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Absolute Configuration: R-S Sequence Rules Table of Contents

To name the enantiomers of a compound unambiguously, their names must include the "handedness" of the molecule. The method that has been developed to do this is formally known as R,S nomenclature.

Introduction

The method of unambiguously assgning the handiness 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 Cahn ingold system, there are two ways of experimentally determining an enantiomer's absolute configuration:

  • 1. X-ray diffraction analysis. Note that there is no correlation between the sign of rotation and the structure of a particular enantiomer.

  • 2. Chemical correlation with a molecule whose structure has already been determined via X- ray diffraction.

However, for non-lab 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.

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.

Absolute Configuration: R-S Sequence Rules Table of Contents To name the enantiomers of a compound unambiguously,X-ray diffraction analysis. Note that there is no correlation between the sign of rotation and the structure of a particular enantiomer. 2. Chemical correlation with a molecule whose structure has already been determined via X- ray diffraction. However, for non-lab 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. 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. Look at the first picture, then draw a curved arrow from the highest priority ( 1 ) substituent to the lowest priority (4 ) substituent. If the arrow goes in a counterclockwise direction ( left when leaving the 12'o clock position), the configuration at stereocenter is considered S ("Sinister" → L atin= "left"). If, however, the arrow turns clockwise,( Right when leaving the 12'o clock position) then the stereocenter is labeled R ("Rectus" → Latin= "right"). " id="pdf-obj-0-27" src="pdf-obj-0-27.jpg">

Look at the first picture, then draw a curved arrow from the highest priority (1) substituent to the lowest priority (4) substituent. If the arrow goes in a counterclockwise direction (left when leaving the 12'o clock position), the configuration at stereocenter is considered S ("Sinister" → Latin= "left"). If, however, the arrow turns clockwise,(Right when leaving the 12'o clock position) then the stereocenter is labeled R("Rectus" → Latin= "right").

The R or S is then added as a prefix ,in parenthesis, to the name of the specific enantiomer we are concerned about.

Example

1

(R)-2-Bromobutane

(S)-2,3- Dihydroxypropanal

Sequence rules to assign priorities to substituents

Before you can apply the R and S nomenclature to a stereocenter, you have to prioritize your substituents. Follow these rules to prioritize:

Rule 1

First look at the atoms that are directly attached to the stereocenter of the compound. A substituent that has a higher atomic number takes precedence over a substituent that has a lower atomic number. Hydrogen is the lowest possible priority substituent, because it has the lowest atomic number.

  • 1. When you are dealing with isotopes, the atom with the higher atomic mass receives higher priority.

  • 2. When visualizing the molecule, the lowest priority substituents should always go away from the viewer (dashed line indicates going away from the viewer). To understand how this works or looks, imagine that you have a clock and a pole.

  • 3. Attach the pole to the back of the clock, so that when you look at the face of the clock the pole points away from you. That is the same way the lowest priority substituent should point away from you.

  • 4. Then, draw an arrow from the highest priority atom to the 2nd highest priority atom to the 3rd highest priority atom. Since you have placed the 4th highest priority atom in the back, you arrow should seem like it is going across the face of a clock. If it is going clockwise, then it is an R-enantiomer; If it is going counterclockwise, it is an S-enantiomer.

When looking at a problem with wedges and dashes: if the lowest priority atom is not on the dashed line going away from you, you must rotate the molecules so that the lowest priority bond is facing away from you. Remember that

Wedges mean coming towards the viewer.

Dashes mean going away from you.

Rule 2

When you have two substituents with equal rank, you must proceed along the two substituent chains until you find a point of difference. First, you determine which of the chains has the first connection to an atom with the highest priority-the highest atomic number. That chain will have the higher priority. If the chains are similar keep going down the chain, until you can find a point of difference. For example: an ethyl substituent will take priority over a methyl substituent. At the connectivity of the stereocenter, both have a Carbon, which are equal in rank. Going down the chains, a methyl has only has Hydrogen atoms attached to it while the ethyl has another Carbon attached to it. The Carbon on the ethyl is the first point of difference and has a bigger atomic number than Hydrogen:therefore the ethyl takes priority over the methyl.

Rule 2 When you have two substituents with equal rank, you must proceed along the two

Rule 3

If a chain is connected to the same kind of atom twice or three times. Check to see if the atom it is connected to has a greater atomic number than any of the atoms that the competing chain is connected to.

If none of the atoms connected to the competing chain(s),at the same point, has a greater atomic number: the chain bonded to the same atom multiple times has the greater priority

If however, one of the atoms connected to the competing chain has a bigger atomic number:

then that chain will have the higher priority.

