Organic chemistry ii

Organic Chemistry II arranged by Putri Nur Aulia 1

ORGANIC CHEMISTRY II

CHAPTER I

BIFUNCTIONAL COMPOUNDS


CHAPTER I

BIFUNCTIONAL COMPOUNDS

1.1 Introduction

In organic molecules, functional groups are atom or atoms which are

responsible for the characteristic properties of that molecule with the exceptions

of double and triple bonds which are also functional groups. Some common

functional groups are -COOH (carboxylic acids), -CHO (aldehyde), -

CONH2 (amide), -CN (nitrile), -OH (alcohol) etc. When two of such

different functional groups are present in a single organic molecule then it is

called bifunctional molecule, which has properties of two different types of

functional groups.

Many of bifunctional molecules are used to

produce medicine, catalysts and also used in condensation

polymerization like polyester, polyamide etc.

1.2 Nomenclature

Nomenclature of multifunctional compounds: The longest chain

containing the suffix is chosen, the priority for choosing the suffix being

carboxylic acid, -CO2H, > carboxylic acid derivative, -COX > aldehyde, -CHO >

ketone, -CO-, > alcohol, -OH > amine, -NH2. The second and other groups are

labelled as substituents. e.g.

CH3CH(OH)CH2CO2H is 3- hydroxybutanoic acid;

HOCH2CH2CH2COCH3 is 5-hydroxypentan-2-one;

CH3CH(OH)CH2C(CH3)(NH2)CH3 is 4-amino-4-methylpentan-2-ol;

CH3COCO2H is 2- oxopropanoic acid, (the =O of an aldehyde or ketone is called

oxo when it has to be named as a substituent).

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The carbon-carbon double and triple bonds are always incorporated in the

chain, with lower priority than the other groups. [e.g. CH2=CHCH(OH)CH3 is

but-3-en-2-ol; CH3C≡CCH2CO2H is pent-3-yn-oic acid.]

For compounds with larger carbon skeletons a further condensation of

structural may be used.

represents propylcyclohexane. Each line represents two carbon

atoms joined by a single bond, and hydrogens which are present are not shown.

The number of H's is such to satisfy the valency of carbon, 4.

Benzene is C6H6 and is the parent of

aromatic compounds. Each carbon in the benzene ring has one hydrogen attached.

As a second resonance structure with the double bonds in the other three

positions can be drawn, the resonance hybrid of benzene is often represented as a

hexagon with a circle inside:

1.3 How Can A Pure Be A mixture of Two (or More) Molecules


1H- NMR Spectroscopy Using D2O as Co-Solvent

1.3.1 Keto-enol Tautomerism


Carbonyl Group Tautomer

Solvent Effect


Enols and Enolates

Unsymmetrical Ketones


Implications of Enolisation


Acid Catalysed Halogenations of Enols

The Hell-Volhard –Zelinsky Reaction


The Aldol Reaction


The Knoevenagel Condensation

The Claisen Condensation


The Dieckman Reaction

β- Dicarbonyl Compounds


Decarboxylation of β-Ketoacids

Aklylation of Dymethil Malonates



CHAPTER II

HETEROCYCLIC COMPOUNDS


CHAPTER II

HETEROCYCLIC COMPOUNDS

2.1 Introduction

Compounds classified as heterocyclic probably constitute the largest and

most varied family of organic compounds. After all, every carbocyclic compound,

regardless of structure and functionality, may in principle be converted into a

collection of heterocyclic analogs by replacing one or more of the ring carbon

atoms with a different element. Even if we restrict our consideration to oxygen,

nitrogen and sulfur (the most common heterocyclic elements), the permutations

and combinations of such a replacement are numerous.

2.2 Nomenclature

Devising a systematic nomenclature system for heterocyclic compounds

presented a formidable challenge, which has not been uniformly concluded. Many

heterocycles, especially amines, were identified early on, and received trivial

names which are still preferred. Some monocyclic compounds of this kind are

shown in the following chart, with the common (trivial) name in bold and a

systematic name based on the Hantzsch-Widman system given beneath it in blue.

The rules for using this system will be given later. For most students, learning

these common names will provide an adequate nomenclature background.

An easy to remember, but limited, nomenclature system makes use of an

elemental prefix for the heteroatom followed by the appropriate carbocyclic name.


A short list of some common prefixes is given in the following table, priority

order increasing from right to left. Examples of this nomenclature are: ethylene

oxide = oxacyclopropane, furan = oxacyclopenta-2,4-diene, pyridine =

azabenzene, and morpholine = 1-oxa-4-azacyclohexane.

Element Oxygen sulfur selenium nitrogen phosphorous silicon boron As

Valence II II II III III IV III III

Prefix Oxa Thia Selena Aza Phospha Sila Bora Arsa

The Hantzsch-Widman system provides a more systematic method of

naming heterocyclic compounds that is not dependent on prior carbocyclic names.

It makes use of the same hetero atom prefix defined above (dropping the final "a"),

followed by a suffix designating ring size and saturation. As outlined in the

following table, each suffix consists of a ring size root (blue) and an ending

intended to designate the degree of unsaturation in the ring. In this respect, it is

important to recognize that the saturated suffix applies only to completely

saturated ring systems, and the unsaturated suffix applies to rings

incorporating the maximum number of non-cumulated double bonds. Systems

having a lesser degree of unsaturation require an appropriate prefix, such as

"dihydro"or "tetrahydro".

Ring Size 3 4 5 6 7 8 9 10

Suffix

Unsaturated

Without N

Saturated

irene

irane

ete

etane

ole

olane

ine

inane

epine

epane

ocine

ocane

onine

onane

ecine

ecane

Despite the general systematic structure of the Hantzsch-Widman system,

several exceptions and modifications have been incorporated to accommodate

conflicts with prior usage. Some examples are:

• The terminal "e" in the suffix is optional though recommended.


• Saturated 3, 4 & 5-membered nitrogen heterocycles should use

respectively the traditional "iridine", "etidine" & "olidine" suffix.

• Unsaturated nitrogen 3-membered heterocycles may use the traditional

"irine" suffix.

• Consistent use of "etine" and "oline" as a suffix for 4 & 5-membered

unsaturated heterocycles is prevented by their former use for similar

sized nitrogen heterocycles.

• Established use of oxine, azine and silane for other compounds or

functions prohibits their use for pyran, pyridine and silacyclohexane

respectively.

Examples of these nomenclature rules are written in blue, both in the

previous diagram and that shown below. Note that when a maximally unsaturated

ring includes a saturated atom, its location may be designated by a "#H " prefix to

avoid ambiguity, as in pyran and pyrrole above and several examples below.

When numbering a ring with more than one heteroatom, the highest priority atom

is #1 and continues in the direction that gives the next priority atom the lowest

number.

All the previous examples have been monocyclic compounds. Polycyclic

compounds incorporating one or more heterocyclic rings are well known. A few

of these are shown in the following diagram. As before, common names are in

black and systematic names in blue. The two quinolines illustrate another nuance


of heterocyclic nomenclature. Thus, the location of a fused ring may be indicated

by a lowercase letter which designates the edge of the heterocyclic ring involved

in the fusion, as shown by the pyridine ring in the green shaded box.

Heterocyclic rings are found in many naturally occurring compounds.

Most notably, they compose the core structures of mono and polysaccharides, and

the four DNA bases that establish the genetic code.

2.3 Preparation and Reactions

2.3.1 Three-Membered Rings

Oxiranes (epoxides) are the most commonly encountered three-

membered heterocycles. Epoxides are easily prepared by reaction of

alkenes with peracids, usually with good stereospecificity. Because of the

high angle strain of the three-membered ring, epoxides are more reactive

that unstrained ethers. Addition reactions proceeding by electrophilic or

nucleophilic opening of the ring constitute the most general reaction class.

Example 1 in the following diagram shows one such transformation,

which is interesting due to subsequent conversion of the addition

intermediate into the corresponding thiirane. The initial ring opening

is stereoelectronically directed in a trans-diaxial fashion, the intermediate

relaxing to the diequatorial conformer before cyclizing to a 1,3-

oxathiolane intermediate.

Other examples show similar addition reactions to thiiranes and

aziridines. The acid-catalyzed additions in examples 2 and 3, illustrate the

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influence of substituents on the regioselectivity of addition. Example 2

reflects the SN2 character of nucleophile (chloride anion) attack on the

protonated aziridine (the less substituted carbon is the site of addition).

The phenyl substituent in example 3 serves to stabilize the developing

carbocation to such a degree that SN1 selectivity is realized. The reduction

of thiiranes to alkenes by reaction with phosphite esters (example 6) is

highly stereospecific, and is believed to take place by an initial bonding of

phosphorous to sulfur.

Examples 7 and 8 are thermal reactions in which both the

heteroatom and the strained ring are important factors. The α-lactone

intermediate shown in the solvolysis of optically active 2-bromopropanoic

acid (example 9) accounts both for the 1st-order kinetics of this reaction

and the retention of configuration in the product. Note that two inversions

of configuration at C-2 result in overall retention. Many examples

of intramolecular interactions, such as example 10, have been documented.

An interesting regioselectivity in the intramolecular ring-opening reactions

of disubstituted epoxides having a pendant γ-hydroxy substituent has been

noted. As illustrated below, acid and base-catalyzed reactions normally

proceed by 5-exo-substitution (reaction 1), yielding a tetrahydrofuran

product. However, if the oxirane has an unsaturated substituent (vinyl or

phenyl), the acid-catalyzed opening occurs at the allylic (or benzylic)

carbon (reaction 2) in a 6-endo fashion. The π-electron system of the

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substituent assists development of positive charge at the adjacent oxirane

carbon, directing nucleophilic attack to that site.

2.3.2 Four-Membered Rings

Preparation

Several methods of preparing four-membered heterocyclic

compounds are shown in the following diagram. The simple procedure of

treating a 3-halo alcohol, thiol or amine with base is generally effective,

but the yields are often mediocre. Dimerization and elimination are

common side reactions, and other functions may compete in the reaction.

In the case of example 1, cyclization to an oxirane competes with thietane

formation, but the greater nucleophilicity of sulfur dominates, especially if

a weak base is used. In example 2 both aziridine and azetidine formation

are possible, but only the former is observed. This is a good example of

the kinetic advantage of three-membered ring formation. Example 4

demonstrates that this approach to azetidine formation works well in the

absence of competition. Indeed, the exceptional yield of this product is

attributed to the gem-dimethyl substitution, the Thorpe-Ingold effect,

which is believed to favor coiled chain conformations. The relatively rigid

configuration of the substrate in example 3, favors oxetane formation and

prevents an oxirane cyclization from occurring. Finally, the Paterno-Buchi

photocyclizations in examples 5 and 6 are particularly suited to oxetane

formation.

Reactions

Reactions of four-membered heterocycles also show the influence

of ring strain. Some examples are given in the following diagram. Acid-

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catalysis is a common feature of many ring-opening reactions, as shown

by examples 1, 2 & 3a. In the thietane reaction (2), the sulfur undergoes

electrophilic chlorination to form a chlorosulfonium intermediate followed

by a ring-opening chloride ion substitution. Strong nucleophiles will also

open the strained ether, as shown by reaction 3b. Cleavage reactions of β-

lactones may take place either by acid-catalyzed acyl exchange, as in 4a,

or by alkyl-O rupture by nucleophiles, as in 4b. Example 5 is an

interesting case of intramolecular rearrangement to an ortho-ester. Finally,

the β-lactam cleavage of penicillin G (reaction 6) testifies to the enhanced

acylating reactivity of this fused ring system. Most amides are extremely

unreactive acylation reagents, thanks to stabilization by p-π resonance.

Such electron pair delocalization is diminished in the penicillins, leaving

the nitrogen with a pyramidal configuration and the carbonyl function

more reactive toward nucleophiles.

