Cahn—Ingold—Prelog Rules — Stereochemistry

by Adam Le Gresley, PhD

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    00:01 In the previous lecture we discussed the formation sigma and pi bonds. And, also their influence upon the organization and structure of the individual molecules. That is to say whether they are tetrahedral, whether they were planer, or whether they were linear. Now I would like to introduce a different concept here, which is the concept of chirality, steric chemistry, and isomerism.

    00:23 Chiral compounds take the name from the effect they have on the plane of polarized light.

    00:28 That is the light that is polarized and travels in one direction of one angle. Chiral compounds can rotate that plane of light to the left or right depending on what type of enantiomer they are. To give you an idea of what that means and what an enantiomer is, there is a diagram shown here on the board, which shows a mirror image of one molecule. Molecules or ions that exist as optical isomers such as they are shown are said to be chiral. So stereoisomerism, isomers in stereoisomerism exists with the same order of attachment of atoms in their molecules with different orientation of their atoms or groups or indeed their atoms in space. So let’s break that down. Let’s look at configurational isomers and conformal isomers.

    01:23 Configurational isomers are stereoisomers that do not readily interconvert at room temperature and can in principle be separated. Conformational isomers are far more difficult to separate.

    01:34 These are otherwise referred to as conformers or rotamers and they are produced by rotation around sigma bonds. Bear in mind, it is possible to rotate around sigma bond. At room temperature this happens all the time but it is not typically possible to rotate around either a double or triple bond because atoms are always rotating on sigma bonds at room temperature and pressure.

    01:58 It’s often very difficult to separate out conformers unless there is restricted rotation. This we may see if we move on to the organic chemistry section in module three.

    02:09 And it is the stereochemical isomers that I want to talk about. This is where for example you have a central atom with four species attached to it. Atoms are otherwise which are completely different. It is that we intend to concentrate on, optical isomers. So as I said before, chirality is best expressed as a mirror image of the one thing. We can see this in nature. And these are images which are non superimposable. I take the example of the shell as shown here on the board, which is of the origins of chirality being from the Greek word “cheir” or “hands”. And here we have picture of some hands as you can see the left or right hand are not directly superimposable on top of each other.

    03:04 Therefore they are considered chiral in nature. We even see this in the universe with spiral galaxies which themselves are non superimposable and therefore chiral. Okay, let’s relate this back to the chemistry shall we.

    03:18 Chirality and enantiomers, as shown before in perspective, a mirror plane with two molecules on either side which are the mirror image of each other. And I would like you to just to take a couple of moments to try to superimpose one of those molecules shown on the board on top of the other one, so that all the colors match up. You won’t be able to do it, not without cheating. And this is directly the result of the dissymmetry or the lack of symmetry in a molecule and if you look at this you can always spot a chiral carbon otherwise known as a stereogenic carbon. And this is where you have a carbon with four different atoms or groups attached and this is an element of dissymmetry. Such a carbon atom is known as the chiral or stereogenic center. Carbon atoms carrying four different groups will always exhibit chirality. There is no plane of symmetry through the molecule and so therefore must be chiral. Okay, so aside from the observation that when you actually have a single carbon you can have four different groups attached and yes, this gives you a distribution which is chiral. The importance of it relates directly to nature and those targets within medicinal chemistry that we would use. DNA itself is chiral. If we break DNA down, we are showing here the ribonucleic, the ribose part of ribonucleic acid, you can see here that carbon 4, indicated by the green arrow, actually has four different substituents on it. Therefore it must be chiral. In this case it is known as a D-sugar. D because it is dextrorotationary, rotating the plane of polarized light to the right. Many of these units together form a structure which you will undoubtedly be familiar with, which is DNA. DNA shown here, which is a collection of bases linked together by ribose sugar units and phosphates on the back bone, giving rise to this highly ordered structure, an essential blue print for life as we know it.

