Chem 215 F11 Notes Dr. Masato Koreeda - Page 1 of 18. Date: November 9, 2011

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1 Chem F Notes Dr. Masato Koreeda - Page of 8. Date: November 9, 0 Chapters.8; -,,, and 7: Carbohydrates Part I Carbohydrate nomenclature: Carbohydrates: Polyhydroxylated aldehydes and ketones and their equivalents Important constituents of both plants and animals D-glucose: The primary source of energy in the human body e.g., (C)n C exoses: Sugars possessing six carbon atoms. Pentoses: Sugars possessing five carbon atoms. Aldoses: Sugars containing an aldehyde group. Ketoses: Sugars containing a ketone group. Monosaccharides: Carbohydrates that do not undergo cleavage on hydrolysis (treatment with water) to smaller molecules. I. Stereochemistry anomeric carbon equatorial one hemiacetal form of D-glucose open-chain form of D-glucose anomeric carbon axial another hemiacetal form of D-glucose These are anomers and (C-) epimers. Glucose reacts like an aldehyde since small amounts of the open-chain form are present at equilibrium. Glucose has stereocenters = stereoisomers possible 8 pairs of enantiomers () Fischer projection formulas (a) (+)-Glyceraldehyde: configurational reference compound for all monosaccharides This stereochemistry is defined as "D" if the is projected to the right. C D-(+)-glyceraldehyde vertical bonds go in and horizontal bonds come out sign of optical rotation at the sodium D-line (89 nm) small upper-case D configurational designation C C C R C R-(+)-glyceraldehyde S-(-)-Glyceraldehyde has an L-configuration. D-Stereochemistry and the sign of optical rotation have no direct correlation, although many D sugars are dextrorotatory (d or +).

2 Chem F Notes Dr. Masato Koreeda - Page of 8. Date: November 9, 0 I. Stereochemistry () Fischer projection (cont d) The configurational relatioship was established between D-glyceraldehyde and the naturally occurring positive-rotating grape sugar, (+)-glucose. D D D D-glucose D-fructose (found in many fruits) D--deoxyribose (found in DNA) [an aldohexose] [a ketohexose] [a deoxyaldopentose] (in its open-chain (in its open-chain (in its open-chain aldehyde form) aldehyde form) keto form) The Fischer projection of (+)-glucose The more oxidized end of the chain (i.e., the aldehyde in this case) on top of the Fischer chain. The first chiral center from the bottom of the chain determines the configuration (i.e., D or L). "view" "view" through the surface of the paper "view" "view" C (+)-glucose zig-zag conformation: most favorable, natural conformation in solution. all eclipsed! not a natural, stable conformation! C D-(+)-glucose D-configuration C D-(+)-glyceraldehyde For the conversion from the curved, eclipsed chain structure to the Fischer projection: C 90 rotation C "rotate" along the C -C -bond "rotate" along the C -C -bond Look from this direction through the surface of the paper for the Fischer projection.

3 Chem F Notes Dr. Masato Koreeda - Page of 8. Date: November 9, 0 Carbohydrate families: All aldoses are called reducing sugars because of the aldehyde group; they reduce certain metal ions and can be easily oxidized. Two well known reagents for reducing sugars are: ) Ag(I) Ag (0) in Na/ (Tollens test) ) Cu(II)S (blue) in Na/ red Cu (Benedict s reagent) Note: In addition to aldoses, ketoses are also reducing sugars. α-ydroxyketones in general react with these reagents and can readily be oxidized. aldotriose: aldotetraoses: pentoses: C D-glyceraldehyde C D-erythrose C D-threose C D-ribose: found in RNA C L-arabinose L! exoses: There are stereoisomers and 8 of these are D-sugars. Mnemonics for 8 D-aldohexoses: allose altrose glucose mannose gulose idose galactose talose All altruists gladly make gum in gallon tanks. C C Remember the structures of D-glucose and D-glyceraldehyde. memorize the structures of any other sugars. You don t need to ) Which of the eight D-hexoses shown above represent epimeric pairs? ) Draw the Fischer projection structures of L-glucose, D-galactose (C- epimer of D- glucose; a milk sugar), and D-mannose (C- epimer of D-glucose). ) Draw the Fischer projection structure of L-alanine, ( C)-C(N + )C(=) -.

