The Carbohydrates [C(H 2 O)] n Title Emil Hermann Fischer (1852-1919)

The Carbohydrates[C(H2O)]n

Emil Hermann Fischer (1852-1919)

http://classes.yale.edu/chem220a/studyaids/history/chemists/fischer.html

C6-CH2OH

CHO

C5-OH

C4-OH

C2-OH

C3-OH

The Fischer-Rosanoff Convention

F-R Convention

OH on the right of the highestnumbered chiral carbon = D-series.

Fischer-Rosanoff D- and L-Series

OH on the left of the highest numbered chiral carbon = L-series.

D/L Series

The D-Aldohexoses

C4 4 right 4 left

8 right

C2

2 right 2 left 2 right 2 leftC3

right left right left

right left leftright

AlloseAltrose

Glucose

Mannose

Gulose GalactoseIdose Talose

All altruists gladly make gum in gallon tanks [L. Fieser]

D-Aldohexoses

Reactions of Aldoses

3 equiv. PhNHNH2 3 equiv. PhNHNH2

OHOHOH

HOCHO

CH2OH

CHO

OHOHOHOH

CH2OH

+ PhNH2 + NH3

=N-NHPh

=N-NHPh

CH2OH

OHOH

OHosazone

CO2H

OHOHOHOH

CH2OH

aldonic acid

Br2/H2O Br2/H2O

aldonic acid

HO

CO2H

OHOHOH

CH2OH

alditol

OHOHOHOH

CH2OH

CH2OH

alditol

NaBH4NaBH4

OHOHOH

CH2OH

CH2OH

HO

achiral

CO2H

OHOHOHOH

CO2H

aldaric acid aldaric acid

CO2H

OHOHOH

CO2H

HO

HNO3 HNO3

achiral

More on Osazones

1 equiv.PhNHNH2

=N-NHPh

OH

OHOH

CH2OH

HO

D-glucose phenylhydrazone

CHO

OH

OHOH

CH2OH

HO

D-glucose

OHOH

HO

CHO

CH2OH

HO

D-mannose

OHOH

CH2OH

CH2OH

HO

D-fructose

O

OHOH

HO=N-NHPh

CH2OH

HO

D-mannosephenylhydrazone

1 equiv.PhNHNH2

3 equiv.PhNHNH2

Ca(OH)2Ca(OH)2

(Lobry de Bruyn-Alberda van Eckenstein rearrangement, 1895)

Osazones

+ PhNH2 + NH3

2 equiv.PhNHNH2

2 equiv.PhNHNH2

=N-NHPh

=N-NHPh

CH2OH

OHOH

HO

Chain Lengthening and Shortening of Aldoses

OHOHOH

CH2OH

CHO

OHOHOH

HO

CN

CH2OH

CN

OHOHOHOH

CH2OH

HCN

Fischer-Kiliani Synthesis

HCN

Fischer-Kiliani Synthesis

Pd/BaSO4

pH 4.5, H2

Pd/BaSO4

pH 4.5, H2

CHO

OHOHOHOH

CH2OH

HO

CHO

OHOHOH

CH2OH

Fe+++

H2O2

Ruff Degradation

CO2Ca1/2

OHOHOHOH

CH2OH

HOOHOHOH

CH2OH

CO2Ca1/2

Br2/H2O Br2/H2O

Aldonic acid as Ca salt

F-K and Ruff

Interrelationship of the D-Series of Aldosesvia Chain Lengthening and Degradation

D-Series Interrelationship

The Aldohexoses

D-series

L-series

But which one is (+)-glucose?

Which one is Glucose?

Rosanoff Formulation of C6 Aldaric Acids and Alditols

Terminal groups identical; CO2H or CH2OH

Aldaric Acids/Alditols

1 2 3 4 5 6 7 8

9 10 11 12 13 14 15 16

Fischer’s Proof: Part 1

(+)-Glucose forms an optically active aldaric acid and optically active alditol.

