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Home / Introduction to Assigning (R) and (S): The Cahn-Ingold-Prelog Rules

Stereochemistry and Chirality

By James Ashenhurst

Last updated: December 6th, 2022 |

Assigning  R and  S Configurations With the Cahn-Ingold-Prelog (CIP) Rules

Table of Contents

(Advanced) References and Further Reading

This post was co-authored by Matt Pierce of Organic Chemistry Solutions .  Ask Matt about scheduling an online tutoring session here .

1. Chiral Centers And The Problem Of Naming

Previously on MOC we’ve described enantiomers : molecules that are non-superimposable mirror images of each other. Perhaps the most memorable example is these “enantiocats”.

drawing-of-enantiocats-master-organic-chemistry-graeme-mackay-look-at-the-legs

Each of these cats is said to be “chiral”: they lack a plane of symmetry.

What causes molecules to have chirality?

The most common source of chirality is a “chiral centre”: typically a  tetrahedral  carbon attached to four different “groups”, or “substituents”.  For each chiral centre there are  two  (and only two!) different ways of arranging the 4 different substituents, which gives rise to two different configurations.  [If you don’t believe there are only two, see Single Swap Rule ].

The purpose of this post is to introduce and describe the nomenclature we use to describe these configurations: the (R)/(S) notation, or Cahn-Ingold Prelog Rules.

Let’s look at a simple example.

Both of these molecules are 1-bromo-1-chloroethane. But they are not  exactly the same molecule, in the same way that your left shoe is not exactly the same as your right. They are non-superimposable mirror images of each other. How do we communicate this difference?

One way would be to describe their physical properties. For example, although these two molecules have the same boiling point, melting point, and share many other physical properties, they rotate plane-polarized light in equal and opposite directions, a property called  optical rotatio ( See Optical Rotation and Optical Activity ) We could use (+)-1-bromo-1-chloroethane to refer to the isomer that rotates polarized light to the right (clockwise, or “dextrorotatory”) and use (-)-1-bromo-1-chloroethane to refer to the isomer that rotates polarized light to the left (counterclockwise, or “levorotatory”).

However this nomenclature suffers from a serious problem. There is no simple correlation between the arrangement of substituents around a chiral centre and the direction in which polarized light is rotated. Another solution is needed.

2. The Cahn Ingold Prelog (CIP) System For Naming Chiral Centers

A solution to this quandary was proposed by Robert Cahn, Chris Ingold, and Vladimir Prelog in 1966. The resulting “CIP” protocol works as follows:

We should reiterate that the designations (R) and (S) bear no relationship to whether a molecule rotates plane-polarized light clockwise (+) or counterclockwise (-). For example the most common naturally occurring configuration of the amino acid alanine is (S), but its optical rotation (in aqueous acid solution) is (+).

3. What About When #4 Is Not In The Back?

That seems simple enough! “Is that it?”, you might ask.

Uh, no. As it happens, there’s a few bumps in the road toward determining (R)/(S) once we get beyond the simple example above.

These “trickier cases” fall into three main categories.

We’re not going to be able to fully address all of these issues in this post. But we can certainly deal with #1 and make some headway with #2. We’ll deal with #3 in a future post.

4. Determining R/S When The #4 Substituent Is In Front (i.e. on a “Wedge”): A Short Cut

Let’s first consider the molecule below. The name of this molecule is ( R )-1-fluoroethanol. It is listed below with priorities assigned based on atomic number. In this case F>O>C>H. So F is #1 and H is #4. The tricky part here is that the #4 priority is pointing out of the page (on a “wedge”).

How do we determine (R)/(S) in this case?  There are two ways to do it.

Many instructors will tell you to “simply” rotate the molecule in your head so that the #4 priority is on a dash. Then you can assign R or S in the traditional way. This “simple” advice is not always an easy task for beginners.

Thankfully, it is technically unnecessary to perform such a mental rotation.

Here’s  a way around this. When the #4 priority is on a wedge you can just reverse the rules. So now we have two sets of rules:

If the #4 priority is on a dash :

If the #4 priority is on a wedge , reverse the typical rules:

R and S can easily be assigned to either picture of the molecule. I still encourage you to use a model kit and learn how to do so, however. Organic chemistry is much easier to understand, and much more beautiful, if you can master how to visualize a tetrahedral carbon atom.

5. Determining R/S When The #4 Group Is In The Plane Of The Page?

What if the #4 priority is in the plane of the paper, for example on a line? In this case it’s impossible to assign R and S in the traditional way. You’d have a 50:50 shot of getting it correct: not good odds. Again, if you can redraw the molecule in your head, then it’s better to just do that. If you can’t do this reliably then you need to learn the “single swap” concept.

Here’s how it works.  Swapping any two groups on a chiral centre will flip the configuration of the chiral centre from R to S (and vice versa). [ We previously talked about the “single swap rule” here ]

Knowing this, we can do a nifty trick.

Here’s an example. Note that here  I first switched #4 and #3, but the main point is to switch two groups so that #4 is out of the plane of the paper.

This method always works, assuming you’ve determined the four priorities accurately. (It also works for cases when #4 is on a wedge).

However, sometimes we’re not in the position of dealing with 4 different atoms attached to a chiral carbon. For instance, it’s possible to have chiral carbons which are attached to 4  carbons . So how do we break the ties in these cases?

6. Determining CIP Priorities: Breaking “Ties” With The “Dot Technique”

The quick answer is to use the “dot technique”. Here’s how it works. Let’s do it for 4-ethyl-4-methyloctane, above.

3. Compare each list, atom by atom. In our example, since C>H, (C,H,H) takes priority over (H,H,H) so the CH 3 group is assigned priority #4.