2.3.3`Five-Membered Rings

Preparation

Commercial preparation of furan proceeds by way of the aldehyde,

furfural, which in turn is generated from pentose containing raw materials

like corncobs, as shown in the uppermost equation below. Similar

preparations of pyrrole and thiophene are depicted in the second row

equations. Equation 1 in the third row illustrates a general preparation of

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substituted furans, pyrroles and thiophenes from 1,4-dicarbonyl

compounds, known as the Paal-Knorr synthesis. Many other procedures

leading to substituted heterocycles of this kind have been devised. Two of

these are shown in reactions 2 and 3. Furan is reduced to tetrahydrofuran

by palladium-catalyzed hydrogenation. This cyclic ether is not only a

valuable solvent, but it is readily converted to 1,4-dihalobutanes or 4-

haloalkylsulfonates, which may be used to prepare pyrrolidine and

thiolane.

Dipolar cycloaddition reactions often lead to more complex five-

membered heterocycles.

Indole is probably the most important fused ring heterocycle in this

class. The first proceeds by an electrophilic substitution of a nitrogen-

activated benzene ring. The second presumably takes place by formation

of a dianionic species in which the ArCH2(–) unit bonds to the deactivated

carbonyl group. Finally, the Fischer indole synthesis is a remarkable

sequence of tautomerism, sigmatropic rearrangement, nucleophilic

addition, and elimination reactions occurring subsequent to

phenylhydrazone formation. This interesting transformation involves the

oxidation of two carbon atoms and the reduction of one carbon and both

nitrogen atoms.

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Reactions

The chemical reactivity of the saturated members of this class of

heterocycles: tetrahydrofuran, thiolane and pyrrolidine, resemble that of

acyclic ethers, sulfides, and 2º-amines, and will not be described here. 1,3-

Dioxolanes and dithiolanes are cyclic acetals and thioacetals. These units

are commonly used as protective groups for aldehydes and ketones, and

may be hydrolyzed by the action of aqueous acid.

It is the "aromatic" unsaturated compounds, furan, thiophene and pyrrole

that require our attention. In each case the heteroatom has at least one pair

of non-bonding electrons that may combine with the four π-electrons of

the double bonds to produce an annulene having an aromatic sextet of

electrons. This is illustrated by the resonance description at the top of the

following diagram. The heteroatom Y becomes sp2-hybridized and

acquires a positive charge as its electron pair is delocalized around the ring.

An easily observed consequence of this delocalization is a change in

dipole moment compared with the analogous saturated heterocycles,

which all have strong dipoles with the heteroatom at the negative end. As

expected, the aromatic heterocycles have much smaller dipole moments,

or in the case of pyrrole a large dipole in the opposite direction. An

important characteristic of aromaticity is enhanced thermodynamic

stability, and this is usually demonstrated by relative heats of

hydrogenation or heats of combustion measurements. By this standard, the

three aromatic heterocycles under examination are stabilized, but to a

lesser degree than benzene.

Additional evidence for the aromatic character of pyrrole is found

in its exceptionally weak basicity (pKa ca. 0) and strong acidity (pKa = 15)

for a 2º-amine. The corresponding values for the saturated amine

pyrrolidine are: basicity 11.2 and acidity 32.

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Another characteristic of aromatic systems, of particular

importance to chemists, is their pattern of reactivity with electrophilic

reagents. Whereas simple cycloalkenes generally give addition reactions,

aromatic compounds tend to react by substitution. As noted for benzene

and its derivatives, these substitutions take place by an initial electrophile

addition, followed by a proton loss from the "onium" intermediate to

regenerate the aromatic ring. The aromatic five-membered heterocycles all

undergo electrophilic substitution, with a general reactivity order: pyrrole

>> furan > thiophene > benzene. Some examples are given in the

following diagram. The reaction conditions show clearly the greater

reactivity of furan compared with thiophene. All these aromatic

heterocycles react vigorously with chlorine and bromine, often forming

polyhalogenated products together with polymers. The exceptional

reactivity of pyrrole is evidenced by its reaction with iodine (bottom left

equation), and formation of 2-acetylpyrrole by simply warming it with

acetic anhydride (no catalyst).

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There is a clear preference for substitution at the 2-position (α) of

the ring, especially for furan and thiophene. Reactions of pyrrole require

careful evaluation, since N-protonation destroys its aromatic character.

Indeed, N-substitution of this 2º-amine is often carried out prior to

subsequent reactions. For example, pyrrole reacts with acetic anhydride or

acetyl chloride and triethyl amine to give N-acetylpyrrole. Consequently,

the regioselectivity of pyrrole substitution is variable, as noted by the

bottom right equation.

An explanation for the general α-selectivity of these substitution

reactions is apparent from the mechanism outlined below. The

intermediate formed by electrophile attack at C-2 is stabilized by charge

delocalization to a greater degree than the intermediate from C-3 attack.

From the Hammond postulatewe may then infer that the activation energy

for substitution at the former position is less than the latter substitution.

Functional substituents influence the substitution reactions of these

heterocycles in much the same fashion as they do for benzene. Indeed,

once one understands the ortho-para and meta-directing character of these

substituents, their directing influence on heterocyclic ring substitution is

not difficult to predict. The following diagram shows seven such reactions.

Reactions 1 & 2 are 3-substituted thiophenes, the first by an electron

donating substituent and the second by an electron withdrawing group.

The third reaction has two substituents of different types in the 2 and 5-

positions. Finally, examples 4 through 7 illustrate reactions of 1,2- and

1,3-oxazole, thiazole and diazole. Note that the basicity of the sp2-

hybridized nitrogen in the diazoles is over a million times greater than that

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of the apparent sp3-hybridized nitrogen, the electron pair of which is part

of the aromatic electron sextet.

Other possible reactions are suggested by the structural features of

these heterocycles. For example, furan could be considered an enol ether

and pyrrole an enamine. Such functions are known to undergo acid-

catalyzed hydrolysis to carbonyl compounds and alcohols or amines. Since

these compounds are also heteroatom substituted dienes, we might

anticipate Diels-Alder cycloaddition reactions with appropriate

dienophiles. As noted in the upper example, furans may indeed be

hydrolyzed to 1,4-dicarbonyl compounds, but pyrroles and thiophenes

behave differently. The second two examples, shown in the middle,

demonstrate typical reactions of furan and pyrrole with the strong

dienophile maleic anhydride. The former participates in a cycloaddition

reaction; however, the pyrrole simply undergoes electrophilic substitution

at C-2. Thiophene does not easily react with this dienophile.

The bottom line of the new diagram illustrates the remarkable influence

that additional nitrogen units have on the hydrolysis of a series of N-

acetylazoles in water at 25 ºC and pH=7. The pyrrole compound on the left

is essentially unreactive, as expected for an amide, but additional nitrogens

markedly increase the rate of hydrolysis. This effect has been put to

practical use in applications of the acylation reagent 1,1'-

carbonyldiimidazole (Staab's reagent).

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Another facet of heterocyclic chemistry was disclosed in the course

of investigations concerning the action of thiamine (following diagram).

As its pyrophosphate derivative, thiamine is a coenzyme for several

biochemical reactions, notably decarboxylations of pyruvic acid to

acetaldehyde and acetoin. Early workers speculated that an "active

aldehyde" or acyl carbanion species was an intermediate in these reactions.

Many proposals were made, some involving the aminopyrimidine moiety,

and others, ring-opened hydrolysis derivatives of the thiazole ring, but

none were satisfactory. This puzzle was solved when R.

Breslow (Columbia) found that the C-2 hydrogen of thiazolium salts was

unexpectedly acidic (pKa ca. 13), forming a relatively stable ylide

conjugate base. As shown, this rationalizes the facile decarboxylation of

thiazolium-2-carboxylic acids and deuterium exchange at C-2 in neutral

heavy water.

Appropriate thiazolium salts catalyze the conversion of aldehydes

to acyloins in much the same way that cyanide ion catalyzes the formation

of benzoin from benzaldehyde, the benzoin condensation. Note that in

both cases an acyl anion equivalent is formed and then adds to a carbonyl

function in the expected manner. The benzoin condensation is limited to

aromatic aldehydes, but the use of thiazolium catalysts has proven broadly

effective for aliphatic and aromatic aldehydes. This approach to acyloins

employs milder conditions than the reduction of esters to enediol

intermediates by the action of metallic sodium .

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The most important condensed ring system related to these

heterocycles is indole. Some electrophilic substitution reactions of indole

are shown in the following diagram. Whether the indole nitrogen is

substituted or not, the favored site of attack is C-3 of the heterocyclic ring.

Bonding of the electrophile at that position permits stabilization of the

onium-intermediate by the nitrogen without disruption of the benzene

aromaticity.

2.3.4 Six-Membered Rings

Properties

The chemical reactivity of the saturated members of this class of

heterocycles: tetrahydropyran, thiane and piperidine, resemble that of

acyclic ethers, sulfides, and 2º-amines, and will not be described here. 1,3-

Dioxanes and dithianes are cyclic acetals and thioacetals. These units are

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commonly used as protective groups for aldehydes and ketones, as well as

synthetic intermediates, and may be hydrolyzed by the action of aqueous

acid. The reactivity of partially unsaturated compounds depends on the

relationship of the double bond and the heteroatom (e.g. 3,4-dihydro-2H-

pyran is an enol ether).

Fully unsaturated six-membered nitrogen heterocycles, such as

pyridine, pyrazine, pyrimidine and pyridazine, have stable aromatic rings.

Oxygen and sulfur analogs are necessarily positively charged, as in the

case of 2,4,6-triphenylpyrylium tetrafluoroborate.

From heat of combustion measurements, the aromatic stabilization

energy of pyridine is 21 kcal/mole. The resonance description drawn at the

top of the following diagram includes charge separated structures not

normally considered for benzene. The greater electronegativity of nitrogen

(relative to carbon) suggests that such canonical forms may contribute to a

significant degree. Indeed, the larger dipole moment of pyridine compared

with piperidine supports this view. Pyridine and its derivatives are weak

bases, reflecting the sp2 hybridization of the nitrogen. From the polar

canonical forms shown here, it should be apparent that electron donating

substituents will increase the basicity of a pyridine, and that substituents

on the 2 and 4-positions will influence this basicity more than an

equivalent 3-substituent. The pKa values given in the table illustrate a few

of these substituent effects. Methyl substituted derivatives have the

common names picoline (methyl pyridines), lutidine (dimethyl pyridines)

and collidine (trimethyl pyridines). The influence of 2-substituents is

complex, consisting of steric hindrance and electrostatic components. 4-

Dimethylaminopyridine is a useful catalyst for acylation reactions carried

out in pyridine as a solvent. At first glance, the sp3 hybridized nitrogen

might appear to be the stronger base, but it should be remembered that


N,N-dimethylaniline has a pKa slightly lower than that of pyridine itself.

Consequently, the sp2 ring nitrogen is the site at which protonation occurs.

The diazines pyrazine, pyrimidine and pyridazine are all weaker

bases than pyridine due to the inductive effect of the second nitrogen.

However, the order of base strength is unexpected. A consideration of the

polar contributors helps to explain the difference between pyrazine and

pyrimidine, but the basicity of pyridazine seems anomalous. It has been

suggested that electron pair repulsion involving the vicinal nitrogens

destabilizes the neutral base relative to its conjugate acid.

2.4 Electrophilic Substitution of Pyridine

Pyridine is a modest base (pKa=5.2). Since the basic unshared electron pair

is not part of the aromatic sextet, as in pyrrole, pyridinium species produced by N-

substitution retain the aromaticity of pyridine. As shown below, N-alkylation and

N-acylation products may be prepared as stable crystalline solids in the absence of

water or other reactive nucleophiles. The N-acyl salts may serve as acyl transfer

agents for the preparation of esters and amides. Because of the stability of the

pyridinium cation, it has been used as a moderating component in complexes with

a number of reactive inorganic compounds. Several examples of these stable and

easily handled reagents are shown at the bottom of the diagram. The

poly(hydrogen fluoride) salt is a convenient source of HF for addition to alkenes

and conversion of alcohols to alkyl fluorides, pyridinium chlorochromate

(PCC) and its related dichromate analog are versatile oxidation agents and the

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tribromide salt is a convenient source of bromine. Similarly, the reactive

compounds sulfur trioxide and diborane are conveniently and safely handled as

pyridine complexes.

