The Carbohydrates
[C(H2O)]n
Emil Hermann Fischer (1852-1919)
The Fischer-Rosanoff Convention
CHO
CHO
CHO
H
OH
H
OH
C2-OH
H
OH
H
OH
C3-OH
H
OH
H
OH
H
OH
H
OH
CH2OH
C4-OH
C5-OH
CH2OH
Fischer Projections
Rosanoff Modification
C6-CH2OH
Fischer-Rosanoff D- and 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.
The D-Aldohexoses
C5
8 right
C3
2 right 2 left
C4
4 right 4 left
C2
right left right left
right left right left
Allose
Glucose
Altrose
2 right
Gulose
Mannose
2 left
Galactose
Idose
Talose
All altruists gladly make gum in gallon tanks [L. Fieser]
Reactions of Aldoses
CHO
=N-NHPh
OH
OH
OH
OH
CH2OH
3 equiv. PhNHNH2
HNO3
osazone
NaBH4
3 equiv. PhNHNH2
CH2OH
OH
OH
OH
OH
CH2OH
CH2OH
alditol
achiral
CO2H
OH
OH
OH
OH
CO2H
aldaric acid
achiral
HO
OH
OH
OH
HNO3
NaBH4
+ PhNH2 + NH3
OH
OH
OH
OH
aldonic acid
=N-NHPh
OH
OH
OH
CH2OH
Br2/H2O
CO2H
CHO
Br2/H2O
CO2H
HO
CH2OH
HO
OH
OH
OH
CO2H
aldaric acid
CH2OH
CO2H
HO
OH
OH
OH
OH
OH
OH
CH2OH
CH2OH
alditol
aldonic acid
More on Osazones
CHO
OH
HO
CH2OH
Ca(OH)2
O
OH
OH
CH2OH
CH2OH
D-glucose
D-fructose
1 equiv.
PhNHNH2
OH
Ca(OH)2
=N-NHPh
2 equiv.
PhNHNH2
=N-NHPh
HO
OH
OH
(Lobry de BruynAlberda van Eckenstein
rearrangement, 1895)
3 equiv.
PhNHNH2
HO
HO
HO
HO
OH
OH
=N-NHPh
CHO
CH2OH
D-mannose
1 equiv.
PhNHNH2
2 equiv.
PhNHNH2
=N-NHPh
HO
HO
OH
OH
OH
OH
OH
OH
CH2OH
CH2OH
CH2OH
+ PhNH2 + NH3
D-mannose
phenylhydrazone
D-glucose phenylhydrazone
Chain Lengthening and Shortening of Aldoses
CN
CN
CHO
OH
OH
OH
OH
HCN
Fischer-Kiliani
Synthesis
CO2Ca1/2
OH
OH
OH
OH
CH2OH
Br2/H2O
OH
OH
OH
OH
CH2OH
OH
OH
OH
CH2OH
Fe+++
H2O2
Ruff
Degradation
Pd/BaSO4
pH 4.5, H2
HO
Fischer-Kiliani
Synthesis
CH2OH
CH2OH
CHO
HCN
OH
OH
OH
Pd/BaSO4
pH 4.5, H2
CO2Ca1/2
HO
OH
OH
OH
CH2OH
Aldonic acid as Ca salt
CHO
Br2/H2O
HO
OH
OH
OH
CH2OH
Interrelationship of the D-Series of Aldoses
via Chain Lengthening and Degradation
The Aldohexoses
But which one is (+)-glucose?
D-series
L-series
Rosanoff Formulation of C6 Aldaric Acids and Alditols
Terminal groups identical; CO2H or CH2OH
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
1
2
3
4
5
6
7
X
X
X
X
9
10
11
12
13
14
15
8
16
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.
1
2
X
3
4
7
8
X
X
X
X
X
X
X
9
10
11
12
5
13
6
14
15
16
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?
•Arabinose is either
X
or
•Arabinose forms an optically active
aldaric acid (arabinaric acid)
and optically active alditol
(arabitol) as its borax complex.
X
X
X
X
•Arabinose is
and not
•(+)-Glucose is one of these structures
X
Fischer’s Proof: Part 4
The pentose (+)-xylose affords optically inactive xylaric acid and optically
inactive xylitol as its borax complex.
• (+)-Xylose can only be one of the following:
X X
Fischer-Kiliani synthesis of (+)-xylose leads to two new hexoses, (+)-gulose
and (+)-idose, both of which form optically active aldaric acids.
• These enantiomers cannot be (+)-xylose because their Fischer-Kiliani hexoses
(already eliminated) would lead to one optically active and one optically
inactive aldaric acid.
