Essentials of Organic Chemistry

436 HETEROCYCLES

Box 11.7 (continued)

H1 receptor antagonist H2 receptor antagonists

H3C HH HH
HN N NN NN
S CH3 S CH3
S O
O H3C N H3C
CN N NO2
NMe2 N ranitidine
diphenhydramine H3C cimetidine

H3C
HH
NN
S CH3

N
NO2

nizatidine

Cimetidine contains an imidazole ring comparable to histamine, a sulfur atom (thioether group) in the side-
chain, and a terminal functional group based upon a guanidine (see Section 4.5.4). Ranitidine bears considerable
similarity to cimetidine, but there are some important differences. The heterocycle is now furan rather than
imidazole, and the guanidine has been modified to an amidine (see Section 4.5.4). A newer drug, nizatidine, is
a variant on ranitidine with a thiazole heterocyclic ring system.

11.7.3 Reactivity of 1,3-azoles by the possibility of forming a dialkylimidazolium
salt; the first-formed protonated N -alkylimidazole
Electrophiles can add to N-3, the azomethine =N–, can be deprotonated by imidazole, then alkylated
of 1,3-azoles as they can to the pyridine nitrogen. N- further.
Alkylation is complicated in the case of imidazole

N MeI Me Me Me
N N imidazole N MeI N
H
N − H+ N NI
H
Me
dimethylimidazolium salt

N-Acylation is mechanistically similar, and mono- alkylation and acylation it is the =N– that acts as the
acylation can be accomplished by using two molar nucleophile; this carries the only lone pair. However,
equivalents of imidazole to one of the acylating proton loss occurs from the other nitrogen, giving
agent, the second mole serving to deprotonate the the impression that the N–H has been alkylated or
first-formed N -3-acylimidazolium salt. Note that in acylated.

N Ac2O Ac Ac N
N N − H+ N
H N
N ≡
H
N

Ac

N-1-acetylimidazole

The 1,3-diazoles are much less susceptible to thiophene, but are more reactive than pyridine. Imida-
electrophilic substitution than pyrrole, furan, and zole is the most reactive, and may be nitrated readily.

FIVE-MEMBERED RINGS WITH TWO HETEROATOMS 437

Substitution occurs at C-5, but tautomerism then leads with no particularly unfavourable resonance forms.
to the 4(5) mixture. The position of substitution may There is less delocalization after attack at C-2; one
be predicted from a consideration of resonance struc- of the resonance forms has an unfavourable electron-
tures: attack at C-5 provides maximum delocalization deficient nitrogen.

N HNO3 H N N N − H+ N H
H H O2N N
5 N
O2N N O2N N H O2N N
N H2SO4 O2N N H H

HH

electrophilic attack N N N N
at C-2 less favourable H H H
2
NE NE NE
N H H H

H unfavourable
electron-deficient
cation

In general, the 1,3-diazoles do not react by nucle- sodium amide, are more likely to remove the NH
ophilic substitution, although imidazole can partic- proton (pKa 14.2) (see Section 11.7.1). However,
ipate in the Chichibabin reaction with substitution oxazole and thiazole do not have any NH, and the
at C-2; the position of substitution is equivalent most acidic proton is that at C-2. The electronegative
to that noted with pyridine (see Section 11.4.1). oxygen and sulfur are able to support an adjacent
Nucleophilic species that are strong bases, like negative charge.

N n-BuLi N
S 2H S

Me Me Me
N NaOD N D2O N

S H D2O S SD

thiazolium ylid

It is found that quaternary salts of 1,3-azoles ylid (or ylide; pronounced il-ide). This ylid, with neg-
are deprotonated at C-2 in the same way. Rates of ative charge on carbon, is potentially a nucleophilic
deprotonation are considerably faster because of the species. Thus, it is found that both oxazolium and thi-
influence of the quaternary centre that provides a azolium salts undergo H–D exchange at C-2 remark-
favourable inductive effect. The conjugate base bear- ably quickly under basic conditions, illustrating very
ing opposite charges on adjacent atoms is termed an simply this nucleophilic behaviour.

Box 11.8

The thiazolium ring in thiamine

Thiamine (vitamin B1), in the form of thiamine diphosphate (TPP), is a coenzyme of some considerable
importance in carbohydrate metabolism. Dietary deficiency leads to the condition beriberi, characterized
by neurological disorders, loss of appetite, fatigue, and muscular weakness. We shall study a number of

438 HETEROCYCLES

TPP-dependent reactions in detail in Chapter 15. At this stage, we should merely examine the structure of thiamine,
and correlate its properties with our knowledge of heterocycles.

Thiamine contains two heterocyclic rings, a pyrimidine and a thiazole, the latter present as a thiazolium salt.
The pyrimidine portion is unimportant for our understanding of the chemistry of TPP, though it may play a role
in some of the enzymic reactions.

nucleophilic attack of

carbanion onto carbonyl:

NH2 aldol-type reaction decarboxylation of
β-iminium acid
N NS H

N acidic O O
thiamine diphosphate
hydrogen H3CHO H
(TPP) B O
H3C CO2H
H

OPP R1 R1 R1
N N N
S S S

R2 R2 R2
TPP
thiazolium ylid
(TPP anion)

The proton in the thiazolium ring is relatively acidic (pKa about 18) and can be removed by even weak bases
to generate the carbanion or ylid; an ylid is a species with positive and negative charges on adjacent atoms. This
ylid is an ammonium ylid with extra stabilization provided by the sulfur atom.

The ylid can act as a nucleophile, and is also a reasonable leaving group. Prominent among TPP-dependent
reactions is the oxidative decarboxylation of pyruvic acid to acetyl-CoA; this reaction links the glycolytic pathway
to the Krebs cycle (see Section 15.3). Addition of the thiazolium ylid to the carbonyl group of pyruvic acid is
the first reaction of this sequence, and this allows the necessary decarboxylation, the positive nitrogen in the ring
acting as an electron sink. In due course, the thiazolium ylid is regenerated as a leaving group. We shall look at
this sequence in more detail in Section 15.8.

11.7.4 1,2-Azoles: pyrazole, isoxazole, and pyrazole has pKa 2.5 and isoxazole pKa − 3.0. The
isothiazole higher basicity in pyrazole is probably related to the
symmetry of the contributing resonance structures.
As in the 1,3-azoles, the =N–nitrogen carries a The greater electron-withdrawing effect of oxygen
lone pair of electrons and 1,2-azoles are thus compared with sulfur is reflected in the basicity of
potentially basic. However, the direct linking of the isothiazole (pKa − 0.5).
two heteroatoms has a base-weakening effect. Thus,
pyrazolium
pyrazolium isoxazolium isothiazolium

NN H ONH N H N H NN H
H pKa −3.0 S N H
pKa 2.5
H

pKa −0.5 equivalent resonance structures

11.8 Heterocycles fused to a benzene a benzene ring, and these have long-established triv-
ring ial names, e.g. indole, quinoline, and isoquinoline.

Many interesting and important heterocyclic com- Systematic names can be derived by relating
pounds contain fused ring systems. Some of the back to the parent heterocycle and using the prefix
common ones are the result of fusing a heterocycle to benzo to indicate its fusion to benzene. It is necessary
to define which of the bonds in the heterocycle is

HETEROCYCLES FUSED TO A BENZENE RING 439

4 3 5 4 5 4 c c
5 6 3 6 3 b b
12 aN
6 7 2 7 N2 aN
7 N 8 8 H
H N 1 pyridine
pyrrole
1

indole quinoline isoquinoline
benzo[b]pyrrole benzo[b]pyridine benzo[c]pyridine

fused to benzene, and this is accomplished through from the heteroatom. Where we have two similar
use of a bond descriptor, a lower case italic letter heteroatoms, lettering is chosen to produce the lower
in square brackets. Thus, indole is benzo[b]pyrrole, alternative. Thus, quinazoline is benzo[d]pyrimidine,
quinoline is benzo[b]pyridine, and isoquinoline, an not benzo[e]pyrimidine. Where the heteroatoms are
isomer of quinoline with a different type of fusion, different, just as we number from the atom of higher
becomes benzo[c]pyridine. atomic number, we also letter from the same atom.
Hence, benzo[d]isoxazole is quite different from
A few other examples are shown below. Note that benzo[c]isoxazole.
the bonds of the heterocycle are lettered starting

4 3 c 4 3 c 4 3 cN b
5 b 5 b 5 d
12 aO 12 aS N
6 6 6 Na
7 O furan 7 S thiophene 7 12 H
imidazole
N
H

benzo[b]furan benzo[b]thiophene benzimidazole
benzo[d]imidazole

5 4 N dc 4 3 c 4 3
6 da N 5 b 5
N3 1 N2 1 O2
cNb eb 6 O dN 6 N
7 2 7 Oa 7
8 Na
N isoxazole

1

quinazoline pyrimidine benzo[d]isoxazole benzo[c]isoxazole
benzo[d]pyrimidine

The final fused ring system is then given a which Kekule´ form of a benzene or pyridine ring
completely new numbering system, different from is drawn. The three versions of quinoline shown
that of the heterocycle. Typically, this starts adjacent are simply contributing resonance forms. However,
to the bridgehead atom, then proceeds around the some structures, such as isoindole, benzo[c]furan, or
fused ring. The major criterion is to generate the benzo[c]isoxazole above, can only be drawn in one
lowest number for the first heteroatom. way without invoking charge separation.

Note that, in most cases, we have little regard for

Kekulé forms of pyridine ring

N NN N N
quinoline Kekulé forms of benzene ring H H

indole

NH O
benzo[c]furan
isoindole
benzo[c]pyrrole

440 HETEROCYCLES

11.8.1 Quinoline and isoquinoline the nitrogen carries a lone pair in an sp2 orbital
(see Section 11.3). Alkyl halides and acyl halides
Quinoline and isoquinoline are benzopyridines. They also react at nitrogen to give N -alkyl- and N -acyl-
behave by showing the reactivity associated with quinolinium salts. The N -alkyl salts are stable, but
either the benzene or the pyridine rings. the N -acyl salts hydrolyse rapidly in the presence of
water.
Quinoline is basic with a pKa of 4.9, similar
to that of pyridine (pKa 5.2). As with pyridine,

RX RCOX

NX N H2O NX
R
N-alkylquinolinium halide RO
N-acylquinolinium halide

Quinoline is much more reactive towards elec- first, further inhibiting reaction (see Section 11.4).
trophilic substitution than pyridine, but this is This is again true in quinoline, so that the proto-
because substitution occurs on the benzene ring, not nated system is involved in the reaction, and the
on the pyridine. We have already seen that pyridine benzene ring undergoes substitution. With a nitrat-
carbons are unreactive towards electrophilic reagents, ing mixture of HNO3 –H2SO4, the products are 5-
with strongly acidic systems protonating the nitrogen and 8-nitroquinoline in roughly equivalent amounts.

NO2

HNO3 +
N H2SO4 NN

0˚C NO2

5-nitroquinoline 8-nitroquinoline

approx 1:1

This may be rationalized by considering the sta- undergoes preferential electrophilic substitution at the
bility of intermediate addition cations. When the α-positions (see Section 8.4.4). Whilst we may be
electrophile attacks at C-5 or C-8, the intermediate a little unhappy about protonation of a quinolinium
cation is stabilized by resonance, each having two cation to an intermediate that carries two positive
favourable forms that do not perturb the aromaticity charges, we find that N -methylquinolinium salts also
of the pyridinium system. In contrast, for attack at undergo nitration at a similar rate to quinoline; so this
C-6 or C-7 there is only one such resonance form. We mechanism appears correct.
used similar reasoning to explain why naphthalene

5 HE HE E
6
H+ E+ 5 − H+
E+
7 N N NN N
8 H HH H

E attack at C-5 or C-8 gives two favoured resonance
H6 forms with unperturbed pyridinium system

N − H+

H 8N N N
HE H HE H EH
attack at C-6 (or C-7) gives only
one resonance form with
unperturbed pyridinium system

HETEROCYCLES FUSED TO A BENZENE RING 441

Nucleophilic substitution occurs at C-2, and to a amide (see Section 11.4). However, better yields have
lesser extent C-4, as might be predicted from simi- been achieved by performing the reaction at low tem-
lar reactions with pyridine. Chichibabin amination peratures in liquid ammonia solvent, and then oxi-
occurs rather more readily than with pyridine, giv- dizing the intermediate dihydroquinoline salt using
ing 2-aminoquinoline. A typical hydride abstraction potassium permanganate.
process occurs when quinoline is heated with sodium

NaNH2 − H−
N 100˚/ xylene
H N NH2
N NH2 Na

NaNH2 KMnO4 N NH2
liquid NH3 H
N NH2 Na

Quinolines carrying 2- or 4-halo substituents Note, however, that hydroxyls on the benzene ring
undergo nucleophilic substitution readily, in the same would be typical phenols. Again, aminoquinolines
manner as 2- and 4-halopyridines. Hydroxyquinolines follow the pyridine precedent and the tautomeric
with the hydroxyl at positions 2 or 4 exist mainly in imino forms are not observed.
the carbonyl form, i.e. 2-quinolone and 4-quinolone.

NaOEt Cl N OEt O
EtOH N OEt
N Cl N OH NO N
H H
H2O 2-quinolone 4-quinolone
120˚C NH2
N Cl

NH3

N Cl N NH2 N NH N
2-aminoquinoline H 4-aminoquinoline

Both 2-aminoquinoline and 4-aminoquinoline pro- resonance (compare aminopyridines, Section 11.4.3).
tonate first on the ring nitrogen, with 4-aminoquin- No such resonance structures can be drawn for 3-
oline being the more basic, the conjugate acid aminoquinoline, which is much less basic (pKa 4.9).
benefiting from increased charge distribution through

H+

N NH2 N NH2 N NH2
2-aminoquinoline H H
pKa 7.3

442 HETEROCYCLES

NH2 H+ NH2 NH2

N N N
4-aminoquinoline H H
pKa 9.2

Box 11.9

Quinolone antibiotics

The quinolone antibiotics feature as the one main group of antibacterial agents that is totally synthetic, and not
derived from or based upon natural products, as are penicillins, cephalosporins, macrolides, tetracyclines, and
aminoglycosides. The first of these compounds to be employed clinically was nalidixic acid; more recent drugs
in current use include ciprofloxacin, norfloxacin, and ofloxacin

O O F O F O
CO2H F CO2H CO2H CO2H

Me N N N NN N MeN NN
Et HN HN Et O
Me
nalidixic acid ciprofloxacin norfloxacin ofloxacin

‘Quinolone’ as a descriptor is obviously an oversimplification, since nalidixic acid contains two fused pyridine
rings rather than a benzopyridine, and ofloxacin has a morpholine ring fused to the quinolone. Nevertheless,
the quinolone substructure is generally used when referring to this group of antibiotics. The most important
structural features for good antibacterial activity have been found to be a carboxylic acid at position 3, a
small alkyl group at position 1, a 6-fluorine substituent, and a nitrogen heterocycle, often a piperazine, at
position 7.

