8.6: Cyclic Structures of Monosaccharides - Anomers

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Sol Parajon Puenzo
Cañada College

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Objectives

After completing this section, you should be able to

determine whether a given monosaccharide will exist as a pyranose or furanose.
draw the cyclic pyranose form of a monosaccharide, given its Fischer projection.
draw the Fischer projection of a monosaccharide, given its cyclic pyranose form.
draw, from memory, the cyclic pyranose form of D-glucose.
determine whether a given cyclic pyranose form represents the D or L form of the monosaccharide concerned.
describe the phenomenon known as mutarotation.
explain, through the use of chemical equations, exactly what happens at the molecular level during the mutarotation process.

Key Terms

Make certain that you can define, and use in context, the key terms below.

anomer, anomeric centre, alpha anomer, beta anomer, furanose, mutarotation, pyranose

Study Notes

If necessary, before you attempt to study this section, review the formation of hemiacetals discussed in Section 5.10.

Cyclic Monosaccharides

In Section 5-10 it was discussed that the reaction of one equivalent of an alcohol, in the presence of an acid catalyst, adds reversibly to aldehydes and ketones to form a hydroxy ether called a hemiacetal (R₂COHOR') (hemi, Greek, half).

The reversible reaction of an aldehyde with an alcohol in the presence of an acid catalyst to form a hemiacetal via nucleophilic substitution.

Molecules which have both an alcohol and a carbonyl can undergo an intramolecular version of the same reaction forming a cyclic hemiacetal.

Because sugars often contain alcohol and carbonyl functional groups, intramolecular hemiacetal formation is common in carbohydrate chemistry. Five and six-membered rings are favored over other ring sizes because of their low angle and eclipsing strain. Cyclic structures of this kind are termed furanose (five-membered) or pyranose (six-membered), reflecting the ring size relationship to the common heterocyclic compounds furan and pyran shown below.

25.5 furan and pyran.svg — Figure $\PageIndex{1}$: Furan (5-membered ring) and pyran (6-membered ring) structures

Unlike most of the biochemical reactions you will see in this text, sugar cyclization reactions are not catalyzed by enzymes: they occur spontaneously and reversibly in aqueous solution. Sugars are often shown in their open-chain form, however, in aqueous solution, glucose, fructose, and other sugars of five or six carbons rapidly interconvert between straight-chain and cyclic forms. For most five- and six-carbon sugars, the cyclic forms predominate in equilibrium since they are more stable. The size of the cyclic hemiacetal ring adopted by a given sugar is not constant, but may vary with substituents and other structural features.

Aldohexoses usually form pyranose rings, and their pentose homologs tend to prefer the furanose form, but there are many counterexamples.

Pyranose Rings

At equilibrium in aqueous solution, less than 1% of glucose is in an open chain form, with the rest being almost exclusively in its cyclic pyranose form. The 6-member cyclic form of glucose is called glucopyranose.

The best way to understand the the final position of the substituents after the nucleophilic attack, is to change the representations of the conventional Fischer projection, to a wedge/dash version of the Fischer projection, and finally, place the main chain horizontally keeping in mind that on each chiral center, the main chain moves back.

Three representations of glucose. First two structures are the Fischer projection where the carbonyl group is positioned on the top and the third structure represents the Haworth projection of glucose.

Pyranose rings are often drawn in a chair conformation, similar to cyclohexane rings (Organic Chemistry I: Section 4-6), with substituents positioned either in an axial or equatorial position. The pyranose ring is formed by attack of the hydroxyl on carbon 5 of glucose on the aldehyde carbon (also called the anomeric carbon in carbohydrate terminology). The anomeric carbon is a new chirality center (former carbonyl carbon), and two possible diastereomers, called anomers, are produced. The two isomeric forms are referred to by the Greek letters alpha (α) and beta (β). Pyranose rings undergo ring flipping to change between chair conformations.

Figure $\PageIndex{2}$: Glucose in its cyclic pyranose forms. As explained in the text, two anomers are formed by cyclization of glucose. The molecule whose newly formed –OH group at C1 is cis to the oxygen atom on the lowest chirality center (C5) in a Fischer projection is the α anomer. The molecule whose newly formed –OH group is trans to the oxygen atom on the lowest chirality center in a Fischer projection is the β anomer .

By convention, in the drawing of a pyranose, the ring oxygen is placed to the right and the rear of the structure, with the bonds down (top right of the drawing). This is because β-D-glucose (the most abundant sugar) has all the substituents in the equatorial position, indicating the lowest energy structure.

Mutarotation

It is possible to obtain a sample of crystalline glucose in which all the molecules have the α structure or all have the β structure. The α form melts at 146°C and has a specific rotation of +112°, while the β form melts at 150°C and has a specific rotation of +18.7°. When the sample is dissolved in water, however, a mixture is soon produced containing both anomers as well as the straight-chain form, in dynamic equilibrium. The opening and closing repeats continuously in an ongoing interconversion between anomeric forms and is referred to as mutarotation (Latin mutare, meaning “to change”).

