Jones M., Fleming S.A. Organic Chemistry

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22.3 Formation of Carbohydrates 1139

This reaction is a modern variation of the Kiliani–Fischer synthesis (Emil Fischer,

again, and Heinrich Kiliani, 1855–1945). In the first step, sodium cyanide

(NaCN) adds to the ribose carbonyl group to make a cyanohydrin (p. 781). The

key point is that a new stereogenic carbon is generated in this reaction and both

(R) and (S) epimers will be formed. In other words, two products will be

formed, one with the new OH group on the right in the Fischer projection and

one with it on the left.

The second step of the Kiliani–Fischer synthesis, catalytic reduction with poi-

soned palladium (p. 452), gives a pair of imines that are hydrolyzed under the reac-

tion conditions to aldoses, each of them one carbon longer than the starting sugar.

The new sugars differ from each other only in their stereochemistry at C(2).In other

words, they are C(2) epimers.

PROBLEM 22.12 Use the Kiliani–Fischer synthesis starting with D-glyceraldehyde.

What new sugars are formed? It is not necessary to write mechanisms for the

reactions.

PROBLEM 22.13 The following two sugars are produced by Kiliani–Fischer syn-

thesis from an unknown sugar. What is the structure of that unknown sugar?

D-Idose

OHH

HHO

CHO

D-Gulose

OHH

CHO

22.3b Shortening Chains in Carbohydrates The Ruff degradation (Otto

Ruff, 1871–1939) is a method of shortening the backbone of a sugar by removal of

the aldehyde at C(1) and creating a new aldehyde at what was C(2) in the starting

sugar (Fig. 22.21). In this process, the aldehyde carbon of an aldose is first oxidized.

Then, the calcium salt of the resulting carboxylic acid is treated with ferric ion and

hydrogen peroxide to cause decarboxylation and oxidation of what was the C(2) carbon.

Ca Salt of

D-galactonic acid

OHH

HHO

OHH

COO

–

D-Galactose

OHH

HHO

OHH

CHO

D-Lyxose

(41%)

HHO

CHO

1. Br

2. Ca(OH)

1. Fe

(SO

)

O/100 ⬚C

2. 30% H

FIGURE 22.21 The Ruff

degradation shortens the starting

sugar by one carbon. It is the

original aldehyde carbon that is

lost. In this example, the aldehyde

carbon of

D-galactose is oxidized

to give

D-galactonic acid, which is

converted into

D-lyxose.

1140 CHAPTER 22 Carbohydrates

The mechanism of this reaction remains obscure (chemistry is a living science—not

everything is fully understood) but one imagines that radicals are involved. Metal

ions can act as efficient electron-transfer agents, and a guess at the mechanism

might involve formation of the carboxyl radical, decarboxylation, capture of the

hydroxyl radical formed, and a final transformation of the hydrate into the alde-

hyde. Whatever the details of the mechanism, the stereochemistry at the original

C(2) is lost, but there can be no changes at the old C(3), C(4), or C(5).

Just as Nature can synthesize sugars from smaller carbon chains, there is a nat-

ural process called glycolysis (Fig. 22.22) that breaks down glucose into two mol-

ecules of a three-carbon compound called pyruvate.This chain-shortening pathway

is a critical part of the metabolism that occurs in almost all organisms. Glycolysis

provides cells with adenosine triphosphate (ATP) and NADH (p. 814).

+ 2 NAD

+ 2 ADP + 2 NADH2 + 2 ATP

␣-D-Glucopyranose Pyruvate

+ phosphate

– H

–

FIGURE 22.22 Glycolysis is a significant metabolic pathway. It involves ten intermediates and ultimately leads to

pyruvate. Energy storage is a side reaction in glycolysis that stores the glucose until energy demands bring it back into

the metabolic pathway.

Summary

Nature forms,stores,and uses chemical energy.Carbohydrates are the central chem-

ical in this dance of life. Chemists manipulate saccharides many ways, as well.

The Kiliani–Fischer synthesis lengthens a carbohydrate chain by one carbon atom.

The Ruff degradation shortens the chain by one carbon. Both reactions occur with-

out disturbing the remaining stereogenic carbons.