F6 O

CO2H

3

N7 N1
HN R

The quinolones are good general antibiotics for systemic infections, and they are particularly useful for urinary
tract infections because high concentrations are excreted into the urine. The mode of action involves interference
with DNA replication by inhibiting DNA gyrase, a bacterial enzyme related to mammalian topoisomerases that
breaks and reseals double-stranded DNA during replication.

Isoquinoline (pKa 5.4) has similar basicity smoothly to give predominantly 5-nitroisoquinoline;
to quinoline and pyridine, and also undergoes the isoquinolinium cation reacts more readily than the
N -alkylation and N -acylation. Nitration occurs quinolinium cation.

HETEROCYCLES FUSED TO A BENZENE RING 443

NO2

HNO3 + N
N
N H2SO4
0˚C NO2
8-nitroisoquinoline
5-nitroisoquinoline

approx 9:1

Nucleophilic substitution occurs exclusively at benzene resonance in the intermediate anion. Thus,
position 1 in isoquinoline; the alternative position C-3 Chichibabin amination gives 1-aminoisoquinoline.
is quite unreactive. This is explained by the loss of

3 NaNH2 − H− H
NH2
N N N
Na N
1
H NH2 attack at C-3 results in loss
retains benzene resonance NH2 of benzene resonance
1-aminoisoquinoline

Substitution with displacement of halide occurs carbonyl form, whereas 1-aminoisoquinoline is the
readily at C-1 and much less readily at C-3 for the normal tautomer. The basicity of 1-aminoisoquinoline
same reasons, i.e. the loss of benzene resonance if C-3 (pKa 7.6) is similar to that of 2-aminoquinoline
is attacked. 1-Isoquinolone exists completely in the (pKa 7.3).

NH H+ N N
N H H
O
1-isoquinolone NH2 NH2 NH2
1-aminoisoquinoline pKa 7.6

11.8.2 Indole would necessarily destroy aromaticity in the five-
membered ring. Nevertheless, an equilibrium involv-
Indole is the fusion of a benzene ring with a pyrrole. ing the N -protonated cation is undoubtedly set up,
Like quinoline and isoquinoline, indole behaves as an since acid-catalysed deuterium exchange of the N -
aromatic compound. However, unlike quinoline and hydrogen occurs rapidly, even under very mild acidic
isoquinoline, where the reactivity was effectively part conditions. Protonation eventually occurs preferen-
benzene and part pyridine, the reactivity in indole tially on carbon, as with pyrrole; but there is a dif-
is modified by each component of the fusion. The ference, in that this occurs on C-3 rather than on
closest similarity is between the chemistry of pyrroles C-2. This is the influence of the benzene ring. It can
and indoles. be seen that protonation on C-3 allows resonance in
the five-membered ring and charge localization on
Indoles, like pyrroles, are very weak bases. The nitrogen. In contrast, any resonance structure from
conjugate acid of indole has pKa − 3.5; that of pyr- protonation at C-2 destroys the benzene ring aro-
role has pKa − 3.8. As in the case of pyrrole (see maticity.
Section 11.3), nitrogen has already contributed its
lone pair to the aromatic sextet, so N -protonation

444 HETEROCYCLES

3 HH HH

2 H+

N N N N
H H H HH

favourable resonance loss of pyrrole aromaticity;
retains benzene aromaticity

HH

NH NH
H H

unfavourable resonance;
destroys benzene aromaticity

Similar behaviour is encountered with other electrophiles, with substitution occurring at C-3.

HE HE E
N
E+ − H+ H
N
H N N
H H

favourable resonance

HH

NE NE
H H

unfavourable resonance;
destroys benzene aromaticity

Indole is very reactive towards electrophiles, unsuccessful (compare pyrrole), but can be achieved
and it is usually necessary to employ reagents using benzoyl nitrate.
of low reactivity. Nitration with HNO3 –H2SO4 is

O NO2
N
Ph O NO2 H
N
H benzoyl nitrate

Br2 Br
N pyridine
H N
H
MeI Me
N DMF
H N
H

HETEROCYCLES FUSED TO A BENZENE RING 445

OO H3C O H3C O
HOAc
NN
H3C O CH3 H
N
H O
H3C
It is also possible to brominate and methylate
at C-3; however, conditions must be controlled Indole reacts readily as the nucleophile in Man-
carefully, since further electrophilic reactions may nich reactions. This provides convenient access to
then occur. Treatment with acetic anhydride leads to other derivatives, as shown below.
1,3-diacetylindole.

Me Mannich NMe2 NMe3
reaction MeI elimination of
H2C N leaving group
N
N Me H N
H gramine H

HCHO Me2NH KCN

NH2 LiAlH4 CN CN
KCN
N nucleophilic attack
H N on to unsaturated
tryptamine H N iminium cation
H

Thus, quaternization at the side-chain nitrogen allows Simple addition to carbonyl compounds occurs
ready elimination of trimethylamine. This is facili- under mild acidic conditions. Examples given illus-
tated by the electron-releasing ability of the indole trate reaction with acetone, an aldol-like reaction, and
nitrogen, and can be brought about by mild base. conjugate addition to methyl vinyl ketone, a Michael-
By choosing KCN as the mild base, the tran- like reaction. The first-formed alcohol products in
sient 3-methyleneindoleninium salt can be trapped aldol-like reactions usually dehydrate to give a 3-
by cyanide nucleophile, leading to indoleacetonitrile. alkylidene-3H -indolium cation.
Reduction of the nitrile group with LAH provides a
route to tryptamine.

H

nucleophilic addition to O H3C OH H3C CH3
aldehydes and ketones CH3
H3C CH3
nucleophilic addition to H+ N N
conjugated systems H H
N
H CH3
O
O N
CH3 H+ H

N
H

446 HETEROCYCLES

We noted above (see Section 11.5.1) that pyrrole, aromaticity. The indole anion is also formed by loss
though a very weak base, is potentially acidic (pKa of the N–H proton (pKa 16.2) using sodium amide
17.5). This was because the anion formed by losing or sodium hydride, or even a Grignard reagent (see
the proton from nitrogen has a negative charge on the Section 6.3.4) as base.
relatively electronegative nitrogen, but maintains its

MeMgBr NaNH2 NN

N N resonance stabilization
MgBr H of conjugate base
pKa 16.2 MeI
MeI
Me

N C-methylation N N-methylation
H Me

The indole anion is resonance stabilized, with variables; but, as a general rule, if the associated
negative charge localized mainly on nitrogen and metal cation is sodium, then the anion is attacked at
C-3. It can now participate as a nucleophile, e.g. the site of highest electron density, i.e. the nitrogen.
in alkylation reactions. However, this can lead to Where the cation is magnesium, i.e. the Grignard
N -alkylation or C-alkylation at C-3. Which is the reagent, then the partial covalent bonding to nitrogen
predominant product depends upon a number of prevents attack there, and reaction occurs at C-3.

Box 11.10

Indoles in biochemistry

Some rather important indole derivatives influence our everyday lives. One of the most common ones is
tryptophan, an indole-containing amino acid found in proteins (see Section 13.1). Only three of the protein amino
acids are aromatic, the other two, phenylalanine and tyrosine being simple benzene systems (see Section 13.1).
None of these aromatic amino acids is synthesized by animals and they must be obtained in the diet. Despite
this, tryptophan is surprisingly central to animal metabolism. It is modified in the body by decarboxylation (see
Box 15.3) and then hydroxylation to 5-hydroxytryptamine (5-HT, serotonin), which acts as a neurotransmitter
in the central nervous system.

CO2H CO2H

NH2 oxidation HO NH2 – CO2 HO NH2

N N N
H H H
5-hydroxy-L-Trp
L-tryptophan 5-hydroxytryptamine
(L-Trp) (5-HT; serotonin)

Serotonin mediates many central and peripheral physiological functions, including contraction of smooth
muscle, vasoconstriction, food intake, sleep, pain perception, and memory, a consequence of it acting on several

distinct receptor types. Although 5-HT may be metabolized by monoamine oxidase, platelets and neurons possess

a high-affinity mechanism for reuptake of 5-HT. This mechanism may be inhibited by the widely prescribed
antidepressant drugs termed selective serotonin re-uptake inhibitors (SSRI), e.g. fluoxetine (Prozac), thereby

increasing levels of 5-HT in the central nervous system.

HETEROCYCLES FUSED TO A BENZENE RING 447

Migraine headaches that do not respond to analgesics may be relieved by the use of an agonist of the 5-HT1
receptor, since these receptors are known to mediate vasoconstriction. Though the causes of migraine are not

clear, they are characterized by dilation of cerebral blood vessels. 5-HT1 agonists based on the 5-HT structure in
current use include the sulfonamide derivative sumatriptan, and the more recent agents naratriptan, rizatriptan
and zolmitriptan. These are of considerable value in treating acute attacks.

Me2NSO2 NMe2 Me N NMe2
NN N
N
H N
sumatriptan MeNHSO2 H

rizatriptan NMe2

N O NH N
H
naratriptan O zolmitriptan H

Several of the ergot alkaloids also interact with 5-HT receptors. Some are used medicinally, but the most
notorious is the semi-synthetic derivative lysergic acid diethylamide (LSD). This is itself an indole derivative,
though the indole is part of a more complex fused-ring system. Nevertheless, from the structural similarities,
it is not difficult to see why LSD might trigger 5-HT receptors. It has the additional ability to interact with
noradrenaline and dopamine receptors, thus generating a complex pharmacological response. LSD is probably
the most powerful pyschotomimetic known, intensifying and distorting perceptions. Experiences can vary from
beautiful visions to living nightmares, and no two ‘trips’ are alike.

NEt2 NEt2
O
NMe NH2 O NMe NH2 NH2
H H HO

HO

NN N OH OH
HH H OH
dopamine
OH

lysergic acid diethylamide 5-hydroxytryptamine lysergic acid diethylamide noradrenaline

(lysergide; LSD) (serotonin; 5-HT) (lysergide; LSD) (norepinephrine)

Also known to be hallucinogenic are the indole derivatives psilocin and psilocybin found in the so-called
magic mushrooms, Psilocybe species. Ingestion of these small fungi causes visual hallucinations with rapidly
changing shapes and colours. Psilocybin is the phosphate of psilocin; although based on 4-hydroxytryptamine,
they also act on 5-HT receptors.

OH CO2H
O
NH2 MeO NHAc
P
OH HO O

NH2

N N N N
H H H H
psilocin psilocybin melatonin indole-3-acetic acid

Melatonin is N-acetyl-5-methoxytryptamine, a simple derivative of serotonin. It is a natural hormone secreted
by the pineal gland in the brain during the hours of darkness. It is involved in controlling the body’s day–night

448 HETEROCYCLES

rhythm, the ability to sleep during the night, and to stay awake during the day. When given as a drug, melatonin
induces sleep, and adjusts the internal body clock. It is now used as a means of reducing the effects of jet-lag.

Plants also require hormones to trigger their growth patterns. One of these is indole-3-acetic acid, which
controls cell elongation and is produced in the growing shoot tips.

One of the major subdivisions of plant alkaloids is termed the indole alkaloid group. All contain the basic
indole heterocycle, and many have valuable pharmacological activity that can be exploited in drug materials. The
indole portion is very often fused to another heterocycle; we shall see some typical structures in Section 11.9,
where we shall consider them under fused heterocycles.

11.9 Fused heterocycles interesting, and potentially useful, biological proper-
ties. Note that in some cases the rings are fused so
There is ample scope for increasing structural com- that the heteroatom can be at the ring junction and is
plexity by fusing two or more heterocycles together. thus common to both rings. This gives us even more
Shown below are a few of the ring systems encoun- combinations.
tered in natural compounds, many of which have

OMe

N MeHN O Me NHO OMe
NMe OMe
O
MeO N O NH MeO NH OMe
H HH
harmine Me
psychoactive MeO2C
physostigmine
(eserine) reserpine
antihypertensive
miotic; anticholinesterase

OH OH HH
H NS
HO O
O ON
N O N N O
HO N CO2H

OMe O benzylpenicillin
OMe (penicillin G)
castanospermine camptothecin HO O
antiviral antitumour antibacterial

berberine
antibacterial

We do not wish to consider these further, but instead different rings to indicate the fusion. We use letter-
we shall concentrate on just two groups of fused ing for bonds in one heterocycle and numbers for
heterocycles of particular importance, the purines and bonds in the other. Numbering is used for the ‘sub-
pteridines. stituent’ ring and lettering for the ‘root’ ring, and all
are put in square brackets between substituent and
Both purine and pteridine are parent heterocycles root. We do not wish to include a great amount of
for nomenclature purposes. The systematic proce- detail, but we shall use purine and pteridine to illus-
dure for naming fused heterocycles is an extension trate the approach and to provide a modest level of
of that we saw in Section 11.8 where we consid- familiarity for when such names are encountered.
ered a benzene ring fused to a heterocycle. The main
difference is that we have to identify bonds in two

N 4 N3 7 N1 this is the numbering appropriate
for the imidazopyrimidine;
ad 52 6N 2 purine has non-systematic numbering

bNc N1 5N N3
H H
pyrimidine 4
imidazole
3H-imidazo[4,5-d]pyrimidine
purine

FUSED HETEROCYCLES 449

N 4 4 5

ad N 3N N

b Nc 3 2N 6

pyrimidine 2N 1 7

1 N

pyrazine 8

pyrazino[2,3-d]pyrimidine
pteridine

The fused heterocycle is then given its own number- nucleic acids are bonded to a sugar through N-9, the
ing system, starting adjacent to a bridgehead atom to additional potential for tautomerism in the imidazole
generate the lowest number for the first heteroatom. ring is no longer of concern.