Amine oxide derivatives of 3º-amines and pyridine are readily

prepared by oxidation with peracids or peroxides, as shown by the upper right

equation. Reduction back to the amine can usually be achieved by treatment with

zinc (or other reactive metals) in dilute acid.

From the previous resonance description of pyridine, we expect this

aromatic amine to undergo electrophilic substitution reactions far less easily than

does benzene. Three examples of the extreme conditions required for electrophilic

substitution are shown on the left. Substituents that block electrophile

coordination with nitrogen or reduce the basicity of the nitrogen facilitate

substitution, as demonstrated by the examples in the blue-shaded box at the lower

right, but substitution at C-3 remains dominant. Activating substituents at other

locations also influence the ease and regioselectivity of substitution. The amine

substituent in the upper case directs the substitution to C-2, but the weaker

electron donating methyl substituent in the middle example cannot overcome the

tendency for 3-substitution. Hydroxyl substituents at C-2 and C-4 tautomerize

to pyridones, as shown for the 2-isomer at the bottom left.

Pyridine N-oxide undergoes some electrophilic substitutions at C-4 and others at

C-3. The coordinate covalent N–O bond may exert a push-pull influence, as

illustrated by the two examples on the right. Although the positively charged

nitrogen alone would have a strong deactivating influence, the negatively charged

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oxygen can introduce electron density at C-2, C-4 & C-6 by π-bonding to the ring

nitrogen. This is a controlling factor in the relatively facile nitration at C-4.

However, if the oxygen is bonded to an electrophile such as SO3, the resulting

pyridinium ion will react sluggishly and preferentially at C-3.

The fused ring heterocycles quinoline and isoquinoline provide additional

evidence for the stability of the pyridine ring. Vigorous permanganate oxidation

of quinoline results in predominant attack on the benzene ring; isoquinoline yields

products from cleavage of both rings. Note that naphthalene is oxidized to

phthalic acid in a similar manner. By contrast, the heterocyclic ring in both

compounds undergoes preferential catalytic hydrogenation to yield

tetrahydroproducts. Electrophilic nitration, halogenation and sulfonation generally

take place at C-5 and C-8 of the benzene ring, in agreement with the preceding

description of similar pyridine reactions and the kinetically favored substitution of

naphthalene at C-1 (α) rather than C-2 (β).

2.5 Other Reactions of Pyridine

Thanks to the nitrogen in the ring, pyridine compounds undergo

nucleophilic substitution reactions more easily than equivalent benzene

derivatives. In the following diagram, reaction 1 illustrates displacement of a 2-

chloro substituent by ethoxide anion. The addition-elimination mechanism shown

for this reaction is helped by nitrogen's ability to support a negative charge. A

similar intermediate may be written for substitution of a 4-halopyridine, but

substitution at the 3-position is prohibited by the the failure to create an

intermediate of this kind. The two Chichibabin aminations in reactions 2 and 3 are


remarkable in that the leaving anion is hydride (or an equivalent). Hydrogen is

often evolved in the course of these reactions. In accord with this mechanism,

quinoline is aminated at both C-2 and C-4.

Addition of strong nucleophiles to N-oxide derivatives of pyridine proceed

more rapidly than to pyridine itself, as demonstrated by reactions 4 and 5. The

dihydro-pyridine intermediate easily loses water or its equivalent by elimination

of the –OM substituent on nitrogen.

Because the pyridine ring (and to a greater degree the N-oxide ring) can

support a negative charge, alkyl substituents in the 2- and 4-locations are activated

in the same fashion as by a carbonyl group. Reactions 6 and 7 show alkylation and

condensation reactions resulting from this activation. Reaction 8 is an example of

N-alkylpyridone formation by hydroxide addition to an N-alkyl pyridinium cation,

followed by mild oxidation. Birch reduction converts pyridines to

dihydropyridines that are bis-enamines and may be hydrolyzed to 1,5-dicarbonyl

compounds. Pyridinium salts undergo a one electron transfer to generate

remarkably stable free radicals. The example shown in reaction 9 is a stable (in

the absence of oxygen), distillable green liquid. Although 3-halopyridines do not

undergo addition-elimination substitution reactions as do their 2- and 4-isomers,

the strong base sodium amide effects amination by way of a pyridyne intermediate.

This is illustrated by reaction 10. It is interesting that 3-pyridyne is formed in

preference to 2-pyridyne. The latter is formed if C-4 is occupied by an alkyl

substituent. The pyridyne intermediate is similar to benzyne.

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2.6 Some Polycyclic Heterocycles

Heterocyclic structures are found in many natural products. Examples of

some nitrogen compounds, known as alkaloids because of their basic properties,

were given in the amine chapter. Some other examples are displayed in the

following diagram. Camptothecin is a quinoline alkaloid which inhibits the DNA

enzyme topoisomerase I. Reserpine is an indole alkaloid, which has been used for

the control of high blood pressure and the treatment of psychotic behavior.

Ajmaline and strychnine are also indole alkaloids, the former being an

antiarrhythmic agent and latter an extremely toxic pesticide. The neurotoxins

saxitoxin and tetrodotoxin both have marine origins and are characterized by

guanidiniun moieties. Aflatoxin B1 is a non-nitrogenous carcinogenic compound

produced by the Aspergillus fungus.

Porphyrin is an important cyclic tertrapyrrole that is the core structure of

heme and chlorophyll. Derivatives of the simple fused ring heterocycle purine

constitute an especially important and abundant family of natural products. The

amino compounds adenine and guanine are two of the complementary bases that

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are essential components of DNA. Structures for these compounds are shown in

the following diagram. Xanthine and uric acid are products of the metabolic

oxidation of purines. Uric acid is normally excreted in the urine; an excess serum

accumulation of uric acid may lead to an arthritic condition known as gout.

Caffeine, the best known of these, is a bitter, crystalline alkaloid. It is

found in varying quantities, along with additional alkaloids such as the cardiac

stimulants theophylline and theobromine in the beans, leaves, and fruit of certain

plants. Drinks containing caffeine, such as coffee, tea and some soft drinks are

arguably the world's most widely consumed beverages. Caffeine is a central

nervous system stimulant, serving to ward off drowsiness and restore alertness.

Paraxantheine is the chief metabolite of caffeine in the body.

Sulfur heterocycles are found in nature, but to a lesser degree than their

nitrogen and oxygen analogs. Two members of the B-vitamin complex, biotin and

thiamine, incorporate such heterocyclic moieties. These are shown together with

other heterocyclic B-vitamins in the following diagram.

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Terthienyl is an interesting thiophene trimer found in the roots of

marigolds, where it provides nemicidal activity. Studies have shown that UV

irradiation of terthienyl produces a general phototoxicity for many organisms.

Polymers incorporating thiophene units and fused systems such as

dithienothiophene have interesting electromagnetic properties, and show promise

as organic metal-like conductors and photovoltaic materials. The charge transfer

complex formed by tetrathiofulvalene and tetracyanoquinodimethane has one of

the highest electrical conductivities reported for an organic solid.



CHAPTER III

CARBOHYDRATES


CHAPTER III

CARBOHYDRATES

3.1 Introduction

Carbohydrates, along with lipids, proteins, nucleic acids, and other

compounds are known as biomolecules because they are closely associated with

living organisms.

Carbohydrates are compounds of tremendous biological importance:

– they provide energy through oxidation

– they supply carbon for the synthesis of cell components

– they serve as a form of stored chemical energy

– they form part of the structures of some cells and tissues

Carbohydrates, or saccharides (saccharo is Greek for ―sugar) are

polyhydroxy aldehydes or ketones, or substances that yield such compounds on

hydrolysis.

Carbohydrates include not only sugar, but also the starches that we find in

foods, such as bread, pasta, and rice. The term carbohydrates comes from the

observation that when you heat sugars, you get carbon and water (hence, hydrate

of carbon).


3.2 Classes of carbohydrates

Monosaccharides contain a single polyhydroxy aldehyde or ketone unit

(e.g., glucose, fructose).

Disaccharides consist of two monosaccharide units linked together by a

covalent bond (e.g., sucrose).

Oligosaccharides contain from 3 to 10 monosaccharide units (e.g.,

raffinose).

Polysaccharides contain very long chains of hundreds or thousands of

monosaccharide units, which may be either in straight or branched chains

(e.g., cellulose, glycogen, starch).

3.3 The stereochemistry of carbohydrates

Glyceraldehyde, the simplest carbohydrate, exists in two isomeric

forms that are mirror images of each other:


3.3.1 Streoisemers

These forms are stereoisomers of each other.

Glyceraldehyde is a chiral molecule — it cannot be superimposed on

its mirror image. The two mirror-image forms of glyceraldehyde are

enantiomers of each other.

3.3.2 Chirality and handedness

Chiral molecules have the

same relationship to each other that

your left and right hands have when

reflected in a mirror.

A. Chiral Carbon

Chiral objects cannot be superimposed on their mirror images —

e.g., hands, gloves, and shoes. Achiral objects can be superimposed on the

mirror images — e.g., drinking glasses, spheres, and cubes. Any carbon

atom which is connected to four different groups will be chiral, and will


have two nonsuperimposable mirror images; it is a chiral carbon or a

center of chirality. – If any of the two groups on the carbon are the same,

the carbon atom cannot be chiral. Many organic compounds, including

carbohydrates, contain more than one chiral carbon.

Examples : Chiral Carbon Atoms

Identify the chiral carbon atoms (if any) in each of the following

molecules:

B. 2n Rule

When a molecule has more than one chiral carbon, each carbon can

possibly be arranged in either the right-hand or left-hand form, thus if

there are n chiral carbons, there are 2n possible stereoisomers.

Maximum number of possible stereoisomers = 2n


Examples : Number of Streoisomers

What is the maximum number of possible stereo-isomers of the following

compounds?

C. Fischer Projections

Fischer projections are a convenient way to represent mirror images

in two dimensions.

Place the carbonyl group at or near the top and the last achiral

CH2OH at the bottom.


3.4 Naming Streoisomers

When there is more than one chiral center in a carbohydrate, look

at the chiral carbon farthest from the carbonyl group: if the hydroxy

group points to right when the carbonyl is ―up‖ it is the D-isomer,and

when the hydroxy group points to the left, it is the L-isomer.

3.4.1. Optical Activity

A levorotatory (–) substance rotates polarized light to the left [e.g.,

l-glucose; (-)-glucose]. A dextrorotatory (+) substance rotates polarized

light to the right [e.g., d-glucose; (+)-glucose]. Molecules which rotate the

plane of polarized light are optically active. Many biologically important

molecules are chiral and optically active. Often, living systems contain

only one of the possible stereochemical forms of acompound, or they are

found in separate systems.

– D-lactic acid is found in living muscles; D-lactic acid is present in

sour milk.

– In some cases, one form of a molecule is beneficial, and the

enantiomer is a poison (e.g., thalidomide).

– Humans can metabolize D-monosaccharides but not L-isomers;

only L-amino acids are used in protein synthesis

3.5 Monosaccharides

3.5.1 Classification of Monosaccharides

The monosaccharides are the simplest of the carbohydrates, since they

contain only one polyhydroxy aldehyde or ketone unit.


Monosaccharides are classified according to the number of carbon

atoms they contain:

No. Of

Carbon

Class Of

monosaccharides

3

4

5

6

triose

tetrose

pentose

hexose

The presence of an aldehyde is indicated by the prefix aldo- and a

ketone by the prefix keto-.

Thus, glucose is an aldohexose (aldehyde + 6 Cs) and ribulose is a

ketopentose (ketone + 5 Cs)


3.5.2 The Family of D-aldoses


3.5.3 The family of D-ketoses

3.5.4 Phisical properties of Monosaccharides

Most monosaccharides have a sweet taste (fructose is sweetest;

73% sweeter than sucrose).

They are solids at room temperature.

They are extremely soluble in water:

– Despite their high molecular weights, the presence of large

numbers of OH groups make the monosaccharides much

more water soluble than most molecules of similar MW.

– Glucose can dissolve in minute amounts of water to make a

syrup (1 g / 1 ml H2O).


