Organic Chemistry III

Mohammad Jafarzadeh Faculty of Chemistry, Razi University

Organic Chemistry, Structure and Function (7th edition) By P. Vollhardt and N. Schore, Elsevier, 2014 1 24. Carbohydrates

Take a piece of bread and place it in your mouth. After a few minutes it will begin to taste distinctly sweet, as if you had added sugar to it. The acid and enzymes in your saliva have cleaved the starch in the bread into its component units: glucose molecules. You all know glucose as dextrose or grape sugar. The polymer, starch, and its monomer, glucose, are two examples of carbohydrates.

Carbohydrates are major contributors to our daily diets, in the form of sugars, fibers, and starches, such as bread, rice, and potatoes. They function as chemical energy-storage systems, being metabolized to water, carbon dioxide, and heat or other energy. They also serve as building units of fats and nucleic acids.

Carbohydrates are considered to be polyfunctional, because they possess multiple functional groups. Glucose, C6(H2O)6, and many related simple members of this compound class form the building blocks of the complex carbohydrates and have the empirical formulas

Cn(H2O)n, essentially hydrated carbon. As a result, they are highly water soluble.

2 24-1 NAMES AND STRUCTURES OF CARBOHYDRATES

The simplest carbohydrates are the sugars, or saccharides. As chain length increases, the increasing number of stereocenters gives rise to a multitude of diastereomers. Fortunately for chemists, nature deals mainly with only one of the possible series of enantiomers.

Sugars are polyhydroxycarbonyl compounds and many form stable cyclic hemiacetals, which affords additional structural and chemical variety.

Carbohydrate is the general name for the monomeric (monosaccharides), dimeric (disaccharides), trimeric (trisaccharides), oligomeric (oligosaccharides), and polymeric (polysaccharides) forms of sugar (saccharum, Latin, sugar).

A monosaccharide, or simple sugar, is an aldehyde or ketone containing at least two additional hydroxy groups. Thus, the two simplest members of this class of compounds are 2,3-dihydroxypropanal (glyceraldehyde) and 1,3-dihydroxyacetone.

Complex sugars are those formed by the linkage of simple sugars through ether bridges.

3 1074 CHAPTER 24 Carbohydrates

CHO Sugars are classiﬁ ed as aldoses and ketoses A HOOC OH Carbohydrate is the general name for the monomeric (monosaccharides), dimeric (disac- A charides), trimeric (trisaccharides), oligomeric (oligosaccharides), and polymeric (polysac- CH2OH charides) forms of sugar (saccharum, Latin, sugar). A monosaccharide, or simple sugar, is an aldehyde or ketone containing at least two additional hydroxy groups. Thus, the two O simplest members of this class of compounds are 2,3-dihydroxypropanal (glyceraldehyde) O and 1,3-dihydroxyacetone (margin). Complex sugars (Section 24-11) are those formed by the linkage of simple sugars through ether bridges. Aldehydic sugars are classi! ed as aldoses; those with a ketone function are called ketoses. Aldehydic sugars are classified as aldoses; those with a ketone function areOn thecalled basis of their chain length, we call sugars trioses (three carbons), tetroses (four carbons), ketoses. On the basis of their chain length, we call sugars trioses (three carbons),pentoses (! ve carbons), hexoses (six carbons), and so on. Therefore, 2,3-dihydroxypropanal tetroses (four carbons), pentoses (five carbons), hexoses (six carbons),O and so on(glyceraldehyde). is an aldotriose, whereas 1,3-dihydroxyacetone is a ketotriose. 1074 CHAPTER 24 Carbohydrates2,3-Dihydroxypropanal Glucose, also known as dextrose, blood sugar, or grape sugar (glykys, Greek, sweet), is (Glyceraldehyde) Therefore, 2,3-dihydroxypropanal (glyceraldehyde) is an aldotriose, whereasa pentahydroxyhexanal1,3- and hence belongs to the class of aldohexoses. It occurs naturally in (An aldotriose) many fruits and plants and in concentrations ranging from 0.08 to 0.1% in human blood. A dihydroxyacetone is a ketotriose. corresponding isomeric ketohexose is fructose, the sweetest natural sugar (some synthetic CHO Sugars areCH classiﬁ2OH ed as aldoses and ketoses A A sugars are sweeter), which is also present in many fruits (fructus, Latin, fruit) and in honey. HOOC OH CarbohydrateCP isO the general name forAnother the monomeric important natural(monosaccharides), sugar is the aldopentose dimeric (disac- ribose, a building block of the ribonucleic A charides), trimericA (trisaccharides), oligomericacids (Section (oligosaccharides), 26-9). and polymeric (polysac- CH2OH charides) formsCH 2ofOH sugar (saccharum, Latin, sugar). A monosaccharide, or simple sugar,

is an aldehyde or ketone containing at least two additional hydroxyConstitutional groups. Thus, the two CHO CH2OH O simplest members of this class of compounds Aare 2,3-dihydroxypropanalisomers (glyceraldehyde)A O and 1,3-dihydroxyacetoneO (margin). ComplexHOO CsugarsOH (Section 24-11) are those formedCPO by CHO the linkage of simple sugarsO through ether bridges.A A A HOOOC H HOOOC H HOOC OH Aldehydic sugars are classi! ed as aldoses; thoseA with a ketone function are calledA ketoses. A On the basis of their chain length, we call sugarsHOO CtriosesOH (three carbons), tetroses (fourHOO Ccarbons),OH HOOC OH pentoses (! ve carbons), hexoses (six carbons), Aand so on. Therefore, 2,3-dihydroxypropanalA A O (glyceraldehyde) is an aldotriose, whereas 1,3-dihydroxyacetoneHOOC OH is a ketotriose. HOOC OH HOOC OH O Glucose, also known as dextrose, blood sugar,A or grape sugar (glykys, Greek, sweet),A is A 2,3-Dihydroxypropanal CH OH CH OH CH OH (Glyceraldehyde) a pentahydroxyhexanal1,3-Dihydroxyacetone and hence belongs to the class2 of aldohexoses. It occurs naturally2 in 2 (An aldotriose) many fruits(A and keto plantstriose) and in concentrations ranging fromO 0.08 to 0.1% in human blood.O A O OO4 O O corresponding isomeric ketohexose is fructose, the sweetest natural sugar (some synthetic O CH2OH O O A sugars are sweeter), which is also present in many fruits (fructus, Latin, fruit) and in honey. O O O O CPO Another important natural sugar is the aldopentoseO ribose,O a building block of the ribonucleic O A acids (Section 26-9). CH OH 2 Glucose Fructose Ribose Constitutional (An aldohexose) (A ketohexose) (An aldopentose) CHO CH2OH A isomers A O HOOC OH CPO CHO O A ExerciseA 24-1 A HOOOC H HOOOC H HOOC OH A To whichA classes of sugars do the followingA monosaccharides belong? HOOC OH HOOC OH HOOC OH CHO 2OHCH A A A A HOOC OH HOOC OH HOOC OH A O CHO HOCH CPO A AA A A A 1,3-Dihydroxyacetone CH2OH (a) HCCOHH2OH (b) HOCH C H(c)2OH HOCH A A A (A ketotriose) O HCOH O HCOH OHCOH OO O O A O A A O 2OHCH 2OHCH 2OHCH O Erythrose LyxoseO Xylulose O O O O O O

Glucose A Fructosedisaccharide is derived from twoRibose monosaccharides by the formation of an ether (An aldohexose) (usually,(A keto acetal)hexose) bridge (Sections 17-7 and(An aldo 24-11).pentose Hydrolysis) regenerates the monosaccharides. Diabetics need to monitor the Ether formation between a mono- and a disaccharide results in a trisaccharide, and repetition glucose levels in their blood carefully, as with the simple of this process eventually produces a natural polymer (polysaccharide). Polysaccharides “glucometer”Exercise 24-1 shown. constitute the framework of cellulose and starch (Section 24-12). To which classes of sugars do the following monosaccharides belong?

CHO 2OHCH A A CHO HOCH CPO A A A (a) HCOH (b) HOCH (c) HOCH A A A HCOH HCOH HCOH A A A 2OHCH 2OHCH 2OHCH Erythrose Lyxose Xylulose

CHO Sugars are classiﬁ ed as aldoses and ketoses A HOOC OH Carbohydrate is the general name for the monomeric (monosaccharides), dimeric (disac- A charides), trimeric (trisaccharides), oligomeric (oligosaccharides), and polymeric (polysac- CH2OH charides) forms of sugar (saccharum, Latin, sugar). A monosaccharide, or simple sugar, is an aldehyde or ketone containing at least two additional hydroxy groups. Thus, the two O simplest members of this class of compounds are 2,3-dihydroxypropanal (glyceraldehyde) O and 1,3-dihydroxyacetone (margin). Complex sugars (Section 24-11) are those formed by the linkage of simple sugars through ether bridges. Aldehydic sugars are classi! ed as aldoses; those with a ketone function are called ketoses. On the basis of their chain length, we call sugars trioses (three carbons), tetroses (four carbons), pentoses (! ve carbons), hexoses (six carbons), and so on. Therefore, 2,3-dihydroxypropanal O (glyceraldehyde) is an aldotriose, whereas 1,3-dihydroxyacetone is a ketotriose. 2,3-Dihydroxypropanal Glucose, also known as dextrose, blood sugar, or grape sugar (glykys, Greek, sweet), is (Glyceraldehyde)Glucose, alsoa pentahydroxyhexanalknown as dextrose, and henceblood belongssugar, to theor classgrape of aldohexoses.sugar (glykys It occurs, Greek, naturallysweet), in is a (An aldotriosepentahydroxyhexanal) many fruits and plantshence andbelongs in concentrationsto the rangingclass offromaldohexoses 0.08 to 0.1% .in human blood. A corresponding isomeric ketohexose is fructose, the sweetest natural sugar (some synthetic CH2OH A An isomeric sugarsketohexose are sweeter),is fructose,which is alsothe presentsweetest in many fruitsnatural (fructus,sugar, Latin,which fruit) andis alsoin honey.present in CPO many fruits (fructus,Another importantLatin, fruit) naturaland sugarin ishoney the aldopentose. ribose, a building block of the ribonucleic A acids (Section 26-9). CH2OH Natural sugar of aldopentose, ribose, is a building block of the ribonucleic acids. Constitutional CHO CH2OH A isomers A O HOOC OH CPO CHO O A A A HOOOC H HOOOC H HOOC OH A A A HOOC OH HOOC OH HOOC OH A A A HOOC OH HOOC OH HOOC OH O A A A 1,3-Dihydroxyacetone CH2OH CH2OH CH2OH (A ketotriose) O O O OO O O O O O O O O O O O O

Glucose Fructose Ribose 5 (An aldohexose) (A ketohexose) (An aldopentose)

Exercise 24-1 To which classes of sugars do the following monosaccharides belong?