4 Chem F Notes Dr. Masato Koreeda - Page of 8. Date: November 9, 0 I. Stereochemistry: () Mutarotation β- equatorial open-chain form of D-glucose axial β anomer α anomer [α] D +8.7 virtually no concentration of this species [α] D + in the equilibrium mixture; only a transient intermediate. β D-(+)-glucopyranose or β D-glucose α- α D-(+)-glucopyranose or α D-glucose After the equilibrium is reached, the optical rotation of the mixture shows: [α] D +. Therefore, the mixture consists of % of β-d- and 7% of α-d-glucopyranose. Based on: X ( - X) = Note: () Pyranose vs furanose () n pyranose -membered ring pyran () n furanose -membered ring furan () β vs α stereochemistry: anomeric stereoisomers (see pages - for definitions) Cyclic sugars such as furanoses and pyranoses: the stereochemistry at the anomeric carbon relative to that at the stereo-defining center whether the sugar is D or L. If a D-sugar and the non-ether part of the ring For D-sugars: drawn in front and the ether portion drawn β behind a group (usually, R, or X) ponting up at the anomeric center (i.e., at C-) is defined as β and the one pointing down is α defined as α. non-ether part of the ring The C- group such as C, C(=) usually adopts an equatorial orientation. The α or β has nothing to do with the axial or equatorial orientation of the group attached at C-. For L-sugars definition is reversed For L-sugars: equatorial axial Examples β- equatorial equatorial α- equatorial β- β D-glucose enantiomers!! β L-glucose α L-glucose α β

5 Chem F Notes Dr. Masato Koreeda - Page of 8. Date: November 9, 0 α- or β- at the anomeric carbon Taken from: The anomeric center: The new center of chirality generated by hemiacetal or hemiketal ring closure is called the anomeric center. The two stereoisomers are referred to as anomers, designated α or β according to the configurational relationship between the anomeric center and a specified anomeric reference atom. The anomeric reference atom and the anomeric configurational symbol (α or β): The anomeric reference atom is the configurational atom of the parent, unless multiple configurational prefixes are used. If multiple configurational prefixes are used, the anomeric reference atom is the highest-numbered atom of the group of chiral centers next to the anomeric center that is involved in the heterocyclic ring and specified by a single configurational prefix. In the α anomer, the exocyclic oxygen atom at the anomeric center is formally cis, in the Fischer projection (i.e., the same side with respect to the carbon main chain), to the oxygen attached to the anomeric reference atom; in the β anomer these oxygen atoms are formally trans. The anomeric symbol α or β, followed by a hyphen, is placed immediately before the configurational symbol D or L of the trivial name or of the configurational prefix. D-Sugars anomeric reference position configurational atom (D) C α! at C- (anomeric center) same side of the ring configurational C atom (D) α-d-glucopyranose anomeric reference position configurational atom (D) C β! at C- (anomeric center) and on the opposite sides of the ring configurational atom (D) C β-d-glucopyranose L-Sugar α! at C- (anomeric center) same side of the ring anomeric reference position configurational atom (L) configurational atom (L) α-l-arabinopyranose

