What is Mutarotation?

All About Mutarotation

• The OH group on C-1 of sugars can have two possible configurations. This gives rise to two stereoisomers (called “anomers”) :  the “α-” anomer and the “β-” anomer.
• If you take pure “α” or pure “β” and measure their optical rotation in water, an interesting thing happens. The optical rotation slowly changes over time!
• The term “mutarotation” (literally “change in rotation”) refers to the observed change in the optical rotation of the α- and β- anomers of glucose upon dissolution in solvent. Due to ring-chain tautomerism, the α- and β- forms slowly interconvert until equilibrium is established.

Table of Contents

1. Mutarotation Is The Change In Optical Rotation Observed When Pure α- Or β- Anomers Are Dissolved In Water (or other solvents)
2. Mutarotation Is Possible When α- Or β- Anomers Can Interconvert
3. Mutarotation Is A Consequence Of Ring-Chain Tautomerism
4. Mutarotation Is A General Property Of Cyclic Sugars Bearing A Hemiacetal
5. Notes
6. (Advanced) References and Further Reading

1. Mutarotation Is The Change In Optical Rotation Observed When Pure α- or β- Anomers Are Dissolved In Water (or other solvents)

In the previous article on ring-chain tautomerism, we saw that there are two isomers of D-glucose in its 6-membered ring (“pyranose”) form.

These two diastereomers – which, to make matters more confusing, are called “anomers” in the context of sugar chemistry –  differ in the orientation of the hydroxyl group on C-1. (Note that C-1 is a hemiacetal. )

• In the “alpha” (α) anomer, the OH group on C-1 is on the opposite side of the ring as the chain on C-5.
• In the “beta” (β) anomer, the OH group on C-1 is on the same side of the ring as the C-5 substituent.

Each of these two forms can be synthesized and isolated as pure compounds.

• The alpha (α)  anomer of D-glucose has a specific rotation of +112 degrees in water.
• The beta (β)  anomer of D-glucose has a specific rotation of +19 degrees. (18.7 actually, but rounding up to 19).

Here’s the interesting thing. When either anomer is dissolved in water, the value of the specific rotation changes over time, eventually reaching the same value of +52.5°. 

• The specific rotation of α-D-glucopyranose decreases from +112° to +52.5°.
• The specific rotation of β-D-glucopyranose increases from +19° to +52.5°.

This behaviour is called mutarotation (literally, “change in rotation”).

2. Mutarotation Is Possible  When α- and β- Anomers Can Interconvert

Hold on.  Isn’t specific rotation of a molecule supposed to remain the same?

Yes – if it is indeed the same molecule! 

And therein lies the answer to the puzzle. For when the solutions whose specific rotations have changed to +52.5° are analyzed, they are found to no longer consist of 100% alpha (α) or 100% beta (β) anomers, but instead a ratio of alpha (α) (36%) and beta (β) (64% ) isomers.

Wait. What happened here? How did the alpha convert to the beta, and vice-versa?

3. Mutarotation Is A Consequence Of Ring-Chain Tautomerism

You may recall how we said in the last post on ring-chain tautomerism that the cyclic hemiacetal forms of sugars are in equilibrium with the straight-chain (“linear”) form.

That means that even if you start with a 100% pure sample of either the alpha or beta anomer, once it has been dissolved in water it can equilibrate, via the straight-chain form, to the other anomer.
If A is in equilibrium with B, and B is in equilibrium with C, then A is in equilibrium with C. That’s the Zeroth Law of Thermodynamics [Note 1].

The 36:64 ratio of alpha (α) to beta (β) represents the distribution of isomers when D-glucose is in equilibrium in water at 25° C.

Is mutarotation unique to glucose?

4. Mutarotation Is A General Property Of Cyclic Sugars Bearing A Hemiacetal 

No – it’s a general property of sugars, as well as (chiral) cyclic hemiacetals in general.