Example 2

A 1-Methylethyl substituent will take precedence over an Ethyl substituent. Connected to the first carbon, ethyl onl

one other Carbon whereas the 1-Methylethyl has two Carbons attached to the first Carbon; this is the first point of difference. Therefore, 1-Methylethyl will rank higher in priority than Ethyl, as shown below:

one other Carbon whereas the 1-Methylethyl has two Carbons attached to the first Carbon; this is

However:

Remember that being double or triple bonded to an atom means that the atom is connected to the same atom twice in such a case you would follow the same method as above.

one other Carbon whereas the 1-Methylethyl has two Carbons attached to the first Carbon; this is
Caution!! Keep in mind that priority is determined by the first point of difference along the

Caution!!

Keep in mind that priority is determined by the first point of difference along the two similar substituent chains. Afte have reached the first point of difference, the rest of the chain is irrelevant.

Caution!! Keep in mind that priority is determined by the first point of difference along the

When you are looking for the first point of difference on similar substituent chains, you may encounter branching. If is branching, we choose the branch that is higher in priority. When the two substituents have similar branches, you r the elements within the branches until you reach a point of difference.

After all your substituents have been prioritized in the correct manner, you can now name/label the

After all your substituents have been prioritized in the correct manner, you can now name/label the molecule R or S

  • 1. Put the lowest priority substituent in the back (dashed line).

  • 2. Go from 1 to 2 to 3. (it is helpful to draw or imagine an arcing arrow that goes from 1--> 2-->3)

  • 3. Determine if the direction from 1 to 2 to 3 clockwise or counterclockwise i) If it is clockwise it is R ii) if it is counterclockwise it is S.

USE YOUR MODELING KIT: Making models will help you visualize the structure. When you make a model, make sure the lowest priority is pointing away from you. Then determine what direction you have to go 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 your lowest priority bond is not pointing to the back, mentally rotate it so that it is. However, it would help you greatly when learning organic chemistry to get one.

If you have a modeling kit use it to help you solve the following practice problems.

Problems

Are the following R or S?

Answers (1) S I > Br > F > H. The lowest priority substituent, H, is

Answers

(1) S

I > Br > F > H. The lowest priority substituent, H, is already going towards the back. It turns left going from I to Br to F, so it's a S.

(2) R Br > Cl > CH 3 > H.

You have to switch the H and Br in order to place the H, the lowest priority, in the

back. Then, going from Br to Cl, CH 3 is turning to the right, giving you a R.

(3) Neither R or S

This molecule is achiral. Only chiral molecules can be named R or S.

(4) R

OH > CN > CH 2 NH 2 > H. The H, the lowest priority, has to be switched to the back. Then, going from OH to CN to CH 2 NH 2 , you are turning right, giving you a R.

(5) S

COOH > C triple bond CH > HOH 2 C > H. You have to switch H with COOH so that H is going towards the back. Then, going from COOH to C triple bond CH to HOH 2 C, you are turning left, giving you a S.

Determining R/S Nomenclature at a Glance in Three Easy Steps

Note: With this method you never have to

switch

groups to see what the stereochemistry is. Using the "drive-the-car" analogy, what we are doing here is defining the steering wheel in relation to the steering column (which is normally behind the steering wheel):

Determining R / S Nomenclature at a Glance in Three Easy Steps Note: With this method

1. Determine the priorities of the four attached groups from highest (1) to lowest (4).

This is the same as in all methods.

2. Draw the steering

wheel. Draw a curved arrow around from 1 to 2 to 3 and back to 1 and note which direction this arrow goes, clockwise (cw) or counterclockwise (ccw).

Determining R / S Nomenclature at a Glance in Three Easy Steps Note: With this method

The distinct feature of this method is that you make a full circle, from 1 to 2 to 3 to 1, completely ignoring the lowest priority group.

3a. If the lowest priority group is behind the steering wheel, then this is the standard orientation: clockwise isR and counter-clockwise is S. (Turning the steering wheel clockwise turns the car to the right--R.) Note that Fischer projections are best depicted as “bow ties” with horizontal

groups coming out and vertical groups going back from the central carbon atom.

3b. If the lowest priority group is in front of this curved arrow, then the assignment is reversed: clockwise is Sand counterclockwise is R. (Basically, you are looking at the steering wheel from the perspective of the engine compartment!)

Determining R / S Nomenclature at a Glance in Three Easy Steps Note: With this method

Absolute and Relative Configurations

The precise arrangement of substituents at a stereogenic center is known as the absolute configuration of the molecule. This is usually accomplished by solving the x-ray crystal structure of a molecule, a method that is not always readily available, or by inference based on chemical reactions of specific stereochemistry involving a compound whose absolute configuration is known.

The arrangement of atoms in an optically active molecule, based on chemical interconversion from or to a known compound, is a relative

configuration.

Relative, because there is no way of knowing just by

looking at a structure whether the assignment of (+) or (-) is correlated to a particular isomer, R or S.

If the name of a compound includes both the sign of rotation and the designation R or S then the absolute configuration of that compound is known.

