Assigning the configuration (R or S) of a chiral center

Reading Time: 8 minutes

🖐️ Before we begin,

 

Let’s review what a chiral center is. A chiral center (also called a stereocenter, stereogenic center, or asymmetric center) is an sp³ hybridized carbon atom with four different atoms or groups bonded to it.

 

 

Fun Fact! Chiral centers are hugely important in organic chemistry because the arrangement of atoms around them can dramatically influence a molecule’s physical, chemical, and biological properties.

 

• For example, (R)-limonene smells like oranges, while (S)-limonene smells like lemons.
• On a more serious note, (R)-thalidomide was used to treat morning sickness in pregnant women, while its enantiomer, (S)-thalidomide, caused severe birth defects in the 1950s.

 

This historical example highlights the importance of distinguishing stereoisomers in drug development.

 

So, how do scientists identify and assign R or S configurations? That’s exactly what we’ll learn in this guide!

 

 

Challenge 1: The fourth priority is on a dash

 

Question:

Assign the configuration (R or S) of the chiral center in this compound

 

 

Let’s walk through the steps together and solve this step by step!

 

Step 1: Identify the four atoms attached to the chiral center

 

First, locate the chiral center.

 

 

Remember: Hydrogen atoms are often omitted in skeletal structures unless bonded to a heteroatom (like N, O, or S). In this case, the chiral center has one hidden hydrogen atom. Since the chlorine atom is on a wedge, the hydrogen atom must be on a dash.

 

 

 

Quick Check! Can you identify all four groups? Write them down before moving on.

 

The groups attached to the chiral center are:

H, C, C, and Cl.

 

Step 2: Assign priorities based on atomic number

 

The group with the highest atomic number gets the highest priority (1), and the group with the lowest atomic number gets the lowest priority (4).

 

Question: Which group has the highest atomic number? Which has the lowest?

 

From highest to lowest atomic number:

Cl (1) > C (?) > C (?) > H (4)

 

 

Step 3: Resolve ties, if any

 

In this challenge, we have two groups attached to the chiral center that are both carbons. So, how do we determine which carbon gets (2) and which gets (3)?

 

Here’s how:

 

Make a list: For each carbon, write down the three atoms it’s bonded to (other than the chiral center itself).

• Left Carbon (C): H, H, C
• Right Carbon (C): H, H, Cl

 

 

 

Compare the lists: Look for the first point of difference between the two lists. The point of difference is C vs. Cl, and chlorine wins because it has a higher atomic number than carbon.

 

Assign priorities:

• Right Carbon (Cl attached) gets 2nd priority.
• Left Carbon (no Cl) gets 3rd priority.

 

 

Pro Tip 💡

 

If there’s still no difference, keep going further down the chain until you find a point of distinction. If a double or triple bond is involved, treat it as if the atom is bonded to multiple identical atoms.

 

Therefore,

Cl (1) > C, with Cl (2) > C, no Cl (3) > H (4)

 

Quick Recap: When two atoms have the same atomic number, compare their bonded atoms, one by one, until a difference is found.

Step 4: Is the fourth priority on a dash?

 

 

Yes! The fourth priority (H) is already on a dash, pointing away from you. This means we can directly determine the configuration by observing the 1-2-3 sequence.

 

 

Step 5: Determine the direction of the 1-2-3 sequence

 

Trace the path from 1 → 2 → 3:

 

• If the path is clockwise, the configuration is R (rectus, right).
• If the path is counterclockwise, the configuration is S (sinister, left).

Test Yourself! What direction is the 1-2-3 sequence?

 

 

The 1-2-3 sequence is counterclockwise, so the configuration is S.

 

 

Challenge 2: The fourth priority is on a wedge!

 

Question:

Assign the configuration (R or S) of the chiral center in this compound

 

 

Let’s walk through the steps together!

 

Step 1: Identify the four atoms attached to the chiral center

 

• First, locate the chiral center in the molecule.
• Identify the four groups attached to it.

 

 

Quick Check! Can you spot the four groups? Jot them down before moving on.