Mutarotation is the change in specific rotation of a chiral compound due to epimerization.

At equilibrium, the mixture consists of about 36% α-D-glucose, 64% β-D-glucose, and less than 0.02% of the open-chain aldehyde form. The observed rotation of this solution is +52.7°. The beta anomer is preferred because β-D-glucopyranose is the only aldohexose which can be drawn with all its bulky substituents (-OH and -CH₂OH) in equatorial positions, making it the most stable of the eight D-aldohexoses, which probably accounts for its widespread prevalence in nature.

Haworth projection of reversible ring-opening of alpha-D-glucopyranose to beta-D-glucopyranose. The hydroxyl group at C 1 is axial in alpha and equatorial in beta form.

The most abundant form of fructose in aqueous solution is also a six-membered ring. Fructose in aqueous solution forms a six-membered cyclic hemiketal called fructopyranose when the hydroxyl oxygen on carbon #6 attacks the ketone carbon (carbon #2, the anomeric carbon in fructose).

In this case, the β anomer is heavily favored in equilibrium by a ratio of 70:1, because it is the lower energy chair conformation, which has three of the five substituents (including the bulky CH₂OH group) in the equatorial position. In the minor α anomer, the bulkier -CH₂OH group and one more -OH occupy an axial position.
Notice in the above figure that the percentages of α and β anomers present at equilibrium do not add up to 100%. Fructose also exists in solution as a five-membered cyclic hemiketal, referred to in carbohydrate nomenclature as fructofuranose. In the formation of fructofuranose from open-chain fructose, the hydroxyl group on the fifth carbon attacks the ketone.

Furanose Rings

Fructose also exists in solution as a five-membered cyclic hemiketal, referred to in carbohydrate nomenclature as fructofuranose. In forming fructofuranose from open-chain fructose, the hydroxyl group on the fifth carbon attacks the ketone.

In aqueous solution, then, fructose exists as an equilibrium mixture of 70% β-fructopyranose, 23% β-fructofuranose, and smaller percentages of the open chain and cyclic α-anomers (Figure $\PageIndex{3}$). The β-pyranose form of fructose is one of the sweetest compounds known, and is the main component of high-fructose corn syrup. The β-furanose form is much less sweet.

The Fischer and Haworth projection of beta-D-fructopyranose and beta-D-fructofuranose. Formation of pyranose and furanose anomers form through the hydroxyl group addition to C 2 carbonyl. — Figure $\PageIndex{3}$: Pyranose and furanose forms of fructose in aqueous solution. The two pyranose anomers result from addition of the C6 –OH group to the C2 carbonyl; the two furanose anomers result from addition of the C5 –OH group to the C2 carbonyl.

Although we have been looking at specific examples for glucose and fructose, other five- and six-carbon monosaccharides also exist in solution as equilibrium mixtures of open chains and cyclic hemiacetals and hemiketals. Shorter monosaccharides (four-carbon monosaccharides or smaller) are unlikely to undergo analogous ring-forming reactions due to the inherent instability of three- and four-membered rings.

The naturally occurring form of D-Ribose (C₅H₁₀O₅) is a component of the ribonucleotides from which RNA is built, and so this compound is necessary for coding, decoding, regulating, and expressing genes.

At room temperature in solution, about 79% of d-ribose is present in pyranose forms β-d-ribopyranose (59%), α-d-ribopyranose (20%) and 20% in the furanose forms β-d-ribofuranose (13%), α-d-ribofuranose (7%) with only about 0.1% of the linear form present.^[1]

Figure $\PageIndex{4}$: β-d-ribofuranose is the configuration present in ribonucleotides.

Drawing Cyclic Structures of Monosaccharides

The cyclic forms of sugars are commonly depicted as Haworth projections. This convention, first suggested by the English chemist Walter N. Haworth, shows molecules drawn as planar rings with darkened edges representing the side facing toward the viewer. The structure is simplified to show only the functional groups attached to the carbon atoms. Any group written to the right in a Fischer projection appears below (bottom face) the plane of the ring in a Haworth projection, and any group written to the left in a Fischer projection appears above (top face) the plane in a Haworth projection.

Glucopyranose Fisher to Haworth — Figure: Conversion of the Fischer projection of D-glucose to the Haworth projection of ß-D-glucose

When converting a Fischer projection (line) to a Haworth projection, you must first identify the type of monosaccharide involved. If the carbohydrate represents an aldohexose, the pyranose ring is typically used. A pyranose is a cyclic structure that contains five carbon atoms and an oxygen. If the carbohydrate represents aldopentose, the furanose ring is typically used. The furanose ring contains four carbon atoms and an oxygen.