CHO 2OHCH A A CHO HOCH CPO A A A (a) HCOH (b) HOCH (c) HOCH A A A HCOH HCOH HCOH A A A 2OHCH 2OHCH 2OHCH Erythrose Lyxose Xylulose

A disaccharide is derived from two monosaccharides by the formation of an ether (usually, acetal) bridge (Sections 17-7 and 24-11). Hydrolysis regenerates the monosaccharides. Diabetics need to monitor the Ether formation between a mono- and a disaccharide results in a trisaccharide, and repetition glucose levels in their blood carefully, as with the simple of this process eventually produces a natural polymer (polysaccharide). Polysaccharides “glucometer” shown. constitute the framework of cellulose and starch (Section 24-12). A disaccharide is derived from two monosaccharides by the formation of an ether (usually, acetal) bridge. Hydrolysis regenerates24-1the Namesmonosaccharides and Structures. Ether of Carbohydratesformation betweenCHAPTERa 24 1075 mono- and a disaccharide results in a trisaccharide, and repetition of this process eventually produces a natural polymer (polysaccharide). Polysaccharides constitute the frameworkMostof cellulose sugars andare starchchiral. and optically active With the exception of 1,3-dihydroxyacetone, all the sugars mentioned so far contain at least Most sugarsone stereocenter.are chiral Theand simplestoptically chiral sugaractive is 2,3-dihydroxypropanal (glyceraldehyde), with one asymmetric carbon. Its dextrorotatory form is found to be R and the levorotatory enan- With thetiomerexception S, as shownof 1,3 in-dihydroxyacetone, the Fischer projectionsall ofthe the sugarsmolecule.mentioned Recall that, soby farconvention,contain at least one stereocenterthe horizontal. The linessimplest in Fischerchiral projectionssugar representis 2,3- dihydroxypropanalbonds to atoms above the(glyceraldehyde), plane of the with one asymmetricpage (Sectioncarbon 5-4). . Its dextrorotatory form is found to be R and the levorotatory enantiomer S. Fischer Projections of the Two Enantiomers Model Building of 2,3-Dihydroxypropanal (Glyceraldehyde)

that of "-(1)-2,3-dihydroxypropanal ["-(1)-glyceraldehyde] are then labeled "; those with the Mirror plane opposite con! guration at that stereocenter are named #. Two diastereomers that differ in the All stereocenters stereochemistry of only one stereocenter (the same in each one) are also called epimers (margin). switch configuration Designation of a DL and an Sugar D-Allose L-Allose CHO CH OH 2 Epimers H OH O CHO CHO HO H H OH HOHHO H H OH H OH H OH H OH H OH HO H H OH H OH Highest-numbered Highest-numbered H OH H OH CH2OH CH2OH stereocenter stereocenter DL-Aldose -Ketose CH2OH CH2OH Only one The ",# nomenclature divides the sugars into two groups. As the number of stereo- stereocenter centers increases, so does the number of stereoisomers. For example, the aldotetrose switches configuration 2,3,4-trihydroxybutanal has two stereocenters and hence may exist as four stereoisomers: D-Allose D-Altrose two diastereomers, each as a pair of enantiomers. The next higher homolog, 2,3,4,5- tetrahydroxypentanal, has three stereocenters, and therefore eight stereoisomers are possible: four diastereomeric pairs of enantiomers. Similarly, 16 stereoisomers (as eight enantiomeric pairs) may be formulated for the corresponding pentahydroxyhexanal. Like many natural products, these diastereomers have common names that are often used, mainly because the complexity of these molecules leads to long systematic names. This chapter will therefore deviate from our usual procedure of labeling molecules system- atically. The isomer of 2,3,4-trihydroxybutanal with 2R,3R con! guration is called erythrose; its diastereomer, threose. Note that each of these isomers has two enantiomers, one belonging to the family of the " sugars, its mirror image to the # sugars. The sign of the optical rotation is not correlated with the " and # label (just as in the R,S notation: (2) Does not necessarily correspond to S, and (1) does not necessarily correspond to R; see Section 5-3). For example, "-glyceraldehyde is dextrorotatory, but "-erythrose is levorotatory. 24-1 Names and Structures of Carbohydrates CHAPTER 24 1075

Most sugars are chiral and optically active With the exception of 1,3-dihydroxyacetone, all the sugars mentioned so far contain at least one stereocenter. The simplest chiral sugar is 2,3-dihydroxypropanal (glyceraldehyde), with one asymmetric carbon. Its dextrorotatory form is found to be R and the levorotatory enantiomer S, as shown in the Fischer projections of the molecule. Recall that, by convention, the horizontal lines in Fischer projections represent bonds to atoms above the plane of the page (Section 5-4).

Fischer Projections of the Two Enantiomers Model Building of 2,3-Dihydroxypropanal (Glyceraldehyde)

CHO CHO CHO CHO ´ ´ HOH is the same as HC# !OH HO H is the same as HO# !HC ≥ ≥ CH OH CH OH 2 CH2OH 2 CH2OH R)-(؉)-2,3-Dihydroxypropanal (S)-(؊)-2,3-Dihydroxypropanal Enantiomers) [D-(؉)-Glyceraldehyde] [L-(؊)-Glyceraldehyde] 25؇C 25؇C ؊8.7) CHO CHO ؍ ؉8.7) ([␣]D ؍ D[␣]) HOHHO H Even though R and S nomenclature is perfectly satisfactory for naming sugars, an older Even systemthough isR stilland in Sgeneralnomenclature use. It was isdevelopedperfectly beforesatisfactory the absolutefor connaming! gurationsugars, of sugarsan older H OH HO H systemwasis established,still in general and it relatesuse. allInstead sugars toof 2,3-dihydroxypropanalR and S, it uses the(glyceraldehyde).prefixes D Insteadfor the (+)H OH HO H of R and S, it uses the pre! xes " for the (1) enantiomer of glyceraldehyde and # for the enantiomer of glyceraldehyde and L for the (-) enantiomer. H OH HO H (2) enantiomer (Real Life 5-2). Those monosaccharides whose highest-numbered stereocenter Those(i.e.,monosaccharides the one farthest fromwhose the aldehydehighest -ornumbered keto group)stereocenter has the same (iabsolute.e., the conone! gurationfarthest as from CH2OH CH2OH the aldehydethat of "-(or1)-2,3-dihydroxypropanalketo group) has the ["-(same1)-glyceraldehyde]absolute configuration are then labeledas ";that thoseof withD- the(+) -2,3- Mirror plane dihydroxypropanalopposite con! guration[D-(+) -atglyceraldehyde] that stereocenter areare namedthen #.labeled Two diastereomersD; those thatwith differthe inopposite the stereochemistry of only one stereocenter (the same in each one) are also called epimers (margin). All stereocenters configuration at that stereocenter are named L. switch configuration Designation of a DL and an Sugar D-Allose L-Allose CHO CH OH 2 Epimers H OH O CHO CHO HO H H OH HOHHO H H OH H OH H OH H OH H OH HO H H OH H OH Highest-numbered Highest-numbered H OH H OH CH2OH CH2OH stereocenter stereocenter DL-Aldose -Ketose 7 CH2OH CH2OH Only one The ",# nomenclature divides the sugars into two groups. As the number of stereo- stereocenter centers increases, so does the number of stereoisomers. For example, the aldotetrose switches configuration 2,3,4-trihydroxybutanal has two stereocenters and hence may exist as four stereoisomers: D-Allose D-Altrose two diastereomers, each as a pair of enantiomers. The next higher homolog, 2,3,4,5- tetrahydroxypentanal, has three stereocenters, and therefore eight stereoisomers are possible: four diastereomeric pairs of enantiomers. Similarly, 16 stereoisomers (as eight enantiomeric pairs) may be formulated for the corresponding pentahydroxyhexanal. Like many natural products, these diastereomers have common names that are often used, mainly because the complexity of these molecules leads to long systematic names. This chapter will therefore deviate from our usual procedure of labeling molecules system- atically. The isomer of 2,3,4-trihydroxybutanal with 2R,3R con! guration is called erythrose; its diastereomer, threose. Note that each of these isomers has two enantiomers, one belonging to the family of the " sugars, its mirror image to the # sugars. The sign of the optical rotation is not correlated with the " and # label (just as in the R,S notation: (2) Does not necessarily correspond to S, and (1) does not necessarily correspond to R; see Section 5-3). For example, "-glyceraldehyde is dextrorotatory, but "-erythrose is levorotatory. 24-1 Names and Structures of Carbohydrates CHAPTER 24 1075

Fischer Projections of the Two Enantiomers Model Building of 2,3-Dihydroxypropanal (Glyceraldehyde)