•1, 7, 9, 15 eliminated: plane of symmetry, achiral

X

X

X

X

Fischer Proof: 1


(+)-Glucose and (+)-mannose form the same osazone. If 1, 7, 9, and 15are not related to (+)-glucose, then they are not related to (+)-mannose norare 2, 8, 10, and 16 related to (+)-glucose.

1 2 3 4 5 6 7 8

9 10 11 12 13 14 15 16

X

X

X

X

X

X

X

X


(+)-Arabinose affords (-)-glucose and (-)-mannose by Kiliani-Fischer synthesis.

What is the structure of arabinose?

(+)-Arabinose must be of the opposite series (D/L)as (+)-glucose and have the same absolute configuration at C3-5 as (-)-glucose and (-)-mannose.

Fischer Proof:3

•Arabinose is either

•or

•Arabinose forms an optically active aldaric acid (arabinaric acid) and optically active alditol (arabitol)

•Arabinose is

X

X

X X

XX

•(+)-Glucose is one of these structures

F P:3, con’t


The pentose (+)-xylose affords optically inactive xylaric acid and opticallyinactive xylitol as its borax complex.

• (+)-Xylose can only be one of the following: XX

• These enantiomers cannot be (+)-xylose because their Fischer-Kiliani hexoses(already eliminated) would lead to one optically active and one opticallyinactive aldaric acid.

• (+)-Xylose must be one of the remaining two structures.

Fischer-Kiliani synthesis of (+)-xylose leads to two new hexoses, (+)-guloseand (+)-idose, both of which form optically active aldaric acids.

Fischer Proof:4


•(+)-Gulose/(+)-Idose

•(+)-Xylose

•(+)-Arabinose

•(+)-Glucose/(+)-Mannose

Fischer Proof:5

or


(+)-Glucose and (-)-gulose form the same optically active aldaric acid, glucaric acid.

identical

identical

• (+)-Glucose must be either

Fischer Proof:5, con’t

• Mannaric acid is formed from a single hexose.


identical

identical

rotate 180o

rotate 180o

• (+)-Mannose must be one of these hexoses, the C2 epimer of (+)-glucose.

mannaric acid

Fischer Proof:5, con’t-2


But which enantiomer of glucose is (+)-glucose?

D-glucose L-glucose

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.

Fischer Proof:6

(-)-Galactose

Identical Achiral Mucic Acid (An Aldaric Acid)

A Flaw in the Fischer Scheme

(+)-Galactose(+)-Galactose

(+)-Glucose (-)-Glucose

Fischer’s Flaw

"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

QuickTime™ and aTIFF (LZW) decompressor

are needed to see this picture.

2

4

8

16

mirror plane

Rosanoff’s Reorganization of the Carbohydrates

-series-series

•Arranged by successive Kiliani syntheses

• The D- and L- assignments were Fischer’s based on chemical correlation with D-(+)-glucose, an unreliable scheme.

Rosanoff’s Wheel

Optical Activity Configuration

Fischer-1891 +/- d,l

Rosanoff-1906 +/-

Today +/- = d,l D,L

Evolution of Signage

Evolution of Signage

The D-Series of Aldoses

(+)-glyceraldehyde

(+)-threose(-)-erythrose

(-)-ribose (-)-arabinose (+)-xylose (-)-lyxose

(+)-altrose(+)allose (+)-glucose (+)-mannose (-)-gulose (-)-idose (+)-galactose (+)-talose

aldotriose

aldotetrose

aldohexose

aldopentose

All altruists gladly make gum in gallon tanks [L. Fieser]