11.9.1 Purines NH2 NH N
NN
Purines, along with pyrimidines (see Box 11.5), tautomerism
feature as bases in the nucleic acids, DNA and RNA. HN
A purine is the product of fusing a five-membered
imidazole ring onto a six-membered pyrimidine ring. N N N N
The accepted numbering system unfortunately is H H
non-systematic, and treats purine as a pyrimidine
derivative, the pyrimidine ring being numbered first adenine, A
and separately from the other ring.
preferred form
in nucleic acids

67 OH N O N
N
1N 5 N tautomerism
HN
8

2 N 4 N 9 H2N N N H2N N N
H H H
3

purine guanine, G

N N tautomerism N H preferred form
N in nucleic acids

NN NN Purines are quite weak bases. The conjugate
H 7H-purine acid of purine itself has pKa 2.5. Protonation is
found to be predominantly on N-1, though all three
9H-purine possible N -protonated forms are produced. This is
perhaps unexpected, in that protonation on N-7
Purine in solution exists as a roughly equimolar would provide a cation that is resonance stabilized
mixture of two tautomeric forms, 9H -purine and 7H - in the imidazole ring. However, the observed pKa
purine, tautomerism involving the imidazole ring as more closely resembles that of pyrimidine (pKa
we have noted earlier (see Section 11.7.2). The purine 1.3) rather than that of imidazole (pKa 7.0). Amino
systems in nucleic acids, adenine and guanine, are groups increase basicity (adenine pKa 4.3), though
aminopurines. The amino group is on the pyrimidine the oxygen substituent in guanine reduces the effect
ring and, as with aminopyrimidines, these compounds of the amino group (guanine pKa 3.3). In the
exist as their amino tautomers (see Section 11.6.2). aminopurines, the position of protonation appears to
Guanine also has an oxygen substituent on the be N-1 in adenine, whereas it is N-7 in guanine;
pyrimidine ring, and this adopts the carbonyl form, this presumably reflects the opposing effects provided
also following the behaviour of oxypyrimidines (see by amino groups (electron donating) and carbonyl
Section 11.6.2). Because adenine and guanine in groups (electron withdrawing).

450 HETEROCYCLES

protonation at N-1 protonation at N-7
H
7 H N N H
N NN N N
1N N
NN N
N N NN H H
H H

purine pKa 2.5

NH2 O
NN
4 N3 HN N

5 N3 2 N N H2N N N
H H
6N2 N1
H adenine guanine
1 pKa 4.3 pKa 3.3
imidazole
pyrimidine pKa 7.0
pKa 1.3

Purine has an acidic pKa of 8.9, making it N-9 proton is lost giving an anion with substantial
somewhat more acidic than phenol (pKa 10), and resonance delocalization of charge.
a stronger acid than imidazole (pKa 14.2). The

NN N N N N N N N N
N N N N N N N N
N N
H

purine

pKa 8.9

The acidities of adenine (pKa 9.8) and guanine and charge in the conjugate base can be delocalized
(pKa 9.9) are similar, though different protons are to the more favourable electronegative oxygen. The
removed. Adenine loses the N-9 proton, but guanine effect is most pronounced in uric acid, a metabolite
of purines (see Box 11.11).
is ionized at N-1. N-1 is part of an amide-like system,

O O O
N N
HN N H2N N N H2N N N
N N
H2N N N H H
H

guanine
pKa 9.9

Box 11.11

Uric acid, a purine metabolite

Nucleic acid degradation in humans and many other animals leads to production of uric acid, which is then
excreted. The process initially involves purine nucleotides, adenosine and guanosine, which are combinations of
adenine or guanine with ribose (see Section 14.1). The purine bases are subsequently modified as shown.

FUSED HETEROCYCLES 451

O O xanthine O
HN
HN N N oxidase HN H
N

O

H2N N N O N N O N N
H H H H H

guanine xanthine uric acid

NH2 O xanthine O O
NN HN oxidase HN
xanthine
N N N
oxidase HN alloxanthine is
N N N an inhibitor of
H
N N N ON N xanthine oxidase
H H H H

adenine hypoxanthine allopurinol alloxanthine

The amino groups are replaced with oxygen. Although here a biochemical reaction, the same can be achieved
under acid-catalysed hydrolytic conditions, and resembles the nucleophilic substitution on pyrimidines (see
Section 11.6.1). The first-formed hydroxy derivative would then tautomerize to the carbonyl structure. In the
case of guanine, the product is xanthine, whereas adenine leads to hypoxanthine. The latter compound is also
converted into xanthine by an oxidizing enzyme, xanthine oxidase. This enzyme also oxidizes xanthine at C-8,
giving uric acid.

Uric acid is not a carboxylic acid, but is a relatively strong acid with pKa 5.8. It has an ‘all-amide’ structure,
and there are four potential sites for loss of a proton. Deprotonation occurs at N-9. Loss of this proton generates
a conjugate base in which the charge can be delocalized to oxygen, giving maximum charge distribution. One
resonance form is particularly favourable in having aromaticity in both rings.

O H O H O H O H
HN N HN N HN N HN N
ON ON ON
O O O O
H N H N H N
O N N
H H

uric acid favourable;
both rings aromatic
pKa 5.8

Impaired purine metabolism can lead to a build up of uric acid, and deposition of salts of uric acid as crystals
in the joints. This causes the painful condition known as gout. One way of treating gout is to reduce uric acid
biosynthesis by specific inhibition of the enzyme xanthine oxidase. The hypoxanthine analogue allopurinol is a
drug that is used for this purpose. Allopurinol resembles hypoxanthine, though it contains a pyrazole ring rather
than an imidazole ring. Allopurinol is oxidized by the enzyme to alloxanthine. This product then acts as an
inhibitor of the enzyme, binding to the enzyme, but not being modified further and not being released.

Box 11.12

Caffeine, theobromine, and theophylline

After the nucleic acid purines adenine and guanine, the next most prominent purine in our everyday lives is
probably caffeine. Caffeine, in the form of beverages such as tea, coffee, and cola, is one of the most widely
consumed and socially accepted natural stimulants. Closely related structurally are theobromine and theophylline.
Theobromine is a major constituent of cocoa, and related chocolate products. Caffeine is also used medicinally,

452 HETEROCYCLES

Box 11.12 (continued)

but theophylline is much more important as a drug compound because of its muscle relaxant properties, utilized
in the relief of bronchial asthma.

O Me O H O Me
Me N Me N HN N

N N

ON N ON N ON N
Me Me Me

caffeine theophylline theobromine

These compounds competitively inhibit phosphodiesterase, resulting in an increase in cyclic AMP (see
Box 14.3) and subsequent release of adrenaline. This leads to the major effects: a stimulation of the central
nervous system (CNS), a relaxation of bronchial smooth muscle, and induction of diuresis. These effects vary in
the three compounds. Caffeine is the best CNS stimulant, and has weak diuretic action. Theobromine has little
stimulant action, but has more diuretic activity and also muscle relaxant properties. Theophylline also has low
stimulant action and is an effective diuretic, but it relaxes smooth muscle better than caffeine or theobromine.

It has been estimated that beverage consumption may provide the following amounts of caffeine per cup
or average measure: coffee, 30–150 mg (average 60–80 mg); instant coffee, 20–100 mg (average 40–60 mg);
decaffeinated coffee, 2–4 mg; tea, 10–100 mg (average 40 mg); cocoa, 2–50 mg (average 5 mg); cola drink,
25–60 mg. The maximal daily intake should not exceed about 1 g to avoid unpleasant side effects, e.g. headaches,
restlessness. An acute lethal dose is about 5–10 g.

Caffeine and theobromine may be obtained in large quantities from natural sources, or they may be obtained
by total or partial synthesis. Theophylline is usually produced by total synthesis.

11.9.2 Pteridines shall look at the structures of two rather important
pteridine-based biochemicals, namely folic acid and
In pteridines, we have a pyrimidine ring fused to riboflavin. In the latter case, the pteridine is also
a pyrazine ring. There are, of course, a number fused further to a benzene ring, giving an even
of possible ways of combining these two six- more complex ring system, a benzo[g]pteridine. The
membered ring systems; pteridines are pyrazino[2,3- accompanying diagram shows the derivation of the
d]pyrimidines (see Section 11.9). fused-ring nomenclature. The oxygenated form of the
benzopteridine found in riboflavin is also called an
We do not want to consider the chemistry of isoalloxazine.
the pteridine ring system here, but instead we

N N 4 5 c d eN f N N
N N N N
ad 3N N
bg
bN c 2N 6
aN N
1 7

N

8

pyrimidine pyrazine pteridine benzo[g]pteridine
pyrazino[2,3-d]pyrimidine

Box 11.13

Folic acid

Folic acid (vitamin B9) is a conjugate of a pteridine unit, p-aminobenzoic acid, and glutamic acid. Deficiency
of folic acid leads to anaemia, and it is also standard practice to provide supplementation during pregnancy to
reduce the incidence of spina bifida.

FUSED HETEROCYCLES 453

H2N N N pyrazine ring
HN N
O H
N CO2H

H
N

a pteridine p-amino- O CO2H
benzoic acid L-Glu

(PABA)

folic acid

NADPH dihydrofolate
reductase
H2N N H (DHFR) dihydrofolate N H
HN N reductase N
O N H (DHFR) H2N N
N H
NADPH HN H
H N
N
CO2H O H
N CO2H

O CO2H O CO2H
tetrahydrofolic acid
dihydrofolic acid
(FH2) (FH4)

Folic acid becomes sequentially reduced in the body by the enzyme dihydrofolate reductase to give dihydrofolic
acid (FH2) and then tetrahydrofolic acid (FH4). Reduction occurs in the pyrazine ring portion.

Tetrahydrofolic acid then functions as a carrier of one-carbon groups for amino acid and nucleotide
metabolism. The basic ring system is able to transfer methyl, methylene, methenyl, or formyl groups, and it
utilizes slightly different reagents as appropriate. These are shown here; for convenience, we have left out the
benzoic acid–glutamic acid portion of the structure. These compounds are all interrelated, but we are not going
to delve any deeper into the actual biochemical relationships.

H2N N H H H
HN N H2N N N H2N N N
O
5 HN N HN
O H N
N HN
H HN10 O HN
HO
FH4 N 10-formyl-FH4 O
N 5-formyl-FH4
(folinic acid)

H2N N H H2N N H H2N N H
HN N HN N HN N
O O O
N N N
Me HN N N

N 5-methyl-FH4 N 5,N 10-methylene-FH4 N 5,N 10-methenyl-FH4

454 HETEROCYCLES

Box 11.13 (continued)

In any case, you might be able to analyse some of the relationships on a purely chemical basis. For example,
tetrahydrofolic acid reacts readily and reversibly with formaldehyde to produce N5,N10-methylene-FH4. You
could consider N-5 of the reduced pteridine ring reacting with formaldehyde (a one-carbon reagent) to give
an iminium cation, which could then cyclize via nucleophilic attack of N-10. We might also consider reducing
the iminium cation with, say, borohydride to give the N-methyl derivative. These are not necessarily the same
as what is occurring in the enzymic reactions, but they should help to make the structures appear rather more
familiar.

H H H H
H2N N N H2N N N H2N N N H2N N N

HN 5 − H2O HN
N HN HN N
O H HN10
FH4 H H NN

O HN ON ON
HH HH N 5,N10 -methylene-FH4
OH H

OH nucleophilic iminium cation nucleophilic attack
attack on carbonyl
formation on iminium cation

Now we have seen that the usual reagent for biological methylations is S-adenosylmethionine (SAM) (see

Box 6.4). One occasion where SAM is not employed, for fairly obvious reasons, is the regeneration of methionine
from homocysteine, after a SAM methylation. For this, N 5-methyl-FH4 is the methyl donor, with vitamin B12
(see Box 11.4) also playing a role as coenzyme.

Ad

R OH S CO2H S CO2H
H3C H3C
methylation NH2
using SAM NH2
FH4 methylation using
S-adenosylmethionine N 5-methyl-FH4 N 5-methyl-FH4

(SAM)

R O CH3 Ad HS CO2H
H S CO2H
NH2
NH2 homocysteine
S-adenosylhomocysteine

R O CH3

Another vitally important methylation reaction involving folic acid derivatives is the production of the nucleic

acid base thymine from uracil. Uracil is found in RNA, and thymine is a component of DNA; thymine is

the methyl derivative of uracil. For continuing DNA synthesis, it is necessary to methylate uracil. In practice,

it is the nucleotide deoxyuridylate (dUMP) that is methylated to deoxythymidylate (dTMP) (see Section 14.1).
The methylating agent employed here is N5,N 10-methylene-FH4. As a consequence of this reaction, N5,N 10-
methylene-FH4 is converted into dihydrofolic acid. To keep the reaction flowing, this is reduced to FH4, and
further N5,N10-methylene-FH4 is produced using a one-carbon reagent. In this process, the one-carbon reagent
comes from the amino acid serine, which is transformed into glycine by loss of its hydroxymethyl group. The

chemistry of the transformations is fairly complex and outside our requirements.

FUSED HETEROCYCLES 455

H L-Ser Gly H O
H2N N N H2N N N
HN
HN N HN
O H N ON
deoxyribose-P
HN ON
N 5,N 10-methylene-FH4 dUMP
FH4

NADPH H O CH3
H2N N N HN
dihydrofolate
reductase

HN N ON
O HN deoxyribose-P

FH2 dTMP

Folic acid derivatives are essential for DNA synthesis, in that they are cofactors for certain reactions in purine
and pyrimidine biosynthesis, including the uracil–thymine methylation just described. They are also cofactors
for several reactions relating to amino acid metabolism. The folic acid system thus offers considerable scope for
drug action.