Indicate the arrangement of the hydroxyl group attached to the anomeric carbon to identify the sugar as an alpha or beta anomer. The α and β anomers are determined with respect to carbon 6. If the molecule represents a D-sugar, carbon 6 will be above the plane of the ring (top face) and form an L-sugar, carbon 6 will be below the plane of the ring (ring). The α anomer occurs when the OH on the anomeric carbon is trans to carbon 6 and the β anomer occurs when the OH on the anomeric carbon is cis to carbon 6. If the cyclic structure contains a furanose, since carbon 1 is not included within the ring, that carbon group would be arranged in the opposite direction of the OH group.

The remaining chiral centers (carbons 2, 3, and 4 of the pyranose or carbons 3 and 4 of the furanose) are arranged based on the directions of the hydroxyl from the Fischer projection structures. Groups to the left of the Fischer projection would point up (top face), while groups to the right would point down (bottom face).

Since the Fischer Projection of any given carbohydrate is always the same, the Haworth Projection is essentially always the same. The only difference between the Haworth Projection of the alpha or beta form of a single carbohydrate is how the OH (and carbon-1 if furanose ring) is arranged around the anomeric carbon to determine whether the molecule is alpha or beta.

Exercise $\PageIndex{1}$

D-Glucose is the most abundant aldohexose, and that abundance in nature means stability. Draw α-D-glucopyranose and β-D-glucopyranose, without looking for the structure of glucose.

Answer

Exercise $\PageIndex{2}$

Draw the two chair conformations of β-D-mannose, being sure to clearly show each non-hydrogen substituent as axial or equatorial. Predict which conformation is likely to be more stable, and explain why.

Answer

Exercise $\PageIndex{3}$

Draw the following in their most stable chair conformation: β-D-galactopyranose and β-D-mannopyranose. Which one is expected to be the more stable chair?

Answer

Because both have one axial OHs, their chair conformations should have roughly the same stability.

Structures of beta D-galactopyranose and beta-D-mannopyranose. The C 4 hydroxyl group of beta galactopyranose is equatorial and C 2 hydroxyl group of beta mannopyranose is axial.

Exercise $\PageIndex{4}$

Draw β-L-galactopyranose in its more stable chair conformation, and label the substituents as either axial or equatorial.

Answer

Exercise $\PageIndex{5}$

Draw the cyclic structure of α-D-altrose.

Answer

Exercise $\PageIndex{6}$

Draw the cyclic structure for β-D-galactose. Identify the anomeric carbon.

Answer

beta_D-galactose_(with_anomeric_carbon_highlighted).png

To identify the structure, we should first start with the Fischer projection of D-galactose. Since it is an aldohexose, we will start with the pyranose ring. The beta anomer was requested, so the OH on the anomeric carbon (C1) is cis to C6. Since C6 is top face (pointing up), the OH will be top face. Carbons 2, 3, and 4 are then arranged based on the Fischer projection arrangement at those carbons (C2 right, C3 left, and C4 left).

Exercise $\PageIndex{7}$

Given that the aldohexose D-mannose differs from D-glucose only in the configuration at the second carbon atom, draw the cyclic structure for α-D-mannose.

Answer

Exercise $\PageIndex{8}$

Draw the cyclic structure for β-D-glucose. Identify the anomeric carbon.

Answer

Exercise $\PageIndex{9}$

a) Identify the anomeric carbon of each of the sugars shown below, and specify whether the structure shown is a hemiacetal or hemiketal.

b) Draw mechanisms for the cyclization of the open-chain forms to the cyclic forms shown.

Answer

Exercise $\PageIndex{10}$

Draw a mechanism for the conversion of α-glucopyranose to open-chain glucose.

Answer

$6.5. 12$

Exercise $\PageIndex{11}$

Identify the following monosaccharide, write its full name, and draw its open-chain form as a Fischer projection.

a- clipboard_e119eec86c1bbd292812a206e53d8215a-removebg-preview.png b- The ball-and-stick model of an alpha aldohexose monosaccharide.

Answer

a- β-D-idopyranose. b-α-D-Allopyranose

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Objectives

Key Terms

Study Notes

Cyclic Monosaccharides

Pyranose Rings

Mutarotation

Furanose Rings

Drawing Cyclic Structures of Monosaccharides

Exercise \(\PageIndex{1}\)

Exercise \(\PageIndex{2}\)

Exercise \(\PageIndex{3}\)

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Exercise \(\PageIndex{5}\)

Exercise \(\PageIndex{6}\)

Exercise \(\PageIndex{7}\)

Exercise \(\PageIndex{8}\)

Exercise \(\PageIndex{9}\)

Exercise \(\PageIndex{10}\)

Exercise \(\PageIndex{11}\)