D-Aldohexoses

Fischer Projections of Glucose

D-(+)-Glucose

CHO

OH

OH

HOH2C

HO

OH

=

rotate C5 about C4 by 120o

form hemiacetals between C5-OH and C1

CHO

OH

OH

OH

HO

CH2OH

2

3

4

5

Fischer Projections

C

OH

OH

O

HO

CH2OH

HO C

OH

OH

O

HO

CH2OH

OH

Fischer Projections of Glucopyranose Anomers

-D-(+)-Glucopyranose -D-(+)-Glucopyranose

rightalpha

leftbeta

Anomers

Haworth Projections of Glucopyranose Anomers

O

CH2OH

OH

OH

OH

OHO

CH2OH

OH

OH

OH

OH


up (top)beta

down (bottom)alpha

Chair Conformations of Glucopyranose Anomers


up (top)beta

down (bottom)alpha

O

OH

HO

HO

OH

OH

O

OH

HO

HO

OH

OH

Conformational Glucopyranose

How an Old Salt Remembers

starboard

right

fewer letters

port

left

alphabeta

downup

bottomtop

more letters

red light green light

Old Salt

Mutarotation of Anomers

-D-(+)-Glucopyranose

O

OH

HO

HO

OH

OH

-D-(+)-Glucopyranose

O

OH

HO

HO

OH

OH

Crystallizes above 98oC

pure -anomer mp 150oC[]D = +18.7o

Crystallizes below 98oC

pure -anomer mp 146oC[]D = +112.2o

H2O H2O

equilibrium mixture[] = +52.6o

Mutarotation

Ring Sizes of Hexoses

Ring Sizes of Hexoses

Hexose Pyranose Form (%/%) Furanose Form

allose 92 8

altrose 70 30

glucose ~100(36.5/63.5) <1

mannose ~100(67/33) <1

gulose 97 3

idose 75 25

galactose 93(27.5/72.5) 7

talose 69 31

fructose 67 33

Periodic Acid Cleavage of Carbohydrates as a Diagnostic Tool

CH2=O +

OH

CHOCH2=O + HCO2H

OH

OH

HOH2O

HIO4

HIO4

OH

OH2 CH2=O

HIO4

OH

OH

OH

HIO4

Formaldehyde (CH2O) arises from a primary alcohols

Formic acid (HCO2H) arises from a secondary alcohols

Periodic Acid Cleavage of Carbohydrates as a Diagnostic Tool

OH

OH

CHOHIO4

OH

OH

OH

HIO4

2 CH2=O + HCO2H

CH2=O + 2 HCO2H

HIO4

OH

OH

O CH2=O + OH

CO2H HIO4 CH2=O + CO2

• RCH2OH CH2=O

• R2CHOH HCO2H

• RCH=O HCO2H

CO2• R2C=O

Periodic Acid Diagnostic

Periodic Acid Cleavage of Carbohydrates

HCO2H

HCO2HHCO2H

HCO2HHCO2H

H2COCH2OH

CHO

HOOHOH

OH

D-glucose

CH2OH

HOOHOH

CH2OH

HO

D-mannitol

H2CO

HCO2HHCO2HHCO2HHCO2H

H2CO

H2CO

HCO2HHCO2HHCO2H

H2CO

CO2

HOOHOH

CH2OH

O

OH

D-fructose

Periodic on Carbohydrates

Methylation of Pyranosides

HOHO

HO

OHO

OCH3

HOHO

HO

OHO

OH

CH3OH, H+

CH3OO

OCH3

CH3OCH3O

OCH3

CH3IAg2O (CH3)2SO4

NaOH

CH3OO

OH

CH3OCH3O

OCH3H3O+

Methylation

Ring Size of Pyranosides

CH3OO

OH

CH3OCH3O

OCH3

CH3O

CH3O

O

CH3O

OCH3

CO2H

OCH3

OCH3

CO2H

CO2H

CH3O

OCH3

CO2H

CO2H

CH3O

HNO3

HNO3

via oxidation of the enol of the ketone

HNO3

Ring Size

Periodic Acid Cleavage of Methyl -Glucopyranoside

HOHO

HO

OHO

OCH3

OHO

OCH3

OHC

OHCHCO2H

HIO4

H3O+

OH

OH

CHO

+ OHCCHO + CH3OH

D-glyceraldehyde

glyoxal

Periodic on Glycosides

OHO

HOHO

HO

OCH3

OHO

HOHO

HOOCH3

Methyl -D-glucoside Methyl -D-glucoside

maltase

-D-glucose

OHO

HOHO

HOOH

OHO

HOHO

HO

OH

emulsin

-D-glucose

Enzymatic Cleavage of Glucosides

H3O+

Enzymes

The Silver Mirror Test

Methyl -D-glucoside

OHO

HOHO

HO OCH3

non-reducing sugar (a glycoside)