• (+)-Xylose must be one of the remaining two structures.
Fischer’s Proof: Part 5
•(+)-Arabinose
•(+)-Glucose/(+)-Mannose
•(+)-Xylose
•(+)-Gulose/(+)-Idose
Fischer’s Proof: Part 5
(+)-Glucose and (-)-gulose form the same
optically active aldaric acid, glucaric acid.
identical
or
identical
• (+)-Glucose must be either
Fischer’s Proof: Part 5
• (+)-Mannose must be one of these hexoses,
the C2 epimer of (+)-glucose.
identical
rotate 180o
mannaric acid
rotate 180o
identical
• Mannaric acid is formed from
a single hexose.
Fischer’s Proof: Part 6
But which enantiomer of glucose is (+)-glucose?
Just Guess!
D-glucose
L-glucose
• 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.
A Flaw in the Fischer Scheme
(+)-Glucose
(-)-Glucose
Identical
Achiral
Mucic Acid
(An Aldaric Acid)
(+)-Galactose
(-)-Galactose
"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
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.
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
2
4
8
-series
16
mirror plane
-series
Evolution of Signage
Optical Activity
Configuration
Fischer-1891
+/-
d,l
Rosanoff-1906
+/-

+/- = d,l
D,L
Today
The D-Series of Aldoses
aldotriose
(+)-glyceraldehyde
aldotetrose
(-)-erythrose
(+)-threose
aldo
pentose
(-)-ribose
(-)-arabinose
(+)-xylose
(-)-lyxose
aldo
hexose
(+)allose (+)-altrose (+)-glucose
(+)-mannose (-)-gulose (-)-idose (+)-galactose
All altruists gladly make gum in gallon tanks [L. Fieser]
(+)-talose
Fischer Projections of Glucose
CHO
OH
2
HO
CHO
OH
HO
3
4
OH
5
OH
CH2OH
D-(+)-Glucose
=
OH
form hemiacetals between
C5-OH and C1
HOH2C
OH
rotate C5 about C4 by 120o
Fischer Projections of Glucopyranose Anomers
left
beta
HO
right
alpha
C
OH
HO
C
OH
OH
HO
OH
OH
O
O
CH2OH
b-D-(+)-Glucopyranose
CH2OH
a-D-(+)-Glucopyranose
Haworth Projections of Glucopyranose Anomers
up (top)
beta
down (bottom)
alpha
CH2OH
CH2OH
OH
O
O
OH
OH
OH
OH
OH
b-D-(+)-Glucopyranose
OH
OH
a-D-(+)-Glucopyranose
Chair Conformations of Glucopyranose Anomers
down (bottom)
alpha
up (top)
beta
OH
OH
O
O
HO
HO
OH
HO
HO
OH
OH
OH
b-D-(+)-Glucopyranose
a-D-(+)-Glucopyranose
How an Old Salt Remembers
port
starboard
left
right
red light
green light
fewer letters
more letters
beta
alpha
up
down
top
bottom
Mutarotation of Anomers
OH
OH
O
O
HO
HO
OH
HO
HO
OH
OH
OH
b-D-(+)-Glucopyranose
a-D-(+)-Glucopyranose
Crystallizes above 98oC
pure b-anomer
mp 150oC
[a]D = +18.7o
H2 O
Crystallizes below 98oC
equilibrium
mixture
[a] = +52.6o
ba
H2O
pure a-anomer
mp 146oC
[a]D = +112.2o
Ring Sizes of Hexoses