    05:41 Another place where chirality is encountered is in the formation of proteins. I have shown here an example of an amino acid. In this case, a simple representation of any amino acid that you will come across, otherwise known as the alpha amino acids. The term alpha is just a nomenclature to denote where the chirality is actually occurring which is on the carbon between the amine group, the NH2 and the carboxylic acid group COOH. In nature, by and large, they exist in their levorotationary forms. L amino acids are the common amino acids. There are exceptions to this. However, it is these individual amino acids which polymerise together to form an alpha helix polypeptide, which goes on to form the essential proteins that regulate every aspect of every organism. I also want to introduce you to something else which you will also, may also be familiar with, and this is how the chirality can influence directly the biochemical interaction, that a specific drug or food stuff can have with a given receptor. Because biology is by its very nature consisting of chiral controlled proteins, proteins with a given stereochemistry, it doesn't come or shouldn’t come as too much of a surprise that their interaction with other small molecules will depend very much on their chirality as well. We see this in how the body detects these two examples of small molecules. We see (S)-carvone which has the odor picked out by the chiral receptors in the nose of caraway seeds. And we also have R-carvone, which is instantly recognizable as spearmint. Note the difference between the two. They contain the same number of carbons, same number of hydrogens and oxygen as shown there. However, if you look at the lower part of that cyclic ring, you will see that the bond moving forward and the bond moving backward impart a degree of chirality at that stereogenic center which is detectable by human beings.

    08:09 Let's apply that to something more medical. Ephedrine, for example shown in green is used as a bronchodilators, in bronchitis and asthma. In fairness, not used as often anymore, salbutamol and a number of other derivatives have succeeded it but the principle remains the same. In this particular case, the mixture of R and S, enantiomers here, so R next to the oxygen and S next to the nitrogen impart on it, a completely different medical profile to pseudoephedrine which is actually on the market for use as a decongestant.

    08:48 Note looking at stereochemistry you can say that they have dissimilar stereochemistry or where you have two individual stereogenic carbons. This is otherwise known as diastereochemistry.

    09:03 Another medical example is thalidomide. You may already be familiar with the story of thalidomide, but here is one of the background stories to it in terms of the structure. If you compare the two structures of (S)-thalidomide which is the enantiomer of (R)-thalidomide, you should be aware that the (R)-thalidomide is actually quite an effective remedy against morning sickness in pregnant women. However, the S thalidomide is a teratogen, that is it causes genetic mutations in children, causing all sorts of birth defects including Phocomelia and amelia with only 8000 surviving in the first year.

    09:48 Okay, so we have talked about the importance, the relevance, and how often it occurs. That is great. What we need to do now is understand how we can best define a chirality, how to give names to the two different enantiomers, how we can identify those enantiomers, and very important in the case of for example of thalidomide and other drug molecules, how we can separate them. We also, want to bear in mind if we cannot separate them, how might we synthesize one enantiomer over the other preferentially. To this I will introduce you to some basic asymmetric synthesis.

    10:29 Right, okay, so we talked earlier on in this lecture about alpha, levorotationary, dextrorotationary, that is all very well and good. And there is even a very archaic L and D nomenclature that was used as well. But the current IUPAC accepted nomenclature used to define stereochemistry within a molecule is known as the Cahn-Ingold- Prelog rules. As you can see, we got an idealized molecule here. It consists of a central carbon to which is attached four different things.

    11:07 CH3, hydrogen, an OH group, and a bromine atom. As you can probably instantly recognize, there are four different substituent groups on this carbon therefore it must be chiral.

    11:20 But the process by which we assign under Cahn-Ingold- Prelog Rules, the designation of it as an enantiomer is by ranking first the attack substituents to the chiral center according to their atomic number. So that is the first thing we do. And in this system it’s relatively straight forward. Bromine is a halogen, has the largest atomic mass. Therefore, it must automatically take priority. The second is an OH group. Of course, the oxygen having an atomic mass of 16 is the next highest. Finally, carbon with an atomic mass of 12.

    11:59 So as you can see we are able to easily assign orders of priority according to the atomic mass that we have on our substituent group. And unlike other systems of nomenclature, if there is any similarity at any substituent you need to continue moving away from the stereogenic center, until such time as difference in atomic constituents is found. Multiple bonds count as multiple substituents of the same atom and this will become important when we start looking at other functional groups.

    12:40 But to give you a very simple example what that 0.3, means is that if for example you have a double bond, this actually counts as a carbon to which is bonded two CH3 groups.

    12:54 So where it becomes important in these rules, which are effectively man-made to help us decide our chemistry, we need to consider the number of bonds. What you then do, is you rotate the lowest priority group to the back. Now obviously in a two dimensional environment such as that we are in, this is rather difficult to do but it is a test for you to ensure that you have been paying attention. You need to visualize in your mind this tetrahedral structure, where the bond is dashed, imagine that is pushed backwards. Where the bond is thick, imagine this is coming towards you. And then try and picture this tetrahedral structure and rotate it on the bromine axis to move the hydrogen towards the back. By moving the hydrogen towards the back, what we are effectively doing is bringing the bromine, the OH, and the CH3 group, round to the front and what we can then do is consider in what order of priority the atoms can be linked together, counting from one to two to three. So if we rotate that system around, all the way around, we see it is possible for us to count bromine, then OH, then CH3. When we can count in order of priority, in a clockwise direction on the face of a tetrahedral molecule, we can assign it as R. If on the other hand, we can count from one to two to three on the face of our tetrahedral molecule, which contains those three highest priority associated atoms and substituents or we can go in an anticlockwise direction, then it is otherwise known as S. These have their origins in the term for Rectus or right and S, sinister. The process is by using this said to assign the configuration to any chiral molecule that you will come across. So, I have shown here a simple example.