Mammals must obtain their tetrahydrofolate requirements from their diet, but microorganisms are able to
synthesize this material. This offers scope for selective action and led to the use of sulfanilamide and other
antibacterial sulfa drugs, compounds that competitively inhibit the biosynthetic enzyme (dihydropteroate synthase)
that incorporates p-aminobenzoic acid into the structure (see Box 7.23).

Rapidly dividing cells need an abundant supply of dTMP for DNA synthesis, and this creates a need for
dihydrofolate reductase activity. Specific dihydrofolate reductase inhibitors have become especially useful as
antibacterials, e.g. trimethoprim, and antimalarial drugs, e.g. pyrimethamine.

H2N N OMe H2N N H2N N N Me
OMe N

N N N methotrexate
NH2 N
trimethoprim OMe H
NH2 N
NH2 Cl O CO2H CO2H
pyrimethamine

These are pyrimidine derivatives and are effective because of differences in susceptibility between the enzymes
in humans and in the infective organism. Anticancer agents based on folic acid, e.g. methotrexate, inhibit
dihydrofolate reductase, but they are less selective than the antimicrobial agents and rely on a stronger binding
to the enzyme than the natural substrate has. They also block pyrimidine biosynthesis. Methotrexate treatment is
potentially lethal to the patient, and is usually followed by ‘rescue’ with folinic acid (N5-formyl-tetrahydrofolic
acid) to counteract the folate-antagonist action. The rationale is that folinic acid ‘rescues’ normal cells more
effectively than it does tumour cells.

Box 11.14

Riboflavin

Riboflavin (vitamin B2) is a component of flavin mononucleotide (FMN) and flavin adenine dinucleotide
(FAD), coenzymes that play a major role in oxidation–reduction reactions (see Section 15.1.1). Many key enzymes
involved in metabolic pathways are actually covalently bound to riboflavin, and are thus termed flavoproteins.

456 HETEROCYCLES

Box 11.14 (continued)

Riboflavin contains an isoalloxazine ring linked to the reduced sugar ribitol. The sugar unit in riboflavin is the
non-cyclic ribitol, so that FAD and FMN differ somewhat from the nucleotides we encounter in nucleic acids.

O

H3C N OH
NH
HO OH
H3C N N O OH OH
OH ribitol

riboflavin OH

(vitamin B2) OH OH

H3C N O flavin

NH2 NH

NN O O H3C N NO
OH
adenine
adenine N PP flavin
N CH2 O O O ≡ P ribitol

O OH OH OH OH ribose P
HO OH FMN

FAD

Riboflavin is widely available in foods; dietary deficiency is uncommon, but it manifests itself by skin problems
and eye disturbances.

The flavin nucleotides are typically involved in the oxidations creating double bonds from single bonds. The
flavin takes up two hydrogen atoms, represented in the figure as being derived by transfer of hydride from the
substrate and a proton from the medium.

HH

C O C O
C C

H H

H3C N NH dehydrogenase H3C N
NH

H3C N N O H3C N N O

RH RH
FAD
FMN FADH2
FMNH2
oxidizing agent;
can remove hydride reducing agent;
in reverse reaction
can supply hydride

Reductive sequences involving flavoproteins may be represented as the reverse reaction, where hydride is

transferred from the coenzyme, and a proton is obtained from the medium. The reaction mechanism shown
here is in many ways similar to that in NAD+ oxidations, i.e. a combination of hydride and a proton (see

Box 11.2); it is less easy to explain adequately why it occurs, and we do not consider any detailed explanation
advantageous to our studies. We should register only that the reaction involves the N=C–C=N function that spans

both rings of the pteridine system.

SOME CLASSIC AROMATIC HETEROCYCLE SYNTHESES 457

11.10 Some classic aromatic NN N
heterocycle syntheses

Our study of heterocyclic compounds is directed pri- NN N
marily to an understanding of their reactivity and H
importance in biochemistry and medicine. The syn-
thesis of aromatic heterocycles is not, therefore, a We can insert the heteroatom into the rest of the
main theme, but it is useful to consider just a carbon skeleton, or attempt to join two units, one
few examples to underline the application of reac- of which contains the heteroatom, by means of C–C
tions we have considered in earlier chapters. From and C–heteroatom linkages. To make the new bonds,
the beginning, we should appreciate that the syn- two reaction types are most frequently encountered.
thesis of substituted heterocycles is probably not Heteroatom–C bond formation is achieved using the
best achieved by carrying out substitution reactions heteroatom as a nucleophile to attack an electrophile
on the simple heterocycle. It is often much eas- such as a carbonyl group (see Section 7.7.1). Aldol-
ier and more convenient to design the synthesis type reactions may be exploited for C–C bond
so that the heterocycle already carries the required formation (see Section 10.3), employing enamines
substituents, or has easily modified functions. We and enols/enolate anions (see Section 10.5).
can consider two main approaches for heterocy-
cle synthesis, here using pyridine and pyrrole as
targets.

N−C bond formation O OH − H2O
N
nucleophilic attack of N H N
amine onto carbonyl HH imine
O OH
N
H2N

O O − H2O − H+
HN N
N N
H H enamine
iminium
cation

C−C bond formation OO
attack of carbon
nucleophile onto carbonyl

OO

enolate anion OH O − H2O O
O OH H+ H
OH OH
enol OH NH2 OH NH
O NH2 H+

enamine

458 HETEROCYCLES

We shall now look at some synthetic procedures The product is a 1,4-dihydropyridine, which is sub-
that merit the descriptor ‘classic’ because of their sequently transformed into the pyridine by oxidation.
general application, and their longevity – some have Several separate reactions occur during this synthe-
been around for more than 100 years. Do not worry sis, and the precise sequence of events may not be
about remembering the names: these commemorate quite as shown below – they may be in a different
the originators, and we should instead concentrate order.
on the chemistry, which we shall see is usually a
combination of processes we have already met. The normal Hantzsch synthesis leads to a symmet-
rical product. The diesters formed may be hydrolysed
11.10.1 Hantzsch pyridine synthesis and decarboxylated using base to give pyridines with
less substitution. Note that we are using the ester
In its simplest form, this consists of the condensa- groups as activating species to facilitate enolate anion
tion of a β-ketoester with an aldehyde and ammonia. chemistry (see Section 10.9)

aldol reaction followed by tautomerism
to enamine
dehydration Me imine formation

EtO2C MeCHO EtO2C H CO2Et CO2Et NH3 CO2Et
Me
O Me O H2N Me HN Me O Me

Michael-like nucleophilic attack of reagents
enamine on to unsaturated ketone
note: ketone is more electrophilic Me Me
than ester CHO
CO2Et EtO2C CO2Et
EtO2C

Me Me Me O O Me
O NH2 NH3

proton transfers; − H+ − 3 H2O

tautomerism + H+ Me
CO2Et
Me nucleophilic Me
addition N Me
H
EtO2C CO2Et EtO2C CO2Et EtO2C
− H2O Me
Me Me Me N
O NH2 HO H Me

oxidation HNO3

ester hydrolysis; Me
Me decarboxylation

heat KOH EtO2C CO2Et

Me N Me Me N Me

11.10.2 Skraup quinoline synthesis salt or nitrobenzene. The first step is acid-catalysed
dehydration of glycerol to the unsaturated aldehyde
The most general method for synthesizing quinolines acrolein. Variations of the Skraup synthesis use
employs aniline or a substituted aniline, glycerol, different acroleins instead of glycerols.
sulfuric acid, and an oxidizing agent such as a ferric

SOME CLASSIC AROMATIC HETEROCYCLE SYNTHESES 459

acid-catalysed O
OH dehydration

H2SO4

OH OH acrolein
glycerol (propenal)

Michael-like nucleophilic H+ proton loss and electrophilic cyclization,
addition onto unsaturated OH tautomerism of enol promoted by amino
aldehyde susbstituent
OH O
OH
− H+
H+
NH2 N N
HH H N
H

reagents oxidation of acid-catalysed OH OH
O dihydroquinoline dehydration − H+ H
to quinoline
− H2O
O

NH2 N NN N

HH H

The initial product is a dihydroquinoline; it is formed 11.10.3 Bischler–Napieralski isoquinoline
via Michael-like addition, then an electrophilic aro- synthesis
matic substitution that is facilitated by the electron-
donating amine function. A mild oxidizing agent is Isoquinolines are easily prepared by the reaction of
required to form the aromatic quinoline. The Skraup an acyl derivative of a β-phenylethylamine with a
synthesis can be used with substituted anilines, pro- dehydrating agent, e.g. P2O5, then using a catalytic
vided these substituents are not strongly electron dehydrogenation to aromatize the intermediate 3,4-
withdrawing and are not acid sensitive. dihydroisoquinoline.

amide formation possible formation of cyclization via
iminium-type system electrophilic substitution
CH3COCl
NH2 P2O5

NH N N N
O CH3 H HH H

O CH3 O CH3 HO CH3

reagents − H2O

NH2 Pd−C N
O Cl N

CH3 CH3 catalytic CH3
dehydrogenation

The crucial cyclization step is represented here as and an iminium-type system, a resonance form of
an electrophilic attack involving the aromatic ring the amide, suitably coordinated to the phosphorus

460 HETEROCYCLES

reagent. The cyclizing agent P2O5 also dehydrates the 11.10.4 Pictet–Spengler
intermediate hydroxyamine to a dihydroisoquinoline. tetrahydroisoquinoline synthesis
The isoquinoline is then obtained by heating over
a catalyst, effectively reversing a catalytic hydro- This approach to the isoquinoline ring, albeit a
genation reaction (see Section 9.4.3), facilitated by reduced isoquinoline, is mechanistically similar to
the generation of aromaticity in the product. As the Bischler–Napieralski synthesis, in that it involves
in the Skraup synthesis above, electron-withdrawing electrophilic attack of an iminium cation on to an
substituents on the aromatic ring will deactivate aromatic ring. In this case, the imine intermediate
it towards electrophilic attack, whereas electron- is formed by reacting a phenylethylamine with an
donating substituents will favour the reaction. aldehyde.

formation of loss of proton reagents
iminium ion restores aromaticity HO
HO HO
HO HO

NH2 NH NH NH NH2
CHO H CH3 CHO
CH3
CH3 electrophilic attack CH3 CH3
facilitated by phenol
group in para position

We have already met this reaction as an analogue hydroxyl, the whole process, imine formation and
of the Mannich reaction (see Box 10.7), which we cyclization, can occur under ‘physiological’ condi-
then interpreted as nucleophilic attack of an electron- tions, pH 6–7 at room temperature. In nature, this
rich phenolic ring on to an iminium cation. Is it is precisely how tetrahydroisoquinoline alkaloids are
electrophilic or nucleophilic? It matters little; they biosynthesized, though the reactions are enzyme con-
are the same, though the descriptor used depends trolled.
upon which species you consider the more important,
the nucleophilic phenol or the electrophilic iminium 11.10.5 Knorr pyrrole synthesis
cation. For effective cyclization, we need an electron-
donating substituent para to the point of ring closure, This approach to the five-membered pyrrole ring
since the Mannich-type electrophile is less reactive reacts an α-aminoketone with a β-ketoester. The
than the phosphorus-linked intermediates in the Bis- mechanism will probably involve imine formation
chler–Napieralski synthesis. It is also found that a then cyclization via an aldol-type reaction using
similar group in the ortho position does not work, the enamine nucleophile. Dehydration leads to the
though we could still write an acceptable mecha- pyrrole. Only the key parts of this sequence are shown
nism. With a good electron-donating substituent like below.

imine formation imine-enamine
tautomerism
H
Me O CO2Et Me O CO2Et Me O CO2Et

EtO2C NH2 O Me aldol-type reaction with enamine

EtO2C N Me EtO2C N Me nucleophile
H

reagents

Me CO2Et Me CO2Et OH CO2Et
EtO2C N Me Me
O Me − H+
O H
EtO2C − H2O EtO2C N Me
H
NH2

SOME CLASSIC AROMATIC HETEROCYCLE SYNTHESES 461

The synthesis works well only with an activated ester of the α-aminoketone to a dihydropyrazine occurs
like ethyl acetoacetate. Otherwise, self-condensation more readily than the cyclization.

Me O H2N CO2Et − H2O Me H
N CO2Et

EtO2C NH2 O Me EtO2C N Me
H

a dihydropyrazine

11.10.6 Paal–Knorr pyrrole synthesis mechanism below shows successive nucleophilic
additions of amino groups on to the carbonyls; but,
The other major route to pyrroles is the interaction since no intermediates have been isolated, the precise
of a 1,4-dicarbonyl compound with ammonia. The sequence of steps is speculative.

nucleophilic imine formation imine−enamine
addition tautomerism

Me Me NH3 Me Me Me Me Me Me

OO HO NH2O NH O NH2O

reagents nucleophilic
addition

Me Me − H2O
OO
Me N Me Me N Me
NH3 H H OH

Note, however, that this synthesis gives furans followed by dehydration. The heteroatom is thus
if no ammonia is included. This would involve derived from a carbonyl oxygen. The procedure
nucleophilic attack of an enol tautomer of the works well, and is usually carried out with acid
substrate on to the other carbonyl to give a hemiketal, catalyst under non-aqueous conditions.

hemiketal
formation

Me Me − H2O
OH O
Me Me Me O Me Me O Me
OO OH

11.10.7 Fischer indole synthesis enamine tautomer of this hydrazone, and proceeds
because the cyclic flow of electrons forms a strong
The most useful route to indoles is the Fischer indole C–C bond whilst cleaving a weak N–N bond. This
synthesis, in which an aromatic phenylhydrazone produces what appears to be a di-imine. One of
is heated in acid. The phenylhydrazone is the these is involved in rearomatization and creates an
condensation product from a phenylhydrazine and an aromatic amine. This then attacks the other imine
aldehyde or ketone. Ring closure involves a cyclic function, and we get the nitrogen equivalent of a
rearrangement process. hemiketal (see Section 7.2). Finally, acid-catalysed
elimination of ammonia gives the aromatic indole
The hydrazine behaves as an amine towards a system.
carbonyl compound and forms the imine-like product,
a hydrazone. The cyclic rearrangement involves the

462 HETEROCYCLES

tautomerism to

Me Me tautomerism cyclic enamine (aromatic
H to enamine rearrangement
O H amine) Me
NH2 Me Me Me
N
H N N N N NH
phenylhydrazine H NH NH NH2 H
H H H

a phenylhydrazone nucleophilic attack of
amine onto imine
reagents (or iminium cation)

Me − NH3 Me Me
Me Me N NH3
H N NH2
O N HH
NH2
H elimination
N of ammonia
H

Unfortunately, the reaction fails with acetaldehyde itself. It is possible to use the ketoacid pyruvic acid
and cannot, therefore, be used to synthesize indole instead and decarboxylate the product to yield indole.