CHO CHO CHO CHO ´ ´ HOH is the same as HC# !OH HO H is the same as HO# !HC ≥ ≥ 24-1 NamesCH OHand Structures of Carbohydrates CHAPTERCH OH 24 1075 2 CH2OH 2 CH2OH R)-(؉)-2,3-Dihydroxypropanal (S)-(؊)-2,3-Dihydroxypropanal Enantiomers) [D-(؉)-Glyceraldehyde] [L-(؊)-Glyceraldehyde] ؊8.7) CHO CHO ؍ ؉8.7) 25؇C ؍ 25؇C Most sugars are chiral and optically active([␣]D ([␣]D With the exception of 1,3-dihydroxyacetone, all the sugars mentioned so far contain at least HOHHO H Even though R and S nomenclature is perfectly satisfactory for naming sugars, an older one stereocenter. The simplest chiral sugar is 2,3-dihydroxypropanal (glyceraldehyde), with H OH HO H one asymmetric carbon. Its dextrorotatory systemform is isfound still to in be general R and theuse. levorotatory It was developed enan- before the absolute con! guration of sugars tiomer S, as shown in the Fischer projectionswas ofestablished, the molecule. and Recall it relates that, all by sugars convention, to 2,3-dihydroxypropanal (glyceraldehyde). Instead H OH HO H of R and S, it uses the pre! xes " for the (1) enantiomer of glyceraldehyde and # for the the horizontal lines in Fischer projections represent bonds to atoms above the plane of the H OH HO H page (Section 5-4). (2) enantiomer (Real Life 5-2). Those monosaccharides whose highest-numbered stereocenter (i.e., the one farthest from the aldehyde or keto group) has the same absolute con! guration as CH2OH CH2OH Fischer Projections of the Two Enantiomers Model Building that of "-(1)-2,3-dihydroxypropanal ["-(1)-glyceraldehyde] are then labeled "; those with the Mirror plane of 2,3-Dihydroxypropanalopposite (Glyceraldehyde) con! guration at that stereocenter are named #. Two diastereomers that differ in the All stereocenters CHO CHO stereochemistryCHO of only one stereocenter (theCHO same in each one) are also called epimers (margin). ´ ´Two diastereomers that differ in the stereochemistry of only oneswitchstereocenter (the same in configuration HOH is the same as HC# !OH HO H is the same as HO# each!HC one) are also called epimer. ≥ Designation≥ of a DL and an Sugar D-Allose L-Allose CH2OH CH OH CH2OH CH OH 2 CHO 2 CH OH R)-(؉)-2,3-Dihydroxypropanal (S)-(؊)-2,3-Dihydroxypropanal 2 Enantiomers Epimers) D-(؉)-Glyceraldehyde] [L-(؊)-Glyceraldehyde]H OH O] 25؇C 25؇C ؊8.7) CHO CHO CHO CHO ؍ ؉8.7) ([␣]D ؍ D[␣]) HO H H OH HOHHO H HOHHO H Even though R and S nomenclature is perfectly satisfactory for namingH sugars, OHan older H OH system is still in general use. It was developed before the absolute con! guration of sugars H OH HO H H OH H OH was established, and it relates all sugars to 2,3-dihydroxypropanal (glyceraldehyde). Instead H OH HO H of R and S, it uses the pre! xes " for the (1) enantiomer of glyceraldehydeH and #OH for the HO H H OH H OH H OH HO H Highest-numbered (2) enantiomer (Real Life 5-2). Those monosaccharides whoseHighest-numbered highest-numbered stereocenter H OH H OH CH2OH CH2OH stereocenter (i.e., the one farthest from the aldehyde or keto group) has the stereocentersame absolute con! guration as CH2OH CH2OH DL-Aldose -Ketose CH2OH CH2OH that of "-(1)-2,3-dihydroxypropanal ["-(1)-glyceraldehyde] are then labeled "; those with the Mirror plane opposite con! guration at that stereocenter are named #. Two diastereomers that differ in the Only one The ",# nomenclature divides the sugars into two groups. As the number of stereo- stereocenter stereochemistry of only one stereocenter (the same in each one) are also called epimers (margin). All stereocenters centers increases, so does the number of stereoisomers. switch For example, the aldotetrose switches configuration configuration Designation of2,3,4-trihydroxybutanal a DL and an Sugar has two stereocenters andD -Allosehence may exist asL-Allose four stereoisomers: D-Allose D-Altrose two diastereomers, each as a pair of enantiomers. The next higher homolog, 2,3,4,5- CHO CH OH tetrahydroxypentanal,2 has three stereocenters, and therefore eightEpimers stereoisomers are possible: 8 H OH four diastereomericO pairs of enantiomers. Similarly, 16 stereoisomers (as eight enantiomeric CHO CHO HO H pairs)H may beOH formulated for the corresponding pentahydroxyhexanal. Like many natural products, these diastereomersHOH have commonHO names H that are often H OH H OH used, mainly because the complexity of these moleculesH OH leads to longH systematicOH names. This chapter will therefore deviate from our usual procedure of labeling molecules system- H OH HO H H OH H OH atically. The isomer of 2,3,4-trihydroxybutanal with 2R,3R con! guration is called erythrose; Highest-numbered Highest-numbered H OH H OH CH2OH CH2OH stereocenter stereocenter its diastereomer, threose. Note that each of these isomers has two enantiomers, one belong- DL-Aldose -Ketose ing to the family of the " sugars, its mirror image toCH the2OH # sugars. TheCH sign2OH of the optical Only one The ",# nomenclature divides the sugarsrotation into istwo not groups. correlated As the with number the " of and stereo- # label (just as in stereocenterthe R,S notation: (2) Does not centers increases, so does the number ofnecessarily stereoisomers. correspond For example, to S, and the (1 aldotetrose) does not necessarily correspondswitches to R; see Section 5-3). configuration 2,3,4-trihydroxybutanal has two stereocentersFor example,and hence " may-glyceraldehyde exist as four stereoisomers:is dextrorotatory, butD-Allose "-erythrose is levorotatory.D-Altrose two diastereomers, each as a pair of enantiomers. The next higher homolog, 2,3,4,5- tetrahydroxypentanal, has three stereocenters, and therefore eight stereoisomers are possible: four diastereomeric pairs of enantiomers. Similarly, 16 stereoisomers (as eight enantiomeric pairs) may be formulated for the corresponding pentahydroxyhexanal. Like many natural products, these diastereomers have common names that are often used, mainly because the complexity of these molecules leads to long systematic names. This chapter will therefore deviate from our usual procedure of labeling molecules system- atically. The isomer of 2,3,4-trihydroxybutanal with 2R,3R con! guration is called erythrose; its diastereomer, threose. Note that each of these isomers has two enantiomers, one belonging to the family of the " sugars, its mirror image to the # sugars. The sign of the optical rotation is not correlated with the " and # label (just as in the R,S notation: (2) Does not necessarily correspond to S, and (1) does not necessarily correspond to R; see Section 5-3). For example, "-glyceraldehyde is dextrorotatory, but "-erythrose is levorotatory. The D,L nomenclature divides the sugars into two groups. As the number of stereocenters increases, so does the number of stereoisomers. For example, the aldotetrose 2,3,4- trihydroxybutanal has two stereocenters and hence may exist as four stereoisomers: two diastereomers, each as a pair of enantiomers.

The next higher homolog, 2,3,4,5-tetrahydroxypentanal, has three stereocenters, hence eight stereoisomers are possible (23 = 8): four diastereomeric pairs of enantiomers.

Similarly, 16 stereoisomers (as eight enantiomeric pairs) may be formulated for the corresponding pentahydroxyhexanal (24 = 16).

The isomer of 2,3,4-trihydroxybutanal with 2R,3R configuration is called erythrose; its diastereomer, threose.

Note that each of these isomers has two enantiomers, one belonging to the family of the D sugars, its mirror image to the L sugars. The sign of the optical rotation is not correlated with the D and L label (just as in the R,S notation). 9 1076 CHAPTER 24 Carbohydrates

Model Building Stereoisomeric 2,3,4-Trihydroxybutanals: Erythrose (2 Enantiomers) and Threose (2 Enantiomers) Diastereomers

Enantiomers Enantiomers

CHO OHC CHO OHC H R OH HO S H HO S H H R OH H R OH HO S H H R OH HO S H

CH2OH HOCH2 CH2OH HOCH2 2R,3R 2S,3S 2S,3R 2R,3S

O O O O O O O O R S S R R S R S O O O O O O O O

D-(؊)-Erythrose L-(؉)-Erythrose D-(؊)-Threose L-(؉)-Threose

Mirror Mirror 10 plane plane

As mentioned previously, an aldopentose has three stereocenters and hence 23 5 8 stereoisomers. There are 24 5 16 such isomers in the group of aldohexoses. Why then use the !," nomenclature even though it designates the absolute con# guration of only one stereocenter? Probably because almost all naturally occurring sugars have the D con! guration. Evidently, somewhere in the structural evolution of the sugar molecules, nature “chose” only one con# guration for one end of the chain. The amino acids are another example of such selectivity (Chapter 26). Figure 24-1 shows Fischer projections of the series of !-aldoses up to the aldohexoses. To prevent confusion, chemists have adopted a standard way to draw these projections: The carbon chain extends vertically and the aldehyde terminus is placed at the top. In this convention, the hydroxy group at the highest-numbered stereocenter (at the bottom) points to the right in all ! sugars. Figure 24-2 shows the analogous series of ketoses.

Exercise 24-2 Give a systematic name for (a) !-(2)-ribose and (b) !-(1)-glucose. Remember to assign the R and S con# guration at each stereocenter.

HO H H OH

*C *C Exercise 24-3

* C CHO HOCH2 Redraw the hashed-wedged line structure of sugar A (shown in the margin) as a Fischer projection OH H and # nd its common name in Figure 24-1. A

In Summary The simplest carbohydrates are sugars, which are polyhydroxy aldehydes (aldoses) and ketones (ketoses). They are classi# ed as ! when the highest-numbered stereocenter is R, " when it is S. Sugars related to each other by inversion at one stereocenter are called epimers. Most of the naturally occurring sugars belong to the ! family. Why then use the D,L nomenclature even though it designates the absolute configuration of only one stereocenter?

Probably because almost all naturally occurring sugars have the D configuration.

Evidently, somewhere in the structural evolution of the sugar molecules, nature “chose” only one configuration for one end of the chain. The amino acids are another example of such selectivity.

Fischer projections of the series of D-aldoses and D-ketoses:

The carbon chain extends vertically and the aldehyde terminus is placed at the top. In this convention, the hydroxy group at the highest-numbered stereocenter (at the bottom) points to the right in all D sugars.