    15:15 If we rotate our bromine all the way around, so that we have our OH on the left hand side and the CH3 on the right hand side, you can see in the case of unknown chirality, we can assign it R or rectus.

    15:32 What I would like you to do, for the next few minutes is to attempt to assign using Cahn-Ingle-Prelog Rules, the configuration of these enantiomers. Identify the carbon center, assign the priority groups, and then determine whether or not, the order of priority one, two, or three is clockwise, rectus, or anticlockwise, sinister. Next what I would like you to do, is attempt to draw the structure of R2 bromobutane. Based on your understanding, that there must be a chiral center in them. Right, identifying an enantiomer, is problematic and the reason for this being that, with the exception of the biological interactions that I showed you earlier on, where one will give rise to one biological response and one enantiomer will give rise to another biological response, there are chemically and physically no real differences between the two. They would boil at the same temperature, they will melt at the same temperature, they will undergo the same reactions and this is problematic.

    16:41 However, as I said before, enantiomers can rotate the plane of polarised light in equal degrees, at opposite directions. Also as I said, the enantiomer which rotates the plane of polarized light to the right is given the denotation of plus, and the enantiomer which rotates the plane of polarized light to the left is given the designation minus.

    17:08 Bear in mind, and I do stress this because it can get confusing. This is an experimental observation of what an individual molecule does to the plane of polarised light. Plus means it rotates it to the right, negative means it rotates it to the left. But there is no correlation between what is experimentally observed, and what we have just assigned under Cahn-Ingle-Prelog Rules. So you can actually have something which you designate as being rectus which actually rotates the plane of polarised light to the left. It’s counterintuitive, but it is something you need to be aware of. A racemic mixture, i.e. a mixture containing two enantiomers, equal concentrations, will not rotate the plane of polarized light at all. They will cancel each other out.

    17:58 Something else to bear in mind, and this has been exploited on several occasions from a medical perspective. When trying to isolate one particular enantiomer from a mixture, from racemate, and that is that enantiomers react differently with other chiral compounds, mostly because they form diastereomers as we will see. This and the other ways of doing it, also consider for example, separation of chiral molecules on a chiral column, but this can be quite expensive. And now I want to draw your attention to the idea of asymmetric synthesis. As I said before because chemically and physically two enantiomers will have a similar properties, it is very difficult to separate them. Possible by reacting them with other chiral molecules where the diastereomers will have different physical and chemical properties. But there is another way of doing it, and this is where I want to draw your attention to some Nobel prize winners for this particular area. One of them William S. Knowles, who came up with the enantiomeric selective synthesis of levodopa used in the treatment of Parkinson’s Disease. Also, Ryoji Noyori responsible for the enantiomeric selective synthesis of carbapenem. Carbapenem is a very important beta-lactam based antibiotic as you may be aware. In fact it is one of the broadest spectrum of all of the beta-lactam antibiotics and is generally considered the last line of defense in the treatment of gram negative bacterial infection.

    19:32 And finally Prof. Barry Sharpless who used the first asymmetric catalysis synthesis for the development of Paclitaxel which is a very important anticancer drug.

    About the Lecture

    The lecture Cahn—Ingold—Prelog Rules — Stereochemistry by Adam Le Gresley, PhD is from the course Chemistry: Introduction.

    Included Quiz Questions

    1. Assign the configuration to the chiral molecules
    2. Determine the molecular mass of chiral molecules
    3. Determine the chemical behavior of a solution containing a chiral compound
    4. Determine the molarity of a solution containing a chiral compound
    5. Determine the normality of a solution containing a chiral compound
    1. Multiple substituents at the chiral atom
    2. Single substituent at the chiral atom
    3. No substitution at the chiral atom
    4. Another chiral atom attached to the chiral atom
    5. A substituent equivalent to hydrogen atom attached to the chiral atom

    Author of lecture Cahn—Ingold—Prelog Rules — Stereochemistry

     Adam Le Gresley, PhD

    Adam Le Gresley, PhD

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