Me CO2H − CO2 N
pyruvic acid CO2H
N heat H
O indole
H
N NH2
H

12

Carbohydrates

12.1 Carbohydrates intermediary metabolism that is essential for all
organisms (Chapter 15).
Many aspects of the chemistry of carbohydrates are
not specific to this class of compounds, but are The name carbohydrate was introduced because
merely examples of the simple chemical reactions many of the compounds had the general formula
we have already met. Therefore, against usual Cx(H2O)y, and thus appeared to be hydrates of car-
practice, we have not attempted a full treatment bon. The terminology is now commonly used in a
of carbohydrate chemistry and biochemistry in this much broader sense to denote polyhydroxy aldehydes
chapter. We want to avoid giving the impression and ketones, and their derivatives. Sugars or saccha-
that the reactions described here are something rides are other terms used in a rather broad sense
special to this group of compounds. Instead, we to cover carbohydrate materials. Though these words
have deliberately used carbohydrates as examples of link directly to compounds with sweetening proper-
reactions in earlier chapters, and you will find suitable ties, application of the terms extends considerably
cross-references. beyond this. A monosaccharide is a carbohydrate
usually in the range C3 –C9, whereas oligosaccharide
Carbohydrates are among the most abundant covers small polymers comprised of 2–10 monosac-
constituents of plants, animals, and microorganisms. charide units. The term polysaccharide is used for
Polymeric carbohydrates function as important food larger polymers.
reserves, and as structural components in cell walls.
Animals and most microorganisms are dependent 12.2 Monosaccharides
upon the carbohydrates produced by plants for their
very existence. Carbohydrates are the first products Six-carbon sugars (hexoses) and five-carbon sugars
formed in photosynthesis, and are the products from (pentoses) are the most frequently encountered
which plants synthesize their own food reserves, as monosaccharide carbohydrate units in nature. Primary
well as other chemical constituents. These materials examples of these two classes are the hexoses glucose
then become the foodstuffs of other organisms. The and fructose, and the pentose ribose. Note the suffix
main pathways of carbohydrate biosynthesis and -ose as a general indicator of carbohydrate nature.
degradation comprise an important component of

Essentials of Organic Chemistry Paul M Dewick
© 2006 John Wiley & Sons, Ltd

464 CARBOHYDRATES

1 CHO HO OH 1 CHO HO R O R OH
H 2 OH HO RO
HO 3 H H 2 OH HO OH
H 4 OH R OH H 3 OH β-D-ribose
H 5 OH HO H 4 OH (β-D-Rib)

6 CH2OH β-D-glucose 5 CH2OH
D-glucose (β-D-Glc)
D-ribose

1 CH2OH HO R HO OH 1 CH2OH 1 CH2OH
2O OR 2O 2O

HO 3 H OH H 3 OH HO 3 H
H 4 OH HO H 4 OH H 4 OH
H 5 OH 5 CH2OH
6 CH2OH β-D-fructose 5 CH2OH
D-fructose (β-D-Fru) D-xylulose
D-ribulose

The structures above show some of the fundamen- L-(S)-(−)-glyceraldehyde and consequently be part of
tal features of carbohydrates. Initially, we have drawn an L-sugar.
these compounds in the form of Fischer projections,
a depiction developed for these compounds to indi- CHO CHO
cate conveniently the stereochemistry at each chiral R S
centre (see Section 3.4.10). The Fischer projection is H OH HO H
drawn as a vertical carbon chain with the group of
highest oxidation state, i.e. the carbonyl group, clos- CH2OH CH2OH
est to the top, and numbering takes place from the D-(+)-glyceraldehyde L-(–)-glyceraldehyde
topmost carbon.
CHO
The carbonyl group in glucose and ribose is
an aldehyde; such compounds are termed aldoses. H OH CHO
Fructose, by contrast, has a ketone group and is H OH
therefore classified as a ketose. Glucose could also HO H HO H
be termed an aldohexose and fructose a ketohexose, HO 4 H
whereas ribose would be an aldopentose, names highest H OH
which indicate both the number of carbons and the numbered CH2OH
nature of the carbonyl group. Another aspect of chiral centre H 5 OH
nomenclature is the use of the suffix -ulose to indicate CH2OH L-arabinose
a ketose. Fructose could thus be referred to as a
hexulose, though we are more likely to see this suffix D-glucose
in the names of specific sugars, e.g. ribulose is a
ketose isomer of the aldose ribose. Structures of the various D-aldoses in the range
C3 –C6 are shown below. These compounds are mul-
Each of these compounds has a prefix D- with the tifunctional structures, having a carbonyl group and
name. As we saw in Section 3.4.10, this indicates that several hydroxyls, usually with two or more chiral
the configuration at the highest numbered chiral cen- centres. You will notice that we are comparing the
tre is the same as that in D-(R)-(+)-glyceraldehyde; stereochemistry in the different possible diastereoiso-
the alternative stereochemistry would be related to mers for compounds containing several chiral centres
(see Section 3.4.4). There is a corresponding series of
enantiomeric L-sugars; only a few of these are shown.

MONOSACCHARIDES 465

1 CHO there is also a corresponding series
R of enantiomeric L-sugars, for example:
H OH
CHO
3 CH2OH S
D-(+)-glyceraldehyde HO H

CH2OH
L-(–)-glyceraldehyde

1 CHO CHO CHO CHO
H OH HO H HO H H OH
H OH HO H HO H
H OH
4 CH2OH CH2OH CH2OH CH2OH
D-(–)-erythrose L-(+)-erythrose L-(+)-threose
D-(–)-threose

1 CHO CHO CHO CHO
H OH HO H H OH HO H
H OH HO H HO H
H OH H OH H OH
H OH H OH
5 CH2OH CH2OH CH2OH
D-(–)-ribose CH2OH D-(+)-xylose
D-(–)-arabinose D-(–)-lyxose

1 CHO CHO CHO CHO CHO CHO CHO CHO
H OH HO H H OH HO H H OH HO H
H OH HO H HO H H OH H OH HO H
H OH H OH H OH HO H H OH
H OH H OH H OH H OH H OH HO H HO H HO H
H OH H OH
6 CH2OH CH2OH CH2OH H OH HO H HO H
CH2OH CH2OH CH2OH
D-(+)-allose D-(+)-glucose H OH H OH
D-(+)-altrose CH2OH CH2OH

D-(+)-mannose D-(–)-gulose D-(+)-idose D-(+)-galactose D-(+)-talose

Box 12.1

Synthesis of 14C-labelled glucose

A sequence known as the Kiliani–Fischer synthesis was developed primarily for extending an aldose chain by
one carbon, and was one way in which configurational relationships between different sugars could be established.
A major application of this sequence nowadays is to employ it for the synthesis of 14C-labelled sugars, which in
turn may be used to explore the role of sugars in metabolic reactions.

The synthesis of 14C-labelled D-glucose starts with the pentose D-arabinose and 14C-labelled potassium cyanide,
which react together to form a cyanohydrin (see Section 7.6.1). Since cyanide can attack the planar carbonyl group
from either side, the cyanohydrin product will be a mixture of two diastereoisomers that are epimeric at the new
chiral centre. The two epimers are usually formed in unequal amounts because of a chiral influence from the rest
of the arabinose structure during attack of the nucleophile.

466 CARBOHYDRATES

Box 12.1 (continued)

nucleophilic addition of cyanide to hydrolysis of nitrile group
either face of planar carbonyl yields carboxylic acid
produces epimeric cyanohydrins

H O 14CN 14CN 14CN 14CO2H 14CO2H
H OH HO H
H OH HO H
H+ HO H + HO H
HO H K14CN HO H + HO H

H OH H2O H OH H OH H OH H OH

H OH H OH H OH H OH H OH

CH2OH CH2OH CH2OH CH2OH CH2OH

D-arabinose formation of
heat γ-lactone

HOH2C OH *O HOH2C OH OH
* = 14C O OH + O O

*

HO HO

borohydride reduction of NaBH4
lactone gives hemiacetals
14CHO 14CHO
H OH HO H HOH2C OH HOH2C OH OH
HO H HO H O * OH + O OH
H OH +
H OH H OH *
H OH
CH2OH HO OH HO
[1-14C]-D-glucose CH2OH
[1-14C]-D-mannose OH means configuration not specified;
a mixture of both configurations

(see Section 12.2.3)

The nitrile groups in the product mixture are then hydrolysed to carboxylic acids (see Box 7.9). Upon heating,
the acids readily form cyclic esters (lactones) through reaction of the hydroxyl group on C-4 with the carboxylic
acid, the five-membered ring being most favoured (see Section 7.9.1). The pair of lactones is then reduced using
sodium amalgam under acidic conditions to yield aldehydes, though it has been found that this reaction can
also be achieved using aqueous sodium borohydride. Sodium borohydride reacts readily with lactones, though it
is not usually effective in reducing esters. It is also normally difficult to stop at an aldehyde intermediate (see
Section 7.11), but reduction of a lactone gives initially a hemiacetal; ring opening of the hemiacetal then leads
to the aldehyde. The product will be a mixture of the two epimeric sugars D-glucose and D-mannose, which will
be labelled with 14C in the aldehyde function. Separation of the diastereoisomeric products may be achieved via
fractional crystallization or by chromatography, and may be carried out at either the cyanohydrin stage, or at the
final product stage.

14CHO 14CHO CHO
H OH H 14C OH
CHO K14CN H OH HO H KCN HO H
H OH
H OH H OH H OH
CH2OH + OH H OH
H OH
H CH2OH

CH2OH CH2OH [2-14C]-D-glucose

D-erythose [1-14C]-D-ribose [1-14C]-D-arabinose

MONOSACCHARIDES 467

Note how the process may be modified to extend its versatility. Thus, using 14C-labelled potassium cyanide with
D-erythrose yields a mixture of [1-14C]-D-ribose and [1-14C]-D-arabinose. The sequence could then be repeated on
the latter product, using unlabelled KCN, to give [2-14C]-D-glucose.

12.2.1 Enolization and isomerization on the α-carbon causes further isomerization. Thus,
treatment of D-glucose with dilute aqueous sodium
In common with other aldehydes or ketones that have hydroxide at room temperature leads to an equi-
hydrogen on the α-carbon, enolization is possible librium mixture also containing D-mannose and D-
(see Section 10.1), especially when sugars are treated fructose.
with base. The additional presence of a hydroxyl

H O H OH H reversion to keto
tautomer
HO 1
OH CHO
base-catalysed H 2 OH HO H OH HO H
enolization H HO H
HO H HO

H OH H OH H OH

H OH H OH H OH

CH2OH CH2OH CH2OH

D-(+)-glucose enediol D-(+)-mannose
(65%) (3%)
HO H
H OH 1 CH2OH
OH 2O
HO 3 H
HO H H OH
H OH H OH
H OH CH2OH
CH2OH D-fructose
(32%)

Removal of the α-hydrogen in D-glucose leads to if either D-mannose or D-fructose were treated
enolization (we have omitted the enolate anion in similarly.
the mechanism). Reversal of this process allows
epimerization at C-2, since the enol function is Note that harsher conditions may lead to further
planar, and a proton can be acquired from either face, changes, e.g. epimerization at C-3 in fructose, plus
giving D-mannose as well as D-glucose. Alternatively, isomerization, or even reverse aldol reactions (see
we can get isomerization to D-fructose. This is Section 10.3). In general, basic conditions must be
because the intermediate enol is actually an enediol; employed with care if isomerizations are to be
restoration of the carbonyl function can, therefore, avoided. To preserve stereochemistry, it is usual to
provide either a C-1 carbonyl or a C-2 carbonyl. ensure that free carbonyl groups are converted to
The equilibrium mixture using dilute aqueous sodium acetals or ketals (glycosides, see Section 12.4) before
hydroxide at room temperature consists mainly of basic reagents are used. Isomerization of sugars via
D-glucose and D-fructose, with smaller amounts of enediol intermediates features prominently in the
D-mannose. The same mixture would be obtained glycolytic pathway of intermediary metabolism (see
Box 10.1).

468 CARBOHYDRATES

12.2.2 Cyclic hemiacetals and hemiketals representation of the compound in its cyclic form.
The compounds exist predominantly in the cyclic
Monosaccharide structures may be depicted in open- forms, which result from nucleophilic attack of
chain forms showing their carbonyl character, or in an appropriate hydroxyl onto the carbonyl (see
cyclic hemiacetal or hemiketal forms. Alongside Section 7.2).
the Fischer projections of glucose, ribose, and
fructose shown earlier, we included an alternative

OH hemiacetal 4 6 OH aldehyde 6 OH hemiacetal
HO
HO O 5 OH 4 5O
HO H HO

HO 2 O H HO 2 1 OH
3 HO 3 HO
HO 1 O
OH H pyran
H

α-D-glucose D-glucose β-D-glucose
(α-D-glucopyranose)
(open-chain) (β-D-glucopyranose)

CH2OH hemiacetal 6 CH2OH H aldehyde 6 CH2OH hemiacetal
H O OH
HO OH O HO 5 1 HO 5 OH 1
H H H 4
OH OH O

OH 4

OH 3 2H 3 2H O
α-D-glucose OH furan
(α-D-glucofuranose) OH
D-glucose β-D-glucose

(open-chain) (β-D-glucofuranose)

Both six-membered pyranose and five-membered are usually formed more rapidly, but six-membered
furanose structures are encountered, a particular rings are generally more stable and predominate at
ring size usually being characteristic for any one equilibrium. The names pyranose and furanose are
sugar. Thus, although glucose has the potential to derived from the oxygen heterocycles pyran and
form both six-membered and five-membered rings, furan. Shown below is a reminder of how we can
an aqueous solution consists almost completely of the transform a Fischer projection of a sugar into a cyclic
six-membered hemiacetal form; five-membered rings form (see Box 3.16).