22.4 Reactions of Carbohydrates

22.4a Mutarotation Pure, crystallized α-D-glucopyranose has a specific

rotation (p. 159) of 112°. The pure β anomer has a specific rotation of 18.7°.

However, an aqueous solution of either anomer steadily changes specific rotation

until the value of 52.7° is reached.This phenomenon is called mutarotation and

is common for sugars. Our task is to explain it. The answer comes from the real-

ization that both α- and β-

D-glucopyranose are hemiacetals and exist in solution

in equilibrium with a small amount of the open-chain aldohexose (Fig. 22.23).

CHO

Open chain

(trace)

β Anomer

(64%)

α Anomer

(36%)

FIGURE 22.23 The α and β anomers

of a sugar can equilibrate through the

very small amount of the open form

present at equilibrium.

22.4 Reactions of Carbohydrates 1141

Once the acyclic form is produced, it can re-form the hemiacetal to make both the

α- and β-pyranose. Over time, an equilibrium mixture is formed and it is that

equilibrated pair of anomers that gives the specific rotation of 52.7°.

D-Fructose

(30.9%)

OHH

D-Glucopyranose

(63.4%)

D-Mannopyranose

(2.4%)

Ca(OH)

10 days

Ca(OH)

10 days

FIGURE 22.24 In base, D-glucopyranose equilibrates with D-mannopyranose and D-fructose.

PROBLEM 22.14 Write a mechanism for the acid-catalyzed mutarotation of

D-glucopyranose.

This “name reaction” is even better than it sounds. One might be forgiven for assuming that someone meet-

ing these two chemists on a Dutch street in 1880 might say, “Goedemorgen, Lobry; hoe gaat het, Alberda?,”

should he or she be so presumptuously familiar as to address them by their first names. But that assumption

would be dead wrong! The reaction title, alas, incorporates only parts of their names. The reaction is named

for Cornelius Adriaan van Troostenbery Lobry de Bruijn (1857–1904) and the slightly less spectacularly named

Willem Alberda van Ekenstein (1858–1937).

PROBLEM 22.15 Although D-fructose is shown in Figure 22.24 in the open-chain

form, it exists mostly ( 67%) in the pyranose form and partly ( 31%) in the

furanose form in which the hydroxyl group at C(5) is tied up in hemiacetal for-

mation with the ketone. Draw Fischer projections for the pyranose and furanose

forms of

D-fructose.

The mechanism of the Lobry de Bruijn–Alberda van Ekenstein reaction is sim-

pler than its title. As we have pointed out several times now, the predominant cyclic

forms of these sugars are in equilibrium with small amounts of the open-chain iso-

mers. In base, the α hydrogen in the open aldo form can be removed to produce a

22.4b Epimerization in Base In base, sugars rapidly equilibrate with other

sugars, which is a more profound change than the equilibration of anomers

we saw in the preceding section. Again, let’s use D-glucose as an example. As

shown in Figure 22.24,

D-glucopyranose equilibrates with another D-aldohexose,

D-mannopyranose, and a ketose, D-fructose, when treated with aqueous base. This

process goes by the absolutely delightful name of the Lobry de Bruijn–Alberda van

Ekenstein reaction.

1142 CHAPTER 22 Carbohydrates

D-Glucose

(open form)

OHH

base

protonate

base

protonate

OHH

HHO

Resonance-stabilized

enolate

OHH

D-Mannose

(open form)

–

D-Glucopyranose

D-Mannopyranose

FIGURE 22.25 A mechanism for

the equilibration of

D-glucose and

D-mannose involves formation of an

enolate followed by reprotonation.

resonance-stabilized enolate (Fig. 22.25). Reprotonation regenerates D-glucose, if

reattachment occurs from the same side as proton loss, but

D-mannose if reattach-

ment is from the opposite side.

OHH

Enolate

(remember that protonation

on carbon gives

D-glucose

and

D-mannose)

–

OHH

protonate on

oxygen

OHH

D-FructoseDouble enol

–

FIGURE 22.26 Protonation on oxygen of the enolate generates a double enol, which leads to D-fructose, D-glucose, or

D-mannose.