11 24-1 Names and Structures of Carbohydrates CHAPTER 24 1077

CHO Figure 24-1 D-Aldoses (up to the aldohexoses), their signs of H OH rotation, and their common names. CHO CH2OH CHO D-(؉)-Glyceraldehyde H OH HO H H OH H OH

CH2OH CH2OH D-(؊)-Erythrose D-(؊)-Threose

CHO CHO CHO CHO H OH HO H H OH HO H H OH H OH HO H HO H H OH H OH H OH H OH

CH2OH CH2OH CH2OH CH2OH D-(؊)-Ribose D-(؊)-Arabinose D-(؉)-Xylose D-(؊)-Lyxose

CHO CHO CHO CHO CHO CHO CHO CHO H OH HO H H OH HO H H OH HO H H OH HO H H OH H OH HO H HO H H OH H OH HO H HO H H OH H OH H OH H OH HO H HO H HO H HO H H OH H OH H OH H OH H OH H OH H OH H OH CH OH CH OH CH OH CH OH CH OH CH OH CH OH CH OH 2 2 2 2 2 2 2 2 12 D-(؉)-Allose D-(؉)-Altrose D-(؉)-Glucose D-(؉)-Mannose D-(؊)-Gulose D-(؊)-Idose D-(؉)-Galactose D-(؉)-Talose

CH2OH O

CH2OH 1,3-Dihydroxyacetone

CH2OH O H OH

CH2OH D-(؊)-Erythrulose

CH2OH CH2OH O O H OH HO H H OH H OH

CH2OH CH2OH D-(؉)-Ribulose D-(؉)-Xylulose

CH2OH CH2OH CH2OH CH2OH O O O O H OH HO H H OH HO H H OH H OH HO H HO H H OH H OH H OH H OH Figure 24-2 D-Ketoses (up to the ketohexoses), their signs of CH2OH CH2OH CH2OH CH2OH rotation, and their common .D-(؉)-Psicose D-(؊)-Fructose D-(؉)-Sorbose D-(؊)-Tagatose names 24-1 Names and Structures of Carbohydrates CHAPTER 24 1077

CHO Figure 24-1 D-Aldoses (up to the aldohexoses), their signs of H OH rotation, and their common names. CHO CH2OH CHO D-(؉)-Glyceraldehyde H OH HO H H OH H OH

CH2OH CH2OH D-(؊)-Erythrose D-(؊)-Threose

CHO CHO CHO CHO H OH HO H H OH HO H H OH H OH HO H HO H H OH H OH H OH H OH

CH2OH CH2OH CH2OH CH2OH D-(؊)-Ribose D-(؊)-Arabinose D-(؉)-Xylose D-(؊)-Lyxose

CHO CHO CHO CHO CHO CHO CHO CHO H OH HO H H OH HO H H OH HO H H OH HO H H OH H OH HO H HO H H OH H OH HO H HO H H OH H OH H OH H OH HO H HO H HO H HO H H OH H OH H OH H OH H OH H OH H OH H OH

CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH D-(؉)-Allose D-(؉)-Altrose D-(؉)-Glucose D-(؉)-Mannose D-(؊)-Gulose D-(؊)-Idose D-(؉)-Galactose D-(؉)-Talose

CH2OH O

CH2OH 1,3-Dihydroxyacetone

CH2OH O H OH

CH2OH D-(؊)-Erythrulose

CH2OH CH2OH O O H OH HO H H OH H OH

CH2OH CH2OH D-(؉)-Ribulose D-(؉)-Xylulose

CH2OH CH2OH CH2OH CH2OH O O O O H OH HO H H OH HO H H OH H OH HO H HO H H OH H OH H OH H OH Figure 24-2 D-Ketoses (up to the ketohexoses), their signs of CH2OH CH2OH CH2OH CH2OH rotation, and13 their common .D-(؉)-Psicose D-(؊)-Fructose D-(؉)-Sorbose D-(؊)-Tagatose names 1078 CHAPTER 24 Carbohydrates

24-2 CONFORMATIONS AND CYCLIC FORMS OF SUGARS

Sugars are molecules with multiple functional groups and multiple stereocenters. This structural complexity gives rise to a variety of chemical properties. To enable chemists to focus on the portion of a sugar molecule involved in any given chemical process, several ways of depicting sugars have been developed. We have seen the Fischer representation in Section 24-1; this section shows how to interconvert Fischer and hashed- wedged representations. In addition, it introduces the cyclic isomers that exist in solutions 24-2 CONFORMATIONSofAND simpleCYCLIC sugars. FORMS OF SUGARS

Sugars are molecules with multiple functional groups and multiple stereocenters. This structural complexity givesFischerrise to projectionsa variety of chemical depict all-eclipsedproperties. conformations Several ways of depictingRecallsugars (Sectionhave 5-4) thatbeen the developed Fischer projection. It introduces represents thethe moleculecyclic in isomers an all-eclipsed that exist in solutions of simplearrangementsugars. It can. be translated into an all-eclipsed hashed-wedged line picture. Model Building Fischer projections depict all-eclipsed conformations Fischer Projection and Hashed-Wedged Line Structures for D-(؉)-Glucose

CHO 1CHO H OH 2 180Њ

H OH H# OH H OH H ∑ / A ! A rotation 2 / H OH H OH C 1 3 ! CHO ∑ 2 of C3

3 HO ∑ / ∑ / A A A 1 A HO H HO#!H C3 CHO and C5 A

HO#!H HOCH2 5 C 3 C 1

/ A 6 6 ∑ 4 4 42∑ / C C / CHO

H OH H#!OH HO C∑ CH2OH

4 6 A 5 A

∑ 5 # 5 CH OH /C H OH H OH # # # # # # # # # # # # # # # # # # # # 2 H HOHH OH #! H O 6 H # # OH HO H CH2OH CH2OH H After 180Њ rotation, OH moves from in front of the plane Fischer All-eclipsed of the page to behind it. All-staggered projection hashed-wedged hashed-wedged 14 line structure line structure

A molecular model can help you see that the all-eclipsed form actually possesses a roughly circular shape, as illustrated by the “scrolled” rendition above (center picture). In the subsequent all-eclipsed hashed-wedged line structure, notice that the groups on the right of the carbon chain in the original Fischer projection now project upward (wedged bonds). From this conformer, we can reach the all-staggered form by 1808 rotations of C3 and C5.

Sugars form intramolecular hemiacetals Sugars are hydroxycarbonyl compounds that should be capable of intramolecular hemiacetal formation (see Section 17-7). Indeed, glucose and the other hexoses, as well as the pentoses, exist as an equilibrium mixture with their cyclic hemiacetal isomers, in which the hemiacetals strongly predominate. In principle, any one of the ! ve hydroxy groups could add to the carbonyl group of the aldehyde. However, three- and four- membered rings are too strained, and ! ve- and six-membered rings are the products, the latter usually dominating. The six-membered ring structure of a monosaccharide is called a pyranose, a name derived from pyran, a six-membered cyclic ether (see Sections 9-6 and 25-1). Sugars in the ! ve-membered ring form are called furanoses, from furan (Section 25-3). A molecular model, the groups on the right of the carbon chain in the original Fischer projection now project upward (wedged bonds). From this conformer, we can reach the all- staggered form by 180o rotations of C3 and C5.

Sugars form intramolecular hemiacetals

Sugars are hydroxycarbonyl compounds that should be capable of intramolecular hemiacetal formation. Indeed, glucose and the other hexoses, as well as the pentoses, exist as an equilibrium mixture with their cyclic hemiacetal isomers, in which the hemiacetals strongly predominate.

In principle, any one of the five hydroxy groups could add to the carbonyl group of the aldehyde. However, three- and four-membered rings are too strained, and five- and six- membered rings are the products.

The six-membered ring structure of a monosaccharide is called a pyranose, a name derived from pyran, a six-membered cyclic ether. Sugars in the five-membered ring form are called furanoses, from furan.

15 24-2 Conformations and Cyclic Forms of Sugars CHAPTER 24 1079

Five- and Six-Membered Cyclic Hemiacetal Formation

New stereocenter

Reminder

OH H A H A A A O

Hϩ A O The equilibrium for cyclic A

B 41 H C CA hemiacetal formation is H2C 4 CO 2 OH A A 1 A favorable, in contrast to

H2C A CH2 H2CCHA 2 3 2 3 2 its intermolecular variant. Furanose ring Furan What tips the balance is the relatively more favorable (or, better, less unfavorable) New

stereocenter entropy of cyclization O OH (Section 17-7).

H2C 5 H H C A O A 2 A O

ϩ 5 H

O O H O H2C 4 COB H2C 4 1 C 1 A A O O OH H2CCHA 2 H2C A CH2 3 2 3 2 Pyranose ring Pyran

To depict a !-series sugar correctly in its cyclic form, draw the hashed-wedged line 16 representation of the all-eclipsed structure on the previous page and " ip it upside down, as Model Building shown below. Rotation of C5 places its hydroxy group in position to form a six-membered cyclic hemiacetal by addition to the C1 aldehyde carbon. Similarly, a # ve-membered ring can be made by rotation of C4 to place its OH group in position to bond to C1. The resulting drawings depict the ring in a somewhat arti# cial way: It is shown as if it were planar and from a perspective in which the bottom-most ring bonds (between C2 and C3 in the structures below) are interpreted as being in front of the plane of the page. As we shall see shortly, a slightly modi# ed version of this type of drawing is quite commonly used to depict Animation the cyclic forms of sugars. ANIMATED MECHANISM: Cyclic hemiacetal formation by glucose Cyclic Hemiacetal Formation by Glucose

Leads to pyranose H OH OH Leads to furanose H

∑ / H ∑ HOCH2 ∑ A H / A / 6 / C 1 C CH2OH C OH

HO ∑ 2 Flip 5 6 Rotate C5 by 5

C CHO HO HO ∑ 3 ∑

upside 4 1 120Њ around 4 1 / A 6 C CHO C CHO

4 down / C4–C5 bond /

∑ H 3 2 H 3 2 /

HO /

∑ C 5 CH2OH ∑

∑ A A ∑

∑ C C CC / /

H C H / H H H HO H OH HO OH HO D-Glucose

6 6 CH2OH CH2OH A A 5 H C 5 O HO COO H O A H H A D A D C 4 H 1 C C 4 1C A OH H G A OH H G A A OH A A OH HO 3 2 H 3 2 C C C C A A New A New A H OH stereocenter H OH stereocenter D-Glucofuranose D-Glucopyranose (Less stable, 0.4%) (More stable, 99.6%) (Groups on the right in the original Fischer projection [circled] point downward in the cyclic hemiacetal except at C5, which has been rotated) To depict a D-series sugar correctly in its cyclic form, draw the hashed-wedged line representation of the all-eclipsed structure on the previous page and flip it upside down, as shown below.

Rotation of C5 places its hydroxy group in position to form a six-membered cyclic hemiacetal by addition to the C1 aldehyde carbon. Similarly, a five-membered ring can be made by rotation of C4 to place its OH group in position to bond to C1.

The resulting drawings depict the ring in a somewhat artificial way: It is shown as if it were planar and from a perspective in which the bottom-most ring bonds (between C2 and C3 in the structures below) are interpreted as being in front of the plane of the page.

17 24-2 Conformations and Cyclic Forms of Sugars CHAPTER 24 1079

Five- and Six-Membered Cyclic Hemiacetal Formation

New stereocenter

Reminder

OH H A H A A A O

Hϩ A O The equilibrium for cyclic A

B 41 H C CA hemiacetal formation is H2C 4 CO 2 OH A A 1 A favorable, in contrast to

H2C A CH2 H2CCHA 2 3 2 3 2 its intermolecular variant. Furanose ring Furan What tips the balance is the relatively more favorable (or, better, less unfavorable) New

stereocenter entropy of cyclization O OH (Section 17-7).