Hexose
Pyranose Form (%a/%b)
Furanose Form
allose
altrose
glucose
mannose
gulose
idose
galactose
talose
fructose
92
70
~100(36.5/63.5)
~100(67/33)
97
75
93(27.5/72.5)
69
67
8
30
<1
<1
3
25
7
31
33
Periodic Acid Cleavage of Carbohydrates as a Diagnostic Tool
OH
HIO4
2 CH2=O
OH
OH
OH
HIO4
CHO
HIO4
CH2=O +
CH2=O +
OH
OH
HO
H2O
OH
HIO4
OH
Formaldehyde (CH2O) arises from a primary alcohols
Formic acid (HCO2H) arises from a secondary alcohols
HCO2H
Periodic Acid Cleavage of Carbohydrates as a Diagnostic Tool
OH
OH
HIO4
2 CH2=O + HCO2H
OH
CHO
OH
HIO4
CH2=O + 2 HCO2H
• RCH2OH
CH2=O
• R2CHOH
HCO2H
• RCH=O
HCO2H
• R2C=O
CO2
OH
OH
O
OH
HIO4
CO2H
CH2=O +
OH
HIO4
CH2=O +
CO2
Periodic Acid Cleavage of Carbohydrates
CHO
HCO2H
OH
HO
OH
OH
CH2OH
HCO2H
HCO2H
HCO2H
HCO2H
H2CO
D-glucose
OH
H2CO
O
CO2
OH
OH
HCO2H
HCO2H
HCO2H
HO
CH2OH
HO
HO
OH
OH
CH2OH
D-mannitol
H2CO
HCO2H
HCO2H
HCO2H
HCO2H
H2CO
CH2OH
D-fructose
H2CO
Methylation of Pyranoses:
Pyranosides
OH
OH
O
CH3OH, H+
HO
HO
HO
OH
OCH3
CH3O
CH3O
O
HO
HO
CH3I
Ag2O
O
H3
CH3O
OH
HO
OCH3
(CH3)2SO4
NaOH
OCH3
O+
CH3O
CH3O
O
CH3O
OCH3
Ring Size of Pyranosides
OCH3
CH3O
CH3O
CO2H
O
CH3O
OCH3
HNO3
CH3O
CO2H
CO2H
HNO3
HNO3
CO2H
OCH3
OCH3
CH3O
CH3O
O
CH3O
OCH3
CH3O
OH
CO2H
via oxidation of the enol of the ketone
Periodic Acid Cleavage of Methyl a-Glucopyranoside
OH
OH
HIO4
O
HO
HO
HCO2H
HO
OCH3
H3
O+
CHO
OH
OH
D-glyceraldehyde
+ OHCCHO
glyoxal
O
OHC
+ CH3OH
OHC
OCH3
Enzymatic Cleavage of Glucosides
HO
HO
O
O
HO
HO
HO
HO
HO
OCH3
H3
O+
OCH3
HO
Methyl a-D-glucoside
Methyl b-D-glucoside
maltase
HO
emulsin
HO
O
HO
HO
HO
HO
HO
a-D-glucose
O
OH
HO
OH
b-D-glucose
The Silver Mirror Test
HO
O
Tollens reagent
HO
HO
no reaction
HO
OCH3
Ag(NH3)2+ OH-
Methyl -D-glucoside
non-reducing sugar (a glycoside)
CO2H
HO
Tollens reagent
O
HO
HO
HO
OH
Ag(NH3)2+ OH-
OH
HO
OH
OH
CH2OH
+ Ago
silver mirror
D-glucose
reducing sugar (an aldose)
www.chem-pics.co.uk/download.htm
The Silver Mirror Test
HO
CH2OH
OH
O
HO
O
HO
OH
OH
Ag(NH3)2
+
OH
OH
OH
OH-
OH
HO
OH
OH
CH2OH
b-D-fructofuranose
enediol
CH2OH
D-fructose
Ag(NH3)2+ OHCO2H
Ago
+
CHO
OH
Ag(NH3)2
HO
+
OH-
OH
silver mirror
OH
CH2OH
Aldoses and ketoses are reducing sugars
OH
HO
OH
OH
CH2OH
Disaccharides
and
Polysaccharides
a-D-Glucopyranosyl- b -D-fructofuranoside
orb-D-Fructofuranosyl-a-D-glucopyranoside
OOCR
O
OH
O
HO
HO
acetal
HO
HO
RCOO
RCOO
RCOO
RCOO
O
O
O
HO
O
ketal
RCOO
OOCR
OH
HO
Sucrose
(non-reducing sugar)
RCOO
Olestra
(R=n-CnH2n+1; n=6-8)
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!
