What is the absolute configuration of carbon 4 in glucopyranose?

Question

My colleague and I have been wrestling with the assignment of chirality to the 4th carbon atom in glucopyranose. In the linear form of glucose, the 4^th carbon is definitely (R); therefore it will retain that chirality as it forms the hemiacetal. However, looking at the ring, we are having a hard time figuring out why the 3^rd carbon gets priority over the 5^th by CIP priority rules. Both the 3^rd and 5^th carbons are attached to $\ce{C,H,O}$. The question is where do you go after that to assign priority?

Answer 1

therefore it will retain that chirality as it forms the hemiacetal.

This statement is incorrect. Many chiral centres retain their CIP-descriptor upon reactions that don’t influence them directly, many others do not.

How do you assign CIP priorities? You basically had the same problem in the linear form of D-glucose. You move along the chain in order of priorities, finding the first priority difference and using that to assign the higher-priority side. On C4, you have (read this from left to right, i.e. everything with the same indention at the same time):

1. an oxygen (a)

2. the carbon C3

   1. an oxygen (a)

      • a hydrogen.

   2. the carbon C2 (b)

      • an oxygen (a)

      • a carbon C1 (b) <-- this one is higher priority than on the other side!

      • a hydrogen (c)

   3. a hydrogen (c)

3. the carbon C5

   1. an oxygen (a)

      • a hydrogen

   2. the carbon C6 (b)

      • an oxygen (a)

      • a hydrogen <-- less priority than carbon

      • another hydrogen.

   3. a hydrogen (c)

4. a hydrogen (d)

Following the same method in the pyranose form we get:

1. an oxygen (a)

2. the carbon C5

   1. an oxygen (a)

      • a carbon <-- this one is higher priority than the other side!

   2. the carbon C6 (b)

   3. a hydrogen (c)

3. the carbon C3

   1. an oxygen (a)

      • a hydrogen <-- this is lesser than carbon!

   2. the carbon C2 (b)

   3. a hydrogen (c)

4. a hydrogen (d)

Therefore, the absolute configuration of said atom changes from (R) to (S).

This is actually a pretty common thing that can happen in highly functionalised molecules with very similarly modified carbons. Because we cannot distinguish at any proximate position we need to go far down the chain and a single distal modification can change a lot.

Other examples that would have changed the absolute configuration of carbon C4 without changing its geometry would be:

• methylation at C5
• silyl protection at C5
• oxidation at C5

All of these would make C5’s priority higher than C3’s.