4. If there is still a tie, move the dots to the highest ranking atom in the list (i.e. the atom with highest atomic number). The dots are helpful because they help you to keep track of where you are, which can be important in complex examples.

5. In this case, we keep moving along the chain. By the way, if you ever reach the end of the chain without determining a difference, that means that the groups are identical and it isn’t a chiral centre after all.

6. By this point we have enough information to assign (R)/(S). Since priority #4 is in the front, we can also break out our “opposite rule” for good measure:

7. Conclusion: The Cahn-Ingold-Prelog Rules For Assigning R and S Configurations

In the next post we’ll go into some trickier examples with determining R/S, including how to deal with double bonds, rings, and isotopes. In a future post, we’ll get into determining R/S in the Fischer and Newman projections.

Thanks to Matt Pierce for making major contributions to this article.  

Ask Matt about scheduling an online tutoring session  here .

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01 Bonding, Structure, and Resonance

02 Acid Base Reactions

03 Alkanes and Nomenclature

04 Conformations and Cycloalkanes

05 A Primer On Organic Reactions

06 Free Radical Reactions

07 Stereochemistry and Chirality

08 Substitution Reactions

09 Elimination Reactions

10 Rearrangements

11 SN1/SN2/E1/E2 Decision

12 Alkene Reactions

13 Alkyne Reactions

14 Alcohols, Epoxides and Ethers

15 Organometallics

16 Spectroscopy

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24 Carbohydrates

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Comment section

20 thoughts on “ introduction to assigning (r) and (s): the cahn-ingold-prelog rules ”.

Thank you very much, I now understand the R/S, its not easy to rotate a compound in your mind……

Kindly take my work into consideration in your website.

Abstract:- “The Keval’s Method” is developed for the determination of absolute configuration of a chiral carbon in a Fisher Projection and Wedge-Dash Projection just by simple calculations. This method is easily applicable over both Fisher as well as Wedge-Dash Projection. Various methods for determining absolute configuration have been developed and published till now, some of them used fingers and hands and other used exchanging elements. “Keval’s Method” is the first method in which a chiral carbon is taken to be an origin and the branches to axes, also it is purely calculation based method where absolute configuration is found based on the nature of calculated answer without using fingers and hands and also without exchanging elements.

Your’ Thankfully Keval Chetanbhai Purohit 5th-Computer Engineering, Vishwakarma Government Engineering College, Mo- 7226953531

I was having trouble with this when 4 was in the plane of the page. This technique is so easy. Thanks

Thanks!! You saved my org chem exam

Thank You so much :)

The molecule used to explain the dot technique is labelled as 3-ethyl-3-methyloctane, however shouldn’t the molecule be named as 4-ethyl-4-methyloctane? The branches are on the fourth carbon…

Shoot. You are right. Thanks for the catch. Fixed!

I have a lot of trouble rotating molecules in my head, so these tips feel like magic to me!!! Thank you soooo much :DDDD Btw I also go to McGill!

Thank you so much, you are a true life saver???

What to do if the compound is not denoted using the dash and wedge but simple bond line notation or expanded notation ?

Can you show an example? There has to be some kind of indicator. If all four bonds from the chiral center are shown as simple line notation there is no way to tell if it is R or S. It’s ambiguous.

Thank you so much!! :) This was a great refresher on chirality and you explained it in such a straightforward manner. Appreciate it!

Man this website proved to be a boon for me in quarantine…keep it up🔥🔥 The best content of organic chem I could get in such an incredible way

I just only want to know the CIP system of Nomenclature

During my studies for 11th grade and 12th grade, we had a brilliant Organic Chemistry teacher who taught the concepts beautifully. In addition, I had a passion (more of a “study crush”) on Chemistry in general and Organic Chemistry in particular. To such an extent that this topic of R and S enantiomers is still ingrained in memory. Though I am in a completely different area now of Machine Learning and Analytics in the Healthcare space in Industry, primarily a Software Engg job. Out of sheer curiosity, I googled “Chirality Detection Machine Learning” and voila !! such cool, intereesting papers I came across where they combine Bayesian Learning and Convolutional Neural Networks (Advanced ML Theory) to detect chirality in Nanoparticles. So application of ML in cutting edge Physics. Amazing stuff :!

Most people don’t learn chirality until 2nd year university in north america, so you are ahead of the curve

Thanks. Move the dots. Could not find this before.

Glad you found it useful James!

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Chemistry Steps

Chemistry Steps

R and S configuration same atoms

Organic Chemistry

Stereochemistry, what is the r and s configuration and why do we need it.

If we name these two alkyl halides based on the IUPAC nomenclature rules, we get the name as 2-chlorobutanbe for both:

assigning r and s configuration

However, they don’t look exactly the same as the Cl atom points in different directions – wedge and dash. These molecules are not the same compound – they are non-superimposable mirror images which are known as enantiomers :

assigning r and s configuration

The problem with the wedge and dash notation is that it is not a universal approach and quickly loses validity when we simply look at the molecule from the opposite direction:

assigning r and s configuration

So, we need an extra piece of information to distinguish enantiomers (and other stereoisomers) by their names properly addressing the stereochemistry as well.

Cahn, Ingold, and Prelog developed a system that, regardless of the direction we are looking at the molecule, will always give the same name ( unlike the wedge and dash notation ).

And that is why this is also known as the absolute Configuration or most commonly referred to as the R and S system.

Let’s see how it works by looking first at the following molecule and we will get back to the 2-chlorobutane after that:

assigning r and s configuration

Assigning R and S Configuration: Steps and Rules

To assign the absolute configuration, we need to first locate the carbon(s) with four different groups (atoms) connected to it. These are called chirality centers (chiral center, stereogenic center).

