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CHAPTER 24
Carbohydrates: Polyfunctional Compounds in Nature

24-1

Names and Structures of Carbohydrates

Sugars are classified as aldoses and ketoses.

Carbohydrate is the general name for the various forms of sugars (monsaccharides, disaccharides, trisaccharides, polysaccharides). A monosaccharide, or simple sugar, is an aldehyde or ketone containing at least two additional hydroxy groups. Aldoses are aldehydic sugars. Ketoses are ketotic sugars. Complex sugars are those formed by the linkage of simple sugars through ether bridges. Based on chain length, sugars are called trioses (C3), tetroses (C4), pentoses (C5), and hexoses (C6).

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Glucose, also known as dextrose, blood sugar, or grape sugar is an aldohexose. Glucose is present in many fruits and plants and is present in blood at concentrations of 0.08% - 0.1%. Fructose is an isomeric ketohexose of glucose. Fructose is the sweetest natural sugar and is present in many fruits and in honey. Ribose is an aldopentose and is a building block of the ribonucleic acids.

A disaccharide is derived from two monosaccharides by the formation of an ether (usually, acetal) bridge. Hydrolysis regenerates the monosaccharides. Trisaccharides, tetrasaccharides, and eventually polysaccharides are formed through additional ether bridges. Starch and cellulose are two important biological polysaccharides.

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Most sugars are chiral and optically active.

With the exception of the ketose, 1,3-dihydroxyacetone, most biological sugars contain at least one stereocenter.

The simplest chiral sugar is 2,3-dihydroxypropanal (glyceraldehyde).

The older D-L convention for naming sugars is still in general use. In this convention, monosaccharides whose highest numbered stereocenter has the same absolute configuration as that of D(+)-2,3-dihydroxypropanal (D-glyceraldehyde) are labeled D. Those having the opposite absolute configuration are labled L. Two diastereomers that differ only at one stereocenter are called epimers.

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The D,L nomenclature divides sugars into two groups. For a pentahydroxyhexanal there are 16 stereoisomers divided into two groups: 8 stereoisomers labeled D, and their 8 enantiomers labeled L. Systematic nomenclature of sugar molecules leads to long complex names. As a result, the common names of most sugars are usually used, for example: erythrose and threose for the four aldotetroses.

Note that the D (or R) label does not necessarily imply (+) and L (or S) does not necessarily imply (-). D-glyceraldehyde is detrorotatory. D-erythrose is levorotatory. Almost all naturally occurring sugars have the D absolute configuration.

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24-2

Conformations and Cyclic Forms of Sugars

Fischer projections depict all-eclipsed conformations.

The all-eclipsed Fischer projection representation of a sugar molecule can be translated into an all-eclipsed dashed-wedged line picture:

Rotation at C3 and C5 by 180 degrees leads to the all-staggered conformation.

Sugars form intramolecular hemiacetals.

Hexoses and pentoses exist in solution as an equilibrium mixture with their cyclic hemiacetal isomers, in which the hemiacetals strongly predominate. Six membered rings are the preferred products, however five membered rings are known. Three and four membered rings are too strained to form. Six membered rings are based upon the six membered cyclic ether, pyran, and are called pyranoses. Five membered rings are based upon the five membered cyclic ether, furan, and are called furanoses.

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Upon formation of the hemiacetal, a new stereocenter is created. When the new stereocenter is S in a D-series sugar or R in an Lseries sugar, the diastereoisomer is labeled . When the new stereocenter is R in a D-series sugar or S in an Lseries sugar, the diastereoisomer is labeled . This type of diastereoisomer formation is unique to sugars. These isomers have been given a separate name: anomers. The new stereocenter is called the anomeric carbon.

Fischer, Haworth, and chair cyclohexane projections help depict cyclic sugars.
Fisher projection formulas represent cyclic sugars by drawing an elongated line indicating the bond formed upon cyclization. In the form of a D sugar, the newly formed anomeric hydroxyl points to the right. In the form it points to the left.

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Haworth projection formulas of sugars are written in line notation as a pentagon or hexagon, with the anomeric carbon on the right and the ether oxygen on the top. The bottom bond (between C2 and C3) is assumed to be in front of the plane of the paper and the ring bonds containing the oxygen are assumed to be in the back. For a D sugar, the anomer has the OH group on the anomeric carbon pointing down; the anomer has it pointing up.

The equivalent conformation pictures of glucofuranose and glucopyranose are:

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Most aldohexoses adopt the chair conformation placing the bulky hydroxymethyl group at C5 in the equatorial position. For glucose this means that in the form four of the five substituents are equatorial while only one is axial. The other seven D aldohexoses contain one or more axial substituents.