H2C 5 H H C A O A 2 A O

ϩ 5 H

O O H O H2C 4 COB H2C 4 1 C 1 A A O O OH H2CCHA 2 H2C A CH2 3 2 3 2 Pyranose ring Pyran

To depict a !-series sugar correctly in its cyclic form, draw the hashed-wedged line representation of the all-eclipsed structure on the previous page and " ip it upside down, as Model Building shown below. Rotation of C5 places its hydroxy group in position to form a six-membered cyclic hemiacetal by addition to the C1 aldehyde carbon. Similarly, a # ve-membered ring can be made by rotation of C4 to place its OH group in position to bond to C1. The resulting drawings depict the ring in a somewhat arti# cial way: It is shown as if it were planar and from a perspective in which the bottom-most ring bonds (between C2 and C3 in the structures below) are interpreted as being in front of the plane of the page. As we shall see shortly, a slightly modi# ed version of this type of drawing is quite commonly used to depict Animation the cyclic forms of sugars. ANIMATED MECHANISM: Cyclic hemiacetal formation by glucose Cyclic Hemiacetal Formation by Glucose

Leads to pyranose H OH OH Leads to furanose H

∑ / H ∑ HOCH2 ∑ A H / A / 6 / C 1 C CH2OH C OH

HO ∑ 2 Flip 5 6 Rotate C5 by 5

C CHO HO HO ∑ 3 ∑

upside 4 1 120Њ around 4 1 / A 6 C CHO C CHO

4 down / C4–C5 bond /

∑ H 3 2 H 3 2 /

HO /

∑ C 5 CH2OH ∑

∑ A A ∑

∑ C C CC / /

H C H / H H H HO H OH HO OH HO D-Glucose

Exercise 24-4 Draw the Fischer projection of #-(2)-glucose and illustrate its transformation into the corresponding six-membered cyclic hemiacetal.

In contrast with glucose, which exists primarily as the pyranose, fructose forms both fruc- In contrast withtopyranoseglucose, and fructofuranosewhich exists in a rapidlyprimarily equilibratingas 68the : 32 pyranose,mixture. fructose forms both fructopyranose and fructofuranose in a rapidly equilibrating 68:32 mixture. Model Building Cyclic Hemiacetal Formation by Fructose

OH O O H2C O

HO 6 ∑ C 5 2 COCH2OH

/ 43 1

H O O /

∑ CCO ∑

High-fructose HO / OH Really corn syrup HH (HFCS), was D-Fructose introduced in the 1980s as a cheaper alternative to table sugar (sucrose; Section 24-11) and 6 CH2 O is used in many packaged O H 6 HOCH2 A CH2OH foods and beverages. The A CH2OH D 1 D 1 C 5 2 C label “high-fructose” is C 5 2 C A H HO G A H HO G A A OH commonly misinterpreted. A A OH HO 43 HFCS is produced from corn H 43 C C C C A A New to yield a product that is A A New OH H stereocenter almost entirely glucose. OH H stereocenter (anomeric carbon) (anomeric carbon) Because glucose is less 32% 68% sweet than sucrose, corn D-Fructofuranose D-Fructopyranose syrup is treated with six-membered 19 ؍ five-membered (Pyranose ؍ Furanose) enzymes that isomerize the cyclic sugar) cyclic sugar) glucose to fructose (which is sweeter than sucrose), resulting in HFCS 42 Note that, upon cyclization, the carbonyl carbon turns into a new stereocenter. As a con- (42% fructose), used in sequence, hemiacetal formation leads to two new compounds, two diastereomers (epimers) some beverages, processed differing in the con! guration of the hemiacetal group. If that con! guration is S in a "-series foods, cereals, and baked sugar, that diastereomer is labeled ␣; when it is R in a " sugar, the isomer is called ␤. Hence, goods. Further enrichment for example, "-glucose may form ␣- or ␤-"-glucopyranose or -furanose. Because this type of gives the ingredient in diastereomer formation is unique to sugars, such isomers have been given a separate name: soft drinks, HFCS 55 anomers. The new stereocenter is called the anomeric carbon. (55% fructose), which is about as sweet as sugar. Compare this to sucrose, Working with the Concepts: Relationships Between which is a disaccharide Solved Exercise 24-5 composed of fructose and Sugar Stereoisomers glucose held together by a The anomers ␣- and ␤-glucopyranose should form in equal amounts because they are enantiomers. mutual acetal linkage. This True or false? Explain your answer. labile bond is hydrolyzed in the intestinal tract to its Strategy component sugars, equivalent Be sure that you understand the meanings of enantiomer and diastereomer, and how physical to HFCS 50. In short, the two properties of molecules relate to those stereoisomeric relationships, before you answer this question sweeteners are in essence the about anomers. same, at least chemically. Solution False! Anomers differ in con! guration at only the anomeric carbon (C1). The con! gurations at the remaining stereocenters (C2 through C5) are the same in ␣-glucopyranose as they are in ␤-glucopyranose. Anomers are therefore diastereomers—not enantiomers—and should not form in equal amounts. Enantiomers differ from each other in con! guration at every stereocenter. Upon cyclization, the carbonyl carbon turns into a new stereocenter. As a consequence, hemiacetal formation leads to two new compounds, two diastereomers (epimers) differing in the configuration of the hemiacetal group.

If that configuration is S in a D-series sugar, that diastereomer is labeled �; when it is R in a D sugar, the isomer is called �.

For example, D-glucose may form �- or �-D-glucopyranose or -furanose.

Because this type of diastereomer formation is unique to sugars, such 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

20 24-2 Conformations and Cyclic Forms of Sugars CHAPTER 24 1081

Exercise 24-6 Try It Yourself How is ␣-"-glucopyranose related to ␣-!-glucopyranose? What is the con# guration of the anomeric carbon in ␣-"-glucopyranose, R or S? Answer the same question for ␤-"-glucopyranose and ␤-!- glucopyranose.

How canFischer,we represent Haworth,the stereochemistry and chair cyclohexaneof the cyclic forms projectionsof sugars? help depict cyclic sugars Fischer Howprojections can we represent: We simply the stereochemistrydraw elongated of the lines cyclicto formsindicate of sugars?the bonds One approachformed upon cyclization,usespreserving Fischer projections.the basic We simply“grid” ofdrawthe elongatedoriginal linesformula to indicate. the bonds formed upon cyclization, preserving the basic “grid” of the original formula. Be careful not to confuse In the Fischerthe threeprojection new apicesof ofthe the� ensuingform of rectanglea D sugar, with carbonthe anomeric atoms. OH points toward the right, while in the � form, the anomeric OH is on the left.

Adapted Fischer Projections of Glucopyranoses Not a carbon atom

CH2OH CH2OH CH2OH Not a carbon atom D-(؉)-Glucopyranose ␤-D-(؉)-Glucopyranose-␣ 21 (m.p. 146؇C) (m.p. 150؇C)

Haworth* projections more accurately represent the real three-dimensional structure of the sugar molecule. The cyclic ether is written in line notation as a pentagon or a hexa- gon, the anomeric carbon (in a ! sugar) placed on the right, and the ether oxygen put on top. The substituents located above or below the ring are attached to vertical lines. In relat- ing the Haworth projection to a three-dimensional structure, we interpret the ring bond at the bottom (between C2 and C3) to be in front of the plane of the paper, and the ring bonds containing the oxygen are understood to be in back.

Haworth Projections

HOCH2 HOCH2 6A 6A O O O H H H A5 H H A5 OH Groups on the right in the A A A H A A H A 41 4141 Fischer projection point A H H A A OH H A A OH H A downward in the Haworth H A3 2A OH HO A32A OH HO A32A H formula. A A A A A A OH OH H OH H OH D-(؊)-Erythrofuranose ␣-D-(؉)-Glucopyranose ␤-D-(؉)-Glucopyranose-␣

In a Haworth projection, the ␣ anomer has the OH group at the anomeric carbon pointing down, whereas the ␤ anomer has it pointing up.

*Sir W. Norman Haworth (1883–1950), University of Birmingham, England, Nobel Prize 1937 (chemistry). 24-2 Conformations and Cyclic Forms of Sugars CHAPTER 24 1081

Fischer, Haworth, and chair cyclohexane projections help depict cyclic sugars How can we represent the stereochemistry of the cyclic forms of sugars? One approach uses Fischer projections. We simply draw elongated lines to indicate the bonds formed upon cyclization, preserving the basic “grid” of the original formula. Be careful not to confuse the three new apices of the ensuing rectangle with carbon atoms.

Adapted Fischer Projections of Glucopyranoses Not a carbon atom

S R O M COH HOCOO H HOHOCO In the Fischer projection of H OH H OH H OH the ␣ form of a ! sugar, the Cyclization anomeric OH points toward HO H HO H O HO H O the right. In the Fischer H OH H OH H OH projection of the ␤ form, the anomeric OH is on the left. Haworth projectionsH OHmore accurately representH the real threeH -dimensional structure of the CH2OH CH2OH CH2OH Not a sugar molecule. The cyclic ether is written in line notation as a pentagon carbonor a atomhexagon, the D-(؉)-Glucopyranose ␤-D-(؉)-Glucopyranose-␣ .anomeric carbon (in a D sugar) placed on the(m.p. right,146؇C) and the ether(m.p. 150؇oxygenC) put on top The substituents located above or below the ring are attached to vertical lines. The ring bond at the bottomHaworth*(between projectionsC2 moreand accuratelyC3) assume representto thebe realin front three-dimensionalof the plane structureof the paper, and the ringofbonds the sugarcontaining molecule. Thethe cyclicoxygen etherare is writtenunderstood in line notationto be asin a backpentagon. or a hexa- gon, the anomeric carbon (in a ! sugar) placed on the right, and the ether oxygen put on top. The substituents located above or below the ring are attached to vertical lines. In relat- In a Haworthingprojection, the Haworth theprojection� anomer to a three-dimensionalhas the OH structure,group weat theinterpretanomeric the ring bondcarbon at pointing down, whereasthe bottomthe � (betweenanomer C2has and itC3)pointing to be in frontup. of the plane of the paper, and the ring bonds containing the oxygen are understood to be in back. Groups on the right in the Fischer projection point downward in the Haworth formula. Haworth Projections

In a Haworth projection, the ␣ anomer has the OH group at the anomeric carbon pointing down, whereas the ␤ anomer has it pointing up.

*Sir W. Norman Haworth (1883–1950), University of Birmingham, England, Nobel Prize 1937 (chemistry). The cyclic forms of sugars can be presented mostly as envelope (for furanoses) or chair (for pyranoses) conformations.