This phenomenon was first discovered in 1846 by French chemist Augustin-Pierre Dubrunfaut, who founded a factory for the production of alcohol from beet sugar. While studying the optical rotation of glucose, he noted that freshly dissolved glucose had a rotational value twice that which was previously observed in the literature. He also studied the mutarotation of lactose. (Interestingly, although Dubrunfaut was also the discoverer of fructose, he published no studies on its mutarotation – perhaps because fructose is one of the most rapidly mutarotating sugars) [Ref]

Interestingly, the structures of glucose and fructose had not been established at this point. It was not until 1895 that Tanret first reported on the two anomers of glucose, which readily explained Dubrunfaut’s observations.

Bonus question: given that the mechanism for the forward reaction was given in the previous post, can you draw a mechanism for the interconversion of alpha-D-glucose to beta-D-glucose? [A not uncommon exam question, by the way! [Note 2]

In the next post, we’ll discuss a tangent to ring-chain tautomerism: reducing sugars. 

Next Post: Reducing Sugars

Thanks for reading!

Notes

Note 1. The Zeroth Law Of Thermodynamics: If A is in equilibrium with B, and B is in equilibrium with C, then A is in equilibrium with C.

Note 2.  Try and work out a mechanism for the conversion of alpha-glucopyranose to beta-glucopyranose on your own. I’ll put a link to one solution in the comments. Hover here for a pop-up image. or click on this link.

(Advanced) References and Further Reading

This is a very classical part of organic chemistry. The change in optical activity of glucose solutions was first noted by Dubrunfant in 1846, and it was only in 1890 that the legendary chemist Prof. Emil Fischer proposed that this was due to a chemical cause. In 1896, Tanret isolated what he thought were three forms of glucose: the α form, with [α]_D +105°, the β form, with [α]_D +52.5°, and the γ form, with [α]_D +22°. Now we know that the α and γ forms are distinct species (what we now know as the the α and β forms of D-glucose), and that Tanret’s β form is the equilibrium mixture of the two forms.

1. —Studies of dynamic isomerism. I. The mutarotation of glucose
   T. Martin Lowry, D.Sc.
   J. Chem. Soc. Trans. 1903, 83, 1314-1323
   DOI: 10.1039/CT9038301314
   This paper is credited with introducing the term ‘mutarotation’ in the literature to describe the interconversion of the anomeric forms of glucose.
2. A REVIEW OF DISCOVERIES ON THE MUTAROTATION OF THE SUGARS.2
   C. S. Hudson
   Journal of the American Chemical Society 1910, 32 (7), 889-894
   DOI: 10.1021/ja01925a009
   An old review that covers early work on understanding the mutarotation of glucose, and gives a full coverage of the development of the story up to that time.
3. STUDIES ON THE FORMS OF d-GLUCOSE AND THEIR MUTAROTATION.
   C. S. Hudson and J. K. Dale
   Journal of the American Chemical Society 1917 39 (2), 320-328
   DOI: 10.1021/ja02247a017
   This early paper contains experimental procedures for the isolation of pure a- and b-glucose.
4. Crystallization of β-d-Glucose and Analysis with a Simple Glucose Biosensor
   José I. Reyes-de-Corcuera, Michael A. Teruel, and Daniel M. Jenkins
   Journal of Chemical Education 2009, 86 (8), 959
   DOI: 10.1021/ed086p959
   This paper describes an experiment that can be carried out by undergraduates for observing the mutarotation of glucose.
5. Optically Active Esters of B-Ketonic and B-Aldehydic Acids. Part II. Menthyl Acetoacetate
   Arthur Lapworth and A. C. Osborn Hann.
   J. Chem. Soc. , Trans. 1903, 83, 1114-1129
   DOI: 10.1039/CT9038301114
   An example of mutarotation in a non-sugar system, and one of the earliest examples containing a definitive proof of the role of acid in accelerating keto-enol tautomerism. The authors prepared the menthyl  (not methyl) ester of acetoacetic acid [(+)-menthol is an optically active alcohol readily available from natural sources] and measured its optical activity. They found that the menthyl ester underwent mutarotation to an extent that was dependent on the solvent, with the rate of mutarotation being highly dependent on acid. This demonstrates the establishment of an equilibrium between the keto and enol forms.

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