Mutarotation

There is a balance between the stabilizing anomeric effect (which favors the a anomer) and other factors that contribute to the anomeric preference of a particular sugar, such as solvent effects and sterics (which can favor the p anomer). A good example to illustrate this duality is the mutarotation process. 

Distribution of the Different Isomers of Some Monosaccharides in Aqueous Solution at Equilibrium 

Carbohydrate a-Anomer (%) fi-Anomer (%) a-Anomer (%) (J-Anomer (%) Acyclic (%) 

In spite of their easy interconversion in solntion, a and (3 forms of carbohydrates are capable of independent existence, and many have been isolated in pnre form as crystalline solids. When crystallized from ethanol, o-glncose yields a-o-glncopyranose, mp 146°C, [a]o +112.2°. Crystallization from a water-ethanol mixtnre prodnces (3-d-glncopyranose, mp 148-155°C, [a]o +18.7°. In the solid state the two forms do not interconvert and are stable indefinitely. Their strnctures have been nnambignonsly confirmed by X-ray crystallography. 

The optical rotations just cited for each isomer are those measured immediately after each one is dissolved in water. On standing, the rotation of the solution containing the a isomer decreases from +112.2° to +52.5° the rotation of the solution of the (3 isomer increases from +18.7° to the same value of +52.5°. This phenomenon is called mutarotation. What is happening is that each solution, initially containing only one anomeric form, undergoes equilibration to the same mixture of a- and (3-pyranose forms. The open-chain form is an intermediate in the process. 

The distribution between the a and (3 anomeric forms at equilibrium is readily calculated from the optical rotations of the pure isomers and the final optical rotation of the solution, and is determined to be 36% a to 64% (3. Independent measurements have established that only the pyranose forms of D-glucose are present in significant quantities at equilibrium. 

PROBLEM 25.7 The specific optical rotations of pure a- and p-o-mannopyranose are +29.3° and 17.0°, respectively. When either form is dissolved in water, mutarotation occurs, and the observed rotation of the solution changes until a final rotation of +14.2° is observed. Assuming that only a- and p-pyranose forms are present, calculate the percent of each isomer at equilibrium. 

It s not possible to tell by inspection whether the a- or p-pyranose form of a particular carbohydrate predominates at equilibrium. As just described, the p-pyranose form is the major species preseut iu au aqueous solutiou of D-glucose, whereas the a-pyrauose form predominates in a solution of D-mannose (Problem 25.7). The relative abundance of a-and P-pyranose forms in solution is a complicated issue aud depeuds on several factors. One is solvation of the anomeric hydroxyl group. Au equatorial OH is less crowded aud better solvated by water than an axial one. This effect stabilizes the P-pyranose form in aqueous solution. A second factor, called the anomeric effect, involves an electronic interaction between the ring oxygen and the anomeric substituent and preferentially stabilizes the axial OH of the a-pyranose form. Because the two effects 

Mutarotation occurs slowly in neutral aqueous solution, but can be catalyzed by either acid or base. Mechanism 23.1 shows a four-step, acid-catalyzed mechanism for mutarotation starting with a-o-glucopyranose. Steps 1 and 4 are proton transfers and describe the 

Acid-Catalyzed Mutarotation of o-Glucopyranose THE OVERALL REACTION  

Step 1 Protonation of the oxygen of the pyranose ring by the acid catalyst. In aqueous solution, the acid catalyst is the hydronium ion. 

Mutarotase catalyzes the conversion 4-5 orders of magnitude faster than 2-hy-droxypyridine. Its mechanism, however, is believed to be similar to 2-hydroxy-pyridine in that it involves both a basic group and an acid group at the active site of the enzyme. The enzyme has a specific D-glucose binding site that stereo- 

Essentials of Carbohydrate Chemistry Springer-Verlag New York Inc. 1998 

Many of the reactions of carbohydrates that involve C-1 take place witii the open-chain, aldehyde form, even though it is present in very small amounts for most cariK)hydrates. When the open-chain form reacts, one of the ring forms is converted into the open-chain form, until all of the carbohydrate has reacted. Different carbohydrates have different distributions of the various forms when at equilibrium in water solutions. Table 3.1 gives the various distributions for some carbohydrates. 

Carbohydrate Temp. Pyranose Furanose Open-chain 

Mutarotase catalyzed mutarotation involving carboxylate and carboxyl catalytic groups at the active-site 

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It shows the usual carbohydrate reactions and most resembles mannose in behaviour it exists in OL and fi forms which exhibit mutarotation. 

The two stereoisomeric forms of maltose just mentioned indergo mutarotation when dissolved in water What is the structure of the key intermediate in this process ... 

A particular carbohydrate can mterconvert between furanose and pyra nose forms and between the a and (3 configuration of each form The change from one form to an equilibrium mixture of all the possible hemi acetals causes a change m optical rotation called mutarotation... 