The ether oxygen will be placed usually top right and the anomeric carbon at the right vertex of the envelope or chair.

Although there are exceptions, most aldohexoses adopt the chair conformation that places the bulky hydroxymethyl group at the C5 terminus in the equatorial position.

For glucose, this preference means that, in the � form, four of the five substituents can be equatorial, and one is forced to lie axial; in the � form, all substituents can be equatorial.

This situation is unique for glucose; the other seven D aldohexoses contain one or more axial substituents.

23 1082 CHAPTER 24 Carbohydrates

Exercise 24-7 Draw Haworth projections of (a) ␣-!-fructofuranose; (b) ␤-!-glucofuranose; and (c) ␤-!- arabinopyranose.

Haworth projections are used extensively in the literature, but here, to make use of our knowledge of conformation (Sections 4-3 and 4-4), the cyclic forms of sugars will be presented mostly as envelope (for furanoses) or chair (for pyranoses) conformations (Figures 4-4 and 4-6). As in Haworth notation, the ether oxygen will be placed usually top right and the anomeric carbon at the right vertex of the envelope or chair.

Conformational Pictures of Glucofuranose and -pyranose

HO CH2OH H H ∑ Anomeric CH2OH Anomeric CH2OH Anomeric O carbon O carbon O carbon HO HO H H A H A H A H A H A HO OH HO H HO OH OH OH OH H H H OH H H Equatorial Equatorial Envelope conformation ( ␤ ) Chair conformation Chair conformation ( ␤ ) Axial (␣ ) O O O O O O O O O O O O O O O O O Axial Equatorial (␣ ) ( ␤ ) O

␤-D-Glucofuranose ␣-D-Glucopyranose ␤-D-Glucopyranose Equatorial (One axial –OH group) (All substituents equatorial) ( ␤ ) Most stable form

24 Although there are exceptions, most aldohexoses adopt the chair conformation that places the bulky hydroxymethyl group at the C5 terminus in the equatorial position. For glucose, this preference means that, in the ␣ form, four of the # ve substituents can be equatorial, and one is forced to lie axial; in the ␤ form, all substituents can be equatorial. This situation is unique for glucose; the other seven ! aldohexoses (see Figure 24-1) contain one or more axial substituents.

Exercise 24-8 Using the values in Table 4-3, estimate the difference in free energy between the all-equatorial conformer of ␤-!-glucopyranose and that obtained by ring " ip (assume that DGCH8 OH 5 DGCH8 5 21 2 3 1.7 kcal mol and that the ring oxygen mimics a CH2 group).

In Summary Hexoses and pentoses can take the form of # ve- or six-membered cyclic hemiacetals. These structures rapidly interconvert through the open-chain polyhydroxy- aldehyde or ketone, with the equilibrium usually favoring the six-membered (pyranose) ring. 24-3 ANOMERS OF SIMPLE SUGARS: MUTAROTATION OF GLUCOSE

Glucose precipitates from concentrated solutions at room temperature to give crystals that melt at 146 oC. Structural analysis by X-ray diffraction reveals that these crystals contain only the �-D-(+)-glucopyranose anomer.

When crystalline �-D-(+)-glucopyranose is dissolved in water and its optical rotation 25oC measured immediately, a value [a]D = +112 is obtained. Curiously, this value decreases with time until it reaches a constant +52.7. The process that gives rise to this effect is the interconversion of the � and � anomers.

In solution, the �-pyranose rapidly establishes an equilibrium (catalyzed by acid and base) with a small amount of the open-chain aldehyde, which in turn undergoes reversible ring closure to the � anomer.

The � form has a considerably lower specific rotation (+18.7) than its anomer; therefore, the observed � value in solution decreases.

25 24-3 Anomers of Simple Sugars: Mutarotation of Glucose CHAPTER 24 1083

24-3 ANOMERS OF SIMPLE SUGARS: MUTAROTATION OF GLUCOSE

Glucose precipitates from concentrated solutions at room temperature to give crystals that melt at 1468C. Structural analysis by X-ray diffraction reveals that these crystals contain only the ␣-!-(1)-glucopyranose anomer (Figure 24-3). When crystalline ␣-!-(1)-glucopyranose 25 C is dissolved in water and its optical rotation measured immediately, a value [a]! 8 5 1112 is obtained. Curiously, this value decreases with time until it reaches a constant 152.7. The process that gives rise to this effect is the interconversion of the ␣ and ␤ anomers.

H Figure 24-3 Structure of ␣-D-(1)-glucopyranose, with O 1.102 Å H selected bond lengths and 1.427 Å angles. 1.425 Å CH2 113.8Њ 1.426 Å O 1.095 Å A H 0.971 Å O A HO H H Similarly, a solution of the pureH � anomer (m.p. 150 oC, obtainable by crystallizing glucose

OH 1.389 Å from acetic acid) gradually increases110.6Њ its specific1.525 rotationÅ from +18.7 to +52.7. At this point, a final equilibrium has been reached, with H36109.8.4Њ% of the O� anomer and 63.6% of the � anomer. H

The change in optical rotation observed when a sugar0.969 Å equilibrates with its anomer is called mutarotation (mutare, Latin, to change). Interconversion of � and � anomers is a general property ofIn sugars solution,. the ␣-pyranose rapidly establishes an equilibrium (in a reaction that is catalyzed by acid and base; see Section 17-7) with a small amount of the open-chain alde- This includeshyde, whichall monosaccharidesin turn undergoes reversiblecapable ring closureof existing to the as␤ anomer.cyclic hemiacetals.

Interconversion of Open-Chain and Pyranose Forms of D-Glucose

CHO

CH2OH H OH CH2OH O Hϩ or HOϪ Hϩ or HOϪ O HO HO H HO HO H HO OH H OH OH HO OH H OH H Equatorial CH2OH Axial 36.4% 0.003% 63.6% D-(؉)-Glucopyranose Aldehyde form ␤-D-(؉)-Glucopyranose NMR Spectra of Glucose-␣ 25؇C 25؇C 26 (؉18.7 ؍ [␣]) (؉112 ؍ D[␣]) D The composition of glucose in water is readily measured The ␤ form has a considerably lower speci" c rotation (118.7) than its anomer; there- by 1H NMR spectroscopy. fore, the observed ␣ value in solution decreases. Similarly, a solution of the pure ␤ anomer The " ve hydrogens at C2–C6 (m.p. 1508C, obtainable by crystallizing glucose from acetic acid) gradually increases its bearing only one attached speci" c rotation from 118.7 to 152.7. At this point, a " nal equilibrium has been reached, oxygen appear as overlapping with 36.4% of the ␣ anomer and 63.6% of the ␤ anomer. The change in optical rotation multiplets at ␦ 5 3–4 ppm observed when a sugar equilibrates with its anomer is called mutarotation (mutare, Latin, and are dif" cult to interpret. to change). Interconversion of ␣ and ␤ anomers is a general property of sugars. This includes However, the unique anomeric all monosaccharides capable of existing as cyclic hemiacetals. hydrogens with two appended oxygens show up at lower " eld (see, for example, Table 10-3), Exercise 24-9 for the ␣ anomer at ␦ 5 5.13 (d, J 5 3 Hz) ppm, and for the An alternative mechanism for mutarotation bypasses the aldehyde intermediate and proceeds ␤ anomer at ␦ 5 4.55 (d, J 5 through oxonium ions. Formulate it. 8 Hz) ppm, in the ratio of ϳ1 : 2. Solved Exercise 24-10

Calculate the equilibrium ratio of �- and �-glucopyranose from the specific rotations of the pure anomers and the observed specific rotation at mutarotational equilibrium.

Solution

Let’s designate the mole fraction of the � form as x� and the mole fraction of its � isomer as x�. Their respective specific rotations are given as +112 (�) and +18.7 (�), whereas the equilibrium mixture exhibits a value of +52.7. Thus, we have

+52.7 = (+112)(x�) + (+18.7)(x�)

By the definition of mole fraction, x� + x� = 1, so we can substitute one for the other in the above equation. Solving gives x� = 0.364 and x� = 0.636. Therefore the equilibrium ratio is x� /x� = (0.636)/(0.364) = 1.75.

27 24-4 POLYFUNCTIONAL CHEMISTRY OF SUGARS: OXIDATION TO CARBOXYLIC ACIDS

Simple sugars exist as isomers: the open-chain structure and the � and � anomers of various cyclic forms. Because all of these isomers equilibrate rapidly, the relative rates of their individual reactions with various reagents determine the product distribution of a particular transformation.

The reactions of sugars are divided into two groups, those of the linear form and those of the cyclic forms, because the two structures contain different functional groups.

Although the two forms may sometimes react competitively, reactions of aldoses with oxidizing agents take place at the aldehyde moiety of the open-chain form, not the hemiacetal function of the cyclic isomers.

Because they are polyfunctional compounds, the open-chain monosaccharides undergo the reactions typical of each of their functional groups.

28 24-4 Polyfunctional Chemistry of Sugars CHAPTER 24 1085

Fehling’s and Tollens’sformyltests groupdetect and thereforereducing respondsugars to the standard oxidation tests such as exposure to Fehling’s or Tollens’s solutions (Section 17-14). The ␣-hydroxy substituent in ketoses is Aldoses contain the oxidizablesimilarly oxidized.formyl group and therefore respond to the standard oxidation tests such as exposure to Fehling’s or Tollens’s solutions. The �-hydroxy substituent in ketoses is similarly oxidized. Results of Fehling’s and Tollens’s Tests on Aldoses and Ketoses CHO COOH H OH H OH 2ϩ Ϫ Blue Cu complex, HO , H2O HO H (Fehling’s solution) HHO Cu2O ϩ H OH Brick-red H OH H OH precipitate H OH

CH2OH CH2OH D-Glucose D-Gluconic acid (An aldonic acid)

OOH ϩ ϩϪ OO Ag , NH4 OH, H2O B A (Tollens’s solution) B B RCCHR Ag ϩ RCCR Ketose Silver mirror ␣-Dicarbonyl compound 29

In these reactions, the aldoses are transformed into aldonic acids, ketoses into ␣-dicarbonyl compounds. Sugars that respond positively to these tests are called reducing sugars. All ordinary monosaccharides are reducing sugars. Oxidation of aldoses can give mono- or dicarboxylic acids Aldonic acids are made on a preparative scale by oxidation of aldoses with bromine in buffered aqueous solution (pH 5 526). For example, !-mannose yields !-mannonic acid in this way. Upon subsequent evaporation of solvent from the aqueous solution of the aldonic acid, the ␥-lactone (Section 20-4) forms spontaneously.