CHO turn Fischer CH2OH form cyclic CH2OH
projection hemiacetal
H OH sideways O
H H OH H H OH H H OH
HO H OH H H
H OH HOH2C CHO H H CHO
OH

H OH OH OH H OH HO HO

rotate end groups to bring H OH H OH
OH onto main chain
CH2OH

D-glucose fold chain round

draw in chair HO OH
conformation HO O

OH
HO

H

The pentose ribose is also able to form six- meet ribose in combination with other entities, e.g.
membered pyranose and five-membered furanose nucleosides, it is almost always found in furanose
rings. In solution, ribose exists mainly (76%) in form (see Box 7.2).
the pyranose form; interestingly, however, when we

MONOSACCHARIDES 469

HO O 4 5 OH HO O
OH
HO
OH OH
2 O H β-D-ribopyranose

OH HO OH 3 HO 1 HOH2C O OH
α-D-ribopyranose
OH H HO OH
β-D-ribofuranose
1 CHO D-ribose
(open-chain)
H 2 OH
H 3 OH H
H 4 OH
HOH2C O HO 5 O
5 CH2OH OH
4
D-ribose 1

OH 3 2H
HO OH HO OH

α-D-ribofuranose D-ribose
(open-chain)

Fructose is a ketose and, therefore, forms hemike- though the simple sugar in solution exists primarily
tal ring structures. Like ribose, it is usually found in pyranose form (67%).
in combination as a five-membered furanose ring,

hemiketal H ketone hemiketal
HO HO OH HO 6 H HO O HO OH
O HO 6 O2
O
5 5
2
1 CH2OH OH 4 4 3 1 OH
2O HO 3 1 OH
HO 3 H HO HO
α-D-fructofuranose
D-fructose β-D-fructofuranose
(open-chain)

H 4 OH

H 5 OH HO HO 5 HO H HO
6 CH2OH HO R O 6 OH O HO O
S
D-fructose OH

OH 4 32 OH
OH
OH OH OH 1 OH
β-D-fructopyranose
α-D-fructopyranose D-fructose
(open-chain)

12.2.3 The anomeric centre practice, this translates to the anomeric hydroxyl
being ‘up’ in the case of β-D-sugars and α-L-sugars.
Since the carbonyl group is planar and may be It is interesting to note that the descriptors α
attacked from either side, two epimeric structures or β were originally assigned to the two forms
(anomers) are possible in each case, and in solution of glucose based on the order in which they
the two forms are frequently in equilibrium, because crystallized out from solution. Without changing the
hemiacetal or hemiketal formation is reversible nomenclature for these two compounds, α or β are
(see Section 7.2). The two anomers are designated now assigned on a much more rigid stereochemical
α or β by comparison of the chiralities at the basis.
anomeric centre and at the highest numbered chiral
centre. If these are the same (RS convention), the By convention, the ring form of sugars is drawn
anomer is termed β, or α if they are different. In with the ring oxygen to the rear and the anomeric car-
bon furthest right. Wedges and the bold bond help to

470 CARBOHYDRATES

emphasize how we are looking at the chair-like structures we tend to omit these, and then the lower
pyranose ring. However, to speed up the drawing of bonds always represent the nearest part of the ring.

for ease of drawing, OH the lower bonds OH
O O
we usually omit bold HO always represent the HO
bonds and wedges HO nearest part of the ring HO HO
HO OH OH

β-D-glucose β-D-glucose

Since there are two anomeric forms, and these of either stereochemistry. This is the wavy or wiggly
are often in equilibrium via the acyclic carbonyl bond, and to display our indecision further we usually
compound, we can use a new type of bond to indicate site it halfway between the two possible positions (see
that the configuration is not specified and could be Section 7.2).

OH OH OH
O O
HO ≡ HO OH HO O
HO HO HO HO or HO or a mixture
OH
HO
OH

D-glucose β-D-glucose α-D-glucose

wavy bond;
configuration not specified

It follows that, when we dissolve a sugar such as The most stable conformation of the cyclic sugar
glucose or ribose in water, we create a mixture of is mainly determined by a minimization of steric
various equilibrating structures. The relative propor- interactions, i.e. the maximum number of equatorial
tions of pyranose and furanose forms, and of their substituents (see Section 3.3.2). It follows that the
respective anomers for the eight aldohexoses, are preferred conformation for β-D-glucose will be that
shown in Table 12.1. In each case, the proportion of with all substituents equatorial; the alternative has
non-cyclic form is very small (<1%). all substituents axial. Carbohydrate chemists have
introduced a neat way of referring to the two

Table 12.1 Equilibrium proportions of pyranose and furanose forms
of aldohexoses in watera

Aldohexose α-Pyranose β-Pyranose α-Furanose β-Furanose
form (%) form (%) form (%) form (%)

Allose 16 76 3 5

Altrose 27 43 17 13

Glucose 36 64 <1 <1

Mannose 66 34 <1 <1

Gulose 16 81 <1 3

Idose 39 36 11 14

Galactose 29 64 3 4

Talose 37 32 17 14

aThe proportion of non-cyclic form is <1%.

MONOSACCHARIDES 471

Box 12.2

Ring size and anomeric form of common sugars

Sugars exist predominantly in cyclic hemiacetal or hemiketal forms, and whilst both six-membered pyranose and
five-membered furanose structures are encountered, a particular ring size is usually characteristic for any one
sugar, especially when it is found in combination with other entities in natural structures. The most commonly
encountered monosaccharides and their usual anomers are shown here. By convention, the ring form is drawn
with the ring oxygen to the rear and the anomeric carbon furthest right. Also shown are the accepted abbreviations
for these sugars.

CHO CHO CHO CHO
H OH H OH HO H
HO H HO H HO H H OH
H OH HO H
H OH H OH H OH H OH
H OH
CH2OH CH2OH HO H
D-(+)-glucose D-(+)-galactose CH2OH
D-(+)-mannose HO H
HO OH OH OH
HO RO HO RO OH CH3
HO R HO O L-(−)-rhamnose
R OH R OH
HO HO R OH OH
HO S
β-D-mannose
β-D-glucose β-D-galactose (β-D-Mann) R
(β-D-Glc) (β-D-Gal) O
HO
HO

OH
α-L-rhamnose

(α-L-Rha)
[preferred conformation]

CHO CHO CHO CH2OH
H OH H OH H OH O
HO H HO H H OH
H OH HO H H OH HO H
H OH
CH2OH CH2OH CH2OH H OH
D-(+)-xylose L-(+)-arabinose D-(−)-ribose CH2OH
D-(−)-fructose

R O OH O HO R O R OH HO R HO OH
R OH S R OH OR
HO HO OH
HO HO HO HO β-D-ribose OH
(β-D-Rib) HO

β-D-xylose α-L-arabinose β-D-fructose
(β-D-Xyl) (α-L-Ara) (β-D-Fru)

The two anomers are designated α or β by comparison of the chiralities at the anomeric centre and at the highest
numbered chiral centre. If these are the same (RS convention), the anomer is termed β, or α if they are different.
Note that the D and L prefixes are assigned on the basis of the chirality (as depicted in Fischer projections) at the
highest numbered chiral centre and its relationship to D-(R)-(+)-glyceraldehyde or L-(S)-(−)-glyceraldehyde (see
Section 3.4.10).

The stereochemistries of the various substituents may be deduced by considering the implications of the Fischer
projection (see Box 3.16).

472 CARBOHYDRATES

conformers, in that the left-hand conformer of glucose 4 OH OH
is termed 4C1, and the right-hand one 1C4. The ‘C’ O OH
indicates chair conformation, the superscript numeral HO
is the carbon atom that is above the plane of the HO 1 OH OH
ring, and the subscript numeral is which carbon atom HO O1
is below the plane of the ring. For this description,
we consider the pyranose ring as originally planar, β-D-glucose 4
distorted to a chair by pushing carbons 1 and 4 out
of the plane. 4C1 conformer OH OH

At first glance, the preferred conformation for 1C4 conformer
L-hexoses, e.g. α-L-rhamnose, appears different from
that of the D-hexoses. This is readily rational- we can easily follow the anomeric substituent. Since
ized by considering the preferred conformation of α-L-glucose is the enantiomer of α-D-glucose, we can
α-L-glucose – the α-anomer is chosen simply because draw the mirror image representation, then rotate this
so that the heterocyclic oxygen comes to the required
position.

mirror image rotate 180º

OH HO OH

HO O O OH ≡ HO O
HO HO OH HO OH
HO
HO HO
OH

α-D-glucose α-L-glucose α-L-glucose

preferred conformation

Note that you may also encounter another ver- groups, but is quite uninformative about the shape of
sion of the cyclic form referred to as the Haworth the molecule, and whether the substituents are equa-
representation (see Box 3.16). This shows the ring torial or axial. In really bad cases, authors omit the
as a planar system, and is commonly used in hydrogen atoms, giving an ambiguous structure – do
biochemistry books. However, we know that five- lines mean methyl or hydrogen? Haworth represen-
membered and six-membered rings are certainly not tations may be easier to draw, but you are strongly
planar. The Haworth representation nicely reflects encouraged to use the more informative conforma-
the up–down relationships of the various substituent tional structures.

β-D-glucose β-D-ribose

CH2OH OH
O
H O OH HOH2C O OH HO OH
H H HO O
OH HO OH OH H
HO H HO OH
H
HO H OH conformational
representation
H OH H

Haworth conformational Haworth
representation representation representation

CH2OH often seen, but careless HOH2C O OH
O OH versions that omit
hydrogens; don't think
OH the lines mean methyls! OH
HO

OH OH

ALDITOLS 473

One of the consequences of forming a cyclic hemi- acetylated to give the β-acetate, whereas α-D-glucose
acetal or hemiketal is that the nucleophilic hydroxyl will specifically give the α-acetate. These two forms
adds to the carbonyl group and forms a new hydroxyl. do not equilibrate merely by dissolving in solvent,
This new group is susceptible to many normal although they can be interconverted by some other
chemical reactions of hydroxyls, e.g. esterification, means, e.g. nucleophilic substitution reactions with
and this type of reaction effectively freezes the car- acetate (compare Section 6.3.2). If we wish to con-
bohydrate into one anomeric form, since the ring- sider esterification of the α–β mixture, we could use
opening and equilibration can now no longer take the unspecified wavy bond representation shown on
place. Consider esterification of glucose with acetic the right.
anhydride (see Section 7.9.1). β-D-Glucose will be

OH OH OH
O O
HO HO O HO
HO HO HO HO HO
OH these isomers OH
interconvert readily
HO
OH

β-D-glucose α-D-glucose D-glucose

Ac2O Ac2O Ac2O

AcO OAc OAc AcO OAc these isomers do not AcO OAc
AcO O AcO O interconvert readily AcO O

AcO AcO OAc
OAc OAc

penta-O-acetyl-β-D-glucose penta-O-acetyl-α-D-glucose penta-O-acetyl-D-glucose

12.3 Alditols of aldoses is the more satisfactory reaction, in that a
single product is formed. On the other hand, reduction
Reduction of the aldehyde or ketone group in a of ketoses generates a new chiral centre, and two
sugar is readily achieved using a variety of reducing epimeric alditols will result. Thus, treatment of
agents. Reduction occurs on the small amount of D-glucose with sodium borohydride gives D-glucitol,
open-chain form present at equilibrium. As the open- also known as D-sorbitol. It should be noted that LAH
chain form is removed, the equilibrium is disturbed is not a satisfactory reducing agent for this reaction
until total reduction is achieved. The products are because of the several hydroxyl groups present (see
polyhydroxy compounds termed alditols. Reduction Section 7.5).

reduction of CH2OH reduction CH2OH reduction CH2OH CHO
CHO aldehyde of ketone of ketone HO H
HO H
H OH H OH O HO H
H OH
HO H NaBH4 HO H NaBH4 HO H NaBH4 HO H NaBH4 H OH

H OH H OH H OH H OH CH2OH
D-mannose
H OH H OH H OH H OH

CH2OH CH2OH CH2OH CH2OH

D-glucose D-glucitol D-fructose D-mannitol
(sorbitol)

474 CARBOHYDRATES

On the other hand, borohydride reduction of the 12.4 Glycosides
ketose D-fructose will give a mixture of D-glucitol
and its epimer, D-mannitol. A better approach The cyclic hemiacetal and hemiketal forms of
to D-mannitol would be reduction of the aldose monosaccharides are capable of reacting with an
D-mannose. D-Glucitol (sorbitol) is found naturally alcohol to form acetals and ketals (see Section 7.2).
in the ripe berries of the mountain ash (Sorbus The acetal or ketal product is termed a glycoside,
aucuparia), but is prepared semi-synthetically from and the non-carbohydrate portion is referred to as
glucose. It is half as sweet as sucrose, is not an aglycone. In the nomenclature of glycosides we
absorbed orally, and is not readily metabolized in replace the suffix -ose in the sugar with -oside.
the body. It finds particular use as a sweetener for Simple glycosides may be synthesized by treating
diabetic products. D-Mannitol also occurs naturally in an alcoholic solution of the monosaccharide with an
manna, the exudate of the manna ash Fraxinus ornus. acidic catalyst, but the reaction mixture usually then
This material has similar characteristics to sorbitol, contains a mixture of products. This is an accepted
but is used principally as a diuretic. It is injected problem with many carbohydrate reactions; it is often
intravenously, is eliminated rapidly into the urine, and difficult to carry out selective transformations because
removes fluid by an osmotic effect. of their multifunctional nature.