24-3

Anomers of Simple Sugars: Mutarotation of Glucose

The specific rotation of pure -D-(+)-glucopyranose in water is +112o while specific rotation of pure -D-(+)-glucopyranose is +18.7o. If either anomer is placed in water, the initial value of the specific rotation slowly changes to a constant value of +52.7o. This change in specific rotation is cause by the slow formation of an equilibrium mixture of and anomers, a process called mutarotation. This is a property of all sugars.

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24-4

Polyfunctional Chemistry of Sugars: Oxidation to Carboxylic Acids

Fehlings and Tollenss tests detect reducing sugars.

The formyl group in an aldose and the -hydroxy group in a ketose can be oxidized by Cu2+ (Fehlings test) or by Ag+ (Tollens test). Aldoses are oxidized to aldonic acids, while ketoses are oxidized to dicarbonyl compounds.

Oxidation of aldoses can give mono- or dicarboxylic acids.

Aldonic acids can be prepared by oxidizing aldoses using bromine in buffered aqueous solution (pH = 5-6). Upon evaporation of water, the lactone spontaneously forms.

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More vigorous oxidation causes reaction at the primary hydroxyl group as well as at the carbonyl group to form an aldric acid.

24-5

Oxidative Cleavage of Sugars

Periodic acid, HIO4, causes C-C bond cleavage between vicinal diols to give carbonyl compounds.

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Exhaustive oxidation of a sugar with HIO4 results in a mixture of one carbon compounds. Analysis of this mixture is useful in the elucidation of the structure of the original sugar.

The number of equivalents of HIO4 consumed indicates the number of carbon atoms in the sugar. Each one-carbon fragment produced carries the same number of hydrogen substituents as it did in the original sugar. CHO HCOOH CHOH HCOOH C=O CO2 CH2OH CH2O

24-6

Reduction of Monosaccharides to Alditols

The same reagents used to reduce aldehydes and ketones to alcohols can be used to reduce aldoses and ketoses to polyhydroxy compounds called alditols.

D-Glucitol is found in red seaweed in concentrations as high as 14%. It is also found in many berries, cherries, plums, pears, and apples.

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24-7

Carbonyl Condensations with Amine Derivatives

The carbonyl function in aldoses and ketoses will undergo condensation reactions with amine derivatives. Treatment of a sugar with phenylhydrazine yields the corresponding hydrazone. A second molecule of phenylhydrazine then adds forming an osazone.

Osazones are stable and no further molecules of phenylhydrazine react. Osaxones, unlike their parent sugars, crystallize readily to form solids with well defined melting points, simplifying isolation and characterization of many sugars.

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24-8

Ester and Ether Formation: Glycosides

Sugars can be esterfied and methylated.

Monosaccharides can be converted into esters by standard techniques. Excess reagent converts all hydroxyl groups, including the anomeric hydroxyl.

Williamson ether synthesis allows complete methylation of sugars.

The acetal function can be selectively hydrolized:

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The hemiacetal functional group of a sugar can be selectively converted into the acetal. Such sugar acetals are called glycosides.

Glycosides give negative Fehlings and Tollens tests and are unreactive toward reagents that attack carbonyl groups.

Neighboring hydroxy groups in sugars can be linked as cyclic ethers.

Neighboring pairs of hydroxyls can form cyclic ether derivatives when treated with carbonyl compounds.

This reaction works best with cis hydroxyl groups, which allow a relatively unstrained five or six membered ring to form. Cyclic acetal and ether formation is often employed to protect selected alcohol functions.

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24-9

Step-by-Step Buildup and Degradation of Sugars

Cyanohydrin formation and reduction lengthens the chain.

Reaction of an aldose with HCN followed by separation of the two diastereomers formed and then partial reduction of the nitrile group yields a new aldose, lengthened by one carbon.

A modified palladium catalyst allows selective reduction of the nitrile to the imine which hydrolyzes to an aldehyde under the reaction conditions. This sequence is an improved and shortened version of the Kiliani-Fischer synthesis of chain-extended sugars.

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Ruff degradation shortens the chain.

The Ruff degradation removes the carbonyl group of an aldose and converts the neighboring carbon into an aldehyde functionality. Oxidation by aqueous bromine, followed by exposure to H2O2 in the presence of ferric salts removes the aldehyde carbon as CO2 and oxidizes the neighboring carbon to an aldehyde.

The mechanism of the Ruff degradation takes place by two oneelectron oxidations.