6 Chem F Notes Dr. Masato Koreeda - Page of 8. Date: November 9, 0 For simple aldoses up to aldohexoses, and ketoses up to hepto--uloses,* the anomeric reference atom and the configurational atom are the same. β! at C- (anomeric center) C and on the opposite sides of the ring anomeric reference position configurational atom (D) C C configurational atom (D) C C methyl β-d-galactofuranoside If multiple configurational prefixes are used, the anomeric reference atom is the highestnumbered atom of the group of chiral centers next to the anomeric center that is involved in the heterocyclic ring and specified by a single configurational prefix. In the α anomer, the exocyclic oxygen atom at the anomeric center is formally cis, in the Fischer projection (i.e., the same side with respect to the carbon main chain), to the oxygen attached to the anomeric reference atom; in the β anomer these oxygen atoms are formally trans. The anomeric symbol α or β, followed by a hyphen, is placed immediately before the configurational symbol D or L of the trivial name or of the configurational prefix. anomeric reference position configurational atom (L) C 7 C same side of the ring D-manno L-glycero α! at C- (anomeric center) 7 C C methyl L-glyceroα-D-manno-heptopyranoside * C 7 C D-mannohepto--ulose

7 Chem F Notes Dr. Masato Koreeda - Page 7 of 8. Date: November 9, 0 I. Stereochemistry: () aworth projection formulas push down push up above the plane of the ring α-d-glucopyranose in the chair form above the plane of the ring C α-d-glucopyranose in a aworth projection formula C β-d-glucopyranose in a aworth projection formula ()-. Drawing the pyranose (-membered ring) aworth projection structure from the Fischer projection structure of D-glucose: C The Fischer projection structure of D-glucose. hemiacetal; α-anomer C Alternatively, Rotate! C. Turn the Fischer projection on the plane of the paper by 90 clockwise α-d-glucopyranose or C C hemiacetal; β-anomer C β-d-glucopyranose This may be easier!! C. Curve the Fischer main carbon chain as defined.. Rotate along the C -C bond by 0 counterclockwise to bring the C to the same plane as the C aldehyde. Make the -membered ring by connecting C - and C aldehyde C. C C r tie up directly! C make a ring Curve the chain as defined.

8 Chem F Notes Dr. Masato Koreeda - Page 8 of 8. Date: November 9, 0 I. Stereochemistry: () aworth projection formulas ()-. Drawing the furanose (-membered ring) aworth projection structure from the Fischer projection structure of D-glucose: C The Fischer projection structure of D-glucose. Alternatively, Rotate! C. Turm the Fischer projection on the plane of the paper by 90 clockwise. hemicaetal; α-anomer C α-d-glucofuranose C C C or β-anomer β-d-glucofuranose. Curve the Fischer main carbon chain as defined (C through C ). C C C. Rotate along the C -C bond by 0 counterclockwise to bring the C - to the same plane as the C- aldehyde. Make the -membered ring by connecting C - and C aldehyde C. r connect and make a ring! C make a ring Curve the chain as defined. () Draw the pyranose and furanose structures, both in β-anomeric forms, of L-ketohexose shown below. They exist as hemiketals. C C The Fischer projection structure of an L- ketohexose.. Rotate the Fischer projection on the plane of the paper by 90 clockwise C furanose C pyranose C answers: β-l-pyranose β-l-furanose

9 Chem F Notes Dr. Masato Koreeda - Page 9 of 8. Date: November 9, 0 Carbohydrate stereochemistry practice examples I. Draw the α-pyranose forms and β-furanose forms of each of the following. For pyranose forms draw as a aworth projection and as a conformational representation (i.e., chair form). (a) (b) (c) (d) C C C C C C C C II. Draw the open-chain form as a Fischer projection for each of the following. (a) (b) (c) C C (d) C (e) C C

10 Chem F Notes Dr. Masato Koreeda - Page 0 of 8. Date: November 9, 0 Chapters.8, -,,, and 7: Carbohydrates - Part II II. Glycosides A general term used to describe organic molecules covalently bound to carbohydrate molecules (through anomeric bonds). () Formation of glycosides C-epimers; anomers; diastereomers α-anomer anomeric carbon β-anomer anomeric carbon C, 0.7 % Cl, 0 C (short time) Kinetic conditions (for this reaction)! C anomeric carbon C α-anomer methyl α-d-glucofuranoside + C C anomeric carbon β-anomer methy β-d-glucofuranoside C, % Cl, rt Thermodynamic conditions! MAJR PRDUCT anomeric carbon C α-anomer ~% methyl α-d-glucopyranoside + ~% MINR PRDUCT methyl β-d-glucopyranoside C anomeric carbon β-anomer In general, (-membered) furanosides are formed preferentially under the kinetic conditions, whereas (-membered) pyranosides are formed under the thermodynamic conditions, i.e., more stable. Five membered systems have a number of eclipsing interactions, thus less stable.