In our molecule, we only have one carbon with four different groups and that is the one with the bromine and we are going to assign the absolute configuration of this chiral center.

assigning r and s configuration

For this, you need to follow the steps and rules of the Cahn-Ingold-Prelog system.

Give each atom connected to the chiral center a priority based on its atomic number . The higher the atomic number, the higher the priority.

So, based on this, bromine gets priority one, the oxygen gets priority two, the methyl carbon is the third and the hydrogen is the lowest priority-four:

assigning r and s configuration

Draw an arrow starting from priority one and going to priority two and then to priority 3:

assigning r and s configuration

If the arrow goes clockwise , like in this case, the absolute configuration is R .

As opposed to this, if the arrow goes counterclockwise then the absolute configuration is S .

As an example, in the following molecule, the priorities go Cl > N > C > H and the counterclockwise direction of the arrow indicates an S absolute configuration:

assigning r and s configuration

So, remember: Clockwise – R , Counterclockwise – S .

Now, let’s see what would be the absolute configuration of the enantiomer:

assigning r and s configuration

The priorities are still the same since all the groups around the carbon are the same. Starting from the bromine and going to the oxygen and then the carbon, we can see that this time the arrow goes counterclockwise. If the arrow goes counterclockwise , the absolute configuration is S .

assigning r and s configuration

And this is another important thing to remember:

All the chirality centers in enantiomers are inverted (every R is S , every S is R in the enantiomer).

So, we discussed the roles of priorities 1, 2, and 3 but what about the lowest priority? We did not mention anything about the arrow going to it. Is it part of the game and how do you use it?

The lowest priority does not affect the direction of the arrow. However, this is very important, and it is a requirement when assigning the R and S configuration, that;

The lowest priority must point away from the viewer .

In other words, the lowest priority must be a dashed line to assign the R and S based on the direction of the arrow as we just did:

assigning r and s configuration

With that in mind, how can we assign the absolute configuration of this molecule where the hydrogen is a wedge line pointing towards us?

R and S When the lowest priority is a wedge

assigning r and s configuration

You have two options here:

Option one. Turn the molecule 180 o such that the hydroxyl is now pointing towards you and the hydrogen is pointing away. This allows to have the molecule drawn as needed – the lowest priority pointing backward as it is supposed to be for determining the R and S configuration:

assigning r and s configuration

Next, assign the priorities; chlorine-number one, oxygen-two, carbon-three and the H as number four.

assigning r and s configuration

The arrow goes clockwise , therefore the absolute configuration is R .

The problem with this approach is that sometimes you will work with larger molecules and it is impractical to redraw the entire molecule and swap every single chirality center.

For example, look at biotin with all these hydrogens pointing forward. Not the best option to redraw this molecule changing all the hydrogens and keeping the rest of the molecule as it should be.

assigning r and s configuration

This is why we have the second approach which is what everyone normally follows.

Here, you leave the molecule as it is with the hydrogen pointing towards you . Continue as you would normally do by assigning the priorities and drawing the arrow.

assigning r and s configuration

The only thing you have to do at the end is change the result from R to S or from S to R .

In this case, the arrow goes counterclockwise but because the hydrogen is pointing towards us, we change the result from S to R .

Of course, either approach should give the same result as this is the same molecule drawn differently.

assigning r and s configuration

R and S When Group #4 is not a Wedge or a Dash

There is a third possibility for the position of group 4 and that is when it is neither pointing away or towards you. This means we cannot determine the configuration as easily as if the lowest priority was pointing towards or away from us, and then switch it at the end as we did when group 4 was a wedge line.

As an example, what would be the configuration of this molecule?

assigning r and s configuration

For this, there is this simple yet such a useful trick making life a lot easier. Remember it:

Swapping any two groups on a chiral center inverts its absolute configuration ( R to S , S to R ):

assigning r and s configuration

Notice that these are different molecules. We are not talking about rotating about an axis or a single bond, in which case the absolute configuration(s) must stay the same. We are actually converting to a different molecule by swapping the groups to make it easier determining the R and S configuration.

Let’s do this on the molecule mentioned above:

The lowest priority group is in the drawing plane , so what we can do is swap it with the one that is pointing away from us (Br). After determining the R and S we switch the result since swapping means changing the absolute configuration and we need to switch back again.

assigning r and s configuration

The arrow goes counterclockwise indicating S  configuration and this means in the original molecule it is R.

Alternatively, which is more time-consuming, you can draw the Newman projection of the molecule looking from the angle that places group 4 in the back (pointing away from the viewer):

assigning r and s configuration

The lowest priority group is pointing and therefore, the clockwise direction of the arrow indicates an R configuration.

These two articles will be very helpful when dealing with stereochemistry in Newman projectiopns:

R and S when Atoms (groups) are the same

Sometimes it happens that two or more atoms connected to the chiral center are the same and it is not possible to assign the priorities right away.

For example, let’s go back to the 2-chlorobutane starting with the wedge chlorine:

assigning r and s configuration

Chlorine is the first priority, then we have two carbons and a hydrogen which gets the lowest priority. We need to determine the second priority comparing two carbon atoms and there is a tie since they both (obviously) have the same atomic number.

What do you do? You need to look at the atoms connected to the ones you compare:

assigning r and s configuration

The carbon on the left (CH 3 ) is connected to three hydrogens, while the one on the right is connected to two hydrogens and one carbon. This extra carbon gives the second priority to the CH 2 and the CH 3 gets priority three.

The arrow goes clockwise, so this is the ( R )-2-chlorobutane.

And if these atoms were identical as well, we’d have to move farther away from the chiral center and repeat the process until we get to the first point of difference.

