Pyranoses and Furanoses: Ring-Chain Tautomerism In Sugars

by James

in Carbohydrates

The Many Forms Of Glucose

What’s the structure of glucose?

A simple question! but one with many “right” answers.

The first question to ask, which we covered in our recent post on D- and L- sugars, is: “Which enantiomer are you talking about?”.  If, by “glucose”, you mean the enantiomer we commonly encounter as table sugar, then you’re referring to D-glucose. In its open chain form, when drawn as a Fischer projection, D-glucose looks like this:

The fact that I had to specify “open-chain form” might tip you off that something is amiss. That’s because glucose, like a snake that bites its own tail, or a belt – can adopt a cyclic form as well. And not just one cyclic form, but several!

Before diving into these, it’s worth a quick refresher on the two main functional groups in glucose (and other sugars) which make this possible: hydroxyl groups and aldehydes (or ketones, in the case of keto-sugars like fructose). 

Hydrates, Hemiacetals, and Cyclic Hemiacetals

You may recall that aldehydes (and ketones, but we’ll focus on aldehydes here) can reversibly react with water to form “hydrates“. Hydrates form readily in solution, but they tend not to be easy to isolate; the equilibrium tends to favor the starting aldehyde. [Note 1].

[Refresher on mechanism – click here to bring up a picture of the mechanism at work]

Similarly, aldehydes can react with alcohols to form hemiacetals. Like hydrate formation, hemiacetal formation is an equilibrium and the equilibrium tends to favor the starting aldehyde. [If you heat with acid, excess alcohol and sequester the water that forms, it forms an acetal ; this is not in equilibrium with the hemiacetal,  which is why acetals are a great protecting group for aldehydes/ketones]. 

Mechanism, if you need a refresher [link to image]

Here’s the twist – and the relevance to glucose. If the alcohol and the aldehyde are part of the same molecule, then it’s possible for the hemiacetal formation to be intramolecular, forming a cyclic hemiacetal in the process. The mechanism is exactly the same as in the previous case.  Note the difference is that I’ve just drawn ONE extra bond (in blue)

In the case above (5-hydroxy pentanal), we form a six-membered ring.

Here’s how it works, step by step:

So, you might ask: what’s the “correct” structure of this molecule – the “linear” or the “cyclic” form?

The answer is that since these two forms are in equilibrium,  they are both “correct” structures of this molecule, even though they are structural isomers of each other. 

You might recall seeing a similar type of situation with certain ketones and aldehydes, where a ketone is in equilibrium between a “keto-” form and an “enol” form which are themselves structural isomers of each other. We called that keto-enol tautomerism.  (click here to see an example)

The equilibrium between the linear and cyclic form of 5-hydroxy pentanal (above) is a different type of tautomerism we call ring-chain tautomerism. 

Ring-Chain Tautomerism In Glucose: The “Pyranose” Form

This is exactly what happens in glucose. The alcohol on C-5 of glucose can react with the aldehyde (C-1) to form a six-membered ring (I skipped drawing in the proton transfer in the drawing below). 

The linear and cyclic forms are structural isomers that exist in equilibrium with each other, so this is another example of ring-chain tautomerism.

The 6-membered cyclic form of sugars is usually called the “pyranose” form in reference to the cyclic ether pyran.

If you’re eagle-eyed, you might have noticed that in the process of forming a new C-O bond, a new chiral centre is formed at C-1. This new chiral centre can have one of two configurations, (S) or (R). Since there are other chiral centers on glucose and their R/S configurations don’t change, that means we’ll end up with a pair of diastereomers: stereoisomers that are not enantiomers. Rather than using the (R) and (S) descriptors, the convention with sugars is to name them according to the orientation of the OH groups on C-1 relative to the C-5 group. These two isomers are referred to as the alpha (α) and beta (β) isomers [footnote 2 for more detail on this]

  • In the alpha (α)  isomer, the OH group on C-1 is on the opposite face of the ring from the CH2OH substituent on C-5. This can be seen from drawing the molecule as a chair, but it is often helpful to draw a hexagonal version of a sugar in perspective (called a “Haworth projection“) that makes the stereochemical relationships more clear.
  • In the beta (β) isomer, the OH group on C-1 is on the same face of the ring relative to the CH2OH substituent on C-5.

At the risk of inciting a pitchfork-wielding mob angry at the introduction of even more terminology,  these two isomers are often referred to as “anomers“, but that is a topic for another day. 

Ring-Chain Tautomerism In Glucose, II – The Furanose Form

But wait! that’s not all, folks!

The pyranose form of glucose is just one of the cyclic forms that glucose can adopt.

It’s also possible for the hydroxyl group on C-4 of glucose to attack the aldehyde. This forms a five-membered ring. We call this form the furanose form, in reference to the cyclic 5-membered ether furan. (Helpful mnemonic: Five = Furanose)

As with the pyranose, forming the 5-membered ring also generates a pair of diastereomers which differ in configuration at C-1.  We likewise call these the alpha and beta forms, as above:

So what’s the structure of glucose? Not so straightforward, is it?

Glucose Has Several Structures, All In Equilibrium With Each Other

We’ve seen five separate isomers so far: the straight chain form, the pyranose form (alpha and beta), and the furanose form (alpha and beta).

In aqueous solution, these five forms are all in equilibrium with each other!

When you dissolve glucose in water, here’s the distribution you get:

The pyranose forms dominate, with a small amount of the open-chain and furanose forms comprising the rest of the mixture.

What about 3 and 4 (or 7) membered rings, you might ask? [ Footnote 3. tl;dr they are insignificant]

Conclusion

Although we’ve mainly discussed glucose in this post because it is the most familiar sugar, ring-chain tautomerism is an important property of all 5- and 6- carbon sugars.

Another familiar example is ribose, which comprises the sugar backbone of RNA:

Fructose is another one.

For Next Time: A Puzzle

Understanding this property of sugars will help us untangle a mystery which baffled early carbohydrate chemists.

  • Pure α-D-glucose has a specific rotation of + 112°.
  • Pure β-D-glucose has a specific rotation of + 19°.
  • Yet when either of these two is dissolved in water, the optical rotation slowly changes to a value of + 52.5° .

Can you guess why?

We’ll talk about that in the next post in this series, on mutarotation (literally, “change in rotation”).

Many thanks to Tom Struble for assistance with this post. 


Notes

  1. Aldehydes with adjacent electron-withdrawing groups tend to form more stable hydrates since the aldehyde carbon is much more electrophilic. Trichloroacetaldehyde (chloral hydrate) often known as “knockout drops”, is a prominent example.
  2. The α / β terminology pre-dates the R/S (Cahn-Ingold Prelog) terminology by several decades. The C-1 carbon is called the “anomeric” carbon and the α and β diastereoisomers are referred to as “anomers”. α and β are defined according to the relationship between the anomeric carbon and the anomeric reference carbon, which is the stereocenter farthest from the anomeric carbon in the ring. In D-glucose in the pyranose form the anomeric carbon is C-1 and the reference carbon is C-5.  Here’s how IUPAC defines it.
  3. They’re not significant. Three and four-membered rings are relatively unstable due to their considerable ring strain, while the rate of seven-membered ring formation is extremely slow, relative to the 5- and 6- membered ring cases. ]

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{ 2 comments… read them below or add one }

Robin

This is a great background/refresher on sugar chemistry, as I do biomass chemistry, so thank you! However, isn’t sucrose table sugar (see intro paragraph)? Glucose is not particularly sweet.

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James

Shoot. Thanks for the reminder, that was a dumb mistake.

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