Sucralose
1,6-Dichloro-1,6-dideoxy-β-D-fructofuranosyl-4-chloro-4-deoxy-α-D-galactopyranoside
Cl
OH
OH
galacto
O
O
HO
HO
HO
OH
gluco
OH
O
HO
O
Cl
O
O
OH
OH
Cl
OH
OH
Sucrose
(non-reducing sugar)
OH
Sucralose
(600 times sweeter than sucrose)
Bees Do It
CHO
OH
OH
HO
HO
O
OH
OH
HO
HO
HO
CH2OH
O
or H3O+
O
D-glucose [a]D = +52.7o
dextrose
HO
OH
invertase
OH
HO
Sucrose [a]D = +66.5o
(non-reducing, non-mutarotating sugar)
O
HO
OH
OH
CH2OH
D-fructose [a]D = -92.4o
levulose
Disaccharides-Cellobiose
HO
HO
O
HO
HO
HO
O
OHO
HO
O
O
HO
HO
OH
HO
b-acetal linkage
n
partial
hydrolysis
H3O+
HO
HO
HO
emulsin,b-glucosidase (termites, ruminants)
4-O-attachment
HO
O
O
OHO
HO
Cellulose (polysaccharide)
OH
HO
Cellobiose (disaccharide)
4-O-(b-D-glucopyranosyl)-D-glucopyranose
Cellobiose-Structure Proof
HO
HO
HO
HO
O
OHO
HO
Br2/H2O
O
OH
HO
HO
O
HO
HO
OH
OHO
HO
CO2H
HO
HO
Cellobiose
permethylation
•hydrolysis ----> only D-glucose
•emulsin ----> b-glucoside
MeO
O
MeO
MeO
MeO
OMe
O
MeO
MeO
MeO
CO2H
•positive Tollens test ----> reducing sugar
H3O+
•shows mutarotation
CHO
CO2H
OMe
OMe
MeO
MeO
OH
OMe
CH2OMe
tetramethoxycarboxylic acid
OMe
OH
CH2OMe
tetramethoxy
aldehyde
HO
HO
O
HO
HO
OHO
HO
O
OH
Cellobiose-Structure Proof
HO
MeO
MeO
MeO
O
MeO
OMe
O
MeO
MeO
CO2H
MeO
CO2H
OMe
MeO
CO2H
CHO
CO2H
OMe
dimethyl
L-tartaric acid
MeO
OMe
OH
CH2OMe
hot
HNO3
OMe
MeO
hot
HNO3
tetramethoxy
aldehyde
OH
OMe
CH2OMe
tetramethoxycarboxylic acid
CO2H
OMe
MeO
CO2H
OMe
OMe
CH2OMe
CO2H
trimethyl
xylaric acid
dimethyl Dglyceric acid
Disaccharides: Maltose
Starches: poly-a-D-glucosides
Malt (barley)
maltase
HO
O
HO
HO
HO
HO
O
O
OH
HO
HO
•hydrolysis ----> only D-glucose
•maltase ----> a-glucoside
•positive Tollens test ----> reducing sugar
•shows mutarotation
•differs from cellobiose at the glycosidic anomeric center
Disaccharides: Lactose
4-O-(b-D-galactopyranosyl)-D-glucose
~5% of human and cow milk
HO
HO
HO
O
OHO
HO
HO
O
OH
HO
•hydrolysis ----> D-glucose and D-galactose
•b-galactosidase (lactase) ----> b-galactoside
•lactose intolerance
•positive Tollens test ----> reducing sugar
•shows mutarotation
Disaccharides: Amygdalin
Laetrile (laevorotatory mandelonitrile), “vitamin 17”
1,6-b-linkage
HO
O
HO
HO
O
HO
O
HO
HO
CN
O
HO
H
b-linkage
Ph
cyanohydrin of
benzaldehyde
1836 - Isolated from bitter almonds by Wohler.
Demonstrated that emulsin produces glucose,
benzaldehyde and prussic acid (HCN)
Touted in some circles as a treatment for cancer.
Cellulose: Chain Length
HO
HO
O
HO
HO
HO
O
OHO
HO
O
O
HO
HO
OH
HO
n
permethylation
MeO
MeO
O
MeO
MeO
MeO
O
O
MeO
MeO
O
O
MeO
MeO
OMe
MeO
n
H3O+
2,3,4,6-tetra-Omethyl D-glucose
(terminal)
MeO
MeO
O
O
HO
MeO
MeO
MeO
MeO
0.6%
OH
MeO
99.4%
OH
2,3,6-tri-Omethyl D-glucose
(chain)
100-200 units
Starches: Plant Polysaccharides
HO
O
HO
HO
HO
HO
O
O
HO
HO
HO
O
O
HO
n
HO
Amylose :
• ~20% water soluble starch; poly 4-O-(a-D-glucoside)
• forms helical structure; blue complex with iodine
OH
Starches: Plant Polysaccharides
Amylopectin:
• ~80% water insoluble starch
branched poly-4-O-(a-D-glucoside)
• permethylation/hydrolysis
90% 2,3,6-tri-O-methyl-D-glucose
~5% 2,3-di-O-methyl-D-glucose
~5% 2,3,4,6-tetra-O-methyl-D-glucose
MeO
HO
O
HO
MeO
HO
MeO
MeO
chain
MeO
O
OH
MeO
OH
junction
Average 20 glucose units /chain
O
MeO
MeO
MeO
terminus
OH
And Finally, a True Story
In March of 1986 I was in California visiting several universities. While at Stanford University, I stopped at 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?”
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.
Response:
My thought:
“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.”
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!
The
End