It is like layers: the first layer is the atoms connected to the chiral center and you are comparing those and only move to the second layer if there is a tie.

assigning r and s configuration

You should never compare any atom of the second layer to a first layer atom regardless of its atomic number. For example, in the following molecule, layer 1 is a tie so we proceed to layer 2 which gives the priority to the carbon connected to the chiral center on the left since it has oxygen connected to it.

assigning r and s configuration

So, we do not compare layer 2 and 3 which would’ve given the priority to the carbon with a Br since Br has a higher atomic number than oxygen. Because the oxygen is connected to a carbon closer to the chiral center, it gives the prioirty to that carbon regardless of what is connected to the carbon atoms on the next layer:

assigning r and s configuration

Double and triple bonds in the R and S configurations

  Let’s do the R and S for this molecule:

assigning r and s configuration

Bromine is the priority and the hydrogen is number four. Carbon “a” is connected to one oxygen and two hydrogens. Carbon “b” is connected to one oxygen and one hydrogen. However, because of the double bond , carbon “b” is treated as if it is connected to two oxygens . The same rule is applied for any other double or triple bond. So, when you see a double bond count it as two single bonds when you see a triple bond cut it as three single bonds .

The arrow goes clockwise, however, the absolute configuration is S , because the hydrogen is pointing towards us.

More Tricks in the R and S configurations

Let’s see this with this molecule:

assigning r and s configuration

Even if only one atom has a higher atomic number than the highest one on the other carbon, the group gets higher priority.

So, one S beats N, O, F because it has a higher atomic number than the others individually.

assigning r and s configuration

assigning r and s configuration

assigning r and s configuration

assigning r and s configuration

assigning r and s configuration

And that should cover most possibilities that I can think of about R and S configurations.

Let me know in the comments if there are any other tips and tricks you would like to be mentioned. 

Practicing R and S is never too much. This 1.5-hour video is a collection of examples taken from the multiple choice quizzes determining the R and S configuration in the context of naming compounds, determining the relationship between compounds, and chemical reactions. 

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Check Also in Stereochemistry:

assigning r and s configuration

Stereochemistry Practice Problems Quiz

Identify all the chiral centers in each molecule and determine the absolute configuration as R or S :

assigning r and s configuration

Identify all the chiral centers in each Fischer projection  and determine the absolute configuration as R or S :

assigning r and s configuration

For each of the following pairs of compounds, determine the relationship between the two compounds: Are they enantiomers or the same compound drawn differently? If you hesitate, determine the absolute configuration of chiral centers (if any:  R or S ).

assigning r and s configuration

Determine the absolute configuration of each chiral center in the following Newman projections:

assigning r and s configuration

15 thoughts on “How to Determine the R and S configuration”

Thanks for sharing this useful article for finding out the Absolute configuartion

This was such a good article to explain things! A big thanku

Thanks for the kind words

Thanks for sharing this article we got a lot of help thanks❤️❤️❤️

Great to hear that, Ali.

I was wondering how the different layers were given priority, as my teacher did not cover that part but still expected us to know R or S configuration. Thanks for explaining it so well visually!

Glad it was helpful, Aron.

Thank you, it really help and Interesting

R and S do not apply to the nitrogen in amines for the same reason as for carbanions. Quaternary ammonium groups, however, can be chiral ( in the last example ). In this section the lower priority group is in the plane , it should be below the plane . Then will it be a R- configuration? It may be S-configuration , do check please.

Correct, the lower priority is the methyl group and it is in the plane. One option to make it appear in the back is to look at the molecule from the opposite direction of where the methyl is pointing – 10 o’clock. From there, the arrow would look like going clockwise based on the priorities assigned shown in the example, so the absolute configuration is R.

Thanks so much for the in-depth article and thorough treatment of techniques to approach chirality! It seems that our textbook just loves to share the basic principles but fails to help when things get sticky–leaving me to flounder on the trick exam questions! I feel much more confident about my knowledge of chirality after reading through your extremely thoughtful article.

Thank you for your feedback. It does take time to write the articles around the situations where I see students getting stuck in the class, and it is great to see it is helpful.

This is so understandable and straight forward. Thanks for the help, it’s really useful.

Thanks for the good feedback!

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Chemistry LibreTexts

6.3: Absolute Configuration and the (R) and (S) System

Learning Objective

USE YOUR MODELING KIT: Models assist in visualizing the structure. When using a model, make sure the lowest priority is pointing away from you. Then determine the direction from the highest priority substituent to the lowest: clockwise (R) or counterclockwise (S).

IF YOU DO NOT HAVE A MODELING KIT : remember that the dashes mean the bond is going into the screen and the wedges means that bond is coming out of the screen. If the lowest priority bond is not pointing to the back, mentally rotate it so that it is. However, it is very useful when learning organic chemistry to use models.

If you have a modeling kit use it as you read through this section and work the practice problems.

Introduction and the Cahn-Ingold-Prelog rules of Priority

To name the enantiomers of a compound unambiguously, their names must include the "handedness" of the molecule. The letters "R" and "S" are determined by applying the Cahn-Ingold-Prelog (CIP) rules. The optical activity (+/-) can also be communicated in the name, but must be empirically derived. There are also biochemical conventions for carbohydrates (sugars) and amino acids (the building blocks of proteins).

The method of unambiguously assigning the handedness of molecules was originated by three chemists: R.S. Cahn, C. Ingold, and V. Prelog and, as such, is also often called the Cahn-Ingold-Prelog rules. In addition to the CIP system, there are two ways of experimentally determining the absolute configuration of an enantiomer:

However, for non-laboratory purposes, it is beneficial to focus on the R/S system. The sign of optical rotation, although different for the two enantiomers of a chiral molecule,at the same temperature, cannot be used to establish the absolute configuration of an enantiomer; this is because the sign of optical rotation for a particular enantiomer may change when the temperature changes.