PROBLEM 22.16 Make a three-dimensional drawing of the enolate in Figure 22.25

to show how both D-glucose and D-mannose can be formed on reprotonation.

If protonation occurs at the enolate oxygen,a “double enol”shown in Figure 22.26

is formed.This compound can re-form a carbon–oxygen double bond in two ways.

The double enol can form either an aldehyde or a ketone. If an aldehyde is gener-

ated,the epimeric aldohexoses

D-glucose and D-mannose shown in Figure 22.25 are

produced. If a ketone is formed, it is

D-fructose that is the product.

22.4 Reactions of Carbohydrates 1143

22.4c Reduction We have already seen one aldose reduction, the reaction of

D-glucose with sodium borohydride to give 1,2,3,4,5,6-hexanehexaol (Fig. 22.10).

Any sugar that has a hemiacetal can be reduced by these conditions (Fig. 22.27).

NaBH

OHH

D-Galactopyranose

D-Galactose

(open form)

Alkoxide 1,2,3,4,5,6-

Hexanehexaol

–

FIGURE 22.27 Reduction of

D-galactopyranose to convert the

aldehyde into an alcohol proceeds

through the small amount of the

open, aldo form present at

equilibrium. As the open form is

used up, it is regenerated through

equilibration with the pyranose form.

WORKED PROBLEM 22.17 Reduction of D-altrose with sodium borohydride in

water gives an optically active molecule, D-altritol. However, the same procedure

applied to D-allose gives an optically inactive product. Explain.

ANSWER This problem is easy, but it is critical for understanding the upcoming

material describing the Fischer proof of the stereochemistry of glucose. The

important point is to see that reduction of the aldehyde to the alcohol makes the

molecule more symmetrical by making both ends of the chain CH

OH groups.

D-Allose becomes a meso compound (and therefore optically inactive) because

the reduced product now has a plane of symmetry. Reduction of D-altrose gives

an alcohol that lacks symmetry and is still optically active.

OHH

Open form of

D-allose

(optically active)

Product

(meso)

Mirror image

of product

The product and

its mirror image

are superimposable,

therefore the

product is

optically inactive

The product and

its mirror image

are not superimposable,

therefore the

product is

optically active

NaBH

OHH

Mirror

OHH

HHO

Open form of

D-altrose

(optically active)

Product

(optically active)

NaBH

OHH

HO OH

Mirror image

of product

1144 CHAPTER 22 Carbohydrates

22.4d Oxidation Sugars contain numerous oxidizable groups, and methods

have been developed in which one or more of them may be oxidized in the pres-

ence of the others. Mild oxidation converts only the aldehyde into a carboxylic acid;

the primary and secondary hydroxyls are not touched. The reagent of choice is

bromine in water, and the product is called an aldonic acid (Fig. 22.28).

OHH

0 ⬚C

D-Glucose

(open form)

D-Gluconic acid

(~ 96%)

In an aldonic acid,

the end groups are

still different

D-Glucopyranose

WEB 3D

FIGURE 22.28 Oxidation of an aldose with bromine in water gives an aldonic acid. Note that the functional groups at

the two ends of the molecule are still different from each other.

PROBLEM 22.18 Write a mechanism for the oxidation shown in Figure 22.28.

Hint for the first step: What reaction is likely between an aldehyde and water?

PROBLEM 22.19 Examination of the NMR and IR spectra of typical aldonic acids

often shows little evidence of the carboxylic acid group. Explain this observation.

OHH

HHO

NaNO

HNO

0 ⬚C, 4 h

D-Galactose

(open form)

COOH

OHH

HHO

COOH

D-Galactaric acid

(89%)

D-Galactopyranose

WEB 3D

FIGURE 22.29 Oxidation of a

sugar with nitric acid generates an

aldaric acid, which has a carboxylic

acid group at each end of the

molecule.

Because the hemiacetal present in most sugars is a latent aldehyde, and because

an aldehyde is susceptible to oxidation, several oxidants have been used to detect

sugars. These metal reagents (usually copper based) undergo a color change as the

More vigorous oxidation of a sugar with nitrous or nitric acid creates an aldaric

acid in which both the aldehyde and the primary alcohol have been oxidized to car-

boxylic acids (Fig. 22.29). Notice that this reaction destroys the difference between

the two ends of the molecule.There is an acid group at both the top and bottom of

the Fischer projection.