Table The Relative sweetness of sugars (sucrose =1.00)

Sugar Relative swetness type

Lactose 0.16 Disaccharides

Galactose 0.22 Monosaccharides

Maltose 0.32 Disaccharides

Xylose 0.40 Monosaccharides

Glucose 0.74 Monosaccharides

Sucrose 1.00 Disaccharides

Invert Sugar 1.30 Mixture of glucose and fructose

Fructose 1.73 monosaccharides

3.5.5 Chemical Properties of Monosaccharides

Monosaccharides do not usually exist in solution in their

―open-chain‖ forms: an alcohol group can add into the carbonyl

group in the same molecule to form a pyranose ring containing a

stable cyclic hemiacetal or hemiketal.


A.Glucose Anomers

In the pyranose form of glucose, carbon-1 is chiral, and thus two

stereoisomers are possible: one in which the OH group points down ( α-

hydroxy group) and one in which the OH group points up ( β-hydroxy

group). These forms are anomers of each other, and carbon-1 is called the

anomeric carbon.

B. Fructose Anomers

Fructose closes on itself to form a furanose ring:


3.5.6 Oxidation of Monosaccharides

Aldehydes and ketones that have an OH group on the carbon

next to the carbonyl group react with a basic solution of Cu2+

(Benedict’s reagent) to form a red-orange precipitate of

copper(I) oxide (Cu2O).

Sugars that undergo this reaction are called reducing sugars.

(All of the monosaccharides are reducing sugars.)

3.5.7 Formation of phosphate Ester

Phosphate esters can form at the 6-carbon of aldohexoses and

aldoketoses.

Phosphate esters of monosaccharides are found in the sugar-

phosphate backbone of DNA and RNA, in ATP, and as

intermediates in the metabolism of carbohydrates in the body.

3.5.8 Glycoside Formation

The hemiacetal and hemiketal forms of monosaccharides

can react with alcohols to form acetal and ketal structures called

glycosides. The new carbon-oxygen bond is called the glycosidic

linkage.

Once the glycoside is formed, the ring can no longer open

up to the open-chain form. Glycosides,therefore, are not reducing

sugars.


3.5.9 Important Monosaccharides

3.6 Disaccharides and Oligosaccharides

Two monosaccharides can be linked together through a glycosidic linkage

to form a disaccharide


3.6.1 Dissacharides

Disaccharides can be hydrolyzed into their mono-saccharide

building blocks by boiling them with dilute acids or reacting

them with the appropriate enzymes.

Disaccharides that contain hemiacetal groups are reducing

sugars.

3.6.2 Important Disaccharides


3.6.3 Oligosaccharides

Oligosaccharides contain from 3 to 10 monosaccharide units.

3.7 Polysaccharides

Polysaccharides contain hundreds or thousands of carbohydrate units.

Polysaccharides are not reducing sugars, since the anomeric carbons are

connected through glycosidic linkages.

We will consider three kinds of polysaccharides, all of which are

polymers of glucose: starch, glycogen, and cellulose.


3.7.1 Starch

Starch is a polymer consisting of D-glucose units. Starches (and

other glucose polymers) are usually insoluble in water because of the high

molecular weight. Because they contain large numbers of OH groups,

some starches can form thick colloidal dispersions when heated in water

(e.g., flour or starch used as a thickening agent in gravies or sauces). There

are two forms of starch: amylose and amylopectin.

A. Starch-Amylose

Amylose consists of long, unbranched chains of glucose

(from 1000 to 2000 molecules) connected by (1 4) glycosidic

linkages.

10%-20% of the starch in plants is in this form. The amylose chain

is flexible enough to allow the molecules to twist into the shape of

a helix. Because it packs more tightly, it is slower to digest than

other starches.

Amylose helices can trap molecules of iodine, forming a

characteristic deep blue-purple color. (Iodine is often used as a test

for the presence of starch.)

B. Starch – Amylopectin

Amylopectin consists of long chains of glucose (up to 105

molecules) connected by (1 4) glycosidic linkages, with (1 6)

branches every 24 to 30 glucose units along the chain. 80%-90% of

the starch in plants is in this form.


3.7.2 Glycogen

Glycogen, also known as animal starch, is structurally similar to

amylopectin, containing both (1 4) glycosidic linkages and (1 6) branch

points. Glycogen is even more highly branched,with branches occurring

every 8 to 12 glucose units. Glycogen is abundant in the liver and muscles;

on hydrolysis it forms D-glucose, which maintains normal blood sugar

level and provides energy.

3.7.3 Cellulose

Cellulose is a polymer consisting of long, unbranched chains of D-

glucose connected by (1 4) glycosidic linkages; it may contain from 300

to 3000 glucose units in one molecule.


Because of the -linkages, cellulose has a different overall shape

from amylose, forming extended straight chains which hydrogen bond to

each other, resulting in a very rigid structure. Cellulose is the most

important structural polysaccharide, and is the single most abundant

organic compound on earth. It is the material in plant cell walls that

provides strength and rigidity; wood is 50% cellulose.

Most animals lack the enzymes needed to digest cellulose, but it

does provide roughage (dietary fiber) to stimulate contraction of the

intestines and help pass food through the digestive system. Some animals,

such as cows, sheep, and horses (ruminants), can process cellulose through

the use of colonies of bacteria in the digestive system which are capable of

breaking cellulose down to glucose; ruminants use a series of stomachs to

allow cellulose a longer time to digest. Some other animals such as rabbits

reprocess digested food to allow more time for the breakdown of cellulose

to occur. Cellulose is also important industrially, from its presence in

wood, paper, cotton, cellophane, rayon, linen, nitrocellulose (guncotton),

photographic films.

3.7.4 Nitrocellulose, Celluloid and Rayon

Guncotton (German, schiessbaumwolle) is cotton which has been

treated with a mixture of nitric and sulfuric acids. It was discovered by


Christian Friedrich Schönbein in 1845, when he used his wife‘s cotton

apron to wipe up a mixture of nitric and sulfuric acids in his kitchen,

which vanished in a flash of flame when it dried out over a fire.

Schönbein attempted to market it as a smokeless powder, but it combusted

so readily it was dangerous to handle. Eventually its use was replaced by

cordite (James Dewar and Frederick Abel, 1891), a mixture of

nitrocellulose, nitroglycerine, and petroleum jelly, which could be

extruded into cords. Celluloid (John Hyatt, 1869) was the first synthetic

plastic, made by combining partially nitrated cellulose with alcohol and

ether and adding camphor to make it softer and more malleable. It was

used in manufacturing synthetic billiard balls (as a replacement for ivory),

photographic film, etc.; it was eventually replaced by less flammable

plastics. Rayon (Louis Marie Chardonnet, 1884) consists of partially

nitrated cellulose mixed with solvents and extruded through small holes,

allowing the solvent to evaporate; rayon was a sensation when introduced

since it was a good substitute for silk, but it was still highly flammable.

3.7.5 Dietary Fiber

Dietary fiber consists of complex carbohydrates, such as cellulose,

and other substances that make up the cell walls and structural parts of

plants. Good sources of dietary fiber include cereal grans, oatmeal, fresh

fruits and vegetables, and grain products. Soluble fiber, such as pectin,

has a lower molecular weight, and is more water soluble. Soluble fiber

traps carbohydrates and slows their digestion and absorption, thereby

leveling out blood sugar levels during the day. Soluble fiber also helps to

lower cholesterol levels by binding dietary cholesterol. Insoluble fiber,

such as cellulose, provides bulk to the stool, which helps the body to

eliminate solid wastes.

3.7.6 Chitin

Chitin is a polymer of N-acetylglucosamine, an amide derivative


of the amino sugar glucosamine, in which one of the OH groups is

converted to an amine (NH2) group. The polymer is extremely strong

because of the increased hydrogen bonding provided by the amide groups.

Chitin is the main component of the cell walls of fungi, the

exoskeletons of arthropods such as crustaceans and insects, and the beaks

of cephalopods. The chitin is often embedded in eithera protein matrix, or

in calcium carbonate crystals. Since this matrix cannot expand easily, it

must be shed by molting as the animal grows.



CHAPTER IV

AMINO ACIDS, PEPTIDES, AND

PROTEINS


CHAPTER IV

AMINO ACIDS, PEPTIDES, AND PROTEINS

4.1 Introduction

Amino acids are molecules containing an amine group (-NH2) and a

carboxylic acid group (-COOH). Naturally occurring amino acids have the

following general formula:

The amino acids are joined by amide linkages called peptide bonds. Chains

with fewer than 50 units are called peptides and the large chains that have

structural or catalytic functions in biology are called proteins.

Here the example of a general protein and its constituent amino acids:

4.2 The Structures and Stereochemistry of -Amino Acids

The term amino acid might mean any molecule containing both an amino

group and any type of acid group; however, the term is almost always used to

refer to an -amino carboxylic acid. The simplest -amino acid is aminoacetic

acid, called glycine. Other common amino acids have side chains (symbolized by

R) substituted on the carbon atom. For example, alanine is the amino acid with a

methyl side chain.


Except for glycine, the -amino acids are all chiral. In all of the chiral

amino acids, the chirality center is the asymmetric carbon atom. Nearly all the

naturally occurring amino acids are found to have the (S) configuration at the

carbon atom. The following pictures shows a Fischer projection of the (S)

enantiomer of alanine, with the carbon chain along the vertical and the carbonyl

carbon at the top. Notice that the configuration of (S)-alanine is similar to that of

L-1-2-glyceraldehyde, with the amino group on the left in the Fischer projection.

Because their stereochemistry is similar to that of L- -glyceraldehyde, the

naturally occurring (S)-amino acids are classified as L-amino acids. Although D-

amino acids are occasionally found in nature, we usually assume the amino acids

under discussion are the common L-amino acids. Remember once again that the

D and L nomenclature, like the R and S designation, gives the configuration

of the asymmetric carbon atom. It does not imply the sign of the optical rotation,

or which must be determined experimentally.

4.2.1 Standard Amino Acids of Proteins

The standard amino acids are 20 common amino acids that are

found in nearly all proteins. The standard amino acids differ from

each other in the structure of the side chains bonded to their


carbon atoms. For additional, all the standard amino acids are L-

amino acids.


4.2.2 Essential Amino Acids

Humans can synthesize about half of the amino acids needed to

make proteins. Other amino acids, called the essential amino acids,

must be provided in the diet. The ten essential amino acids are the

following:

arginine (Arg) valine (Val) methionine (Met)

leucine (Leu) threonine (Thr) phenylalanine (Phe)

histidine (His) isoleucine (Ile)

tryptophan (Trp) lysine (Lys)


4.3 Acid-Base Properties of Amino Acids

Carboxylic acids have acidic properties and react with bases but amines

have basic properties and react with acids. It‘s the reason why amino acids have

both acidic and basic properties.

Amino acids react with strong bases such as sodium hydroxide:

N

H H

C

O

C

H

R

N

H H

C

O

OH

C

H

R + NaOHO Na- + + H2O

In high pH, therefore, amino acids exist in anionic form:

-O

N

H H

C

O

C

H

R

Amino acids react with strong acids such as hydrochloric acid:

OH

N

H H

C

O

OH

C

H

R + HCl

N

H H

C

O

C

H

R

H+Cl-

In low pH, therefore, amino acids exist in cationic form:

OH

N

H H

C

O

C

H

R

H+

Since amino acids have a proton donating group and a proton accepting

group on the same molecule, it follows that each molecule can undergo an acid-

base reaction with itself:

N

H H

C

O

OH

C

H

R

N

H H

C

O

C

H

R

O-

H+


The double ion that is formed as a result of this reaction is called a

Zwitterion. This reaction happens in the solid state. In the solid state, therefore,

amino acids are ionic. This explains why they are solids with a high melting point.

4.4 Isoelectric Points and Electrophoresis

An amino acid bears a positive charge in acidic solution (low pH) and a

negative charge in basic solution (high pH). There must be an intermediate pH

where the amino acid is evenly balanced between the two forms, as the dipolar

zwitterion with a net charge of zero. This pH is called the isoelectric pH or the

isoelectric point.