11 Chem F Notes Dr. Masato Koreeda - Page of 8. Date: November 9, 0 () Mechanism for the formation of anomeric glycosides When protonation occurs on the anometic. β-anomer anomeric carbon lone pair-assisted ionization. When protonation occurs on the ether oxygen atom. C lone pair-assisted ionization. or C C C or C C C stereochem. mixture lone pair-assisted ionization. C C β-anomer rotation along the C -C bond C C C α-anomer C C C Comments: The α-anomeric hemiacetal undergoes similar processes to produce a mixture of anomeric glycosides. Protonation on the lone pairs of the oxygen atoms other than the anomeric (i.e., C -) and ether ring oxygen ones does not lead to the ready elimination of the protonated hydroxyl groups due to the lack of the lone pair-assisted ionization.

12 Chem F Notes Dr. Masato Koreeda - Page of 8. Date: November 9, 0 () ydrolysis of the Glycosidic Linkages a. Lactose milk sugar; disaccharide; reducing sugar (one hemiacetal group) ' ' ' β-d-lactose ' ' ' anomeric carbon β-glycosidic linkage (or bond) anomeric carbon hemiacetal reducing sugar permethylation with Na (excess), (C ) S (excess) or Na (excess), C I (excess) + D-galactose anomeric mixture + All s except the anomeric methylated. D-glucose anomeric mixture C ' C ' C ' ' ' ' C C C C C + All glycosidic bonds get hydrolyzed C C C C + C C,,,-tetra-methyl D-galactose terminal sugar! Taken together, D-lactose must be: (D-galactose)--(D-glucose) attached at the C - of D-glucose; -β-d-galactopyranosyl-(->)-β-d-glucopyranose or β-d-galp-(->)-β-d-glcp. This reaction concept can be used for sequencing polysaccharides. C,,-tri-methyl D-glucose - is free. Thus, the other sugar is attached to the C -. b. Sucrose ( Sugar ): disaccharide; non-reducing sugar (no anomeric hemiacetal nor hemiketals) D-glucose α-glycosidic linkage to glucose D-glucose D-fructose C D-fructose C C C + β-glycosidic linkage to fructose α-glycosidic linkage to glucose β-glycosidic linkage to fructose D-glucose (anomeric mixture) C + D-fructose (anomeric mixture) Both of these are reducing sugars! C Sucrose: -β-d-fructofuranosyl-(<->)-α-d-glucopyranoside or β-d-fruf-(<->)-α-d-glcp f: furanosyl; p: pyranosyl +

13 Chem F Notes Dr. Masato Koreeda - Page of 8. Date: November 9, 0 III. The Anomeric Effect: The inherent preference of electronegative substituents (usually R, SR or halogen atoms) for the axial position at the anomeric carbon; largest for halogen atoms. See: Juaristi, E.; Cuevas, G. The Anomeric Effect; CRC Press: Boca Raton, FL; 99. Examples: () X X = Cl ΔG.8 kcal/mol Br.8 C 0.9 C C 0.8 SC ~ -0. NC -0.9 X Note: % 89% ΔG C = -. kcal/mol () % % ΔG C = -0. kcal/mol So, the inherent anomeric effect (AE) for an may be estimated to be: AE () = ΔG (pyranose) - ΔG (cyclohexane) = -0. (-.) = 0.90 kcal/mol