22.4 Reactions of Carbohydrates 1145

aldehyde is oxidized and the metal reduced. It is this kind of redox reaction that has

given us the term reducing sugar. If a sugar has a hemiacetal, it is in equilibrium with

an aldehyde and so can reduce the metal reagent.

In even more vigorous oxidations, the secondary hydroxyl groups are attacked and

the six-carbon backbone can be ruptured.You already know that vicinal diols (1,2-diols)

are cleaved on treatment with periodate (p. 807). When sugars are treated with perio-

date, mixtures of products are obtained, as the various 1,2-diols are cleaved. Treatment

with periodate can chop the carbon backbone into small fragments, and the structures

of the fragments can often be used in structure determination.

22.4e Osazone Formation Treatment of aldoses with phenylhydrazine under

acidic conditions initiates an odd and very useful reaction. What would we expect? We

know that the cyclic forms of aldoses are in equilibrium with the open-chain isomers,

which contain a free aldehyde group. Aldehydes react with substituted hydrazines to

generate hydrazones (p. 793), and so it is no surprise to see the reaction of Figure 22.30

in which the carbonyl group at C(1) has formed a phenylhydrazone derivative.

PhNHNH

OHH

D-Allose

(open form)

PhNH

OHH

A phenylhydrazone

C(1)

D-Allopyranose

FIGURE 22.30 The small amount of free aldehyde present at equilibrium accounts for

phenylhydrazone formation at C(1).

What is a surprise is to find that in the presence of excess hydrazine not only C(1)

but also C(2) is transformed into a phenylhydrazone.The product is a 1,2-diphenyl-

hydrazone, called an osazone (Fig. 22.31). Here are two clues to the mechanism of

the reaction.First, it takes three equivalents of phenylhydrazine to complete the reac-

tion and, second, aniline and ammonia are by-products.

COOH

3 PhNHNH

Both C(1) and C(2) are

now phenylhydrazones

NHPh

OHH

An osazone

(76%)

2 H

O+

C(1)

C(2)

D-Allopyranose

WEB 3D

FIGURE 22.31 Osazone formation

from an aldose involves conversion

of both C(1) and C(2) into

phenylhydrazones.

The mechanism begins with the reaction at C(1) to form a phenylhydrazone

(p. 793), which consumes the first equivalent of phenylhydrazine.This hydrazone is

an imine and imines are in equilibrium with enamines (p. 796), just as ketones are

in equilibrium with enols.The imine–enamine equilibrium is shown in Figure 22.32.

1146 CHAPTER 22 Carbohydrates

OHH

PhNHNH

NHPhHC

OHH

Phenylhydrazone,

an imine

NHPh

OHH

An enamine and an enol

HNH

FIGURE 22.32 The

phenylhydrazone formed when

an aldose reacts with

phenylhydrazine is an imine

and therefore in equilibrium

with an enamine.This enamine

is also an enol.

PhNHNH

OHH

Ketone

OHH

Diimine

Aniline

NHPh

OHH

n enol and an enamine

HNH

NHPh

NHPhN

OHH

An osazone

NHPh

OHH

New phenylhydrazone

NHPh

OHH

NHPh

N N

FIGURE 22.33 Reaction between

phenylhydrazine and the ketone

form of the substituted enol leads

to a phenylhydrazone different

from the one formed in the

reaction of Figure 22.32. Aniline

is now eliminated to give a

diimine. Reaction with a third

equivalent of phenylhydrazine

leads to the osazone.

Notice that osazone formation destroys the stereogenicity of C(2). Thus,

the same osazone can be formed from two sugars that are epimeric at C(2).

Figure 22.34 makes this point using D-glucose and D-mannose.When we work

through the Fischer proof of the structure of glucose and the other aldohex-

oses, we will make use of this point a number of times, so remember it.

In this case, the enamine is also an enol and is therefore in equilibrium with a ketone

that can react with a second equivalent of phenylhydrazine (Fig. 22.33). Now ani-

line (PhNH

) is eliminated through a series of steps, perhaps as shown in Figure

22.33, to give a diimine, which reacts with the third equivalent of phenylhydrazine

in an exchange of one imine for another to give the final osazone product.