Mutarotation (Section 25 8) The change in optical rotation that occurs when a single form of a carbohydrate is allowed to equilibrate to a mixture of isomeric hemiacetals... 

Isolates from Indian tobacco Q obelia inflata L.), as a cmde mixture of bases, have been recognized as expectorants. The same (or similar) fractions were also used both in the treatment of asthma and as emetics. The principal alkaloid in T. inflata is lobeline (49), an optically active tertiary amine which, unusual among alkaloids, is reported to readily undergo mutarotation, a process normally associated with sugars. Interestingly, it appears that the aryl-bearing side chains in (49) are derived from phenylalanine (25, R = H) (40). 

Properties. Physical properties of the three crystalline forms of dextrose are Hsted in Table 1. In solution, dextrose exists in both the a- and P-forms. When a-dextrose dissolves in water, its optical rotation, [cc], diminishes gradually as a result of mutarotation until, after a prolonged time, an... 

Bicucine, C20H19O7N, H2O. This alkaloid has m.. 222° (dec.) and — 115 4° (N/10, KHO) but in N/HCl it shows mutarotation — 145° to — 100°,due to the formation of an equilibrium mixture of bicucine and bicuculline. Alkaline permanganate oxidises it to 3 4-methylene-dioxyphthalic acid, isolated as the ethylimide. In view of its formation from bicuculline by the action of alkali, Manske has suggested for its formula (II) or (III), the former representing it as the nomarceine (p. 208) analogue of bicuculline, whilst (III) makes it the hydroxy-acid corresponding to the lactone, bicuculline and is preferred. 

Delphinine, C34H47O9N (Walz) or C33H45O9N (J. and C.). The alkaloid crystallises in rhombs, or six-sided plates, m.p. 198-200°, [a]f ° + 25° (EtOH), shows mutarotation in alcoholic solution, and forms an acid oxalate, B. H2C2O4, m.p. 168° dry), a hydrochloride, B. HCl, m.p. 208-210°, and a monobenzoyl derivative, m.p. 171-3°. On alkaline hydrolysis it yields one molecule each of acetic and benzoic acids. The basic, hydrolytic product of this action is delphonine, C24H3g07N, which is amorphous, but can be distilled at a bath temperature of 140° and a pressure of 0-001 to 0-0001 mm. The brittle, possibly semi-crystalline resin so obtained, has m.p, 76-8° and [a]f ° - - 37-5 (EtOH). 

The most familiar of all the carbohydrates is sucrose—common table sugar. Sucrose is a disacchar ide in which D-glucose and D-fructose are joined at then anomeric carbons by a glycosidic bond (Figure 25.7). Its chemical composition is the same ine-spective of its source sucrose from cane and sucrose from sugar beets are chemically identical. Because sucrose does not have a free anomeric hydroxyl group, it does not undergo mutarotation. 

The isolation of several pairs of geometric isomers of 4-unsaturated-5-oxazolones has been described. Generally, only one isomer is obtained when an aldehyde reacts with hippuric acid in the presence of acetic anhydride. Occasionally, mixtures have been separated in base-catalyzed reactions. In acetic anhydride-sulfuric acid or in 100% sulfuric acid, a mixture is obtained, and it has been suggested that sulfuric acid inhibits mutarotation of the intermediate addition product 53, which is a mixture of diastereomers (see, e.g., compound... 

If mutarotation were not a factor, the threo pair would give the isomer having the phenyl group and nitrogen atom in a cis relationship and the erythro pair the isomer with the phenyl and carbonyl groups cis. Since it is doubtful, at least in some cases, that steric integrity is maintained in acetic anhydride prior to elimination, the subsequent... 

Both anomers of o-glucopyranose can be crystallized and purified. Pure a-n-glucopyranose has a melting point of 146 °C and a specific rotation, lo-Jn, of +112.2 pure /3-D-glucopyranose has a melting point of 148 to 155 °C and a specific rotation of +18.7. When a sample of either pure anomer is dissolved in water, however, the optical rotation slowly changes and ultimately reaches a constant value of +52.6. That is, the specific rotation of the a-anomer solution decreases from +112.2 to +52.6, and the specific rotation of the /3-anomer solution increases from +18.7 to +52.6. Called mutarotation, this change in optical rotation is due to the slow conversion of the pure anomers into a 37 63 equilibrium mixture. 

Mutarotation occurs by a reversible ring-opening of each anomer to the open-chain aldehyde, followed by reclosure. Although equilibration is slow at neutral pH, it is catalyzed by both acid and base. 

Glycosides are named by first citing the alkyl group and then replacing the -ose ending of the sugar with -oside. Like all acetals, glycosides are stable to neutral water. They aren t in equilibrium with an open-chain form, and they don t show mutarotation. They can, however, be converted back to the free monosaccharide by hydrolysis with aqueous acid (Section 19.10). 

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