The Cahn-Ingold-Prelog rules of priority are based on the atomic numbers of the atoms of interest. For chirality, the atoms of interest are the atoms bonded to the chiral carbon.

Multiple bonds are treated as if each bond of the multiple bond is bonded to a unique atom. For example, the ethenyl group (CH 2 =CH) has higher priority than the ethyl group (CH 3 CH 2 ). The ethenyl carbon priority is "two" bonds to carbon atoms and one bond to a hydrogen atom compared with the ethyl carbon that has only one bond to a carbon atom and two bonds to two hydrogen atoms. Similarly, the carbon-carbon triple bond of acetylene would give it higher CIP priority than the ethenyl group as summarized below.

CIP carbon tie breakers.png

Stereocenters are labeled R or S

The "right hand" and "left hand" nomenclature is used to name the enantiomers of a chiral compound. The stereocenters are labeled as R or S.

14-new.JPG

Consider the diagram above on the left: a curved arrow is drawn counter-clockwise (c-cw) from the highest priority substituent ( 1 ) to the lowest priority substituent (4 ) in t he S - configuration ("Sinister" → Latin= "left"). T he counterclockwise direction can be recognized by the movement left when leaving the 12 o' clock position. Now consider the diagram above on the right where a curved arrow is drawn clockwise (cw) from the highest priority substituent ( 1 ) to the lowest priority substituent (4 ) in the R configuration ("Rectus" → Latin= "right"). The R or S is then added as a prefix, in parenthesis, to the name of the enantiomer of interest. A locator number is required if there is more than one chiral center. Otherwise, the person reading the name is expected to recognize the chiral center.

The two chiral compounds below are drawn to emphasize the chiral carbon with the full chemical name below each structure.

ch6 sect 3 example.png

Absolute Configurations of Perspective Formulas

Chemists need a convenient way to distinguish one stereoisomer from another. The Cahn-Ingold-Prelog system is a set of rules that allows us to unambiguously define the stereochemical configuration of any stereocenter, using the designations ' R ’ (from the Latin rectus , meaning right-handed) or ' S ’ (from the Latin sinister , meaning left-handed).

The rules for this system of stereochemical nomenclature are, on the surface, fairly simple.

Rules for assigning an R/S designation to a chiral center

1: Assign priorities to the four substituents, with #1 being the highest priority and #4 the lowest. Priorities are based on the atomic number.

2: Trace a circle from #1 to #2 to #3.

3: Determine the orientation of the #4 priority group. If it is oriented into the plane of the page (away from you), go to step 4a. If it is oriented out of the plane of the page (toward you) go to step 4b.

4a: (#4 group pointing away from you ): a clockwise circle in part 2 corresponds to the R configuration, while a counterclockwise circle corresponds to the S configuration.

4b: (#4 group pointing toward you ): a clockwise circle in part 2 corresponds to the S configuration, while a counterclockwise circle corresponds to the R configuration.

We’ll use the 3-carbon sugar glyceraldehyde as our first example. The first thing that we must do is to assign a priority to each of the four substituents bound to the chiral center. We first look at the atoms that are directly bonded to the chiral center: these are H, O (in the hydroxyl), C (in the aldehyde), and C (in the CH 2 OH group).

Assigning R/S configuration to glyceraldehyde:

alt

Two priorities are easy: hydrogen, with an atomic number of 1, is the lowest (#4) priority, and the hydroxyl oxygen, with atomic number 8, is priority #1. Carbon has an atomic number of 6. Which of the two ‘C’ groups is priority #2, the aldehyde or the CH 2 OH? To determine this, we move one more bond away from the chiral center: for the aldehyde we have a double bond to an oxygen, while on the CH 2 OH group we have a single bond to an oxygen. If the atom is the same, double bonds have a higher priority than single bonds. Therefore, the aldehyde group is assigned #2 priority and the CH 2 OH group the #3 priority.

With our priorities assigned, we look next at the #4 priority group (the hydrogen) and see that it is pointed back away from us, into the plane of the page - thus step 4a from the procedure above applies. Then, we trace a circle defined by the #1, #2, and #3 priority groups, in increasing order. The circle is clockwise, which by step 4a tells us that this carbon has the ‘ R ’ configuration, and that this molecule is ( R )-glyceraldehyde. Its enantiomer, by definition, must be ( S )-glyceraldehyde.

Next, let's look at one of the enantiomers of lactic acid and determine the configuration of the chiral center. Clearly, H is the #4 substituent and OH is #1. Owing to its three bonds to oxygen, the carbon on the acid group takes priority #2, and the methyl group takes #3. The #4 group, hydrogen, happens to be drawn pointing toward us (out of the plane of the page) in this figure, so we use step 4b: The circle traced from #1 to #2 to #3 is clockwise, which means that the chiral center has the S configuration.

alt

The drug thalidomide is an interesting - but tragic - case study in the importance of stereochemistry in drug design. First manufactured by a German drug company and prescribed widely in Europe and Australia in the late 1950's as a sedative and remedy for morning sickness in pregnant women, thalidomide was soon implicated as the cause of devastating birth defects in babies born to women who had taken it. Thalidomide contains a chiral center, and thus exists in two enantiomeric forms. It was marketed as a racemic mixture : in other words, a 50:50 mixture of both enantiomers.

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Let’s try to determine the stereochemical configuration of the enantiomer on the left. Of the four bonds to the chiral center, the #4 priority is hydrogen. The nitrogen group is #1, the carbonyl side of the ring is #2, and the –CH 2 side of the ring is #3.

image106.png

The hydrogen is shown pointing away from us, and the prioritized substituents trace a clockwise circle: this is the R enantiomer of thalidomide. The other enantiomer, of course, must have the S configuration.

