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Pyranoses , Furanoses, Straight-Chain Glucose, And Ring-Chain Tautomerism

• Sugars such as glucose exist in equilibrium between their open-chain form and various cyclic forms where an OH group and an aldehyde combine to form a cyclic hemiacetal.
• In the case of glucose, a 5- or 6- membered ring can form, depending on which hydroxyl group adds to the aldehyde. Equilibrium tends to favor the six-membered cyclic form, called “pyranose” since it resembles pyran, although some of the five-membered cyclic form (“furanose“) is also present along with the open-chain form.
• In the process of forming the hemiacetal a new chiral center is created. This gives rise to two diastereomers which for historical reasons are called anomers and designated “alpha” or “beta” depending on the orientation of the -OH group.

Table of Contents

1. Glucose Comes In Many Forms
2. Hydrates, Hemiacetals, and Cyclic Hemiacetals
3. Ring-chain Tautomerism In Glucose: The “Pyranose” Form
4. Ring-Chain Tautomerism In Glocose, II: The “Furanose” Form
5. Glucose Has Several Structures, All In Equlibrium With Each Other?
6. Conclusion: Pyranose vs Furanose vs Open-Chain Forms of Glucose
7. Notes

1. Glucose Comes In Many Forms

What’s the structure of glucose?

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

The first question to ask, which we covered in our recent post on D- and L-听sugars, is: “Which enantiomer are you talking about?”. 听If, by “glucose”, you mean the enantiomer we commonly encounter as blood 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听“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听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 ).听

2. Hydrates, Hemiacetals, and Cyclic Hemiacetals

You may recall听that aldehydes (and ketones, but we’ll focus on aldehydes here) can reversibly react with water to form “hydrates“. (relevant article: Acetals, Hemiacetals, Hydrates). 听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 – hover here听 听 to bring up a picture of the mechanism or .

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

If you need a refresher on the mechanism,听 hover here听 or click this .

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听to be听intramolecular,听forming a听cyclic hemiacetal听in the process. The mechanism is exactly the same as in the previous case.听听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听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听these two forms are in equilibrium, 听they are both “correct” structures of this molecule, even though they are structural isomers of each other.听

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. hover here to see an example or click on this

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

3. 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听a six-membered ring听(I skipped drawing in the proton transfer in the drawing below).听

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 .

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听configurations don’t change, that means we’ll end up with a pair of听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 (伪) and beta (尾) isomers [Note 2] for more detail听on this]

• In the alpha (伪)听 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 (尾)听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听a pitchfork-wielding mob angry at the introduction of even more terminology, 听these two isomers are often referred to as ““, but that is听a topic for another day.听

4. 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听furanose form, in reference to the cyclic 5-membered ether听furan.听(Helpful mnemonic:听Five =听Furanose)

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

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

5. 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? [ Note 3. tl;dr they are insignificant]

6. Conclusion: Pyranose vs Furanose vs Open-Chain Forms Of Glucose

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

Can you guess why?

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

Many thanks to Tom Struble for assistance with this post.听

Notes

Note 1. Aldehydes with adjacent electron-withdrawing groups tend to form more stable hydrates since the aldehyde carbon is much more electrophilic. Trichloroacetaldehyde () often known as “knockout drops”, is a prominent example.

Note 2. The 伪 / 尾 terminology pre-dates the听R/S (Cahn-Ingold Prelog) terminology by several decades.听The C-1 carbon is called the “anomeric” carbon and the听伪 and 尾 diastereoisomers are referred to as “anomers”.听伪 and 尾 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.听 .

Note 3. They’re not significant. Three and four-membered rings are relatively unstable due to their听considerable ring strain, while the rate of seven-membered ring formation is extremely slow, relative to the 5- and 6- membered ring cases. ]

Note 4. From “Ring-Chain Tautomerism of Hydroxy Aldehydes”, Hurd C. D.; Saunders, W. H.听J. Am. Chem. Soc.听1952听74, 5324.
DOI:

SUPER COOL. Reddit user made this amazing stopmotion video of ring-chain tautomerism in glucose
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