Aldonic Acid Preparation and Subsequent Dehydration to Give an Aldonolactone

Br2 oxidizes only here O O M M CHO COH C HO CH2OH

HO H HO H HO H ∑ O HO H Br , H O HO H ⌬ HO H O 2 2 or OH Ϫ2 HBr H H OH H OH ϪH2O H A HO H OH H OH H OH H CH OH CH OH CH OH O 2 2 2 H 83% D-Mannose D-Mannonic acid D-Mannono-␥-lactone

Exercise 24-13 What would the product be if the oxidation of !-mannose took place at the hemiacetal hydroxy group of the cyclic pyranose form, rather than at the carbonyl group of the open-chain isomer, as shown above?

More vigorous oxidation of an aldose leads to attack at the primary hydroxy function as well as at the formyl group. The resulting dicarboxylic acid is called an aldaric, or 24-4 Polyfunctional Chemistry of Sugars CHAPTER 24 1085

formyl group and therefore respond to the standard oxidation tests such as exposure to Fehling’s or Tollens’s solutions (Section 17-14). The ␣-hydroxy substituent in ketoses is similarly oxidized.

Results of Fehling’s and Tollens’s Tests on Aldoses and Ketoses CHO COOH H OH H OH 2ϩ Ϫ Blue Cu complex, HO , H2O HO H (Fehling’s solution) HHO Cu2O ϩ H OH Brick-red H OH H OH precipitate H OH

CH2OH CH2OH D-Glucose D-Gluconic acid (An aldonic acid)

OOH ϩ ϩϪ OO Ag , NH4 OH, H2O B A (Tollens’s solution) B B RCCHR Ag ϩ RCCR Ketose Silver mirror ␣-Dicarbonyl compound

In these reactions, the aldoses are transformed into aldonic acids, ketoses into ␣-dicarbonyl compounds. Sugars that respond positively to these tests are called reducing sugars. All ordinary monosaccharides are reducing sugars. The aldoses are transformed into aldonic acids, ketoses into �-dicarbonyl compounds. SugarsOxidationthat respond of aldosespositively can giveto these mono-tests orare dicarboxyliccalled reducing acidssugars. All ordinary monosaccharidesAldonic acids are madeare reducing on a preparativesugars scale. by oxidation of aldoses with bromine in buffered aqueous solution (pH 5 526). For example, !-mannose yields !-mannonic acid Aldonicin this way.acids Uponare subsequentmade on evaporationa preparative of solventscale fromby theoxidation aqueous of solutionaldoses of thewith bromine in bufferedaldonic acid,aqueous the ␥-lactonesolution (Section(pH 20-4)= 5- 6forms). Upon spontaneously.subsequent evaporation of solvent from the aqueous solution of the aldonic acid, the �-lactone forms spontaneously. Aldonic Acid Preparation and Subsequent Dehydration to Give an Aldonolactone

Br2 oxidizes only here O O M M CHO COH C HO CH2OH

HO H HO H HO H ∑ O HO H Br , H O HO H ⌬ HO H O 2 2 or OH Ϫ2 HBr H H OH H OH ϪH2O H A HO H OH H OH H OH H CH OH CH OH CH OH O 2 2 2 H 83% 30 D-Mannose D-Mannonic acid D-Mannono-␥-lactone

More vigorous oxidation of an aldose leads to attack at the primary hydroxy function as well as at the formyl group. The resulting dicarboxylic acid is called an aldaric, or 1086 CHAPTER 24 MoreCarbohydratesvigorous oxidation of an aldose leads to attack at the primary hydroxy function as well as at the formyl group. The resulting dicarboxylic acid is called an aldaric, or saccharic, acid. saccharic, acid. This oxidation can be achieved with warm dilute aqueous nitric acid This(seeoxidation Section 19-6).can be For achieved example, !with-mannosewarm isdilute convertedaqueous into !nitric-mannaricacid . acidFor underexample, D- mannosethese conditions.is converted into D-mannaric acid under these conditions.

Preparation of an Aldaric Acid

HNO3 oxidizes only here CHO COOH HO H HO H

HO H HNO3, H2O, 60ЊC HO H H OH H OH H OH H OH

CH2OH COOH 44% D-Mannose D-Mannaric acid 31 The preceding syntheses of aldonic and aldaric acids directly from the corresponding aldoses are notable in that they occur in the presence of unprotected secondary hydroxy substituents. This selectivity arises from the intrinsically higher reactivity of the aldehyde function in oxidations (via the corresponding hydrates) and the lesser steric hindrance of primary versus secondary alcohols. To achieve selective conversion of the internal hydroxy groups (leaving the remaining hydroxycarbonyl frame intact) requires more complex protecting-group strategies. You will get a glimpse of such approaches in Section 24-8.

Exercise 24-14 The two sugars !-allose and !-glucose (Figure 24-1) differ in con" guration only at C3. If you did not know which was which and you had samples of both, a polarimeter, and nitric acid at your disposal, how could you distinguish the two? (Hint: Write the products of oxidation.)

In Summary The chemistry of the sugars is largely that expected for carbonyl compounds containing several hydroxy substituents. Oxidation (by Br2) of the formyl group of aldoses gives aldonic acids; more vigorous oxidation (by HNO3) converts sugars into aldaric acids.

24-5 OXIDATIVE CLEAVAGE OF SUGARS

The methods for oxidation of sugars discussed so far leave the basic skeleton intact. A reagent that leads to C–C bond rupture is periodic acid, HIO4. This compound oxidatively degrades vicinal diols to give carbonyl compounds.

Oxidative Cleavage of Vicinal Diols with Periodic Acid O OH / B

ReactionR ∑

H HIO4, H2O CH /

∑ OH CH H B O 77% cis-1,2-Cyclohexanediol Hexanedial

The mechanism of this transformation proceeds through a cyclic periodate ester, which decomposes to give two carbonyl groups. The preceding syntheses of aldonic and aldaric acids directly from the corresponding aldoses are notable in that they occur in the presence of unprotected secondary hydroxy substituents.

This selectivity arises from the intrinsically higher reactivity of the aldehyde function in oxidations (via the corresponding hydrates) and the lesser steric hindrance of primary versus secondary alcohols.

To achieve selective conversion of the internal hydroxy groups (leaving the remaining hydroxycarbonyl frame intact) requires more complex protecting-group strategies.

32 1086 CHAPTER 24 Carbohydrates

saccharic, acid. This oxidation can be achieved with warm dilute aqueous nitric acid (see Section 19-6). For example, !-mannose is converted into !-mannaric acid under these conditions.

Preparation of an Aldaric Acid

HNO3 oxidizes only here CHO COOH HO H HO H

HO H HNO3, H2O, 60ЊC HO H H OH H OH H OH H OH

CH2OH COOH 44% D-Mannose D-Mannaric acid

The preceding syntheses of aldonic and aldaric acids directly from the corresponding aldoses are notable in that they occur in the presence of unprotected secondary hydroxy substituents. This selectivity arises from the intrinsically higher reactivity of the aldehyde function in oxidations (via the corresponding hydrates) and the lesser steric hindrance of primary versus secondary alcohols. To achieve selective conversion of the internal hydroxy groups (leaving the remaining hydroxycarbonyl frame intact) requires more complex protecting-group strategies. You will get a glimpse of such approaches in Section 24-8.

24-5 OXIDATIVE CLEAVAGE OF SUGARS 24-5 OXIDATIVE CLEAVAGE OF SUGARS The methods for oxidation of sugars discussed so far leave the basic skeleton intact. A reagent that leads to C–C bond rupture is periodic acid, HIO4. This compound oxidatively A reagent that leads to C–C bond rupture is periodic acid, HIO4. This compound oxidatively degrades vicinal diols to givedegradescarbonyl vicinalcompounds diols to give. carbonyl compounds.

The mechanism of this transformation proceedsOxidative Cleavagethrough aof cyclicVicinalperiodate Diols with ester,Periodicwhich Acid decomposes to give two carbonyl groups. O OH / B

ReactionR ∑

H HIO4, H2O CH /

24-6 Reduction of Monosaccharides∑ OH to AlditolsCH CHAPTER 24 1087 H B O 77% Mechanism of Periodic Acid Cleavagecis-1,2-Cyclohexanediol of Vicinal Diols Hexanedial

O OH COOH The mechanismC of thisD transformation proceeds through a cyclic periodate ester, which A ϩ HIO4 decomposes to give twoIP carbonylO groups.2 CPO ϩ HIO Mechanism ϪH O 3 COOH 2 C O J A O

Cyclic periodate ester 33

Because most sugars contain several pairs of vicinal diols, oxidation with HIO4 can give complex mixtures. Suf! cient oxidizing agent causes complete degradation of the chain to one-carbon compounds, a technique that has been applied in the structural elucidation of sugars. For example, treatment of glucose with ! ve equivalents of HIO4 results in the formation of ! ve equivalents of formic acid and one of formaldehyde. Similar degradation of the isomeric fructose consumes an equal amount of oxidizing agent, but the products are three equivalents of the acid, two of the aldehyde, and one of carbon dioxide.

Periodic Acid Degradation of Sugars

1 CHO 1 CH2OH 2 H OH 2 O O O O O 3 B 3 HO H 5 HIO4 B HO H 5 HIO4 B B 4 5 HCOH ϩ HCH 4 3 HCOH ϩ 2 HCH ϩ CO2 H OH From From H OH From From From 5 C1–C5 C6 5 C3–C5 C1 C2 H OH H OH and C6 6 6 CH2OH CH2OH D-Glucose D-Fructose

It is found that (1) the breaking of each C–C bond in the sugar consumes one molecule of HIO4, (2) each aldehyde and secondary alcohol unit furnishes an equivalent of formic acid, and (3) the primary hydroxy function gives formaldehyde. The carbonyl group in ketoses gives CO2. The number of equivalents of HIO4 consumed reveals the size of the sugar molecule, and the ratios of products are important clues to the number and arrangement of hydroxy and carbonyl functions. Notice in particular that, after degradation, each carbon fragment retains the same number of attached hydrogen atoms as were present in the original sugar.

Exercise 24-15 Write the expected products (and their ratios), if any, of the treatment of the following compounds with HIO4. (a) 1,2-Ethanediol (ethylene glycol); (b) 1,2-propanediol; (c) 1,2,3-propanetriol; (d) 1,3-propanediol; (e) 2,4-dihydroxy-3,3-dimethylcyclobutanone; (f) "-threose.