Although scientists are still unsure today how thalidomide works, experimental evidence suggests that it was actually the R enantiomer that had the desired medical effects, while the S enantiomer caused the birth defects. Even with this knowledge, however, pure ( R )-thalidomide is not safe, because enzymes in the body rapidly convert between the two enantiomers - we will see how that happens in chapter 12.

As a historical note, thalidomide was never approved for use in the United States. This was thanks in large part to the efforts of Dr. Frances Kelsey, a Food and Drug officer who, at peril to her career, blocked its approval due to her concerns about the lack of adequate safety studies, particularly with regard to the drug's ability to enter the bloodstream of a developing fetus. Unfortunately, though, at that time clinical trials for new drugs involved widespread and unregulated distribution to doctors and their patients across the country, so families in the U.S. were not spared from the damage caused.

Very recently a close derivative of thalidomide has become legal to prescribe again in the United States, with strict safety measures enforced, for the treatment of a form of blood cancer called multiple myeloma. In Brazil, thalidomide is used in the treatment of leprosy - but despite safety measures, children are still being born with thalidomide-related defects.

Exercise 1.: Determine the stereochemical configurations of the chiral centers in the biomolecules shown below.

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Exercise 2. : Should the ( R ) enantiomer of malate have a solid or dashed wedge for the C-O bond in the figure below?

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Exercise 3. : Using solid or dashed wedges to show stereochemistry, draw the ( R ) enantiomer of ibuprofen and the ( S ) enantiomer of 2-methylerythritol-4-phosphate (structures are shown earlier in this chapter without stereochemistry).

Solutions to exercises

Absolute Configurations of Fischer Projections

To determine the absolute configuration of a chiral center in a Fisher projection, use the following two-step procedure.

Step 1 Assign priority numbers to the four ligands (groups) bonded to the chiral center using the CIP priority system.

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Step 2 - vertical option If the lowest priority ligand is on a V ertical bond, then it is pointing away from the viewer.

Trace the three highest-priority ligands starting at the highest-priority ligand ( ① → ② → ③ ) in the direction that will give a V ery correct answer.

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In the compound below, the movement is clockwise indicating an R-configuration. The complete IUPAC name for this compound is (R)-butan-2-ol.

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Step 2 - horizontal option

If the lowest-priority ligand is on a H orizontal bond, then it is pointing toward the viewer.

Trace the three highest-priority ligands starting at the highest-priority ligand ( ① → ② → ③ ) in the direction that will give a H orribly wrong answer. Note in the table below that the configurations are reversed from the first example.

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In the compound below, the movement is clockwise (R) which is Horribly wrong, so the actual configuration is S. The complete IUPAC name for this compound is (S)-butan-2-ol.

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Manipulating Fischer Projections with NO Change to Configuration

A Fischer projection restricts a three-dimensional molecule into two dimensions. Consequently, there are limitations as to the operations that can be performed on a Fischer projection without changing the absolute configuration at chiral centers. The operations that do not change the absolute configuration at a chiral center in a Fischer projections can be summarized as two rules.

Rule 1: Rotation of the Fischer projection by 180º in either direction without lifting it off the plane of the paper does not change the absolute configuration at the chiral center.

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Rule 2: Rotation of three ligands on the chiral center in either direction, keeping the remaining ligand in place, does not change the absolute configuration at the chiral center.

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Manipulating Fischer Projections with Change to Configuration

The operations that do change the absolute configuration at a chiral center in a Fischer projection can be summarized as two rules.

Rule 1: Rotation of the Fischer projection by 90º in either direction changes the absolute configuration at the chiral center.

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Rule 2: Interchanging any two ligands on the chiral center changes the absolute configuration at the chiral center.

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The above rules assume that the Fischer projection under consideration contains only one chiral center. However, with care, they can be applied to Fischer projections containing any number of chiral centers.

Classify the following compounds as R or S?

newest problems.JPG

6. Orient the following so that the least priority (4) atom is paced behind, then assign stereochemistry ( R or S ).

7. Draw ( R )-2-bromobutan-2-ol.

8. Assign R/S to the following molecule.

A = S ; B = R

8. The stereo center is R .

Other Resources

Kahn academy video tutorial on the r-s naming system.

Contributors and Attributions

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Assign sequence priorities to the four substituents by looking at the atoms attached directly to the chiral center.

The Viewing Rule

Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 S     R     Achiral A response to your selection will appear here. A sequence assignment will be shown above.

Configurational drawings of chiral molecules sometimes display structures in a way that does not permit an easy application of the viewing rule. In the example of carvone, shown above, the initial formula directed the lowest priority substituent (H) toward the viewer, requiring either a reorientation display or a very good sense of three-dimensional structure on the part of the reader. The Fischer projection formulas, described later , are another example of displays that challenge even experienced students. A useful mnemonic, suggested by Professor Michael Rathke, is illustrated below. Here a stereogenic tetrahedral carbon has four different substituents, designated 1, 2, 3 & 4 . If we assume that these numbers represent the sequence priority of these substituents (1 > 2 > 3 > 4), then the R and S configurations are defined.

The viewing rule states that when the lowest priority substituent (4) is oriented behind the triangular face defined by the three higher priority substituents (shaded light gray here), a clockwise sequential arrangement of these substituents (1, 2 & 3) is defined as R , and a counter-clockwise sequence as S . Now a tetrahedral structure may be viewed from any of the four triangular faces, and the symmetry of the system is such that a correct R/S assignment is made if the remote out-of plane group has an even number sequence priority (2 or 4), whereas the wrong assignment results when the out-of plane group has an odd priority (1 or 3). Once one recognizes this relationship, the viewing options are increased and a configurational assignment is more easily achieved. For an example, click on the diagram to see the 1:3:4-face, shaded light gray. oriented in front of substituent 2. Note that the R/S assignment is unchanged.

