Reaction of Monosaccharides with Alcohols: Glycoside Formation

1

• Aldoses and ketoses react with an alcohol in the presence of

an acid catalyst to provide acetals called glycosides.

• Regardless of the anomer used as the starting material, both

anomers of the glycoside are formed.

• However, the more stable anomer usually predominates. For

example, the acid-catalysed reaction of glucose with methanol

gives a mixture of methyl glucosides.

11:36 AM

O

HO

HOHO

OHOH

-D-Glucopyranose

CH3OH, HClO

HO

HOHO

OCH3

OH

+O

HO

HOHO

OCH3HO

Methyl D-glucopyranoside Methyl D-glucopyranoside

Aglycone

• Note that despite the presence of a number of other hydroxyl

groups in the sugar, it is only the anomeric hydroxyl group that

is replaced.

Reaction of Monosaccharides with Alcohols: Glycoside formation

2

•The success of this glycosylation at the anomeric centre

depends on the generation of a resonance stabilized oxonium

ion at the anomeric carbon that undergoes a nucleophilic attack

by the nucleophilic alcohol molecules.

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•Equilibriation of the glycosides usually takes place. It is an

example of a reaction that is subject to thermodynamic (or

equilibrium) control.

O

HO

HOHO

OHOH

H+O

HO

HOHO

OOH H

HO

HO

HOHO

HO

H2O+

CH3OH

O

HO

HOHO

OH

OCH3

HO

HO

HOHO

OCH3

OH

-H+

Resonance-stabilized Oxonium ion(All atoms have a complete octate)

Properties of Glycosides

3

• Unlike the free sugars from which they are derived,

glycosides are stable to basic conditions.

• Glycosides may therefore be used with basic reagents and in

basic solutions. This effectively means that the anomeric

centre can effectively be protected as a glycoside at the

beginning of any reaction sequence.

• Since glycosides are incapable of being in equilibrium with

their open-chain forms, they are non-reducing sugars.

• Glycosides do not exhibit mutarotation. Converting the

anomeric hydroxyl group to an ether function

(hemiacetal→acetal) prevents its reversion to the open-chain

form in neutral or basic media.11:36 AM

Hydrolysis of Glycosides

4

• In aqueous acid, acetal formation can be reversed and the

glycoside hydrolysed to an alcohol and the free sugar.

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• Note that the mechanism of hydrolysis is the exact reverse of

that for glycosylation.

Etherification of Monosaccharides

5

• The best conditions for permethylating sugars that can be

employed on both hemi-acetals (lactols) and glycosides

involves treating the sugar with methyl iodide in the presence

of silver oxide. These conditions convert all the free hydroxyl

groups to methyl ethers.

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Etherification of Monosaccharides

6

• Permethylation of monosaccharides with methyl iodide in the

presence of silver oxide depends on the polarisation of the

CH3-I bond with silver oxide making the methyl carbon

strongly electrophilic. Attack by the carbohydrate –OH group,

followed by deprotonation, gives the ether.

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Application of Permethylation in Structure Determination

7

• This reaction has been used to determine the ring size of

glycosides.

• Once all the free hydroxyl groups of a glycoside have been

methylated, the glycoside is subjected to acid-catalysed

hydrolysis. Only the anomeric methoxy group is hydrolysed. .

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O

CH3O

CH3OCH3O

OCH3

OCH3

Methyl 2,3,4,6-tetra-O-Methyl-D-

glucopyranoside

H+

H2O O

CH3O

CH3OCH3O

OH

OCH3

CHO

OCH3H

HCH3O

OCH3H

CH2OCH3

H OH

2,3,4,6-tetra-O-Methyl-D-glucopyranose

H

OCH3

HH OCH3

OCH3 HO

CH3O H

CH3O

Methyl 2,3,5,6-tetra-O-Methyl-

D-glucofuranoside

H

OH

HH OCH3

OCH3 HO

CH3O H

CH3O

H+

H2O

CHO

OCH3H

HCH3O

OHH

CH2OCH3

H OCH3

2,3,5,6-tetra-O-Methyl-D-glucofuranose

Application of Permethylation in Structure Determination

8

• Note that all the hydroxyl groups in the open-chain form of

the sugar except C-5 are methylated. C-5 is not methylated

because it was originally the site of the ring oxygen in the

methylglycoside.