The Ruff degradation gives low yields but is useful in structural elucidations (the Fischer proof).

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24-10 Relative Configurations of the Aldoses: An Exercise in Structure Determination

The structures of the aldotetroses and aldopentoses can be determined from the optical activity of the corresponding aldaric acids.
Starting from D-glyceraldehyde, it is possible to prove unambiguously the structures of the higher D aldoses using Emil Fishers original logic. D-glyceraldyde can be chain extended to a mixture of D-erythrose and D-threose. Oxidation of D-erythrose with nitric acid generates an optically inactive meso-tartaric acid which identifies the structure of D-erythrose, and by default, D-threose.

D-glyceraldyde can be chain extended to a mixture of D-erythrose and D-threose. Oxidation of D-erythrose with nitric acid generates an optically inactive meso-tartaric acid which identifies the structure of Derythrose, and by default, D-threose.

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Subjecting D-erythrose and then D-threose to similar analyses, the structures of D-ribose, D-arabinose, D-xylose, and D-lyxose can be identified.

Symmetry properties also define the structures of the aldohexoses.

The previous analysis can be continued to determine the structures of the eight D-aldohexoses, however the structures of only four of the aldohexoses can be uniquely identified by this method.

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The four hexoses derived from D-xylose and D-arabinose cannot be determined using this method.

Di-acids formed are both optically active.

Di-acids formed are both optically active.

To get around this problem, Fisher devised a procedure to exchange the functionalities at C1 and C6 of a hexose, converting C1 to a primary alcohol and C6 to an aldehyde. Exchanging C1 and C6 for glucose yields a different sugar, Dgulose. Exchanging C1 and C6 for mannose, yields another molecule of mannose.

These results identify the structures of glucose and mannose. The new sugar formed from glucose, gulose, can be matched to one of the remaining unknown structures which determines the structures of both.

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24-11 Complex Sugars in Nature: Disaccharides

Sucrose is a disaccharide derived from glucose and fructose.
Sucrose is a disaccharide composed of glucose and fructose. It is a non-reducing sugar, does not form an osazone, and does not undergo mutarotation. The acetal bridge connecting the two simple sugar molecules therefore must connect the two anomeric carbon atoms.

Treatment of sucrose with aqueous acid decreases the specific rotation from +66.5o to -20o. The enzyme invertase causes the same decrease. This inversion of sucrose is related to the mutarotation of monosaccharides. Hydrolysis of the disaccharide to -D-glucopyranose and D-fructofuranose. Mutarotation of -D-glucopyranose to the equilibrium mixture with the form. Mutarotation of -D-fructofuranose to the slightly more stable -D-fructopyranose.
The resulting mixture, sometimes called invert sugar, has a net negative rotation, inverted from that of the original sucrose solution.

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Acetals link the components of complex sugars.

Other acetal linkages between monomeric sugars are possible. Maltose is obtained in 80% yield by the action of the enzyme amylase on starch:

Maltose is a reducing sugar, forms oszzones, and undergoes mutarotation. Maltose is hydrolyzed to two molecules of glucose by aqueous acid or by the enzyme maltase. Maltose is 1/3 as sweet as sugar.

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Cellobiose is identical to maltose with the exception that the anomeric linkage is instead of .

Aqueous hydrolysis yields two molecules of glucose. A different enzyme, -glucosidase, is required for enzymic hydrolysis. Maltase is specific for the -linkage.

Lactose, or milk sugar, constitutes more than 1/3 of the solid residue remaining upon evaporation of milk.

The linkage between glucose and galactose is . Crystallization from water furnishes only the anomer

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24-12 Polysaccharides and Other Sugars in Nature

Cellulose and starch are unbranched polymers.
Cellulose is a poly--glucopyranoside linked at C4, containing about 3000 monomeric units. Its molecular weight is about 500,000 and it is largely linear.

Hydrogen bonding between adjacent chains accounts for the highly rigid structure of cellulose. Cellulose is abundant in trees and other plants. Cotton fiber is almost pure cellulose. Wood and straw contain about 50% of the polysaccharide.

Starch is also a polyglucose, but the monomeric units are connected by linkages rather than linkages, as in cellulose. Cellulose serves as a major food reserve in plants and (like cellulose) can by cleaved by aqueous acid into glucose. Major sources are corn, potatoes, wheat and rice. Granular starch swells in hot water and can then be separated into two components, amylose (~20%) and amylopectin (~80%). Amylose is less soluble in cold water. Amylose contains a few hundred glucose units (MW, 150,000-600,000). It tends to form helical structures rather than linear structures (cellulose).