This following table show the isoelectric points of standard amino acids.

No Standard Amino Acid Isoelectric Points

1 glycine 6.0

2 alanine 6.0

3 valine 6.0

4 leucine 6.0

5 isoleucine 6.0

6 phenylalanine 5.5

7 proline 6.3

8 serine 5.7

9 threonine 5.6

10 tyrosine 5.7

11 cysteine 5.0

12 methionine 5.7

13 asparagine 5.4


14 glutamine 5.7

15 tyroptophan 5.9

16 aspartic acid 2.8

17 glutamic acid 3.2

18 lysine 9.7

19 arginine 10.8

20 histidine 7.6

Electrophoresis uses differences in isoelectric points to separate mixtures

of amino acids. A streak of the amino acid mixture is placed in the center of a

layer of acrylamide gel or a piece of filter paper wet with a buffer solution. Two

electrodes are placed in contact with the edges of the gel or paper, and a potential

of several thousand volts is applied across the electrodes. Positively charged

(cationic) amino acids are attracted to the negative electrode (the cathode), and

negatively charged (anionic) amino acids are attracted to the positive electrode

(the anode). An amino acid at its isoelectric point has no net charge, so it does not

move.


4.5 Synthesis of Amino Acids

4.5.1 Reductive Amination

When an -ketoacid is treated with ammonia, the ketone reacts to

form an imine.

The imine is reduced to an amine by hydrogen and a palladium

catalyst. Under these conditions, the carboxylic acid is not reduced.

4.5.2 Amination of -Halo Acid

The reactions are: Bromination of a carboxylic acid by treatment

with Br2 and PBr3 then use NH3 or phthalimide to displace Br

4.5.3 The Gabriel–Malonic Ester Synthesis

One of the best methods of amino acid synthesis is a combination

of the Gabriel synthesis of amines with the malonic ester synthesis

of carboxylic acids. The conventional malonic ester synthesis

involves alkylation of diethyl malonate, followed by hydrolysis and

decarboxylation to give an alkylated acetic acid.


4.5.4 The Strecker Synthesis

Step 1:

Step 2:


In a separate step, hydrolysis of -amino nitrile gives an -amino

acids.

4.6 Reaction of Amino Acids

4.6.1 Esterification of the Carboxyl Group

Esters of amino acids are often used as protected derivatives to

prevent the carboxyl group from reacting in some undesired

manner. Methyl, ethyl, and benzyl esters are the most common

protecting groups. Aqueous acid hydrolyzes the ester and

regenerates the free amino acid.

4.6.2 Acylation of the Amino Group: Formation of Amides

Just as an alcohol esterifies the carboxyl group of an amino acid,

an acylating agent converts the amino group to an amide.

Acylation of the amino group is often done to protect it from

unwanted nucleophilic reactions.

4.6.3 Reaction with Nynhidrin

Ninhydrin is a common reagent for visualizing spots or bands of

amino acids that have been separated by chromatography or


electrophoresis. When ninhydrin reacts with an amino acid, one of

the products is a deep violet, resonance-stabilized anion called

Ruhemann’s purple. Ninhydrin produces this same purple dye

regardless of the structure of the original amino acid. The side

chain of the amino acid is lost as an aldehyde.

4.7 Structure and Nomenclature of Peptides

4.7.1 Peptides‘ Structure

Having both an amino group and a carboxyl group, an amino acid

is ideally suited to form an amide linkage. Under the proper

conditions, the amino group of one molecule condenses with the

carboxyl group of another. The product is an amide called a

dipeptide because it consists of two amino acids. The amide

linkage between the amino acids is called a peptide bond.

Although it has a special name, a peptide bond is just like other

amide bonds.

A peptide is a compound containing two or more amino acids

linked by amide bondsbetween the amino group of each amino acid

and the carboxyl group of the neighboring amino acid. Each amino

acid unit in the peptide is called a residue. A polypeptide is a

peptide containing many amino acid residues but usually having a

molecular weight of less than about 5000. Proteins contain more

amino acid units, with molecular weights ranging from about 6000


to about 40,000,000. The term oligopeptide is occasionally used

for peptides containing about four to ten amino acid residues.

The end of the peptide with the free amino group is called the N-

terminal end or the N terminus, and the end with the free

carboxyl group is called the C-terminal end or the C terminus.

Peptide structures are generally drawn with the N terminus at the

left and the C terminus at the right, as bradykinin is drawn here:

4.7.2 Peptide Nomenclature

The names of peptides reflect the names of the amino acid residues

involved in the amide linkages, beginning at the N terminus. All

except the last are given the -yl suffix of acyl groups. Example, for

the peptide above (bradykinin), we can write it:

arginyl prolyl prolyl glycyl phenylalanyl seryl prolyl

phenylalanyl arginine

Or to make it more simple, we can write the abbreviated name:

Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg

Or using single letters, we symbolize by:

RPPGFSPFR

4.7.3 Disulfide Linkages

Amide linkages (peptide bonds) form the backbone of the amino

acid chains we call peptides and proteins. A second kind of

covalent bond is possible between any cysteine residues present.

Cysteine residues can form disulfide bridges (also called disulfide


linkages) which can join two chains or link a single chain into a

ring.

Two cysteine residues may form a disulfide bridge within a single

peptide chain, making a ring.

Figure above shows the structure of human oxytocin, a peptide

hormone that causes contraction of uterine smooth muscle and

induces labor. Oxytocin is a nonapeptide with two cysteine

residues (at positions 1 and 6) linking part of the molecule in a

large ring. In drawing the structure of a complicated peptide,

arrows are often used to connect the amino acids, showing the

direction from N terminus to C terminus. Notice that the C

terminus of oxytocin is a primary amide (Gly. NH2) rather than a

free carboxyl group.


4.8 Peptide Structure Determination

4.8.1 Cleavage of Disulfide Linkages

The first step in structure determination is to break all the disulfide

bonds, opening any disulfide-linked rings and separating the

individual peptide chains. The individual peptide chains are then

purified and analyzed separately. Cystine bridges are easily

cleaved by reducing them to the thiol (cysteine) form. These

reduced cysteine residues have a tendency to reoxidize and re-form

disulfide bridges, however. The following figure shows a more

permanent cleavage involves oxidizing the disulfide linkages with

peroxyformic acid.

This oxidation converts the disulfide bridges to sulfonic acid

groups. The oxidized cysteine units are called cysteic acid residues.

4.8.2 Determination of the Amino Acid Composition

Once the disulfide bridges have been broken and the individual

peptide chains have been separated and purified, the structure of

each chain must be determined. The first step is to determine which

amino acids are present and in what proportions. To analyze the


amino acid composition, the peptide chain is completely

hydrolyzed by boiling it for 24 hours in 6 M HCl. The resulting

mixture of amino acids (the hydrolysate) is placed on the column

of an amino acid analyzer, diagrammed in this figure:

4.8.3 Sequencing from the N Terminus: The Edman Degradation

The most efficient method for sequencing peptides is the Edman

degradation. A peptide is treated with phenyl isothiocyanate,

followed by acid hydrolysis. The products are the shortened

peptide chain and a heterocyclic derivative of the N-terminal

amino acid called a phenylthiohydantoin.

1) Step One

Nucleophilic attack by the free amino group on phenyl

isothiocyanate, followed by a proton transfer, gives a

phenylthiourea.


2) Step Two

3) Step Three

The phenylthiohydantoin derivative is identified by

chromatography, by comparing it with phenylthiohydantoin

derivatives of the standard amino acids. This gives the identity of

the original N-terminal amino acid. The rest of the peptide is

cleaved intact, and further Edman degradations are used to identify

additional amino acids in the chain. This process is well suited to

automation, and several types of automatic sequencers have been

developed.

In theory, Edman degradations could sequence a peptide of any

length. In practice, however, the repeated cycles of degradation

cause some internal hydrolysis of the peptide, with loss of sample

and accumulation of by-products. After about 30 cycles of

degradation, further accurate analysis becomes impossible. A small

peptide such as bradykinin can be completely determined by

Edman degradation, but larger proteins must be broken into smaller

fragments before they can be completely sequenced.



CHAPTER V

LIPIDS AND FAT


CHAPTER V

LIPIDS AND FAT

5.1 Introduction

Lipids are naturally occurring organic molecules that have limited

solubility in water and can be isolated from organisms by extraction with nonpolar

organic solvents. Fats, oils, waxes, many vitamins and hormones, and most

nonprotein cell-membrane components are examples. Note that this definition

differs from the sort used for carbohydrates and proteins in that lipids are defined

by a physical property (solubility) rather than by structure. Of the many kinds of

lipids, we‘ll be concerned in this chapter only with a few: triacylglycerols,

eicosanoids, terpenoids, and steroids.

Lipids are classified into two broad types: those like fats and waxes,

whichcontain ester linkages and can be hydrolyzed, and those like cholesterol and

other steroids, which don‘t have ester linkages and can‘t be hydrolyzed.

5.2 Waxes, Fats, and Oils

Waxes are mixtures of esters of long-chain carboxylic acids with long-

chainalcohols. The carboxylic acid usually has an even number of carbons from16

through 36, while the alcohol has an even number of carbons from24 through 36.

One of the major components of beeswax, for instance, is

triacontylhexadecanoate, the ester of the C30 alcohol 1-triacontanol and theC16

acid hexadecanoic acid. The waxy protective coatings on most fruits, berries,

leaves, and animal furs have similar structures.


Animal fats and vegetable oils are the most widely occurring lipids.

Althoughthey appear different—animal fats like butter and lard are solids,

whereas vegetable oils like corn and peanut oil are liquid—their structures are

closely related. Chemically, fats and oils are triglycerides, or triacylglycerols—

triesters of glycerol with three long-chain carboxylic acids called fatty acids.

Animals use fats for long-term energy storage because they are much less highly

oxidized than carbohydrates and provide about six times as much energy as an

equal weight of stored, hydrated glycogen.

Hydrolysis of a fat or oil with aqueous NaOH yields glycerol and three

fatty acids. The fatty acids are generally unbranched and contain an even number

ofcarbon atoms between 12 and 20. If double bonds are present, they have largely,

although not entirely, Z, or cis, geometry. The three fatty acids of a specific

triacylglycerol molecule need not be the same, and the fat or oil from a given

source is likely to be a complex mixture of many different triacylglycerols. Table

27.1 lists some of the commonly occurring fatty acids, and Table 27.2 lists the

approximate composition of fats and oils from different sources.

More than 100 different fatty acids are known, and about 40 occur

widely.Palmitic acid (C16) and stearic acid (C18) are the most abundant saturated


fatty acids; oleic and linoleic acids (both C18) are the most abundant unsaturated

ones. Oleic acid is monounsaturated because it has only one double bond, whereas

linoleic, linolenic, and arachidonic acids are polyunsaturated fatty acids because

they have more than one double bond. Linoleic and linolenic acids occur in cream

and are essential in the human diet; infants grow poorly and develop skin lesions

if fed a diet of nonfat milk for prolonged periods. Linolenic acid, in particular, is

an example of an omega-3 fatty acid, which has been found to lower blood

triglyceride levels and reduce the risk of heart attack.

The data in the following table show that unsaturated fatty acids generally

have lower melting points than their saturated counterparts, a trend that is also

true for triacylglycerols. Since vegetable oils generally have a higher proportion

of unsaturated to saturated fatty acids than animal fats, they have lower melting

points. The difference is a consequence of structure. Saturated fats have a uniform

shape that allows them to pack together efficiently in a crystal lattice. In

unsaturated vegetable oils, however, the C5C bonds introduce bends and kinks

into the hydrocarbon chains, making crystal formation more difficult. The more

double bonds there are, the harder it is for the molecules to crystallize and the

lower the melting point of the oil. The C5C bonds in vegetable oils can be reduced

by catalytic hydrogenation, typically carried out at high temperature using a nickel

catalyst, to produce saturated solid or semisolid fats. Margarine and shortening are

produced by hydrogenating soybean, peanut, or cottonseed oil until the proper

consistency is obtained. Unfortunately, the hydrogenation reaction is accompanied

by some cis–trans isomerization of the double bonds that remain, producing fats

with about 10% to 15% trans unsaturated fatty acids. Dietary intake of trans fatty

acids increases cholesterol levels in the blood, thereby increasing the risk of heart

problems. The conversion of linoleic acid into elaidic acid is an example.