no reactionTollens reagent

Ag(NH3)2+ OH-

Tollens reagent

Ag(NH3)2+ OH-

OHO

HOHO

HO OH

D-glucose

CO2H

CH2OH

OH

OH

OH

HO+ Ago

silver mirror

reducing sugar (an aldose) www.chem-pics.co.uk/download.htm

Tollens

http://www.chem-pics.co.uk/

http://www.chem-pics.co.uk/

The Silver Mirror Test

Aldoses and ketoses are reducing sugars

O

HO

OH

OHHO

OH

-D-fructofuranose

CH2OH

CH2OH

OH

OH

HO

O

D-fructose

Ag(NH3)2+ OH-

CH2OH

OH

OH

HO

OH

OHenediol

CHO

CH2OH

OH

OH

HOOH

Ag(NH3)2+ OH-

Ago +

silver mirror

Ag(NH3)2+ OH-

CO2H

CH2OH

OH

OH

HOOH

Tollens 2

Disaccharides

and

Polysaccharides

-D-Glucopyranosyl- -D-fructofuranoside

or-D-Fructofuranosyl--D-glucopyranoside

HO

HOHO

HO

HO

HO

OH

OHO

O

O

Sucrose(non-reducing sugar)

RCOO

RCOORCOO

RCOO

RCOO

RCOO

OOCR

OOCRO

O

O

Olestra(R=n-CnH2n+1; n=6-8)

ketal

acetal

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,

Sucrose is Formed from Glucose and Fructose

the prize would be $2,000!

Woodward

Bees Do It

Sucrose []D = +66.5o

(non-reducing, non-mutarotating sugar)

HO

HO

HO

HO

HO

OH

OHO

O

O

HOinvertase

CH2OH

CHO

HOOHOH

OH

D-glucose []D = +52.7o

dextrose

HOOHOH

CH2OH

O

OH

D-fructose []D = -92.4o

levulose

or H3O+

Bees Do It

OHO

HOHO

HO

O

OHO

HOHO

OOHO

HOHO

OH

n

Cellulose (polysaccharide)

partialhydrolysis H3O+

OHO

HOHO

HO

O

OHO

HOHO

OH

Cellobiose (disaccharide)

4-O-(-D-glucopyranosyl)-D-glucopyranose

-acetal linkage

emulsin,-glucosidase (termites, ruminants)

