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1 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 (monosaccharides, 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). 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. Most sugars are chiral and optically active. The simplest chiral sugar is 2,3-dihydroxypropanal (glyceraldehyde). With the exception of the ketose, 1,3-dihydroxyacetone, most biological sugars contain at least one stereocenter. 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 labeled L. Two diastereomers that differ only at one stereocenter are called epimers
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2 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. 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 structure: 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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3 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 α. When the new stereocenter is R in a D-series sugar or S in an Lseries sugar, the diastereoisomer is labeled β. 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 α form of a D sugar, the newly formed anomeric hydroxyl points to the right. In the β form, it points to the left. 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 α anomer has the OH group on the anomeric carbon pointing down; the β anomer has it pointing up. The equivalent conformation pictures of glucofuranose and glucopyranose are:
ehenerenDaldohexosescontainonermoreaxal 82889n msaceethes 24-4 Polyfunctional Cher mistry of Sugars:Oxidation to xidation of aldosescan give mono-or dicarboxylic Fehling'sand Tollens's tests detect reducing odoenbrom g8eas8e9s9e8e5g3cen0t6eanaamgCg 24-5 Oxidative Cleavage of Sugars 一：g0+0 4
4 Most aldohexoses adopt the chair conformation placing the bulky hydroxymethyl group at C5 in the equatorial position. For glucose, this means that in the α form four of the five substituents are equatorial, while only one is axial. The other seven D aldohexoses contain one or more axial substituents. Anomers of Simple Sugars: Mutarotation of Glucose 24-3 The specific rotation of pure α-D-(+)-glucopyranose in water is +112o, while specific rotation of pure β-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 caused by the slow formation of an equilibrium mixture of α and β anomers, a process called mutarotation. This is a property of all sugars. Polyfunctional Chemistry of Sugars: Oxidation to Carboxylic Acids 24-4 Fehling’s and Tollens’s tests detect reducing sugars. The formyl group in an aldose and the α-hydroxy group in a ketose can be oxidized by Cu2+ (Fehling’s test) or by Ag+ (Tollens’s 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 a buffered aqueous solution (pH = 5-6). Upon evaporation of water, the γ lactone spontaneously forms. 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
24-6 Reduction of Monosaccharides to Alditols 一含堂 mnbergeroauhteertaioacensumedhdkatsthe 56e 24-7 Carbonyl Condensations with Amine Derivatives N-NHCH N-NHCJ 24-8 Ester and Ether Formation:Glycosides Williamson ether synthesis allows complete methylation of sugars Sugars can be esterfied and methylated. meric bd OH- 0 The aetafubeselctively hydrolid: 5
5 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 Î HCOOH C=O Î CO2 CHOH Î HCOOH CH2OH Î 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. 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. Osazones, unlike their parent sugars, crystallize readily to form solids with well defined melting points, simplifying isolation and characterization of many sugars. 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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6 The hemiacetal functional group of a sugar can be selectively converted into the acetal. Such sugar acetals are called glycosides. Glycosides give negative Fehling’s and Tollens’s 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. 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. 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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7 Relative Configurations of the Aldoses: an Exercise in Structure Determination 24-10 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 Fisher’s original logic. D-glyceraldyde can be chain-extended to a mixture of Derythrose 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. 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. 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. Gulose, the new sugar formed from glucose, can be matched to one of the remaining unknown structures that determines the structures of both
24-11 Complex Sugars in Nature:Disaccharides f sucrose is related to the mutarotation of 2aa 0hearahedisacehsrndeoa-gucopranoeeand me86h26ee1oea8onee26t2aiooscule ras月8gtucopyanosetothequbrim Acetals link the components of complex sugars. Other acetal linkages be by th 0+ g85io7anmsnoecuesofgucoeyaqueo eet as sugar e the .a f-o-ecepyra Hb-o-ghopyra us hydrolysis yields two molecules of olucose 8
8 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 α-D-glucopyranose and β- D-fructofuranose •Mutarotation of α-D-glucopyranose to the equilibrium mixture with the β form •Mutarotation of β-D-fructofuranose to the slightly more stable β-D-fructopyranose The resulting mixture, sometimes called invert sugar, has a net negative rotation, inverted from that of the original sucrose solution. 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 osazones 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. Cellobiose is identical to maltose with the exception that the anomeric linkage is β instead of α. Aqueous hydrolysis yields two molecules of glucose. A different enzyme, β-glucosidase, is required for enzymic hydrolysis. Maltase is specific for the α-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 β. Crystallization from water furnishes only the α anomer
24-12 Polysaccharides and Other Sugars in Nature lose and starch are unbranched polymers. -0 5o89eme hg2gaon2agem2cmtchainsacaountorth g8aanareoy20o25 Glycogen is a source of energy. ndmt 85ea The enzyme glycogen phos Se2ce0ttg6e2 ●中年年年中◆g 884666 4…。 ●e●0 9
9 24-12 Polysaccharides and Other Sugars in Nature Cellulose and starch are unbranched polymers. Cellulose is a poly-β-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 α linkages rather than β 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). 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. 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 α- 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 α-1,6-glycosidic bonds. Two additional enzymes circumvent this problem, a transferase and an α-1,6-glucosidase
Cell-surface carbohydrates mediate cell-recognition caaoaoonomam Human blood groups:ABand AB. w. 233we8s2egee ga oups have been 9bpcw3rsaoedgoreGeooogo2 repceminru ed the aawaam 。m/ 24 Important Concepts 24 Important Concepts mers 5-memberedra 3. o. HaothPtolectienaaaerBpen2eg nthe right. . Thenmer points dow.the Banomer points up. 10
10 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 non-covalent 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 embedded in the cell membrane. The key features of this class of carbohydrates are illustrated as a molecule of glucosyl cerebroside with 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. 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. 24 Important Concepts 1. Carbohydrates – naturally occurring polyhydroxycarbonyl compounds found as monomers, dimers, oligiomers and polymers. 2. Monosaccharides – • Aldoses – aldehydes • Ketoses – ketones • Chain Length Prefix – tri-, tetr-, pent-, hex-, etc. 3. Stereochemistry – most natural carbohydrates belong to the D family: The stereocenter farthest from the carbonyl group has the same configuration as (R)- (+)-2,3-dihydroxy-propanal (D-(+)-glyceraldehyde). 24 Important Concepts 4. Cyclic Hemiacetals – keto forms of carbohydrates exist in equilibrium with the corresponding cyclic hemiacetals. • 5-membered furanoses • 6-membered pyranoses • The new asymmetric center formed is called the anomeric carbon (α and β). 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 α anomer points down, the β anomer points up