5.3 Soap

Soap has been known since at least 600 bc, when the Phoenicians prepared

a curdy material by boiling goat fat with extracts of wood ash. The cleansing

properties of soap weren‘t generally recognized, however, and the use of soap did

not become widespread until the 18th century. Chemically, soap is a mixture of

the sodium or potassium salts of the long-chain fatty acids produced by hydrolysis

(saponification) of animal fat with alkali. Wood ash was used as a source of alkali

until the early 1800s, when the development of the LeBlanc process for making

Na2CO3 by heating sodium sulfate with limestone became available.

Crude soap curds contain glycerol and excess alkali as well as soap but

can bepurified by boiling with water and adding NaCl or KCl to precipitate the

pure carboxylate salts. The smooth soap that precipitates is dried, perfumed, and

pressed into bars for household use. Dyes are added to make colored soaps,


antiseptics are added for medicated soaps, pumice is added for scouring soaps,

and air is blown in for soaps that float. Regardless of these extra treatments and

regardless of price, though, all soaps are basically the same.

Soaps act as cleansers because the two ends of a soap molecule are so

different.The carboxylate end of the long-chain molecule is ionic and therefore

hydrophilic (Section 2.12), or attracted to water. The long hydrocarbon portion of

the molecule, however, is nonpolar and hydrophobic, avoiding water and

therefore more soluble in oils. The net effect of these two opposing tendencies is

that soaps are attracted to both oils and water and are therefore useful as cleansers.

When soaps are dispersed in water, the long hydrocarbon tails

clustertogether on the inside of a tangled, hydrophobic ball, while the ionic heads

on the surface of the cluster stick out into the water layer. These spherical clusters,

called micelles, are shown schematically in the figure below. Grease and oil

droplets are solubilized in water when they are coated by the nonpolar,

hydrophobic tails of soap molecules in the center of micelles. Once solubilized,

the grease and dirt can be rinsed away.

As useful as they are, soaps also have some drawbacks. In hard water,

whichcontains metal ions, soluble sodium carboxylates are converted into

insoluble magnesium and calcium salts, leaving the familiar ring of scum around

bathtubs and the gray tinge on white clothes. Chemists have circumvented these

problems by synthesizing a class of synthetic detergents based on salts of

longchain alkylbenzenesulfonic acids. The principle of synthetic detergents is the


same as that of soaps: the alkylbenzene end of the molecule is attracted to grease,

while the anionic sulfonate end is attracted to water. Unlike soaps, though,

sulfonate detergents don‘t form insoluble metal salts in hard water and don‘t leave

an unpleasant scum.

5.4 Phospholipids

Just as waxes, fats, and oils are esters of carboxylic acids, phospholipids

areesters of phosphoric acid, H3PO4.

Phospholipids are of two general kinds: glycerophospholipids and

sphingomyelins.Glycerophospholipids are based on phosphatidic acid, which

contains aglycerolbackbone linked by ester bonds to two fatty acids and one

phosphoric acid. Although the fatty-acid residues can be any of the C12–C20 units

typicallypresentin fats, the acyl group at C1 is usually saturated and the one at C2

is usuallyunsaturated. The phosphate group at C3 is also bonded to an amino

alcohol suchas choline [HOCH2CH2N(CH3)3]1, ethanolamine (HOCH2CH2NH2),

or serine[HOCH2CH(NH2)CO2H]. The compounds are chiral and have an l, or R,

configurationat C2.


Sphingomyelins are the second major group of phospholipids. These

compoundshave sphingosine or a related dihydroxyamine as their backbone

andare particularly abundant in brain and nerve tissue, where they are a major

constituent of the coating around nerve fibers.

Phospholipids are found widely in both plant and animal tissues and

makeup approximately 50% to 60% of cell membranes. Because they are like

soaps in having a long, nonpolar hydrocarbon tail bound to a polar ionic head,

phospholipids in the cell membrane organize into a lipid bilayer about 5.0 nm (50

Å) thick.


As shown in the following figure, the nonpolar tails aggregate in the center

of the bilayer in much the same way that soap tails aggregate in the center of a

micelle. This bilayer serves as an effective barrier to the passage of water, ions,

and other components into and out of cells.

5.5 Fatty Acid

Fatty acids, both free and as part of complex lipids, play anumber of key

roles in metabolism – major metabolic fuel (storage and transport of energy), as

essential components of all membranes, and as gene regulators (Table 1). In

addition, dietary lipids provide polyunsaturated fatty acids (PUFAs) that are

precursors of powerful locally acting

metabolites, i.e. the eicosanoids. As part of complex lipids, fatty acids are also

important for thermal and electrical insulation, and for mechanical protection.

Moreover, free fatty acids and their salts may function as detergents and soaps

owing to their amphipathic properties and the formation of micelles.

5.6 Overview of Fatty Acid Structure

Fatty acids are carbon chains with a methyl group at oneend of the

molecule (designated omega, o) and a carboxyl group at the other end (Figure 1).

The carbon atom next to the carboxyl group is called the a carbon, and

thesubsequent one the b carbon. The letter n is also often usedinstead of the

Greekoto indicate the position of the double bond closest to the methyl end. The

systematic nomenclature for fatty acids may also indicate the location of double


bonds with reference to the carboxyl group (D). Figure 2 outlines the structures of

different types of naturally occurring fatty acids.

Figure 1 Nomenclature for fatty acids.

Fatty acids may be namedaccording to systematic or trivial nomenclature.

One systematic way to describe fatty acids is related to the methyl (o) end. This is

used to describe the position of double bonds from the end of the fatty acid. The

letter n is also often used to describe the o position of double bonds.

5.7 Saturated fatty acids

Saturated fatty acids are ‗filled‘ (saturated) with hydrogen.Most saturated

fatty acids are straight hydrocarbon chains with an even number of carbon atoms.

The most common fatty acids contain 12–22 carbon atoms.

5.8 Unsaturated fatty acids

Monounsaturated fatty acids have one carbon–carbondouble bond, which

can occur in different positions. The most common monoenes have a chain length

of 16–22 and a double bond with the cis configuration. This means that the

hydrogen atoms on either side of the double bond are oriented in the same

direction. Trans isomers may be produced


during industrial processing (hydrogenation) of unsaturated oils and in the

gastrointestinal tract of ruminants. The presence of a double bond causes

restriction in the mobility of the acyl chain at that point. The cis configuration

gives a kink in the molecular shape and cis fatty acids are thermodynamically less

stable than the trans forms. The cis fatty acids have lower melting points than the

trans fatty acids or their saturated counterparts.

In polyunsaturated fatty acids (PUFAs) the first double bond may be found

between the third and the fourth carbon atom from the o carbon; these are called

ω-3 fatty acids. If the first double bond is between the sixth and seventh carbon

atom, then they are called o-6 fatty acids. The double bonds in PUFAs are

separated from each other by a methylene grouping.

Figure 2 Structure of different unbranched fatty acids with a methyl end

and a carboxyl (acidic) end.

Stearic acid is a trivial name for a saturated fatty acidwith 18 carbon atoms

and no double bonds (18:0). Oleic acid has 18 carbon atoms and one double bond

in the o-9 position (18:1 o-9), whereaseicosapentaenoic acid (EPA), with multiple

double bonds, is represented as 20:5 ω-3. This numerical scheme is the systematic

nomenclature most commonly used. It is also possible to describe fatty acids

systematically in relation to the acidic end of the fatty acids; symbolized D (Greek


delta) and numbered 1. All unsaturated fatty acids are shown with cis

configuration of the double bonds. DHA, docosahexaenoic acid.

PUFAs, which are produced only by plants and phytoplankton,are

essential to all higher organisms, including mammals and fish. ω-3 and o-6 fatty

acids cannot be interconverted, and both are essential nutrients. PUFAs are further

metabolized in the body by the addition of carbon atoms and by desaturation

(extraction of hydrogen). Mammals have desaturases that are capable of removing

hydrogens only from carbon atoms between an existing double bond and the

carboxyl group (Figure 3). b-oxidation of fatty acids may take place in either

mitochondria or peroxisomes.

Figure

3 Synthesis of ω-3 and o-6 polyunsaturated fatty acids (PUFAs).

There are two families of essential fatty acids that are metabolized in the body as

shown in this figure. Retroconversion, e.g. DHA!EPA also takes place.


5.9 Major Fatty Acids

Fatty acids represent 30–35% of total energy intake inmany industrial

countries and the most important dietary sources of fatty acids are vegetable oils,

dairy products, meat products, grain and fatty fish or fish oils.

The most common saturated fatty acid in animals, plants and

microorganisms is palmitic acid (16:0). Stearic acid (18:0) is a major fatty acid in

animals and some fungi, and a minor component in most plants. Myristic acid

(14:0) has a widespread occurrence, occasionally as a major component. Shorter-

chain saturated acids with 8–10 carbonatoms are found in milk and coconut

triacylglycerols.

Oleic acid (18:1 o-9) is the most common monoenoic fatty acid in plants

and animals. It is also found in microorganisms. Palmitoleic acid (16:1o-7) also

occurs widely inanimals, plants and microorganisms, and is a major component in

some seed oils.

Linoleic acid (18:2 o-6) is a major fatty acid in plantlipids. In animals it is

derived mainly from dietary plant oils. Arachidonic acid (20:4 o-6) is a major

component ofmembrane phospholipids throughout the animal kingdom,but very

little is found in the diet. a-Linolenic acid (18:3 ω-3) is found in higher plants

(soyabean oil and rape seed oils) and algae. Eicosapentaenoic acid (EPA; 20:5ω-

3) and docosahexaenoic acid (DHA; 22:6ω-3) are major fatty acids of marine

algae, fatty fish and fish oils; for example, DHA is found in high concentrations,

especially in phospholipids in the brain, retina and testes.

5.10 Metabolism of Fatty Acids

An adult consumes approximately 85 g of fat daily, most ofit as

triacylglycerols. During digestion, free fatty acids(FFA) and monoacylglycerols

are released and absorbed in the small intestine. In the intestinal mucosa cells,

FFA are re-esterified to triacylglycerols, which are transported via lymphatic

vessels to the circulation as part of chylomicrons. In the circulation, fatty acids are

transported bound to albumin or as part of lipoproteins.


FFA are taken up into cells mainly by protein transportersin the plasma

membrane and are transported intracellularly via fatty acid-binding proteins

(FABP) (Figure 4). FFA are then activated (acyl-CoA) before they are shuttled via

acyl-CoA-binding protein (ACBP) to mitochondria or peroxisomes for b-

oxidation (and formation of energy asATPand heat) or to endoplasmic reticulum

for esterification to different classes of lipid. Acyl-CoA or certain FFA may bind

to transcription factors that regulate gene expression or may be converted to signal

molecules (eicosanoids). Glucose may be transformed to fatty acids (lipogenesis)

if there is a surplus of glucose/energy in the cells.

5.11 Physical Properties of Fatty Acids

Fatty acids are poorly soluble in water in their undissociated(acidic) form,

whereas they are relatively hydrophilicas potassium or sodium salts. Thus, the

actual water solubility, particularly of longer-chain acids, is often very difficult to

determine since it is markedly influenced by pH, and also because fatty acids have

a tendency to associate, leading to the formation of monolayers or micelles. The

formation of micelles in aqueous solutions of lipids is associated with very rapid

changes in physical properties over a limited range of concentration. The point of

change is known as the critical micellar concentration (CMC), and exemplifies the

tendency of lipids to associate rather than remain as single molecules. The CMC

is not a fixed value but represents a small concentration range that is markedly

affected by the presence of other ions and by temperature.