 

 

The atoms bonded to the chiral center are:

H, N, C, and O.

 

Step 2: Assign priorities based on atomic number

 

The atom with the highest atomic number gets the highest priority (1), and the atom with the lowest atomic number gets the lowest priority (4).

 

Question: Which atom/group has the highest atomic number? Which has the lowest?

 

From highest to lowest atomic number, the order is:

O (1) > N (2) > C (3) > H (4).

 

Therefore,

 

 

Step 3: Resolve ties, if any

 

If any two atoms have the same atomic number, compare the next atoms along each chain until you find a difference.

 

Heads up! For this challenge, each atom attached to the chiral center is different, so no ties to resolve.

 

Step 4: Is the fourth priority on a dash?

 

 

In this challenge, the fourth priority (H) is not on a dash. It’s on a wedge. Which means it’s pointing out of the page, toward us. This changes how we assign the configuration!

 

You have two options here:

 

The hard way: Rotate the molecule in your head (or with a model) so that the fourth priority is pointing away (on a dash). If you don’t have a model kit, this can be tricky!

 

 

After rotating, the 1-2-3 sequence appears clockwise (R).

 

 

The easy way (using a trick): Determine the configuration (R or S) based on the 1-2-3 sequence as it appears without rotating. Then, invert the configuration to account for the fourth priority being on a wedge. This saves time and effort, especially in exams!

 

 

Step 5: Determine the direction of the 1-2-3 sequence

 

Using both the hard and easy method, the 1-2-3 sequence in the previous step and the configuration of the chiral center is R!

 

 

Challenge 3: The fourth priority is not on a wedge or a dash? 😱

 

Question:

Assign the configuration (R or S) of the chiral center in this compound

 

 

Step 1: Identify the four atoms attached to the chiral center

 

• First, locate the chiral center in the molecule.
• Identify the four groups attached to it.

 

 

Quick Check! Can you spot the four groups? Jot them down before moving on.

 

 

The atoms bonded to the chiral center are:

Br, C, C, and C.

 

Step 2: Assign priorities based on atomic number

 

The group with the highest atomic number gets the highest priority, and the group with the lowest atomic number gets the lowest priority.

 

Question: Which atom/group has the highest atomic number? Which has the lowest?

 

• Br has the highest atomic number, so it’s (1st priority).
• The remaining three groups are carbons, so we’ll need to resolve ties in the next step.

 

Step 3: Resolve ties, if any

 

For each carbon atom, write down the three atoms it’s bonded to (excluding the chiral center itself). Let’s compare:

 

 

Question: Which carbon atom gets the highest priority? Which gets the lowest?

We can assign priorities as follows:

 

 

Step 4: Is the fourth priority on a dash?

 

Nope! The fourth priority is in the plane of the page (on a line).

Just like in the previous challenge, we can either rotate the molecule in our head or using a model so that the fourth priority is on a dash (the hard way) or we can use a trick to save time.

 

Here’s how we’ll do it the easy way:

 

• Take the 4th priority group (currently in the plane of the page) and swap it with the group that is already on a dash.

 

 

• Now, with the fourth priority on a dash, assign the R or S configuration as usual by following the 1-2-3 sequence.

 

 

• Flip the result:
• • • If the configuration you determine is R, the true configuration is S.
    • If the configuration you determine is S, the true configuration is R.

 

In this case:

• After swapping, the configuration of the chiral center is R.
• Flip it: The true configuration is S.

 

 

Why does this work? 🤔

 

Swapping any two groups in a molecule inverts the stereochemistry. This means:

• An R configuration becomes S, and
• An S configuration becomes R.

 

By flipping your answer after determining the configuration in the swapped arrangement, you’re effectively correcting for the inversion caused by the swap. This ensures you get the correct configuration every time!

 

Step 5: Determine the direction of the 1-2-3 sequence

 

In the swapped arrangement, the 1-2-3 sequence is clockwise, which is R. After flipping, the true configuration of the chiral center is S!