22.4 Reactions of Carbohydrates 1147

PhNHNH

OHH

The same osazone!

OHH

HHO

D-Mannose

NHPhN

NHPh

C(1)

C(2)

OHH

D-Glucose

C(1)

C(2)

FIGURE 22.34

An osazone can

be formed from

two different

carbohydrates that

are epimeric at C(2).

The stereochemistry

at C(2) is destroyed

in the reaction.

FIGURE 22.35 Treatment of a sugar

with excess methyl iodide and silver

oxide leads to formation of a

polyether, in this case a hexaether.

22.4f Ether and Ester Formation Alcohols can be made into ethers. One

classic method in carbohydrate chemistry involves the treatment of a sugar with

excess methyl iodide and silver oxide, which leads to methylation at every free

hydroxyl group in the molecule to form a polyether (Fig. 22.35).

excess

KOH

dioxane

Methyl

D-Glucopyranoside

OCH

(~ 95%)

OPh

ClPh

OCH

FIGURE 22.36 Benzylation through a

series of Williamson ether syntheses.

excess

D-Glucopyranose

(~ 55%)

Methyl 2,3,4,6-tetramethoxy-

D-glucopyranoside

OCH

difference between the alkoxy group at C(1) and the four benzyl ethers.The C(1) alkoxy

group is part of an acetal. The acetal is stable in basic conditions. If the ether-forming

reaction were run on the hemiacetal, then the basic conditions would drive the sugar to

the open-chain form and lead to multiple

products.But use of the acetal produces the

polyether in which neither the alkoxy group

at C(1) nor the pyranose ring connection is

disturbed in the benzylation reaction.

A carbohydrate reacting with acetic

anhydride or acetyl chloride will produce

a polyacetylated compound in which all of

the free hydroxyl groups are esterified

(Fig. 22.37).

98 ⬚C, 8.5 h,

acid catalyst

D-Glucopyranose

A pentaester

(58%)

excess

FIGURE 22.37 The free hydroxyl groups of

glucopyranose are esterified with acetic anhydride.

One of the classic S

2 reactions is the Williamson ether synthesis (p. 315), the for-

mation of an ether from an alkoxide and an alkyl halide. When an aldohexose is treat-

ed with benzyl chloride and potassium hydroxide,a series of Williamson ether syntheses

results in formation of a tetraether and an acetal (Fig. 22.36). Be careful to notice the

1148 CHAPTER 22 Carbohydrates

Notice that in both the alkylation and acylation reactions the oxygen tied up in

the ring remains unaffected by the reaction.It can form neither an ether nor an ester.

The presence of the hemiacetal form allows for selective ether formation when

a sugar is treated with dilute acidic alcohol. The product is an acetal (Fig. 22.38).

The generic name for an acetal of any sugar is glycoside. Pyranose glycosides are

called pyranosides, and furanose glycosides are furanosides.

Why is it that only the hydroxyl group at the anomeric carbon is substituted

by a methoxyl group in this reaction? The first step is protonation of one of the

many OH groups (Fig. 22.39). All the OH groups are reversibly protonated, but

only one protonation leads to a resonance-stabilized cation when a molecule of

cat.

HCl

64 ⬚C, 72 h

D-Glucopyranose

OCH

A glycoside (in this

case a pyranoside)

(~ 50%)

FIGURE 22.38 Treatment of a sugar

with dilute HCl and alcohol converts

only the anomeric OH into an acetal.

Such a molecule is called a glycoside.

D-Glucopyranose

(a hemiacetal)

A pyranoside

(an acetal)

HO HO

protonation

elimination

HO HO

deprotonation

ROH

addition

ROH

OH OH

FIGURE 22.39 All OH groups in a sugar can be reversibly protonated. In addition to the protonation at C(3) shown, the top

reaction represents protonation at C(2), C(4), and C(6).The bottom reaction shows protonation of the OH at the anomeric

C(1). Only in this intermediate can an oxygen “kick out” water and provide resonance stabilization for the resulting cation.

Addition of alcohol at C(1) followed by a deprotonation gives the glycoside.