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Amylopectin is branched, mainly at C6, about once every 20 to 25 glucose units. Its molecular weight is in the millions.

Glycogen is a source of energy.

Glycogen is similar to amylopectin but with a higher frequency of branching (1 per 10 glucose units). Glycogen is the major energy storage polysaccharide in humans and animals. Glycogen is stored in the liver and is the immediate source of blood glucose between meals. Glycogen is also stored in the skeletal muscle and provides a source of energy during strenuous physical activity.

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Glycogen is utilized in the following way: The enzyme glycogen phosphorylase removes a molecule of glucose from a non-reducing end of the glycogen molecule as D-glucopyranosyl 1 phosphate. Because of the high degree of branching (non-reducing ends) many molecules of glycogen phosphorylase can be active at any one time.

Glycogen phosphorylase cannot break -1,6-glycosidic bonds. Two additional enzymes circumvent this problem, a transferase and an -1,6-glucosidase.

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Cell-surface carbohydrates mediate cell-recognition processes.

Interactions between one cell and another, and between one cell and specific chemical species are called cell-recognition processes. These processes usually involve noncovalent binding (often hydrogen bonds) with molecules on the exterior surface of the cell. These recognition processes are based on carbohydrates, present on cell surfaces, which are linked to either lipids or proteins enbedded in the cell membrane. The key features of this class of carbohydrates are illustrated a molecule of glucosyl cerebroside.
A polar, hydrophilic head and two hydrophobic tails.

Other cell surface functions mediated by carbohydrates include: The glycolipid, GM1 pentasaccharide, which binds the cholera toxin. Human blood groups: O, A, B, and AB.

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Modified sugars may contain nitrogen.

In some sugars, one or more of the hydroxyl groups have been replaced by amino groups. These sugars are called glycosylamines when the nitrogen is attached to the anomeric carbon and amino deoxy sugars when the nitrogen is attached elsewhere.

When a sugar is attached by its anomeric carbon to the hydroxy group of another complex residue, it is called a glycosyl group. The remainder of the molecule is called the aglycon.

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24

Important Concepts 1. Carbohydrates Naturally occurring 2. Monosaccharides

Aldoses aldehydes. Ketoses ketones Chain Length Prefix tri-, tetr-, pent-, hex-, etc. belong to the D family: the stereocenter farthest from the carbonyl group has the same configuration as (R)(+)-2,3-dihydroxy-propanal (D-(+)-glyceraldehyde). polyhydroxycarbonyl compounds found as monomers, dimers, oligiomers,and polymers.

3. Stereochemistry Most natural carbohydrates

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Important Concepts 4. Cyclic Hemiacetals - Keto forms of carbohydrates

exist in equilibrium with the corresponding cyclic hemiacetals. 5 membered furanoses 6 memberes pyranoses The new asymmetric center formed is called the anomeric carbon ( and )

5. Haworth Projections A planar pentagon or

hexagon representation of a cyclical D hemiacetal. The anomeric carbon is placed on the right. The ether oxygen is placed at the top. Substituents located above or below the ring are attached to vertical lines. The Anomer points down: the anomer up.

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Important Concepts 6. Mutarotation Attainment of equililbrium between 7. Reactions of Saccharides Characteristic of

carbonyl, alcohol, and hemiacetal groups: Oxidation of aldehyde to an aldonic acid. Double oxidation to aldaric acids. Oxidative cleavage of vicinal diol units. Reduction to alditols Condensations Esterifications Acetal formation anomers in solution. Measured by changes in optical rotation.

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Important Concepts 8. Reducing Sugars Contain hemiacetal functions.

Reduce Tollenss and Fehlingss solutions. If the anomeric carbon is acetalized, the sugar becomes non-reducing.

9. Chain Lengthening Higher sugar synthesis

involves chain lengthening using cyanide ion as the source of new carbon. Chain shortening - Lower sugars are synthesized using Ruff chain shortening. shortening and the symmetry properties of aldaric acids to elucidate the structures of the aldoses.

10. Fischer Proof Utilizes chain lengthening and

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Important Concepts 11. Di- and Higher Saccharides - Formed via ether
formation between monomers. The oxygen bridge usually involves at least one of the hemiacetal hydroxyl groups. of aqueous sucrose as equilibrium is established between its various cyclic and anomeric forms.

12. Inversion of Sucrose Change in optical rotation 13. Modifications Sugars can have modified

backbones. Amino groups may replace hydroxy groups. Other complex substituents. Missing oxygen (deoxyribose) Rarely, L enantiomer are found..

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