14 Chem F Notes Dr. Masato Koreeda - Page of 8. Date: November 9, 0 Explanations for the Anomeric Effect () Repulsive lone pair-lone pair interactions: Equatorial C -C axial equatorial Axial C -C (stabler) equatorial C View through the C - ring bond,-diaxial interactions axial equatorial C View through the C - ring bond Stays away from the ring portion, avoiding the steric repulsion. C C C Ring oxygen axial equatorial repulsive lone pair-lone pair orbital interaction! C repulsive lone pair-lone pair orbital interaction! () The hyperconjugative orbital interaction concept Axial C -C (stabler) axial axial n C σ C -C anti-bonding orbitals n C C C axial C FM interpretation Ring oxygen equatorial repulsive lone pair-lone pair orbital interaction! nly one bad interaction!! σ C -C hyperconjugative, stabilizing orbital interaction: the oxygen lone-pair electrons are delocalizing into the antibonding C - orbital (σ* orbital) of the axial C - bond. This hyperconjugation should make the C - bond shorter and the C-X bond longer. Cl Cl Cl hyperconjudation Bond length comparisons:.å.9å Cl Cl.8Å.7Å.9Å Cl.8Å Cl.Å.78Å

15 Chem F Notes Dr. Masato Koreeda - Page of 8. Date: November 9, 0 Reactions of Carbohydrates () Isomerization of sugars: usually in the presence of acid or base epimer open chain form "ene-diol" ketose C D-glucose C "ene-diol" C D-mannose C C -epimer of D-glucose C C D-fructose Under base-catalyzed conditions C D-glucose Na (0.0%), C 0 h D-glucose (~9%) + C C D-mannose (~%) + C D-fructose C -epimer of D-glucose (~0%) C

16 Chem F Notes Dr. Masato Koreeda - Page of 8. Date: November 9, 0 Mechanism: a a a b b b glucose Protonation at C from the bottom face "ene-diol" mannose a D-fructose C Protonation at C Mechanism under + conditions glucose C= (fructose) Loss of + Protonation at C Protonation at C from the bottom face mannose () Reducing sugars: Sugars that contain a hemiacetal or hemiketal, and are therefore in equilibrium with open form, are called reducing sugars. Tollens test C Ag Na/ C + Ag 0 (silver mirror) Also, with Cu + (CuS ) [deep blue color]/na [Benedict's reagent] reducing sugar Cu (Cu + ) [red ppts]

17 Chem F Notes Dr. Masato Koreeda - Page 7 of 8. Date: November 9, 0 () xidation reactions involving C - or C - and C -s (a) Br in oxidizes only aldoses Br + note: Br + + Br Br + Br + Under the acidic conditions, this hydroxy acid closes to form the six-membered lactone. (b) N oxidation: N is a stronger oxidizing agent than Br, oxidizing both the aldehyde group and the terminal C of an aldose to the corresponding di-acid. C D-galactose (optically active) Both C and C ends get oxidized to C's. N, Δ galactaric acid (meso; optically inactive) () Both (hemiacetal) aldoses and (hemiketal) ketoses undergo reactions observed for aldehydes and ketones, respectively. C N C N * * * CN + C C C C α-/β-d-fructofuranose C C D-fructose NaB C - C C + C C

18 Chem F Notes Dr. Masato Koreeda - Page 8 of 8. Date: November 9, 0 () Reactions of hydroxyl groups and their derivatives Selective reactions of anomeric s and their derivatives under acidic conditions (by an S N process) and glycoside formation of the anomeric bromide (by an S N process). (a) C C C C C Br (gas) C Cl S N C C C C Br C C C C Br K -C Ph The α-bromide formed due mainly to the anomeric effect of Br. S N! (b) * C C N C C (excess) N C C C C S N N * C C C Br (gas) acetic acid (0 C) C C Br K C C N C S N R C more acidic K, Δ R C C C C C C salicin C C Na- C Ph + KBr + KBr