solution of (+)-alanine has a value of [a]_Mixture = 3.7; [a]_{pure enantiomer} = 8.5. Find optical purity and actual enantiomer composition of the sample.^[1]

Solution

Enantiomer excess = optical purity = (3.7/8.5) X 100% = 43.5 % Therefore, 56.5% of the sample is racemic and 43.5% of the sample is the pure (+) isomer. Thus, it can be concluded that the artifact under examination has an actual composition of 71.75% (+) and 28.25% (-) alanine.

Stereochemistry of Amino Acids

Amino acids are building blocks of protein. The general structure of an amino acid has an sp3 hybridized carbon atom linked to four other substituents. Three of the four substituents attached to the carbon of all amino acids are an amino group and a carboxylic acid group and a hydrogen atom. The last substituent is often represented with an R if the amino acid isn’t specified. R can represent one of the twenty different side chains the twenty different amino acids have.

The stereochemistry of amino acids are represented with an L,D system. The L,D system is essentially the same as the R,S system for absolute configuration with the exception that the L,D system is for amino acids. For the L,D system, L is the equivalent of the S absolute configuration leaving D to be the equivalent of the R absolute configuration.

Amino acids exist dominantly in the L absolute confirmation. There is no conclusive evidence for the dominance of the L isomer over the D isomer at the moment. Many speculate that the L isomer became the dominant amino acid configuration due to chance rather than any physical or chemical property. There have been experiments done trying to elucidate the reason behind the dominance of the L isomer. In the experiments, a protein would be artificially synthesized with only amino acids with the D absolute configuration. The conclusion was that the proteins made of only D amino acids were equally as active as the proteins made of L amino acids with the only difference being that the proteins made of D amino acids had reactions that were the reverse of the proteins made of L amino acids.

Chiral Drugs

The majority of chiral medicines are sold as racemic mixtures, even if only one isomer (the "eutomer") is pharmaceutically active. It is usually cheaper to make a racemic mixture, and give twice the dose, than it is to purify the active isomer. The second isomer (the "distomer") is often simply inactive, or less active. The sedative drug thalidomide is a notorious exception, where the distomer causes birth defects. Purifying the eutomer might be pointless anyway - our metabolism can convert the isomers of drugs like ibuprofen and thalidomide.

(S)-amphetamine is a valuable stimulant for treating conditions such as ADHD, and its distomer has weaker and different effects. (S) and (R) amphetamine are not converted in vivo, and different formulations - ranging from pure (S) to a 50:50 racemic mixture of (S) and (R) - can be used to achieve better outcomes for patients.

Multiple Chiral Centers

This is not an A-level Chemistry topic! There are links to Biology here, and historical interest.

In general, molecules with n chiral centers have 2ⁿ stereoisomers or 2^(n-1) enantiomer pairs.. For example, D-glucose is a molecule with 4 stereocenters; It is one of 16 stereoisomers including its enantiomer L-glucose.

The linear forms of the eight D-aldohexoses, in the w:Fischer projection, are

D-Allose
D-Altrose
D-Glucose
D-Mannose
D-Gulose
D-Idose
D-Galactose
D-Talose

As a rule, if every chiral center is different, you have two enantiomers. Otherwise, you have two diastereomers. For example, D-glucose is a (2R,3S,4R,5R) stereoisomer. Its enantiomer, L-glucose, is the (2S,3R,4S,5S) stereoisomer. Galactose is another stereoisomer and its configurations are either (2R,3S,4S,5R) (D-galactose) or (2S,3R,4R,5S) (L-galactose). D-galactose and L-galactose are enantiomers, but D-glucose and D-galactose are diastereomers.

Meso compounds

If a compound has a line of symmetry dividing its two stereocenters, then the molecule can become its own mirror image. The compound is "achiral" (not chiral) and is known as a "meso compound".

Diastereomers

E-Z isomers are diastereomers. Diastereomers are stereoisomers that are not related as mirror images, i.e. diastereomers are any stereoisomers that are not enantiomers. Thus, diastereomers are not mirror images of each other.

The cis and trans prefixes can replace the Z and E prefixes if both C atoms have an H substituents, or if there are only two types of substituent. For example, the names cis-pent-2-ene and (Z)-pent-2-ene are fine, but substituting a chlorine for the H on carbon-2 we get (E)-2-ChloroPent-2-ene.

Because diastereomers are stereoisomers that are not mirror images of each other, they can be distinguished by different physical and chemical properties. Thus, it is possible to separate diastereomers by standard laboratory techniques. Diastereomers arise when stereoisomers of a molecule have different configurations at at least one of their stereocenters (but not all, for they would then be enantiomers). Each stereocenter possesses two configurations, so the number of stereoiosmers is increased by a factor of two. Cis/trans isomerism is a form of diastereomerism (cis-two substituents pointing in the same direction; trans-two substituents pointing in opposite directions).

There are 3 stereocenters in the molecule below. The atoms have been switched in the first and third carbon. This is an example of diastereomerism. If the second carbons atoms were switched also, then these two molecules would be enantiomers.

Stereochemistry for Alkenes

Cis and trans prefixes are not always used when naming alkenes with an E-Z system being used instead. The E-Z system sets priorities for carbon substituents the same way as the R-S system with the difference being that the double-bond having no bearing on the priority, only the two substituents that are single-bonded to the carbon. An E isomer (E comes from the German word "entgegen" which means "opposite") would be where the highest priority substituents on each carbon on the double bond are opposite of each other. A Z isomer (Z comes from the German word "zusammen" which means "together") would be where the highest priority substituents on each carbon on the double bond are on the same side of each other.

Shortcuts for Stereochemistry

A simple method to differentiate between an enantiomer and a diastereomer is to look at the molecules being compared and, assuming they both are in fact stereoisomers, look at each stereocenter. If the carbon substituents of each stereocenter have been switched once, then the molecules are related as enantiomers. If not all of the carbon substituents of each stereocenter have been switched once, then the molecules are related as diastereomers. In this case, the switching of carbon substituents means, for example, that a dashed OH substituent and a wedged H substituent of the same carbon switched to a wedged OH substituent and a dashed H substituent while the other two carbon substituents remain in the same positions. By this logic, if the carbon substituents of the stereocenters have been switched twice, then the molecules are related as enantiomers, not diastereomers.

References

1. Schore, Neil E. (2011). Organic Chemistry Structure and Function 6th edition. W. H. Freeman.

2. Berg, Jeremy Mark, John L. Tymoczko, and Lubert Stryer.Biochemistry. 6th. New York: W H Freeman & Co, 2012.

3. Schore, Neil E. (2007). Organic Chemistry Structure and Function 5th edition. W. H. Freeman.

3. Berg, Jeremy M. (2002). Biochemistry 5th edition. W. H. Freeman.

4. Vollhardt, Peter and Schore, Neil. (2009). Organic Chemistry 9th Edition. W.H. Freeman and Company. ISBN 978-1-4292-0494-1.

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