Exercise 24-16

Would degradation with HIO4 permit the following sugars to be distinguished? Explain. (For structures, see Figures 24-1 and 24-2.) (a) "-Arabinose and "-glucose; (b) "-erythrose and "-erythrulose; (c) "-glucose and "-mannose.

In Summary Oxidative cleavage with periodic acid degrades the sugar backbone to formic acid, formaldehyde, and CO2. The ratio of these products depends on the structure of the sugar.

24-6 REDUCTION OF MONOSACCHARIDES TO ALDITOLS

Aldoses and ketoses are reduced by the same types of reducing agents that convert aldehydes and ketones into alcohols. The resulting polyhydroxy compounds are called alditols. For example, "-glucose gives "-glucitol (older name, "-sorbitol) when treated with sodium borohydride. Because most sugars contain several pairs of vicinal diols, oxidation with HIO4 can give complex mixtures. Sufficient oxidizing agent causes complete degradation of the chain to one-carbon compounds.

Treatment of glucose with five equivalents of HIO4 results in the formation of five equivalents of formic acid and one of formaldehyde.

Similar degradation of the isomeric fructose consumes an equal amount of oxidizing agent, but the products are three equivalents of the acid, two of the aldehyde, and one of carbon dioxide.

It is found that (1) the breaking of each C–C bond in the sugar consumes one molecule of

HIO4, (2) each aldehyde and secondary alcohol unit furnishes an equivalent of formic acid, and (3) the primary hydroxy function gives formaldehyde. The carbonyl group in ketoses gives CO2.

34 24-6 Reduction of Monosaccharides to Alditols CHAPTER 24 1087

Mechanism of Periodic Acid Cleavage of Vicinal Diols

O OH COOH C D A ϩ HIO4 IPO 2 CPO ϩ HIO Mechanism ϪH O 3 COOH 2 C O J A O

Cyclic periodate ester

Periodic Acid Degradation of Sugars

It is found that (1) the breaking of each C–C bond in the sugar consumes one molecule The number of equivalents of HIO4 consumed reveals the size of the sugar molecule, and of HIO4, (2) each aldehyde and secondary alcohol unit furnishes an equivalent of formic acid, andthe (3) theratios primaryof products hydroxy functionare important gives formaldehyde.clues to the The numbercarbonyl groupand arrangementin ketoses gives of hydroxy and carbonyl functions. CO2. The number of equivalents of HIO4 consumed reveals the size of the sugar molecule, and the ratios of products are important clues to the number and arrangement of hydroxy and carbonylAfter functions.degradation, Noticeeach in particularcarbon that,fragment after degradation,retains the eachsame carbonnumber fragmentof retainsattached hydrogen the atomssame numberas were of attachedpresent hydrogenin the original atoms assugar were. present in the original sugar.

35 Exercise 24-15 Write the expected products (and their ratios), if any, of the treatment of the following compounds with HIO4. (a) 1,2-Ethanediol (ethylene glycol); (b) 1,2-propanediol; (c) 1,2,3-propanetriol; (d) 1,3-propanediol; (e) 2,4-dihydroxy-3,3-dimethylcyclobutanone; (f) "-threose.

Exercise 24-16

In Summary Oxidative cleavage with periodic acid degrades the sugar backbone to formic acid, formaldehyde, and CO2. The ratio of these products depends on the structure of the sugar.

24-6 REDUCTION OF MONOSACCHARIDES TO ALDITOLS

Aldoses and ketoses are reduced by the same types of reducing agents that convert 1088 CHAPTER 24aldehydesCarbohydratesand ketones into alcohols. The resulting polyhydroxy compounds are called alditols. D-glucose gives D-glucitol (older name, D-sorbitol) when treated with sodium borohydride. The hydride reducing agent traps the small amount of the open-chain form of the sugar, in this The hydrideway shiftingreducing the equilibriumagent traps fromthe the smallunreactiveamount cyclic ofhemiacetalthe open to- chainthe product.form of the sugar, in this way shifting the equilibrium fromPreparationthe unreactive of an Alditolcyclic hemiacetal to the product. CHO HCHOH H OH H OH CH2OH O HHO HHO HO NaBH4, CH3OH HO OH H OH H OH OH H OH H OH H CH2OH CH2OH D-Glucose D-Glucitol Red seaweed contains relatively (D-Sorbitol) 36 large amounts of D-glucitol. Many alditols are found in nature. !-Glucitol is present in red seaweed in concentrations as high as 14%, as well as in many berries (but not in grapes), in cherries, in plums, in pears, and in apples. It is prepared commercially from !-glucose by high-pressure hydrogenation or by electrochemical reduction. Glucitol is widely used as a sweetener in products such as mints, cough drops, mouthwashes, and chewing gum, where it is often identi" ed by its alternative name, sorbitol. Glucitol is similar in caloric content to glucose. However, the types of bacteria present in the mouth that cause dental caries are less capable of metabolizing glucitol than glucose.

Exercise 24-17

(a) Reduction of !-ribose with NaBH4 gives a product without optical activity. Explain. (b) Similar reduction of !-fructose gives two optically active products. Explain.

In Summary Reduction of the carbonyl function in aldoses and ketoses (by NaBH4) furnishes alditols.

24-7 CARBONYL CONDENSATIONS WITH AMINE DERIVATIVES

As might be expected, the carbonyl function in aldoses and ketoses undergoes condensation reactions with amine derivatives (Section 17-9). For example, treatment of !-mannose with phenylhydrazine gives the corresponding hydrazone, !-mannose phenylhydrazone. Surpris- ingly, the reaction does not stop at this stage but can be induced to continue with additional phenylhydrazine (two extra equivalents). The " nal product is a double phenylhydrazone, also called an osazone (here, phenylosazone). In addition, one equivalent each of benze- namine (aniline), ammonia, and water is generated.

Phenylhydrazone and Phenylosazone Formation A A H O H N NHC6H5 H N NHC6H5 C C C

HHO HO H A C6H5NHNH2 CPN NHC6H5 CH3CH2OH, 2 C6H5NHNH2, HHO ⌬, 30 min HHO CH3CH2OH, ⌬ HHO

H OH ϪH2O H OH ϪC6H5NH2, H OH ϪNH3, H OH H OH ϪH2O H OH

CH2OH CH2OH CH2OH 75% 95% D-Mannose D-Mannose A phenylosazone phenylhydrazone Many alditols are found in nature. D-Glucitol is present in red seaweed in concentrations as high as 14%, as well as in many berries (but not in grapes), in cherries, in plums, in pears, and in apples.

It is prepared commercially from D-glucose by high-pressure hydrogenation or by electrochemical reduction.

Glucitol is widely used as a sweetener in products such as mints, cough drops, mouthwashes, and chewing gum, where it is often identified by its alternative name, sorbitol.

Glucitol is similar in caloric content to glucose. However, the types of bacteria present in the mouth that cause dental caries are less capable of metabolizing glucitol than glucose.

37 1088 CHAPTER 24 Carbohydrates

The hydride reducing agent traps the small amount of the open-chain form of the sugar, in this way shifting the equilibrium from the unreactive cyclic hemiacetal to the product.

Preparation of an Alditol CHO HCHOH H OH H OH CH2OH O HHO HHO HO NaBH4, CH3OH HO OH H OH H OH OH H OH H OH H CH2OH CH2OH D-Glucose D-Glucitol Red seaweed contains relatively (D-Sorbitol) large amounts of D-glucitol. Many alditols are found in nature. !-Glucitol is present in red seaweed in concentrations as high as 14%, as well as in many berries (but not in grapes), in cherries, in plums, in pears, and in apples. It is prepared commercially from !-glucose by high-pressure hydrogenation or by electrochemical reduction. Glucitol is widely used as a sweetener in products such as mints, cough drops, mouthwashes, and chewing gum, where it is often identi" ed by its alternative name, sorbitol. Glucitol is similar in caloric content to glucose. However, the types of bacteria present in the mouth that cause dental caries are less capable of metabolizing glucitol than glucose.

Exercise 24-17

(a) Reduction of !-ribose with NaBH4 gives a product without optical activity. Explain. (b) Similar reduction of !-fructose gives two optically active products. Explain.

In Summary Reduction of the carbonyl function in aldoses and ketoses (by NaBH4) furnishes alditols.

24-7 CARBONYL CONDENSATIONS WITH AMINE DERIVATIVES 24-7 CARBONYL CONDENSATIONS WITH AMINE DERIVATIVES As might be expected, the carbonyl function in aldoses and ketoses undergoes condensation reactions with amine derivatives (Section 17-9). For example, treatment of !-mannose with The carbonyl function in aldoses and ketoses undergoes condensation reactions with amine phenylhydrazine gives the corresponding hydrazone, !-mannose phenylhydrazone. Surpris- derivativesingly,. Treatment the reactionof doesD not-mannose stop at thiswith stage butphenylhydrazine can be induced to continuegives thewith additionalcorresponding hydrazone,phenylhydrazineD-mannose (twophenylhydrazone extra equivalents).. The " nal product is a double phenylhydrazone, also called an osazone (here, phenylosazone). In addition, one equivalent each of benze- Surprisingly,naminethe (aniline),reaction ammonia,does not andstop waterat is thisgenerated.stage but can be induced to continue with additional phenylhydrazine (two extra equivalents). The final product is a double phenylhydrazone, also calledPhenylhydrazonean osazone and(here, Phenylosazonephenylosazone Formation). A A H O H N NHC6H5 H N NHC6H5 C C C

HHO HO H A C6H5NHNH2 CPN NHC6H5 CH3CH2OH, 2 C6H5NHNH2, HHO ⌬, 30 min HHO CH3CH2OH, ⌬ HHO

H OH ϪH2O H OH ϪC6H5NH2, H OH ϪNH3, H OH H OH ϪH2O H OH

CH2OH CH2OH CH2OH 75% 95% D-Mannose D-Mannose A phenylosazone phenylhydrazone 38 The mechanism of osazone synthesis is complex and it constitutes an oxidation at C2 by one equivalent of phenylhydrazine, which in turn is reduced by N–N bond rupture to the component amines.

Once they are formed, the osazones do not continue to react with excess phenylhydrazine but are stable under the conditions of the reaction.

Sugars are well known for their reluctance to crystallize from syrups. Their osazones readily form yellow crystals with sharp melting points, thus simplifying the isolation and characterization of many sugars, particularly if they have been formed as mixtures or are impure.