OH H+ HO OH
HO O
HO O OH2
HO OH OH attack on either face
HO O of planar system
HO H
H
OH
β-D-glucopyranose O
H
hemiacetals H+ HO HO HO H MeOH
HO HO HO
OH H2O or
HO O MeOH MeOH

HO H MeOH
HO
OH

α-D-glucopyranose

CH2OH OH H OH
O O
HO OH O HO HO
H OH HO O HO H
HO Me HO
OH
α- or β-D-glucofuranose H O
H Me

H+ H+

CH2OH CH2OH OH OH
O
HO OH O H HO OH O OMe HO O HO
H H HO OMe HO H
HO
OMe H HO acetals
OH OH H OMe

methyl α-D-glucofuranoside methyl β-D-glucofuranoside methyl β-D-glucopyranoside methyl α-D-glucopyranoside
major product

Reaction of glucose with methanol and gaseous whereas the α-anomer has its anomeric substituent
HCl yields four acetal products, the α- and β-pyran- axial. This so-called anomeric effect apparently
osides and α- and β-furanosides, which may be arises from a favourable electronic stabilization in
separated. The pyranosides are the predominant the axial anomer that is not possible in the equato-
components, and the major product is the α-pyran- rial anomer. It involves overlap from the ring oxygen
oside. This is perhaps unexpected, in that the lone pair, and to achieve this the lone pair and the
β-pyranoside has all its substituents equatorial, substituent must be antiperiplanar.

GLYCOSIDES 475

rotate ≡O simple acetals shown below, where we need consider
only conformational isomerism, some 75% of the
O X axial conformer is present at equilibrium. Without
H lone pair anti-periplanar with the ring oxygen, we would see an equatorial isomer
axial electronegative group predominating (see Section 3.3.2). In the second
X example, the additional stability conferred by the
α-anomer equatorial methyl group increases even further the
proportion of the conformer with the axial methoxyl.

O O O
X OMe
OMe
25% 75%

neither lone pair anti-periplanar with O O
equatorial electronegative group OMe
OMe
The anomeric effect is rather complex and will not 2% 98%
be considered in any detail. It occurs when we have a
heterocyclic ring (O, N, or S), with an electronegative We have noted that an aqueous solution of glucose
substituent (halogen, OH, OR, OCOR, etc.) adjacent exists as an equilibrium mixture containing some
to the heteroatom, and favours the isomer in which 64% of the β-anomer.
the substituent is axial. Thus, with the first of the

solvation increases size of
substituent and favours β-anomer

OH OH

HO O H2O HO O equilibration of anomers
HO OH HO H in aqueous solution

HO HO
H OH

β-D-glucopyranoside α-D-glucopyranoside

(64%) (36%)

Based simply on steric effects, this proportion appears By considering the reversibility of the acetal-
somewhat low, whereas in view of the anomeric forming reactions, it is apparent that treatment of
effect just described the proportion now seems rather either of the two methyl pyranosides with acidic
high. Anomeric effects are observed to be solvent methanol will produce the same equilibrium mixture.
dependent, and hydroxy compounds experience con- A related equilibration occurs with the anomers of
siderable solvation with water through hydrogen glucose, as seen earlier (see Box 7.1, mutarotation of
bonding. This significantly increases the steric size glucose).
of the substituent, and reinforces the steric effects.

HO OH H+ HO OH acid-catalysed
HO O HO O equilibration of anomers

OMe H anomeric effect favours
HO MeOH HO α-anomer

H OMe

methyl β-D-glucopyranoside methyl α-D-glucopyranoside
(34%) (66%)

476 CARBOHYDRATES

It should also be noted that hydrolysis of gly- formation, the equilibrium favouring the aglycone
cosides (acetals or ketals) will occur under acid- plus sugar rather than the glycoside (see Section 7.2).
catalysed conditions if we have an excess of water The sugar product will again be the equilibrium mix-
present. This is a reversal of the process for glycoside ture of anomers.

acid-catalysed hydrolysis of glycosides

OH H+ OH OH attack on either face
O HO OH O of planar system
HO
HO OR OR HO ROH
HO HO HO HO

H H HO H HOH
or

HOH

HO OH H HO OH
HO O HO O

O H
HO H HO

H O
HH
H+
H+

HO OH HO OH
HO O HO O

OH H
HO HO

H OH

Hydrolysis of glycosides can also be achieved by These enzymes mimic the acid-catalysed processes,
the use of specific enzymes, e.g. β-glucosidase for are commercially available, and may be used just like
β-glucosides and β-galactosidase for β-galactosides. a chemical reagent.

Box 12.3

Some examples of natural O-, S-, C-, and N-glycosides

Many different types of glycoside structure are found in nature, especially in plants. Since the presence of a sugar
unit in the structure provides polarity, it is likely that glycosylation is a means by which an organism makes an
aglycone water soluble and transportable. Most of the natural glycosides are compounds in which the aglycone
is an alcohol or a phenol, and such derivatives are termed O-glycosides. O-Glycosides are thus acetals or ketals.
Less commonly, one encounters compounds in which a thiol (RSH) has been bonded to the sugar unit resulting in
a thioacetal (see Section 7.4). These compounds are termed S-glycosides. Some examples of O- and S-glycosides
are shown below.

HO OH CH2OH CH2OH
HO O HO

O
HO

H

O-glycoside: salicin aglycone: salicyl alcohol

GLYCOSIDES 477

HO OH HO H O
HO O C H HCN
N
OH hydrolysis
OH

C
N

O-glycoside: prunasin aglycone: mandelonitrile
(benzaldehyde cyanohydrin)

Salicin is an O-glycoside of a phenol, namely salicyl alcohol. Salicin is a natural antipyretic and analgesic
found in willow bark, and is the template from which aspirin (acetylsalicylic acid, see Box 7.13) was developed.
Prunasin from cherry laurel is an example of a cyanogenic glycoside, hydrolysis of which leads to release of
toxic HCN (see Box 7.7). It is the O-glucoside of the alcohol mandelonitrile, the trivial name for the cyanohydrin
of benzaldehyde. It is the further hydrolysis of mandelonitrile that liberates HCN.

S-Glycosides in nature are quite rare, but there is an important group called glucosinolates. These compounds
are responsible for the pungent properties of mustard, horseradish and members of the cabbage family. One
example is sinigrin, found in black mustard seeds. When seeds are crushed, enzymic hydrolysis liberates the
aglycone, which subsequently rearranges to the pungent principle allylisothiocyanate.

OH OH SH rearrangement
HO OH N
SO N
aglycone: OSO3 C
H
N KS
allylisothiocyanate
OSO3 K
allyl thiohydroximate sulfonate
S-glycoside: sinigrin

O O rearrangement O
S SGlc S SH S

N N N
OSO3 K OSO3 K C
S
S-glycoside: glucoraphanin aglycone: raphanin
sulforaphane

A related glucosinolate glucoraphanin is found in broccoli, and is associated with beneficial medicinal
properties of this vegetable. This is hydrolysed to the isothiocyanate sulforaphane, which is believed to induce
carcinogen-detoxifying enzyme systems.

Other natural glycosides are not acetals or ketals, but analogues in which the nucleophilic species has been
an amine (N-glycosides), or even some carbanionic species so that the sugar becomes attached to carbon
(C-glycosides). It should be noted that the presence of a C–C bond between the sugar and the aglycone means
that C-glycosides are not cleaved by simple hydrolysis, but require an oxidative process.

HO O OH

OH HO O OH

H HO OH CH2OH
O OH aglycone: aloe-emodin anthrone

H

C-glycoside: barbaloin OH

478 CARBOHYDRATES

Box 12.3 (continued)

C-Glycosides are typified by barbaloin, a component of the natural purgative drug cascara, but, as a group, the
N-glycosides are perhaps the most important to biochemistry. N-Glycosidic linkages are found in the nucleosides,
components of DNA and RNA (see Section 14.1). In addition, nucleosides are essential parts of the structures of
crucial biochemicals such as ATP, coenzyme A, NAD+, etc. The amine in these types of compound is part of a
purine or pyrimidine base (see Section 14.1).

NH2

OOO NN

PPP NN
HO O O O CH2
O
OH OH OH

HO OH

N-glycoside: ATP

NH2 NH2
NN NN

HOH2C O NN

N N
H
HO OH
N-glycoside: adenosine aglycone: adenine

Perhaps the most significant group of glycoside derivatives are polysaccharides. In these structures, the aglycone
is itself another sugar, so that the polymer chain is composed of a series of sugar units joined by acetal or ketal
linkages (see Section 12.7). Short carbohydrate polymers may also be found in some of the more complex
O-glycosides, e.g. the heart drug digoxin from Digitalis lanata.

sugar residues are D-digitoxose HO O OO
OH OH

OH

HO O H

O O O H OH
O H
OH O aglycone is a sterol,
OH digoxigenin

OH

digoxin

Making a methyl glucopyranoside is relatively more complex alcohol that is probably not avail-
straightforward in that we can use the alcohol able in excess, and is unlikely to function as a
methanol as solvent, and, since it is thus present suitable solvent. Trying to join together two or
in large excess, this helps to disturb the equilib- more sugars would also be fraught with problems,
rium. The process is much less attractive for a since each sugar contains several hydroxyl groups

GLYCOSIDES 479

capable of acting as the nucleophile. These problems at, combined with the use of protecting groups to
have been overcome by exploiting nucleophilic avoid unwanted couplings. A valuable reagent for
substitution for glycoside synthesis rather than the adding a glucose unit on to a suitable nucleophile
hemiacetal to acetal conversion we have been looking is acetobromoglucose.

anomeric acetyl is
preferentially lost due to
stabilization of cation

OH Ac2O OAc HBr AcO OAc H
O OH O AcO O O
HO AcO
HO HO AcO OAc HOAc OAc Ac
OAc

glucose penta-O-acetylglucose

esterification of all

hydroxyl groups

OAc OAc

AcO O AcO O
AcO AcO

AcO OAc Br
Br

acetobromoglucose nucleophilic attack of bromide;

(tetra-O-acetyl-α-glucopyranosyl bromide) α-anomer is strongly preferred

Glucose is first esterified to penta-O-acetylglucose in the conversion of hemiacetals into acetals (see
using acetic anhydride. Note that the hemiacetal Section 7.2). Acetobromoglucose then results from
hydroxyl is also esterified, and thus any equilibration nucleophilic attack of bromide onto the cationic
with an aldehyde form is now not possible (see system; in acetal formation, the nucleophile would be
Section 7.2). When this penta-acetate is treated with an alcohol. The anomeric effect is considerably larger
HBr, the anomeric acetate is preferentially lost when the substituent is halide than it is with alkoxy
under the acidic conditions, due to the stabilization groups, so the product formed is almost exclusively
conferred by the heterocyclic oxygen. Note that the α-anomer.
this is the same type of intermediate we implicated

OAc CH2OH CH2OH
O
AcO O KOH HO generation of phenolate
AcO anion is better anion; phenols are more
nucleophile acidic than alcohols
AcO than lone pair H2O
Br salicyl alcohol

acetobromoglucose

AcO OAc CH2OH OH CH2OH
AcO O O
KOH HO
O H2O HO O
AcO HO

H H

hydrolysis of ester salicin
protecting groups

480 CARBOHYDRATES

The bromide leaving group is now nicely the product is consequently the esterified β-glucoside
positioned for an SN2 reaction with an incoming derivative. Further base treatment then hydrolyses the
nucleophile; in the example shown, this is the ester functions, liberating the glucoside salicin. As we
phenoxide anion from salicyl alcohol. In the presence shall see in Box 12.4, this type of substitution process
of base, the phenolic group of salicyl alcohol is is similar to the way glucosides (and polysaccharides)
ionized, since phenols are very much more acidic than are produced in nature, though the enzymic reactions
alcohols (see Section 4.3.5). SN2 processes occur do not require any ester protecting groups for the
with inversion of configuration (see Section 6.1), so sugars.

Box 12.4

Biosynthesis of glycosides via UDPsugars

The widespread occurrence of glycosides and polysaccharides in nature demonstrates there are processes for
attaching sugar units to a suitable atom of an aglycone to give a glycoside, or to another sugar to give a
polysaccharide. Linkages tend to be through oxygen, although they are not restricted to oxygen, since S-, N-,
and C-glycosides are also well known (see Box 12.3). The agent for glycosylation is a uridine diphosphosugar,
e.g. UDPglucose. Of course, the uridine portion is itself a glycoside, an N-riboside of the pyrimidine base
uracil (see Section 14.1). The glucosylation process can be envisaged as a simple SN2 nucleophilic displacement
reaction, with an alcohol or phenol nucleophile, and a phosphate derivative as the leaving group. This SN2
displacement is analogous to that seen in the chemical synthesis of glycosides using acetobromoglucose (see
Section 12.4).

OH ROH SN2 reaction O

HO O HN
HO
H ON OH
HO OO O
O CH2 HO O UDP
PP HO OR
OO
uracil HO
OH OH H

HO OH O-β-D-glucoside
ribose

uridine

uridine diphosphoglucose
UDPglucose

SN2 processes occur with inversion of configuration (see Section 6.1), so since UDPglucose has its leaving
group in the α-configuration, the product formed by the SN2 process has the β-configuration. This is the
configuration most commonly found in natural O-glucosides. Some natural products do possess an α-linkage,
however. It appears that such compounds originate via a double SN2 process, in which a nucleophilic group
on the enzyme reacts first with the UDPglucose and then the hydroxy nucleophile displaces the enzymic
group.

Other UDPsugars, e.g. UDPgalactose or UDPxylose, are utilized in the synthesis of glycosides containing
different sugar units. The S-, N-, and C-glycosides are formed by a similar process with the appropriate
nucleophile. This type of reaction is also that used in the biosynthesis of polysaccharides (see Section 12.7),
and in the metabolism of drugs and other foreign compounds via glucuronides (see Box 12.7).