Disaccharides-Cellobiose

4-O-attachment

Cellobiose

OHO

HOHO

HO

O

OHO

HOHO

OH

Cellobiose

Cellobiose-Structure Proof

•positive Tollens test ----> reducing sugar

•hydrolysis ----> only D-glucose

•emulsin ----> -glucoside

permethylation

OMeO

MeOMeO

MeO

OCO2H

OMeMeO

MeOMeO

Br2/H2O OHO

HOHO

HO

OCO2H

OHHO

HOHO

tetramethoxyaldehyde

H3O+

CHO

CH2OMe

OMe

OMe

OH

MeO

tetramethoxy-carboxylic acid

CO2H

CH2OMe

OMe

OH

OMe

MeO

•shows mutarotation

Cellobiose-Str. Proof

OHO

HOHO

HO

O

OHO

HOHO

OH Cellobiose-Structure Proof OMeO

MeOMeO

MeO

OCO2H

OMeMeO

MeOMeO

tetramethoxyaldehyde

CHO

CH2OMe

OMe

OMe

OH

MeO

tetramethoxy-carboxylic acid

CO2H

CH2OMe

OMe

OH

OMe

MeO

hotHNO3

CO2H

CO2H

OMe

MeO

dimethylL-tartaric acid

CO2H

CO2H

OMe

OMeMeO

trimethyl xylaric acid

hotHNO3

CO2H

CH2OMe

OMe

dimethyl D-glyceric acid

Cellobiose-Str. Proof

Disaccharides: Maltose


•hydrolysis ----> only D-glucose

•maltase ----> -glucoside


Starches: poly--D-glucosides

OHO

HOHO

OH

OHO

HOHO

HOO

Malt (barley) maltase

•differs from cellobiose at the glycosidic anomeric center

Maltose

OHO

HOHO

O

OHO

HOHO

OH

HO

Disaccharides: Lactose

4-O-(-D-galactopyranosyl)-D-glucose


•hydrolysis ----> D-glucose and D-galactose


~5% of human and cow milk

•-galactosidase (lactase) ----> -galactoside

•lactose intolerance

http://classes.yale.edu/chem220a/private/more/lactose.htm

Disaccharides: Amygdalin

OHO

HOHO

HO

O

OHOHO

HO

O CN

PhH

Laetrile (laevorotatory mandelonitrile), “vitamin 17”

1,6--linkage

cyanohydrin of benzaldehyde-linkage

Touted in some circles as a treatment for cancer.

1836 - Isolated from bitter almonds by Wohler. Demonstrated that emulsin produces glucose, benzaldehyde and prussic acid (HCN)

OHO

HOHO

HO

O

OHO

HOHO

OOHO

HOHO

OH

n

OMeO

MeOMeO

MeO

O

OMeO

MeOMeO

OO

MeO

MeOMeO

OMe

n

permethylation

OMeO

MeOMeO

MeO OH

OMeO

HOMeO

MeO OH

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

Starches: Plant Polysaccharides


OHO

HOHO

OHO

HOHO

HOO

OHO

HOHO

O

n OH

Amylose :

• ~20% water soluble starch; poly 4-O-(-D-glucoside)

• forms helical structure; blue complex with iodine

Amylopectin:

• ~80% water insoluble starch branched poly-4-O-(-D-glucoside)



Average 20 glucose units /chain

95% 2,3,6-tri-O-methyl-D-glucose

OMeO

HOMeO

MeO OH

chain

2.5% 2,3-di-O-methyl-D-glucose

OHO

HOMeO

MeO OH

junction

2.5% 2,3,4,6-tetra-O-methyl-D-glucose

OMeO

MeOMeO

MeO OH

terminus

• permethylation/hydrolysis

And Finally, a True Story

In March of 1986 I was in California visiting several universities. While at Stanford University, I stopped at the the health center to have a swollen foot examined. The young resident was very attentive. To assess his qualifications, I asked him where he had attended college. “M.I.T.,” he responded. “So you must have had Professor Kemp for organic chemistry,” I countered. “Yes, I did,” he said. Then I asked, “What D-aldohexose forms the same osazone as glucose?”

“I really enjoyed organic chemistry!” Really?

“Organic, don’t remind me!” An honest man?

“I know the mechanism of the aldol condensation.” Wrong chapter!

“I know what a Grignard reagent is.” Wrong test!

“Wait! Give me some time.” “It’s only an hour exam.”

Response: My thought:

Like Diogenes the Cynic in search of an honest man (person), I have posed this question to many a practitioner of the medical and dental professions. Neither Diogenes nor I have fulfilled our quests. However, the responses to my query were often amusing.

The Moral of the Story

Somewhere,…sometime…someone might ask you this question.

What D-aldohexose forms the same osazone as D-glucose?

Your answer will be...

D-Mannose!

TheEnd

The Carbohydrates [C(H 2 O)] n Title Emil Hermann Fischer (1852-1919)

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