5.2 Absolute Configurations: How to Assign R and S

PRE-HEALTH PREP

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

1. Assign priorities to the 4 attached atoms by atomic number.
(The higher the atomic number the higher the priority)
2. For identical atoms list the additional atoms they are bonded to in descending order of atomic number.
(Use the first difference to break the tie; once again the higher the atomic number the higher the priority.)
3. Continue down the chain of atoms until a difference is found.
(If no difference is found then these groups are identical and this is not a chiral center.)
4. For double and triple bonds count each pi bond as a bond to the previous atom in the chain.
5. Make a circle from 1st to 2nd to 3rd priority with the #4 priority facing away from you (a dashed bond).
A right-handed turn (clockwise) indicates R.
A left-handed turn (counter-clockwise) indicates S.

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

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.

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.

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.

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.

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.

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, SHH or OOH.  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:

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.