CYCLIC ACETALS AND KETALS: PROTECTING GROUPS 481

HO OH ROH ROH HO OH SN2 process with
HO O SN2 HO O inversion of configuration

H OR
HO HO

OPPU H

UDPglucose β-glucoside

double SN2 process leads to
retention of configuration

HO OH Enz HO OH ROH HO OH
HO O B HO O Enz SN2 HO O

H SN2 B H
HO HO HO

OPPU H OR

ROH α-glucoside

HOPPU = uridine diphosphate

12.5 Cyclic acetals and ketals: acetal/ketal reaction using hydrolytic conditions (see
protecting groups Section 7.2).

We have just seen that intramolecular reactions In principle, a number of different types of
between the carbonyl group and one or other of the acetal or ketal might be produced. In this section,
hydroxyl functions readily leads to the formation of we want to exemplify a small number of useful
cyclic hemiacetal or hemiketal forms. Further, these reactions in which two of the hydroxyl groups on
products may then be converted into acetals or ketals the sugar are bound up by forming a cyclic acetal
by an intermolecular reaction with another alcohol or ketal with a suitable aldehyde or ketone reagent.
molecule, giving us glycosides. We could also form Aldehydes or ketones react with 1,2- or 1,3-diols
an acetal or ketal by supplying a carbonyl compound under acidic conditions to form cyclic acetals or
and exploiting the hydroxyl groups of the sugar. This ketals. If the diol is itself cyclic, then the two
provides a particularly useful means of protecting hydroxyl groups need to be cis-oriented to allow the
some of the hydroxyl groups whilst other reactions thermodynamically favourable fused-ring system to
are carried out (see Box 7.21); the protecting group form (see Section 3.5.2). Thus, cis-cyclohexan-1,2-
is then easily removed by effectively reversing the diol reacts with acetone to form a cyclic ketal, a
1,2-O-isopropylidene derivative usually termed, for
convenience, an acetonide.

OH CH3 H+, Me2CO O
O CH3 O

OH H+, H2O acetonide

When required, the original diol may be regenerated that a more stable pyranose form does not have cis-
by acid hydrolysis. oriented hydroxyl groups, whereas a less favoured
furanose form does, so that the latter can form cyclic
Sugars are polyhydroxy compounds, and it is not acetals/ketals. The equilibration of pyranose/furanose
always easy to predict which of the hydroxyls will forms (see Section 12.2.2) allows this type of change
react in this way. There are other complicating factors to occur.
too. The ring size (pyranose/furanose) of the product
may differ from that of the starting sugar. It may be

482 CARBOHYDRATES

Thus, D-galactose reacts with acetone to give a a diacetonide. Only the primary alcohol group is left
diketal: the less-favoured α-form has two pairs of unprotected, and is available for further modification,
cis-oriented hydroxyls that can react. It thus yields if desired.

HO OH H+ HO OH Me2CO O OH
O O O

HO HO H+ O
HO OH O
HO O
OH
D-galactopyranose
α-D-galactopyranose

α-anomer has two sets of
neighbouring cis hydroxyls

D-Glucose provides a rather more complicated that the furanose form has two sets of hydroxyls that
picture, unfortunately. Whilst the pyranose α-anomer can react; the product obtained is a diacetonide of
could yield a mono-acetonide, there is no other pair α-D-glucofuranose.
of cis-hydroxyls that can react. However, it turns out

HO

HO O H+ HO OH O H two sets of neighbouring
HO OH H cis hydroxyls
HO
HO

D-glucopyranose OH
OH

α-D-glucofuranose

PhCHO H+ Me2CO Me2CO
H+ H+

H CH3 O

O H3C O O O OH O H
OO HO OH H O
O
HO HO

HO OH O

acetal formation: ketal formation unfavourable; ketal formation:
production of six-membered all-chair one alkyl group must be axial five-membered rings favourable, but
trans-fused system with phenyl equatorial require hydroxyls in cis relationship

Note that a six-membered ketal ring involving the most sugars with respect to cyclic acetal and ketal
hydroxyls at 4 and 6 is not favoured; this is because formation is well documented for those wishing to
such a ring would necessarily force one of the two work with these compounds. The objective here
methyls into an axial position. On the other hand, is merely to illustrate the potential for selective
these two hydroxyls can be employed in forming protection of the hydroxyl groups.
a cyclic acetal with benzaldehyde. Benzaldehyde
shows a tendency to form six-membered ring acetals, 12.6 Oligosaccharides
and because the two substituents are phenyl and
hydrogen, we can have a favourable chair system with The term oligosaccharide is frequently used to
the phenyl equatorial. classify a small polysaccharide comprised of some
two to five monomer units, a name derived from the
It is not the intention to explain all such variations Greek oligos, meaning a few. A pre-eminent example
and add to potential confusion. The behaviour of

OLIGOSACCHARIDES 483

is the disaccharide sucrose, which we commonly centre in the second sugar (glucose) is not indicated;
call ‘sugar’ and utilize widely as a sweetening it could be α or β, as with a monosaccharide (see
agent and as the raw material for sweets and Section 12.2.3). Longhand systematic nomenclature
other confectionary. Other important disaccharides that treats one sugar as a substituent on the other can
are maltose, a hydrolysis product from starch, and also be used. In the systematic names, the ring size
lactose, the main sugar component of cow’s milk. (pyranose or furanose) is also indicated. Thus mal-
tose is 4-O-(α-D-glucopyranosyl)-D-glucopyranose,
OH and lactose becomes 4-O-(β-D-galactopyranosyl)-D-
glucopyranose.
HO O α1→4
Lactulose is a semi-synthetic disaccharide pre-
HO 1 OH pared from lactose, and is composed of galactose
HO 4 linked β1 → 4 to fructose. Galactose is an aldose
O O and exists as a six-membered pyranose ring, whereas
fructose is a ketose and forms a five-membered fura-
HO OH nose ring. Systematically, lactulose is called 4-O-(β-
D-galactopyranosyl)-D-fructofuranose; again, the con-
maltose HO figuration at the anomeric centre of fructose is
unspecified. In abbreviated form, this becomes D-
D-Glc(α1→4)D-Glc Gal(β1 → 4)D-Fru. Lactulose is widely employed as
a laxative. It is not absorbed from the gastrointesti-
4-O-(α-D-glucopyranosyl)-D-glucopyranose nal tract, is predominantly excreted unchanged, and
helps to retain fluid in the bowel by osmosis.
OH OH β1→4 OH
HO O4 O
1O
HO OH
HO HO

lactose OH HO HO OH
D-Gal(β1→4)D-Glc HO OH O
4-O-(β-D-galactopyranosyl)-D-glucopyranose
O 4 OH

1 O
β1→4
HO

If we inspect these structures, we can see that lactulose
they are acetals or ketals equivalent to the glyco- D-Gal(β1→4)D-Fru
sides described above, though the alcohol portion 4-O-(β-D-galactopyranosyl)-D-fructofuranose
is actually one of the hydroxyl groups of a second
monosaccharide structure. The linkages are conve- OH
niently defined by a shorthand system of nomencla-
ture; this indicates the carbons that are joined by the HO O
acetal/ketal bond through the use of numbers and an HO
arrow, together with the configuration α or β at the 1 anomeric centre
anomeric carbon. Note that each monosaccharide is HO
numbered separately and there is no unique number- HO
ing system for the combined structure. Thus, mal- HO O α1→β2
tose becomes D-Glc(α1 → 4)D-Glc, which conveys O2
the information that two molecules of D-glucose anomeric centre
are bonded between carbon-1 of one molecule and
carbon-4 of the second, and that the configuration at HO 1 OH
the anomeric centre (C-1 of the first glucose residue) sucrose
is α.
D-Glc(α1→β2)D-Fru
Similarly, lactose, a combination of D-galactose
and D-glucose, is D-Gal(β1 → 4)D-Glc, the configura- α-D-glucopyranosyl-(1→2)-β-D-fructofuranoside
tion at the anomeric centre of galactose being β. Note
that the configuration at the hemiacetal anomeric Sucrose is composed of glucose and fructose,
and again we have a six-membered pyranose ring
coupled to a five-membered furanose ring. However,
there is a significant difference when we compare
its structure with that of lactulose: in sucrose, the
two sugars are both linked through their anomeric

484 CARBOHYDRATES

centres. In the shorthand representation we thus have 12.7 Polysaccharides
to indicate the configuration at each anomeric cen-
tre, so the linkage becomes α1 → β2. Sucrose is 12.7.1 Structural aspects
thus abbreviated to D-Glc(α1 → β2)D-Fru. System-
atic nomenclature for sucrose is α-D-glucopyranosyl- Polysaccharides fulfil two main functions in living
(1 → 2)-β-D-fructofuranoside, which also includes organisms, as food reserves and as structural ele-
the arrow to avoid confusion. Since the two sugars in ments. Plants accumulate starch as their main food
sucrose are both linked through their anomeric cen- reserve, a material that is composed entirely of glu-
tres, this means that both the hemiacetal/hemiketal copyranose units, but in two different types of poly-
structures are prevented from opening; and, in con- mer, namely amylose and amylopectin. Amylose is
trast to maltose, lactose, and lactulose, there can be no a linear polymer containing some 1000–2000 glu-
open-chain form in equilibrium with the cyclic form. copyranose units linked α1 → 4. Amylopectin is a
Therefore, sucrose does not display any of the prop- much larger molecule than amylose (the number of
erties usually associated with the masked carbonyl glucose residues varies widely, but may be as high
group. as 106), and it is a branched-chain molecule. In addi-
tion to α1 → 4 linkages, amylopectin has branches at
In nature, the formation of oligosaccharides, and about every 20 units through α1 → 6 linkages. These
also of polysaccharides (see Section 12.4), is depen- branches then also continue with α1 → 4 linkages,
dent upon the generation of an activated sugar bound but may have subsidiary α1 → 6 branching, giving a
to a nucleoside diphosphate, typically a UDPsugar. tree-like structure.
As outlined above (see Box 12.4), nucleophilic dis-
placement of the UDP leaving group by a suitable The mammalian carbohydrate storage molecule
nucleophile generates the new sugar derivative. This glycogen is analogous to amylopectin in structure, but
will be a glycoside if the nucleophile is a suit- is larger and contains more frequent branching, about
able aglycone molecule, or an oligosaccharide if the every 10 residues. The branching in amylopectin
nucleophile is another sugar molecule. This reaction, and glycogen is achieved by the enzymic removal
mechanistically of SN2 type, should give an inversion of a portion of the α1 → 4-linked straight chain
of configuration at C-1 in the electrophile, generat- containing several glucose residues, then transferring
ing a product with the β-configuration in the case this short chain to a suitable 6-hydroxyl group.
of UDPglucose, as shown. Many of the linkages A less common storage polysaccharide found in
formed between glucose monomers actually have the certain plants is inulin, which is a relatively small
α-configuration, and it is believed that a double SN2 polymer of fructofuranose, linked through β2 → 1
mechanism operates, which initially involves a nucle- bonds.
ophilic group on the enzyme (see Box 12.4).

OH D-Glc

O O α1→4 OH amylopectin
(up to 106 residues; branching
HO 1 OH OO
D-Glc O about every 20 residues)
HO 4 HO 1
O
HO HO α1→6 glycogen
6O (>106 residues; branching
HO O O α1→4
O
HO 1 OH about every 10 residues)
D-Glc O

amylose HO 4

(1000–2000 residues) D-Glc O

HO

HO
D-Glc O

OXIDATION OF SUGARS: URONIC ACIDS 485

HO HO O OH β1→4 OH O
D-Fru O O O HO
HO 1 O O
HO 2 OH
HO 1 HO 4
D-Glc
D-Fru HO O β2→1 D-Glc cellulose
HO O2
(~8000 residues)
O

inulin
(30–35 residues)

Cellulose is reputedly the most abundant organic activity in adult humans is usually considerably lower
material on Earth, being the main constituent in than in infants. Lactose intolerance is a condition
plant cell walls. It is composed of glucopyranose in certain adults who are unable to tolerate milk
units linked β1 → 4 in a linear chain. Alternate products in the diet. This is a consequence of very
residues are ‘rotated’ in the structure, allowing low lactase levels, such that ingestion of lactose can
hydrogen bonding between adjacent molecules, and lead to adverse reactions, typically gastric upsets.
construction of the strong fibres characteristic of
cellulose, as for example in cotton. Cellulose differs from amylose principally in the
stereochemistry of the acetal linkages, which are α in
12.7.2 Hydrolysis of polysaccharides amylose but β in cellulose. α-Amylase is specific for
α1 → 4 bonds and is not able to hydrolyse β1 → 4
Hydrolysis of polysaccharides (and oligosaccharides) bonds. An alternative enzyme, termed cellulase, is
follows the comments under glycosides above. Thus, required. Animals do not possess cellulase enzymes,
treatment of amylose, amylopectin, or cellulose with and thus cannot digest wood and vegetable fibres that
hot aqueous acid will result in the formation of are predominantly composed of cellulose. Ruminants,
glucose as the sole product, through hydrolysis of such as cattle, are equipped to carry out cellulose
acetal linkages. Under milder, less-forcing conditions, hydrolysis, though this is dependent upon cellulase-
it is possible to isolate short-chain oligosaccharides producing bacteria in their digestive tracts.
as a result of random hydrolysis of linkages.
12.8 Oxidation of sugars: uronic acids
More specific hydrolysis may be achieved by the
use of enzymes. Thus, the enzyme α-amylase in Sugars may be oxidized by a variety of reagents,
saliva and in the gut is able to catalyse hydrolysis of and the most susceptible group in aldoses is the
α1 → 4 bonds throughout the starch molecule to give aldehyde. Use of aqueous bromine as a mild oxidizing
mainly maltose, with some glucose and maltotriose, agent achieves oxidation of the aldehyde group in
the trisaccharide of glucose. Amylose is hydrolysed D-glucose, and the product is the corresponding
completely by this enzyme, but the α1 → 6 bonds carboxylic acid D-gluconic acid. The general term
of amylopectin are not affected. Another digestive used for such a polyhydroxy carboxylic acid is an
enzyme, α-1,6-glucosidase, is required for this aldonic acid. These are named by substituting -onic
reaction. Finally, pancreatic maltase completes the acid for -ose of the sugar. Polyhydroxy carboxylic
hydrolysis by hydrolysing maltose and maltotriose. acids have the potential to form lactones (cyclic
esters, see Section 7.9.1), and D-gluconic acid readily
The milk of mammals contains the disaccharide forms a 1,4-lactone in solution. In principle, both
lactose as the predominant carbohydrate, to the extent five- and six-membered rings might be produced,
of about 4–8%. Lactose, therefore, provides the basic but the five-membered system is favoured (see
carbohydrate nutrition for infants, who metabolize it Section 7.9.1).
via the hydrolytic enzyme lactase. Lactase enzyme