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Title. The Carbohydrates [C(H 2 O)] n. Emil Hermann Fischer (1852-1919). F-R Convention. CHO. C 2 -OH. C 3 -OH. C 4 -OH. C 5 -OH. C 6 -CH 2 OH. The Fischer-Rosanoff Convention. D/L Series. OH on the right of the highest numbered chiral carbon = D-series.

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  1. Title The Carbohydrates [C(H2O)]n Emil Hermann Fischer (1852-1919)

  2. F-R Convention CHO C2-OH C3-OH C4-OH C5-OH C6-CH2OH The Fischer-Rosanoff Convention

  3. D/L Series OH on the right of the highest numbered chiral carbon = D-series. OH on the left of the highest numbered chiral carbon = L-series. Fischer-Rosanoff D- and L-Series

  4. D-Aldohexoses 8 right 2 right 2 left 2 right 2 left 4 right 4 left right left right left right left right left Allose Glucose Gulose Galactose Altrose Mannose Idose Talose The D-Aldohexoses C3 C4 C2 Allaltruists gladly make gum in gallon tanks [L. Fieser]

  5. Rxn of Aldoses CO2H CO2H CHO =N-NHPh CHO HO =N-NHPh OH OH OH OH OH OH OH OH OH OH 3 equiv. PhNHNH2 OH 3 equiv. PhNHNH2 OH OH OH OH HNO3 OH HNO3 OH OH OH OH OH osazone OH NaBH4 NaBH4 CH2OH CO2H CH2OH CH2OH CH2OH CH2OH + PhNH2 + NH3 Br2/H2O Br2/H2O CH2OH CO2H CH2OH CO2H HO HO HO OH OH OH OH OH OH OH OH OH CO2H CH2OH CH2OH alditol aldaric acid aldaric acid alditol aldonic acid aldonic acid achiral achiral Reactions of Aldoses

  6. Osazones CHO CHO Ca(OH)2 Ca(OH)2 HO OH HO HO OH OH (Lobry de Bruyn- Alberda van Eckenstein rearrangement, 1895) OH OH CH2OH CH2OH D-mannose D-glucose 1 equiv. PhNHNH2 3 equiv. PhNHNH2 1 equiv. PhNHNH2 CH2OH =N-NHPh 2 equiv. PhNHNH2 2 equiv. PhNHNH2 =N-NHPh =N-NHPh O =N-NHPh HO OH HO HO HO HO OH OH OH OH OH OH OH OH CH2OH CH2OH CH2OH CH2OH + PhNH2 + NH3 D-fructose D-mannose phenylhydrazone D-glucose phenylhydrazone More on Osazones

  7. F-K and Ruff CN CN HCN Fischer-Kiliani Synthesis HCN Fischer-Kiliani Synthesis HO OH OH OH OH OH OH OH CH2OH CH2OH Fe+++ H2O2 Pd/BaSO4 pH 4.5, H2 Pd/BaSO4 pH 4.5, H2 Ruff Degradation CO2Ca1/2 CO2Ca1/2 CHO CHO CHO Br2/H2O OH HO Br2/H2O HO OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH CH2OH CH2OH CH2OH CH2OH CH2OH Aldonic acid as Ca salt Chain Lengthening and Shortening of Aldoses

  8. D-Series Interrelationship Interrelationship of the D-Series of Aldoses via Chain Lengthening and Degradation

  9. Which one is Glucose? D-series L-series The Aldohexoses But which one is (+)-glucose?

  10. Aldaric Acids/Alditols Rosanoff Formulation of C6 Aldaric Acids and Alditols Terminal groups identical; CO2H or CH2OH

  11. Fischer Proof: 1 • 1, 7, 9, 15 eliminated: plane of symmetry, achiral 9 1 2 10 3 11 12 4 5 13 6 14 7 15 8 16 X X X X Fischer’s Proof: Part 1 (+)-Glucose forms an optically active aldaric acid and optically active alditol.