Let's see how chemists can determine the relative configurations of optically active compounds by chemically interconverting

them

.

Absolute and Relative Configurations The precise arrangement of substituents at a stereogenic center is known as

The reaction of an alcohol with TsCl is known to occur with retention of configuration, that is the group priority of the stereogenic center has not been altered. The reaction of the tosylate with nitrile occurs with inversion, as a result the group priority at the stereogenic center has been altered. The absolute configuration of the parent is known while only the relative configurations of the tosylate and the nitrile are known. The mechanistic aspects behind this will be discussed in more detail in the next chapter.

Fischer Projections

Fischer Projections are abbreviated structural forms that allow one to convey valuable stereochemical information to a chemist without them having to draw a 3D structural representation of a molecule. These

representations are only used for molecules that contain chirality centers, which are then represented as simple

crosses

.

representations are only used for molecules that contain chirality centers, which are then represented as simple

They can be derived by considering the more accurate 3D representation using wedges and assuming the convention that horizontal lines represent bonds coming out of the plane of the paper and vertical lines represent bonds going behind the plane of the paper.

representations are only used for molecules that contain chirality centers, which are then represented as simple

Memory Aid ? A student once told me that she remembered the relative arrangement of the bonds by the fact that the horizontal bonds were coming out to hug her !

When relating one Fischer projection to another it may only be manipulated within the 2D plane in which it is drawn (that is it may not be rotated within 3D space), and only rotated a total a 180 o

representations are only used for molecules that contain chirality centers, which are then represented as simple

A B

Why can't you rotate it 90 o ? A 90 o rotation is equivalent to breaking bonds and exchanging two groups, which would result in the formation of the other enantiomer.

Why can't you rotate it 90 ? A 90 rotation is equivalent to breaking bonds andCahn-Ingold-Prelog rules . The safest method for assigning the configuration is probably to convert it " id="pdf-obj-10-8" src="pdf-obj-10-8.jpg">

CAUTION Fischer projections are often confused with simpler Lewis diagrams. Lewis diagrams, however, are not intended to give any stereochemical information!

Fischer projections a can be used to describe molecules with more than one chirality center.

Why can't you rotate it 90 ? A 90 rotation is equivalent to breaking bonds andCahn-Ingold-Prelog rules . The safest method for assigning the configuration is probably to convert it " id="pdf-obj-10-14" src="pdf-obj-10-14.jpg">

pt>

If a Fischer projection of this type can be divided into two halves that are mirror images than the molecule may be identified as a meso isomer.

Why can't you rotate it 90 ? A 90 rotation is equivalent to breaking bonds andCahn-Ingold-Prelog rules . The safest method for assigning the configuration is probably to convert it " id="pdf-obj-10-22" src="pdf-obj-10-22.jpg">

Assignment of the configuration at a chirality center, in a Fischer projection, is based on the same Cahn-Ingold-Prelog rules. The safest method for assigning the configuration is probably to convert it

to a wedge-hash diagram (as shown above) Alternatively ....

Identify the chirality centers (most commonly an sp 3 C with 4 different

o

o

o

o

o

o

o

groups attached). If the group of lowest priority is placed on a vertical line, this means

the lowest priority group is already positioned away from you as if you were looking along the C-(4) s bond Now assess the direction of high to low priority (1 to 3)

If this is clockwise, then the center is R (Latin: rectus = right)

If this is counter clockwise, then it is S (Latin: sinister = left)

If the group of lowest priority is placed on a horizontal line, this

means the lowest priority group is actually positioned towards you (so we have to be very careful) Now assess the direction of high to low priority (1 to 3)

If this is clockwise, then the center is R (Latin: rectus = right)

If this is counter clockwise, then it is S (Latin: sinister = left)

BUT NOW SWITCH THE ASSIGNMENT (it's like looking at a glass clock face from opposite sides)

Question : Consider the molecules A and B above. What are their configurations ? ANSWER?

Implications in Reactions

In general terms it is easier to destroy the optical purity of a pure enantiomer than to make an optically pure enantiomer.

In the absence of other chiral molecules, reactions will generate achiral products or racemic mixtures.

To appreciate this, think of your hands or feet. They interact with achiral objects without any difference in comfort between the two, but with a chiral

object, they feel different the wrong feet ?

.....

can't you tell when you have got your shoes on

As examples, carbocations and alkenes which are both planar are attacked from either face in equal amounts generating racemic product mixtures. This is because the faces of the systems are equivalent and there is

nothing

to distinguish them.

In order to create non-racemic products, a chiral influence must be used. This could be in the starting material, a reagent, a catalyst or even during purification.

Research into reactions or methods for performing syntheses of single stereoisomers is very important due to requirement to produce optically pure pharmaceutical products, especially where one enantiomer is more effective than the other (remember your body is full of chiral amino acids,

enzymes and proteins

...

)