Ephedrine from Ma Huang: m.p. 35 - 40 º C,   [α] D = –41º,   moderate water solubility [this isomer may be referred to as (–)-ephedrine] Pseudoephedrine from Ma Huang: m.p. 119 º C,   [α] D = +52º,   relatively insoluble in water [this isomer may be referred to as (+)-pseudoephedrine]

For an interesting example illustrating the distinction between a chiral center and an asymmetric carbon Click Here .

(+)-tartaric acid: [α] D = +13º m.p. 172 ºC (–)-tartaric acid: [α] D = –13º m.p. 172 ºC meso -tartaric acid: [α] D = 0º m.p. 140 ºC

To learn more about chemical procedures for achieving resolution Click Here .

Conformations of meso-Tartaric Acid Fischer Projection A eclipsed, achiral B staggered, chiral C staggered, achiral D staggered, chiral

Conformations of Biphenyls

The 1,2-Dichlorocyclohexanes The 1,3-Dichlorocyclohexanes Examine Conformations of cis-1,2-Dichlorocyclohexane Examine Conformations of trans-1,2-Dichlorocyclohexane   Examine Conformations of cis-1,3-Dichlorocyclohexane Examine Conformations of trans-1,3-Dichlorocyclohexane

The 1,4-Dichlorocyclohexanes

This page is the property of William Reusch.   Comments, questions and errors should be sent to [email protected] . These pages are provided to the IOCD to assist in capacity building in chemical education. 05/05/2013

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5.2 Absolute Configurations: How to Assign R and S

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5.1 Overview of Isomers

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5.3 Molecules with...

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Forgot what a chiral center is or how to identify them? Check out 5.1 Overview of Isomerism and Stereoisomers .

Trying to assign R and S with Fischer Projections? Check out 5.4 Fischer Projections .

The Cahn-Ingold-Prelog Rules

Assigning r and s.

The Cahn-Ingold-Prelog system is a set of rules for assigning R and S (absolute configurations) to chiral centers.  The idea is to assign each of the 4 atoms attached to a chiral center a priority, 1 through 4, based primarily on atomic number.  Once the priorities are assigned the spacial arrangement of these 4 atoms will be in one of two configurations: R or S.  The complete rules are summarized in the table above.

To specifically determine the spacial arrangement the rules state that when the #4 priority group is attached by a dashed bond (facing away from you) then a right-handed turn (clockwise) indicates the R configuration, and a left-handed turn (counter-clockwise) indicates the S configuration.

If the #4 priority group is attached by a dashed bond then you're set.  But what if it's not.  Below we'll show examples of how to assign R and S

1) When the #4 priority group is attached by a dashed bond

2) When the #4 priority group is attached by a wedged bond

3) When the #4 priority group is attached by a bond in the plane

Assigning R and S Example 1

In the example above, the chiral centers are attached to 4 different atoms.  This is the easiest possible scenario for assigning priorities as priorities are simply determined by atomic number.  The following shows the 4 atoms arranged in decreasing order of atomic number:

Br > Cl > C > H

When the #4 Priority Group is Attached by a Dashed Bond

This is the easiest of the three scenarios.  When the #4 priority group is attached by a dashed bond (facing away from you) then a right-handed turn (clockwise) indicates the R configuration, and a left-handed turn (counter-clockwise) indicates the S configuration.  In this example, as we move from priority #1 to #2 to #3 we make a right-handed turn which indicates the molecule is in the R configuration.

Assigning R and S Example 1

When the #4 Priority Group is Attached by a Wedged Bond

When the #4 priority group is attached by a wedged bond (facing toward you) you are looking at the molecule from exactly the opposite perspective described by the Cahn-Ingold-Prelog rules.  A right-handed turn from this opposite perspective would be a left-handed turn if looked at from the correct perspective, and a left-handed turn from this opposite perspective would be a right-handed turn from the correct perspective.  The simple solution is to move from priority #1 to #2 to #3 and make your 'turn,' and to just know that the molecule is in the opposite configuration as to what you would determine if the #4 priority group had had a dashed bond.  In this example, as we move from priority #1 to #2 to #3 we make a right-handed turn (which would normally mean R) which indicates the molecule is in the S configuration.

Assigning R and S Example 1b

When the #4 Priority Group is Attached by a Bond in the Plane

When the #4 priority group is attached by a bond in the plane you should have yourself a good cry before attempting to assign its configuration as this is the most challenging of the 3 scenarios.  With the bond in the plane, you are not looking at the molecule from the correct perspective but neither is it the exact opposite of the correct perspective either. If you move from priority #1 to #2 to #3 and assign it as is you'll be correct 50% of the time on average.  If you simply make it the opposite you'll once again be correct 50% of the time on average.

There are 3 ways to approach correctly assigning R and S in such a scenario:

1) Try to visualize the molecule in your mind from the correct perspective.

2) Rotate the other bond in the plane until the #4 priority group is in a position (dashed or wedged) from which you can more easily assign R and S.

3) Switch the position of the #4 priority group with the group that has a dashed bond.  By switching two groups you get the opposite configuration of the original molecule.  But with the #4 priority now in a dashed position it will be straightforward to assign R and S.  Once you've assigned R or S to this molecule, know that the original was in the opposite configuration.

While all of these approaches work, it has been my experience that undergraduate students tend to make fewer errors using the 3rd method which is why it's the method I present in the video lecture for this lesson.