  12. Fischer Proof:2 1 9 2 10 11 3 12 4 5 13 6 14 15 7 16 8 X X X X X X X X Fischer’s Proof: Part 2 (+)-Glucose and (+)-mannose form the same osazone. If 1, 7, 9, and 15 are not related to (+)-glucose, then they are not related to (+)-mannose nor are 2, 8, 10, and 16 related to (+)-glucose.

  13. Fischer Proof:3 Fischer’s Proof: Part 3 (+)-Arabinose affords (-)-glucose and (-)-mannose by Kiliani-Fischer synthesis. (+)-Arabinose must be of the opposite series (D/L)as (+)-glucose and have the same absolute configuration at C3-5 as (-)-glucose and (-)-mannose. What is the structure of arabinose?

  14. F P:3, con’t X X X X X • (+)-Glucose is one of these structures X • Arabinose is either • or • Arabinose forms an optically active • aldaric acid (arabinaric acid) • and optically active alditol • (arabitol) • Arabinose is

  15. Fischer Proof:4 • (+)-Xylose can only be one of the following: X X • These enantiomers cannot be (+)-xylose because their Fischer-Kiliani hexoses • (already eliminated) would lead to one optically active and one optically • inactive aldaric acid. Fischer’s Proof: Part 4 The pentose (+)-xylose affords optically inactive xylaric acid and optically inactive xylitol as its borax complex. Fischer-Kiliani synthesis of (+)-xylose leads to two new hexoses, (+)-gulose and (+)-idose, both of which form optically active aldaric acids. • (+)-Xylose must be one of the remaining two structures.

  16. Fischer Proof:5 • (+)-Arabinose • (+)-Glucose/(+)-Mannose • (+)-Xylose • (+)-Gulose/(+)-Idose Fischer’s Proof: Part 5

  17. Fischer Proof:5, con’t identical identical • (+)-Glucose must be either Fischer’s Proof: Part 5 (+)-Glucose and (-)-gulose form the same optically active aldaric acid, glucaric acid. or

  18. Fischer Proof:5, con’t-2 • (+)-Mannose must be one of these hexoses, • the C2 epimer of (+)-glucose. identical rotate 180o mannaric acid rotate 180o identical Fischer’s Proof: Part 5 • Mannaric acid is formed from • a single hexose.

  19. Fischer Proof:6 But which enantiomer of glucose is (+)-glucose? D-glucose L-glucose Fischer’s Proof: Part 6 Just Guess! • Fischer arbitrarily assigned the D-series to the dextrorotatory enantiomer. • Sixty years later (1951), he was proved correct when Bijvoet • related (+)-glucose to (+)-tartaric acid. • Fischer: All sugars related to D-(+)-glucose by chemical correlation • belong to the D-series.

  20. Fischer’s Flaw (+)-Glucose (-)-Glucose (-)-Galactose (+)-Galactose (+)-Galactose A Flaw in the Fischer Scheme Identical Achiral Mucic Acid (An Aldaric Acid) "Two aldoses can produce the same dibasic acid only if they belong to the same stereochemical family. That this, however, is erroneous as a general proposition, may be readily seen from the fact that the two enantiomorphous galactoses - plainly belong to the opposite families - yield the same mucic acid.” A. M. Rosanoff-1906

  21. Rosanoff’s Wheel 2 4 8 16 -series -series mirror plane Rosanoff’s Reorganization of the Carbohydrates • Arranged by successive Kiliani syntheses • The D- and L- assignments were • Fischer’s based on chemical • correlation with D-(+)-glucose, • an unreliable scheme.

  22. Evolution of Signage Fischer-1891 +/- d,l Rosanoff-1906 +/-  Today +/- = d,l D,L Evolution of Signage Optical Activity Configuration

  23. D-Aldohexoses The D-Series of Aldoses (+)-glyceraldehyde (-)-erythrose (+)-threose (-)-ribose (-)-arabinose (+)-xylose (-)-lyxose (+)allose (+)-altrose (+)-glucose (+)-mannose (-)-gulose (-)-idose (+)-galactose (+)-talose aldotriose aldotetrose aldo pentose aldo hexose Allaltruists gladly make gum in gallon tanks [L. Fieser]