Fatty acids are easily extracted with nonpolar solventsfrom solutions or

suspensions by lowering the pH to form the uncharged carboxyl group. In contrast,

raising the pH increases water solubility through the formation of alkali metal

salts, which are familiar as soaps. Soaps have important properties as association

colloids and are surfaceactive agents.

The influence of a fatty acid‘s structure on its meltingpoint is such that

branched chains and cis double bonds will lower the melting point compared with

that of equivalent saturated chains. In addition, the melting point of a fatty acid


depends on whether the chain is even- or oddnumbered; the latter have higher

melting points.

Saturated fatty acids are very stable, whereas unsaturatedacids are

susceptible to oxidation: the more doublebonds, the greater the susceptibility.

Thus, unsaturatedfatty acids should be handled under an atmosphere of inert gas

and kept away from oxidants and compounds giving rise to formation of free

radicals. Antioxidants may be very important in the prevention of potentially

harmful attacks on acyl chains in vivo (see later).

5.12 Mechanisms of action

The different mechanisms by which fatty acids can influencebiological

systems are outlined in Figure 5.

Figure 5 Mechanisms of action for fatty acids.

Thromboxanes formed inblood platelets promote aggregation (clumping) of blood

platelets. Leukotrienes in white blood cells act as chemotactic agents (attracting

other white blood cells).


5.13 Eicosanoids

Eikosa means ‗twenty‘ in Greek, and denotes the number ofcarbon atoms

in the PUFAs that act as precursors of eicosanoids (Figure 6). These signalling

molecules are called leukotrienes, prostaglandins, thromboxanes, prostacyclins,

lipoxins and hydroperoxy fatty acids. Eicosanoids are important for several

cellular functions such as platelet aggregability (ability to clump and fuse),

chemotaxis (movement of blood cells) and cell growth. Eicosanoids are rapidly

produced and degraded in cells where they execute their effects. Different cell

types produce various types of eicosanoids with different biological effects. For

example, platelets mostly make thromboxanes, whereas endothelial cells mainly

produce prostacyclins. Eicosanoids from the ω-3 PUFAs are usually less potent

than eicosanoids derived from the o-6 fatty acids (Figure 7).

5.14 Substrate specificity

Fatty acids have different abilities to interact with enzymesor receptors,

depending on their structure. For example,EPA is a poorer substrate than all other

fatty acids for esterification to cholesterol and diacylglycerol. Some ω-3fatty acids

are preferred substrates for certain desaturases.

The preferential incorporation of ω-3 fatty acids into some phospholipids

occurs because ω-3 fatty acids are preferred substrates for the enzymes

responsible for phospholipid synthesis. These examples of altered substrate

specificity of ω-3 PUFA for certain enzymes illustrate why EPA and DHA are

mostly found in certain phospholipids.

5.15 Membrane fluidity

When large amounts of vhery long-chain ω-3 fatty acidsare ingested, there

is a high incorporation of EPA and DHA into membrane

phospholipids.Anincreased amountof ω-3 PUFA may change the physical

characteristics of the membranes. Altered fluidity may lead to changes of

membrane protein functions. The very large amount of DHA in

phosphatidylethanolamine and phosphatidylserine in certain areas of the retinal


rod outer segments is probably crucial for the function of membrane

phospholipids in light transduction, because these lipids are located close to the

rhodopsin molecules. It has been shown that the flexibility of membranes from

blood cells is increased in animals fed fish oil, and this might be important for

themicrocirculation. Increased incorporation of very longchain ω-3 PUFAs into

plasma lipoproteins changes the physical properties of low-density lipoproteins

(LDL), lowering the melting point of core cholesteryl esters.


5.16 Requirements for and Uses of Fatty

5.16.1 Acids in Human Nutrition

Although data on the required intake of essential fatty acidsare relatively

few, the adequate intakes of linoleic acid(18:2o-6) and a-linolenic acid (18:3o-3)

should be2% and 1% of total energy, respectively. Present evidence suggests that

0.2–0.3% of the energy should be derived from preformed very long-chain o-3

PUFAs (EPA and DHA) to avoid signs or symptoms of deficiency. This

corresponds to approximately 0.5 g of these o-3 fatty acids per day. It should be

stressed that this is the minimum intake to avoid clinical symptoms of deficiency

(Table 4). It has been suggested that the ratio between o-3 and o-6 fatty acids

should be 1:4 as compared to 1:10 in modern dietary habits, but the experimental

basis for this suggestion is rather weak.

From many epidemiological and experimental studiesthere is relatively

strong evidence that there are significant beneficial effects of additional intake of

PUFA in general and very long-chain o-3 fatty acids (EPA and DHA) in particular.

It is possible that the beneficial effects may be obtained at intakes as low as one or

two fish meals weekly, but many of the measurable effects on risk factors are

observed at intakes of 1–2 g day21 of very long-chain o-3 PUFA. If 1–2 g day21

of EPA and DHA is consumed in combination with proper amounts of fruits and

vegetables, and limited amounts of saturated and trans fatty acids, most people

will benefit with better health for a longer time

5.16.2 Uses of Fatty Acids in the Pharmaceutical/Personal Hygiene

Fatty acids are widely used as inactive ingredients (excipients)in drug

preparations, and the use of lipid formulations as the carriers for active substances

is growing rapidly. The largest amount of lipids used in pharmaceuticals is in the

production of fat emulsions, mainly for clinical nutrition but also as drug vehicles.

Another lipid formulation is the liposome, which is a lipid carrier particle for

other active ingredients. In addition, there has been an increase in the use of lipids

as formulation ingredients owing to their functional effects (fatty acids have

several biological effects) and their biocompatible nature. For instance, very long-


chaino-3PUFAmay be used as a drug to reduce plasma triacylglycerol

concentration and to reduce inflammation among patients with rheumatoid

arthritis. Moreover, fatty acids themselves or as part of complexlipids, are

frequently used in cosmetics such as soaps, fat emulsions and liposomes.



CHAPTER VI

TERPENES


CHAPTER VI

TERPENE

6.1 Introduction

There are many different classes of naturally occurring compounds.

Terpenoids also form a group of naturally occurring compounds majority of

which occur in plants, a few of them have also been obtained from other sources.

The term terpenes originates from turpentine (lat. balsamum terebinthinae).

Turpentine, the so-called "resin of pine trees", is the viscous pleasantly smelling

balsam which flows upon cutting or carving the bark and the new wood of several

pine tree species (Pinaceae). Turpentine contains the "resin acids" and some

hydrocarbons, which were originally referred to as terpenes. Traditionally, all

natural compounds built up from isoprene subunits and for the most part

originating from plants are denoted as terpenes.

Conifer wood, balm trees, citrus fruits, coriander, eucalyptus, lavender,

lemon grass, lilies, carnation, caraway, peppermint species, roses, rosemary, sage,

thyme violet and many other plants or parts of those (roots, rhizomes, stems,

leaves, blossoms, fruits, seed) are well known to smell pleasantly, to taste spicy,

or to exhibit specific pharmacological activities. Terpenes predominantly shape

these properties. In order to enrich terpenes, the plants are carved, e.g. for the

production of incense or myrrh from balm trees; usually, however, terpenes are

extracted or steam distilled, e.g. for the recovery of the precious oil of the

blossoms of specific fragrant roses. These extracts and steam distillates, known as

ethereal or essential oils ("essence absolue") are used to create fine perfumes, to

refine the flavor and the aroma of food and drinks and to produce medicines of

plant origin (phytopharmaca).

The biological and ecochemical functions of terpenes have not yet been

fully investigated. Many plants produce volatile terpenes in order to attract

specific insects for pollination or otherwise to expel certain animals using these

plants as food. Less volatile but strongly bitter-tasting or toxic terpenes also

protect some plants from being eaten by animals (antifeedants). Last, but not least,


terpenes play an important role as signal compounds and growth regulators

(phytohormones) of plants, as shown by preliminary investigations. Many insects

metabolize terpenes they have received with their plant food to growth hormones

and pheromones. Pheromones are luring and signal compounds (sociohormones)

that insects and other organisms excrete in order to communicate with others like

them, e.g. to warn (alarm pheromones), to mark food resources and their location

(trace pheromones), as well of assembly places (aggregation pheromones) and to

attract sexual partners for copulation (sexual pheromones). Harmless to the

environment, pheromones may replace conventional insecticides to trap harmful

and damaging insects such as bark beetles.

The term ‗terpene‘ was originally employed to describe a mixture of

isomeric hydrocarbons of the molecular formula C10H16 occurring in the essential

oils obtained from sap and tissue of plants, and trees. But there is a tendency to

use more general term ‗terpenoids‘ which include hydrocarbons and their

oxygenated derivatives. However the term terpene is being used these days by

some authors to represent terpenoids.

By the modern definition: ―Terpenoids are the hydrocarbons of plant

origin of the general formula (C5H8)n as well as their oxygenated, hydrogenated

and dehydrogenated derivatives.‖

6.2 General Structure

6.2.1 The Isoprene Rule

About 30 000 terpenes are known at present in the literature. Their

basic structure follows a general principle: 2-Methylbutane residues, less

precisely but usually also referred to as isoprene units, (C5)n , build up the

carbon skeleton of terpenes; this is the isoprene rule found by RUZICKA

and WALLACH (Table 1). Therefore, terpenes are also denoted as

isoprenoids. In nature, terpenes occur predominantly as hydrocarbons,

alcohols and their glycosides, ethers, aldehydes, ketones, carboxylic acids

and esters.


Depending on the number of 2-methylbutane (isoprene) subunits

one differentiates between hemi- (C5), mono- (C10), sesqui- (C15), di- (C20),

sester- (C25), tri- (C30), tetraterpenes (C40) and polyterpenes (C5)n with n >

8 according to Table 1.

The isopropyl part of 2-methylbutane is defined as the head, and

the ethyl residue as the tail (Table 1). In mono-, sesqui-, di- and

sesterterpenes the isoprene units are linked to each other from head-to-tail;

tri- and tetraterpenes contain one tail-to-tail connection in the center.

6.2.2 Spescial Isoprene Rule

Ingold suggested that isoprene units are joined in the terpenoid via

‗head to tail‘ fashion. Special isoprene rule states that the terpenoid


molecule are constructed of two or more isoprene units joined in a ‗head to

tail‘ fashion. Head

Tail

But this rule can only be used as guiding principle and not as a

fixed rule. For example carotenoids are joined tail to tail at their central

and there are also some terpenoids whose carbon content is not a multiple

of five.

In applying isoprene rule we look only for the skeletal unit of

carbon. The carbon skeletons of open chain monotrpenoids and sesqui

terpenoids are,

Head head tail

Tail head

Tail Tail tail

Head head

Example:

6.3 Biosynthesis

Acetyl-coenzyme A, also known as activated acetic acid, is the biogenetic

precursor of terpenes (Figure 1). Similar to the CLAISEN condensation, two

equivalents of acetyl-CoA couple to acetoacetyl-CoA, which represents a

biological analogue of acetoacetate. Following the pattern of an aldol reaction,


acetoacetyl-CoA reacts with another equivalent of acetyl-CoA as a carbon

nucleophile to give β-hydroxy-β- methylglutaryl-CoA, followed by an enzymatic

reduction with dihydronicotinamide adenine dinucleotide (NADPH + H+) in the

presence of water, affording (R)- mevalonic acid. Phosphorylation of mevalonic

acid by adenosine triphosphate (ATP) via the monophosphate provides the

diphosphate of mevalonic acid which is decarboxylated and dehydrated to

isopentenylpyrophosphate (isopentenyldiphosphate, IPP). The latter isomerizes in

the presence of an isomerase containing SH groups to γ, γ-

dimethylallylpyrophosphate. The electrophilic allylic CH2 group of γ,γ-

dimethylallylpyrophosphate and the nucleophilic methylene group of

isopentenylpyrophosphate connect to geranylpyrophosphate as monoterpene.

Subsequent reaction of geranyldiphosphate with one equivalent of

isopentenyldiphosphate yields farnesyldiphosphate as a sesquiterpene (Fig.1).