Assigning R and S Example 1c

How to Assign Priorities to Groups with the Same Attached Atom

In the above examples all of the atoms attached to the chiral center were different which made assigning priorities relatively easy.  But that won't be the case with most of the examples you're likely to come across.  Rule #2 in the Cahn-Ingold-Prelog System deals with assigning priorities in such cases.  For organic molecules most of the examples you'll see will have chiral centers attached to more than one carbon atom.  To distinguish between carbon atoms you next look at what 3 additional atoms these carbons are bonded to.  In the next example the chiral center is bonded to a Br (#1 priority), an H (#4 priority) and two carbon atoms.

Assigning R and S Example 2

The carbon on the left is the carbon of a methyl group and is simply bonded to 3 additional hydrogen atoms ( H H H ).  The carbon on the right is the carbon of an ethyl group and is bonded to 1 carbon atom and 2 hydrogen atoms ( C H H ).  When listing the 3 bonded atoms you list them in descending order of atomic number.  The priority is determined in the first place you see a difference by atomic number; the higher the atomic number the higher priority.

In this example the first atom the carbon of the ethyl group is attached to is a carbon, whereas the first atom the carbon of the methyl is attached to is a hydrogen, thus the carbon of the ethyl group will have a higher priority (#2) than the carbon of the methyl group (#3).

The #4 priority group has a dashed bond and as we move from priority #1 to #2 to #3 we make a right-handed turn indicating the configuration of this chiral center is R.

How to Assign Priorities Involving Double and Triple Bonds

A special case occurs when the atoms (usually carbon) attached to the chiral center have double or triple bonds.  When listing the bonded atoms you will list atoms with a double bond twice and atoms with a triple bond three times.  In the next example a the chiral center to an oxygen atom (#1 priority), a hydrogen atom (priority #4) and two carbon atoms.

Assigning R and S 2nd Example

The carbon on the left is bonded to a sulfur atom and two hydrogen atoms ( S H H ).  The carbon on the right has a double bond to oxygen and one bond to a hydrogen atom ( O O H ).  The first difference is sulfur vs oxygen.  As sulfur has a higher atomic number the carbon on the left is assigned the higher priority (#2) than the carbon on the right (#3).

Note that the comparison here was the first point of difference in the bonded atoms.  On just such an example I will have students ask me what to give a higher priority, S HH or O OH .  These students are trying to compare all three bonded atoms at the same time, but the proper comparison is simply the first point of difference, S vs O in this case.

Finally, the lowest priority is bonded with a wedged bond (facing toward you) and so the left-handed turn formed when proceeding from priority #1 to #2 to #3 indicates the R configuration rather than the S.

Assigning Priorities Involving Double and Triple Bonds: 2nd Example

Another special case occurs when the atoms attached to the chiral center have double or triple bonds and have the same 3 bonded atoms listed.  In such a case you have to continue on to the next atoms and list the 3 atoms they are attached to.  However, for an atom that has a double or triple bond from the previous atom in the sequence, you count the pi bonds back to the previous atom when listing the 3 atoms for the most recent atom in the sequence.  Consider the following example:

Assigning R and S Example 4

The chiral center is bonded to an oxygen atom (#1) and a hydrogen atom (#4) and two carbon atoms.  The carbon on the left is bonded to 3 methyl groups ( C C C ), and the carbon on the right is triple bonded to a carbon atom (also C C C ).  So up to this point we have not found a difference, so now we'll evaluate the next set of atoms attached to the above-listed carbon atoms.

The 3 carbon atoms on the left-hand side are all a part of methyl groups and the bonded atoms are listed as H H H.  The triple-bonded carbon on the right is only bonded to one additional atom, a single hydrogen.  It is here that we count the two pi bonds back to the previous carbon atom so that bonded atoms are listed as C C H.  The comparison here comes down to C vs H and carbon has a higher atomic number, therefore the carbon on the right of the chiral center as the higher priority (#2).

Finally, the lowest priority is bonded with a dashed bond (facing away from you) and so the right-handed turn formed when proceeding from priority #1 to #2 to #3 indicates the R configuration.

Organic Chemistry/Chirality/R-S notational system

Stereoisomers are properly named using the Cahn-Ingold-Prelog (CIP) priority rules to decide which parts of the molecule to consider first.

The rules have evolved to cover many situations, but the basic rules are:

Realize that when you do this it will mean that sometimes groups with higher total weights will have lower priority because of a lower weight of the atom that connects them.

R and S Notation [ edit | edit source ]

R- and S-notation use the CIP priority rules for the assignment of the absolute configuration around a stereocenter.

First, assign priorities as described above to each bonded group surrounding the stereocenter (1, highest to 4, lowest).

Second, point the lowest priority (4) atom away from you. Follow the direction of the remaining 3 priorities from highest to lowest priority (lowest to highest number, 1<2<3).

A counterclockwise direction is an S ( sinister , Latin for left) configuration. A clockwise direction is an R ( rectus , Latin for right) configuration.

assigning r and s configuration

R-S system RULES OF PRIORITY ORDER:-

E-Z notation [ edit | edit source ]

The R-/S- notation is valid only for the absolute configuration of a center having single bonds only. In the case of a double bond, the traditional cis / trans nomenclature system is not sufficiently accurate and the E- / Z- is currently preferred.

The basis is again the CIP priority rules.

See main discussion: E-Z notation

assigning r and s configuration

IMAGES

  1. 6.3: Absolute Configuration and the (R) and (S) System

    assigning r and s configuration

  2. How to Determine the R and S configuration

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  3. Absolute Configurations Assigning R and S

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  4. How to assign R and S configuration

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  5. How to Determine the R and S configuration

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  6. Assigning R and S CONFIGURATION

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  8. Absolute Configuration: R-S Sequence Rules

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  11. Designating the Configuration of Chiral Centers

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  12. Absolute Configurations Assigning R and S

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