  24. Fischer Projections CHO CHO OH OH 2 HO HO 3 = OH OH 4 OH HOH2C 5 CH2OH OH rotate C5 about C4 by 120o Fischer Projections of Glucose form hemiacetals between C5-OH and C1 D-(+)-Glucose

  25. Anomers Fischer Projections of Glucopyranose Anomers right alpha left beta HO C C OH OH OH HO HO OH OH O O CH2OH CH2OH b-D-(+)-Glucopyranose a-D-(+)-Glucopyranose

  26. Haworth Haworth Projections of Glucopyranose Anomers up (top) beta down (bottom) alpha b-D-(+)-Glucopyranose a-D-(+)-Glucopyranose

  27. Conformational Glucopyranose down (bottom) alpha up (top) beta O H O H O O H O H O O H H O H O O H O H O H Chair Conformations of Glucopyranose Anomers b-D-(+)-Glucopyranose a-D-(+)-Glucopyranose

  28. Old Salt green light red light beta alpha up down top bottom How an Old SaltRemembers starboard port right left fewer letters more letters

  29. Mutarotation O O H O H O b-D-(+)-Glucopyranose a-D-(+)-Glucopyranose H O H O O H Crystallizes above 98oC Crystallizes below 98oC H O H O O H O H equilibrium mixture [] = +52.6o  pure -anomer mp 150oC []D = +18.7o pure -anomer mp 146oC []D = +112.2o O H H2O H2O Mutarotation of Anomers

  30. Ring Sizes of Hexoses Ring Sizes of Hexoses

  31. Periodic acid HIO4 OH OH OH OH OH CHO HIO4 HIO4 CH2=O + OH OH OH H2O HO HIO4 Periodic Acid Cleavage of Carbohydrates as a Diagnostic Tool 2CH2=O CH2=O + HCO2H Formaldehyde (CH2O) arises from a primary alcohols Formic acid (HCO2H) arises from a secondary alcohols

  32. Periodic Acid Diagnostic HIO4 2 CH2=O + HCO2H • RCH2OH OH CH2=O • R2CHOH HCO2H OH CHO • RCH=O HCO2H CO2H OH HIO4 CH2=O + 2 HCO2H • R2C=O CO2 OH OH OH OH HIO4 HIO4 CH2=O + CH2=O + CO2 O OH Periodic Acid Cleavage of Carbohydrates as a Diagnostic Tool

  33. Periodic on Carbohydrates CHO HCO2H HCO2H HCO2H HCO2H H2CO HCO2H CO2 H2CO HCO2H HCO2H HCO2H H2CO H2CO H2CO HCO2H HCO2H HCO2H HCO2H OH HO OH OH CH2OH D-glucose OH CH2OH O D-fructose HO HO HO OH OH OH OH CH2OH CH2OH D-mannitol Periodic Acid Cleavage of Carbohydrates

  34. Methylation OH OH O O CH3OH, H+ HO HO HO HO HO HO OH OCH3 CH3I Ag2O (CH3)2SO4 NaOH OCH3 OCH3 H3O+ O O CH3O CH3O CH3O CH3O CH3O CH3O OH OCH3 Methylation of Pyranosides

  35. Ring Size CO2H CO2H OCH3 OCH3 O OCH3 HNO3 CH3O CH3O CH3O CH3O CO2H CH3O CO2H CO2H HNO3 HNO3 OCH3 O CH3O OCH3 CH3O CH3O OH via oxidation of the enol of the ketone Ring Size of Pyranosides

  36. Periodic on Glycosides OH OH HIO4 O OHC O HO OHC HCO2H HO HO OCH3 OCH3 H3O+ CHO OH OH + OHCCHO + CH3OH glyoxal D-glyceraldehyde Periodic Acid Cleavage of Methyl -Glucopyranoside

  37. Enzymes H3O+ maltase emulsin -D-glucose -D-glucose Enzymatic Cleavage of Glucosides Methyl -D-glucoside Methyl -D-glucoside