• Once the position of the hydroxyl group in the sugar has

been determined, either by spectroscopy or by converting the

sugar to a known compound, the ring size stands revealed.

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Oxidative Cleavage of Monosaccharides with Periodic Acid

9

• Since carbohydrates contain two or more –OH or C=O

groups on adjacent carbons, they undergo oxidative

cleavage by periodic acid.

• Periodic acid oxidation finds extensive use as an analytical

method in carbohydrate chemistry. Structural information is

obtained by measuring the number of equivalents of periodic

acid that react with a given compound and identifying the

reaction products.

• A vicinal diol (1,2-diol) consumes one equivalent of periodate

and is cleaved to two carbonyl compounds.

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Mechanism of Oxidative Cleavage of Monosaccharides with Periodic Acid

10

• A vicinal diol (1,2-diol) is oxidatively cleaved through a cyclic

periodate ester to two carbonyl compounds.

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Oxidative Cleavage of Monosaccharides with Periodic Acid

11

• -Hydroxy carbonyl compounds also undergo oxidative

cleavage with periodic acid. Their cleavage, however,

provides a carboxylic acid and a carbonyl compound.

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• The cleavage is also postulated to take place through a

cyclic periodate ester intermediate. The cyclic ester

spontaneously breaks down by a cyclic flow of electrons in

which iodine accepts an electron pair.

Oxidative Cleavage of Monosaccharides with Periodic Acid

12

• The cleavage is postulated to take place through a cyclic

periodate ester intermediate. The cyclic ester spontaneously

breaks down by a cyclic flow of electrons in which iodine

accepts an electron pair.

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Oxidative Cleavage of Monosaccharides with Periodic Acid

13

• Given that monosaccharides and their derivatives are

polyhydroxy carbonyl compounds, they undergo oxidative

cleavage in a manner similar to that of vicinal diols and -

hydroxy carbonyl compounds.

• For example, metasaccharinic acid undergoes oxidative

cleavage with periodic acid to provide the products shown

below.

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+

COOH

H OH

HH

OHH

OHH

CH2OH

HIO4

COOH

H OH

HH

OH

O

O H

H

H

OH

+

Metasaccharinic acid Formic acid Formaldehyde

Periodic Acid Cleavage: Structural Determination of Monosaccharides

14

• Periodic acid oxidative cleavage can also be used in

structure determination.

• For example, the structure determination of a previously

unknown methyl glycoside, obtained by the reaction of D-

arabinose with methanol and hydrogen chloride, was

determined on the basis of the products of the oxidative

cleavage with periodic acid.

• The size of the ring was identified as a five-membered ring

because only one mole of periodic acid was consumed per

mole of glycoside and no formic acid was produced.

• Were the ring six membered, two moles of periodic acid

would be required per mole of glycoside and one mole of

formic acid would be produced.11:36 AM

Periodic Acid Cleavage: Structural Determination of Monosaccharides

15

• The structure of a previously unknown methyl glycoside was

identified as a five-membered ring because only one mole of

periodic acid was consumed per mole of glycoside and no

formic acid was produced.

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O

OCH3

OH

OH

HOO

OH

OH

OCH3

HO

1

23

4

5

123

4 5

2 HIO4HIO4

O

O

OCH3

HO

O

O

OCH3

O

O

+ O

H

HO

Formic acid

Furanose Pyranose

• The sodium salt of periodic acid, sodium periodate (NaIO4),

is also equally effective in the oxidative cleavage of 1,2-diols.