  38. Tollens Tollens reagent Ag(NH3)2+ OH- no reaction Methyl -D-glucoside non-reducing sugar (a glycoside) Tollens reagent Ag(NH3)2+ OH- + Ago silver mirror D-glucose reducing sugar (an aldose) The Silver Mirror Test www.chem-pics.co.uk/download.htm

  39. Tollens 2 enediol Ag(NH3)2+OH- -D-fructofuranose D-fructose Ag(NH3)2+OH- Ago+ Ag(NH3)2+ OH- silver mirror The Silver Mirror Test Aldoses and ketoses are reducing sugars

  40. Intro: Di- and Polysaccharides Disaccharides and Polysaccharides

  41. Sucrose/Olestra OOCR OH O O RCOO HO RCOO HO acetal RCOO HO O RCOO O HO O O ketal RCOO HO OOCR OH RCOO HO Olestra (R=n-CnH2n+1; n=6-8) Sucrose (non-reducing sugar) -D-Glucopyranosyl-  -D-fructofuranoside or-D-Fructofuranosyl--D-glucopyranoside

  42. Woodward Sucrose is Formed from Glucose and Fructose This discussion brings to mind a wonderful story told to me by Professor Harry Wasserman (Yale), who during the late 1940's was a graduate student of Professor R. B. Woodward at Harvard. Apparently Woodward had received a notice of a $1,000 prize for the first person to accomplish a chemical synthesis of sucrose. He went into the laboratory and said to his students that all they had to do was connect two molecules of glucose together [...and lose a molecule of water] and they would have themselves $1,000. One student, obviously not overwhelmed by Woodward's stature in the field even at such a young age, replied that if you did it that way, the prize would be $2,000!

  43. Bees Do It CHO OH OH HO O OH HO OH HO CH2OH HO O HO D-glucose []D = +52.7o O dextrose HO invertase OH OH HO O Sucrose []D = +66.5o (non-reducing, non-mutarotating sugar) HO OH OH CH2OH D-fructose []D = -92.4o levulose Bees Do It or H3O+

  44. Cellulose (polysaccharide) -acetal linkage partial hydrolysis H3O+ 4-O-attachment Cellobiose (disaccharide) 4-O-(-D-glucopyranosyl)-D-glucopyranose Disaccharides-Cellobiose Cellobiose emulsin,-glucosidase (termites, ruminants)

  45. Br2/H2O Cellobiose permethylation H3O+ tetramethoxy- carboxylic acid tetramethoxy aldehyde Cellobiose-Structure Proof Cellobiose-Str. Proof • hydrolysis ----> only D-glucose • emulsin ----> -glucoside • positive Tollens test ----> reducing sugar • shows mutarotation

  46. dimethyl L-tartaric acid hot HNO3 hot HNO3 tetramethoxy aldehyde trimethyl xylaric acid tetramethoxy- carboxylic acid dimethyl D-glyceric acid Cellobiose-Structure Proof Cellobiose-Str. Proof

  47. Malt (barley) maltase Disaccharides: Maltose Maltose Starches: poly--D-glucosides • hydrolysis ----> only D-glucose • maltase ----> -glucoside • positive Tollens test ----> reducing sugar • shows mutarotation • differs from cellobiose at the glycosidic anomeric center

  48. hydrolysis ----> D-glucose and D-galactose • -galactosidase (lactase) ----> -galactoside • positive Tollens test ----> reducing sugar Disaccharides: Lactose Lactose 4-O-(-D-galactopyranosyl)-D-glucose ~5% of human and cow milk • lactose intolerance • shows mutarotation

  49. 1,6--linkage cyanohydrin of benzaldehyde -linkage 1836 - Isolated from bitter almonds by Wohler. Demonstrated that emulsin produces glucose, benzaldehyde and prussic acid (HCN) Disaccharides: Amygdalin Laetrile (laevorotatory mandelonitrile), “vitamin 17” Touted in some circles as a treatment for cancer.

  50. permethylation H3O+ 2,3,4,6-tetra-O- methyl D-glucose (terminal) 2,3,6-tri-O- methyl D-glucose (chain) 100-200 units 0.6% 99.4% Cellulose: Chain Length Cellulose: Chain Length

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