However, failing incoporations of 13C-labeled acetate and successful ones

of 13Clabeled glycerol as well as pyruvate in hopanes and ubiquinones showed

isopentenyldiphosphate (IPP) to originate not only from the acetate mevalonate

pathway, but also from activated acetaldehyde (C2, by reaction of pyruvate and

thiamine diphosphate) and glyceraldehyde-3-phosphate (C3). In this way, 1-

deoxypentulose-5-phosphate is generated as the first unbranched C5 precursor of

IPP.


Geranylgeranylpyrophosphate as a diterpene (C20) emerges from the

attachment of isopentenylpyrophosphate with its nucleophilic head to

farnesylpyrophosphate with its electrophilic tail (Fig. 2). The formation of

sesterterpenes (C25) involves an additional head-to-tail linkage of

isopentenylpyrophosphate (C5) with geranylgeranylpyrophosphate (C20). A tail-to-

tail connection of two equivalents of farnesylpyrophosphate leads to squalene as a

triterpene (C30, Fig. 2). Similarly, tetraterpenes such as the carotenoid 16-trans-


phytoene originate from tail-to-tail dimerization of geranylgeranylpyrophosphate

(Fig. 2).

The biogeneses of cyclic and polycyclic terpenes 9,10 are usually assumed

to involve intermediate carbenium ions, but evidence for this in vivo was given

only in some specific cases. In the simple case of monocyclic monoterpenes such

as limonene the allylic cation remaining after separation of the pyrophosphate

anion cyclizes to a cyclohexyl cation which is deprotonated to (R)- or (S)-

limonene.

The non-classical version of the intermediate carbenium ion (also referred

to as a carbonium ion) resulting upon dissociation of the pyrophosphate anion

from farnesylpyrophosphateexplains the cyclization to several cyclic carbenium

ions 8, as demonstrated for some sesquiterpenes (Fig. 3). Additional diversity

arises from 1,2- hydride and 1,2-alkyl shifts (WAGNER-MEERWEIN

rearrangements) and sigmatropic reactions (COPE rearrangements) on the one

hand, and on the other hand from the formation of diastereomers and enantiomers

provided that the cyclizations generate new asymmetric carbon atoms (Fig. 3).

Thus, the non-classical carbenium ion arising from dissociation of the

diphosphate anion from farnesylpyrophosphate permits formation of the

monoyclic sesquiterpenes humulatriene and germacratriene after deprotonation

(Fig.3). A COPE rearrangement of germacratriene leads to elematriene.

Protonation of germacratriene following MARKOWNIKOW orientation initially

provides the higher alkylated and therefore more stable carbenium ion which

undergoes 1,2-hydride shifts resultingin bicyclic carbenium ions with an

eudesmane or guaiane skeleton. Subsequent deprotonations yield diastereomeric


eudesmadienes and guajadienes. Finally, eudesmanes may rearrange to

eremophilanes involving 1,2-methyl shifts (Fig. 3).

A simliar cyclization generates the 14-membered skeleton of cembrane

from which other polycyclic diterpenes are derived. 3,7,11,15-Cembratetraene,

better known as cembrene A, emerges directly from geranylgeranylpyrophosphate

(Fig. 2) involving the 1,14-cyclization of the resulting allylic cation.

The biogenesis of pimarane, the parent compound of many polycyclic

diterpenes, is assumed to arise from iso-geranylgeranylpyrophosphate. After


dissociation of the pyrophosphate anion, the remaining acyclic allylic cation

undergoes a 1,3- sigmatropic hydrogen shift and thereby cyclizes to a monocyclic

carbenium ion which, itself, isomerizes to the ionic precursor of the pimarane

skeleton.

2,3-Epoxysqualene has been shown by isotope labeling to be the biogenetic

precursor of tetracyclic triterpenes with perhydrocyclopenta[a]phenanthrene as


the basic skeleton (also referred to as gonane or sterane). Steroids are derived

from these tetracyclic triterpenes. These include cholestanes (C27), pregnanes

(C21), androstanes (C19) with trans fusion of the rings A and B (5α), estranes

(C18) with a benzenoid ring A (estra-1,3,5-triene; Fig. 4) as well as cholic acid

and its derivatives (C24) with cis fusion of the rings A and B (5β). The biogenetic

origins of tetracyclic triterpenes and steroids are summarized in Table 2.



CHAPTER VII

ALKALOIDS


CHAPTER VII

ALKALOIDS

7.1 Introduction

Alkaloids are a class of "secondary" plant metabolites that traditionally

have been classified as basic compounds derived from amino acids that contain

one or more heterocyclic nitrogen atoms. Although this definition holds for most

known alkaloids recently any N containing secondary compound is considered an

alkaloid if it cannot readily be classified otherwise -- i.e. not an amine, cyanogenic

glycoside, glucosinolate, etc. The word alkaloid is derived from the Arabic al-

qali, a plant from which soda was 1st isolated. The original definition for

alkaloids is pharmacologically active, N-containing basic compounds of plant

origin.

Humans have been using alkaloids in the form of plant extracts for poisons,

narcotics, stimulants and medicines for at least the past several thousand

years. Morphine was isolated from poppy seeds in 1806 although its structure

wasn't known until 1952. The antimalarial properties of quinine, an alkaloid

extracted from the bark of Cinchona spp. trees indigenous to the high eastern

slopes of the Andes Mountains have long been known.

More than 10,000 alkaloids of widely differing structures are now known

from the small fraction of the planet's plants that have so far been

examined. Most medicinal compounds have traditionally been extracted from

plant tissues although modern synthetic chemistry has attempted to synthesize all

important medicinal compounds. Still ~25% of compounds used in western

medicine are plant-derived and most are still derived from plants in traditional

medicine. Recent advances in plant genetic engineering are likely to make plants

the preferred source of many medicinal compounds again in the future with

"Pharming" developments.

Like many secondary metabolites, plants apparently synthesize alkaloids

for defensive purposes. Nicotine and derivatives are among the earliest known

and most potent insecticides. Some plant had already evolved the ability to


synthesize alkaloids at the beginning of angiosperm evolution ~200 million years

ago. Like most natural product chemistry, the accumulation of alkaloids tends to

run in families. The plant families with the highest alkaloid levels are the

Papaveraceae, Berberidaceae, Leguminosae, Boraginaceae, Apocynaceae,

Asclepiadaceae, Liliaceae, Gnetaceae, Ranunculaceae, Rubiaceae, Solanaceae and

Rutaceae.

Most alkaloid skeletons are derived from amino acids with many different

amino acids being alkaloid biosynthetic precursors. Some alkaloid carbon

skeletons are derived from other groups of molecules such as the steroid alkaloids

with the nitrogen from glutamine or another N donor being added in later

biosynthetic steps. Alkaloids are classified based on the structure of the N-

heterocycle.

7.2 Examples of Important Representative Alkaloids and Outline of their

Biosynthetic Origins

Cocaine is an example of a tropane-type of pyrrolidine alkaloid in which

the N-heterocycle is derived from L-ornithine, an amino acid derived from

glutamate. Tropane has a distinctive 3 dimensional structure:

The piperidine group of alkaloids is derived from L-lysine. The heterocycle

structure is:

The pyridine alkaloids are derived from aspartate or phenylalanine. Nicotine is

an example of a pyridine alkaloid.


Quinoline alkaloids such as quinine can be derived from L-tryptophan:

Isoquinoline alkaloids, which have an N-heterocycle isomeric to quinoline, can

be derived from tyrosine. Morphine is an isoquinoline alkaloid:

Indole alkaloids contain an indole ring derived from L-tryptophan. The active

principle of the ergot fungus, agroclavine, is an indole alkaloid.

Purine alkaloids, such as caffeine and theobromine, are purine derivatives so

they are derived from aspartate, glycine and glutamine. Caffeine is a central

stimulant, it can be used clinically as a cardiac and respiratory stimulant and as a

diuretic. Being a DNA base analog, it also has mutagenic


properties. Theobromine, the principal alkaloid of cacao beans (1-3% of seed

weight), is a diuretic, smooth muscle relaxant, cardiac stimulant and vasodilator

like the atropine-containing extract from Egyptian henbane used by

Cleopatra. These are among the simplest alkaloids:

Taxol (paclitaxel), an effective antitumor compound, is an example of a steroid alkaloid (Fig. 1 of Kutchan,

1995; The Plant Cell 7:1059-1070; Fig 24.17 class text).

7.3 Classification of Alkaloids

The alkaloids, as an important and enormously large conglomerate of

naturally occurring nitrogencontaining plant substances having very specific as

well as most diversified pharmacological properties may be classified in a number

of modes and means.

http://www.uky.edu/~dhild/biochem/26/Taxol.jpg


Hegnauer (1963) conveniently classified alkaloids into six important

groups, corresponding to the six amino-acids legitimately considered as the

starting points for their biosynthesis, such as: anthranilic acid, histidine, lysine,

ornithine phenylalanine and tryptophan. Price (1963) further took a leading clue

from the earlier observation and considered in details the alkaloids present in one

of the families, (Rutaceae) and logically placed them in the

following nine chemical-structural categories, namely: acridines, amides, amines,

benzylisoquinolines, canthinones, imidazoles, indolquinazolines,

furoquinolines, and quinazolines.

Another school of thought classifies alkaloids in the following four heads,

namely:

(a) Biosynthetic Classification

In this particular instance the significance solely lies to the precursor from

which the alkaloids in question are produced in the plant biosynthetically.

Therefore, it is quite convenient and also logical to group together all alkaloids

having been derived from the same precursor but possessing different taxonomic

distribution and pharmacological activities.

Examples

(i) Indole alkaloids derived from tryptophan.

(ii) Piperidine alkaloids derived from lysine.

(iii) Pyrrolidine alkaloids derived from ornithine.

(iv) Phenylethylamine alkaloids derived from tyrosine.

(v) Imidazole alkaloids derived from histidine.

(b) Chemical Classification

It is probably the most widely accepted and common mode of

classification of alkaloids for which the main criterion is the presence of the basic

heterocyclic nucleus (i.e., the chemical entity).

Examples

(i) Pyrrolidine alkaloids e.g., Hygrine;


(ii) Piperidine alkaloids e.g., Lobeline;

(iii) Pyrrolizidine alkaloids e.g., Senecionine;

(iv) Tropane alkaloids e.g., Atropine;

(v) Quinoline alkaloids e.g., Quinine;

(vi) Isoquinoline alkaloids e.g., Morphine;

(vii) Aporphine alkaloids e.g., Boldine;

(viii) Indole alkaloids e.g., Ergometrine;

(ix) Imidazole alkaloids e.g., Pilocarpine;

(x) Diazocin alkaloids e.g., Lupanine;

(xi) Purine alkaloids e.g., Caffeine;

(xii) Steroidal alkaloids e.g., Solanidine;

(xiii) Amino alkaloids e.g., Ephedrine;

(xiv) Diterpene alkaloids e.g., Aconitine.

(c) Pharmacological Classification

Interestingly, the alkaloids exhibit a broad range of very specific

pharmacological characteristics. Perhaps this might also be used as a strong basis

for the general classification of the wide-spectrum of alkaloids derived from the

plant kingdom, such as: analgesics, cardio-vascular drugs, CNS-stimulants and

depressants, dilation of pupil of eye, mydriatics, anticholinergics,

sympathomimetics, antimalarials, purgatives, and the like. However, such a

classification is not quite common and broadly known.

Examples

(i) Morphine as Narcotic analgesic;

(ii) Quinine as Antimalarial;

(iii) Strychnine as Reflex excitability;

(iv) Lobeline as Respiratory stimulant;

(v) Boldine as Choleretics and laxatives;

(vi) Aconitine as Neuralgia;

(vii) Pilocarpine as Antiglaucoma agent and miotic;

(viii) Ergonovine as Oxytocic;


(ix) Ephedrine as Bronchodilator;

(x) Narceine as Analgesic (narcotic) and antitussive.

(d) Taxonomic Classification

This particular classification essentially deals with the‘Taxon’ i.e.,

the taxonomic category. The most common taxa are the genus, subgenus, species,

subspecies, and variety. Therefore, the taxonomic classification encompasses the

plethora of alkaloids exclusively based on their respective distribution in a variety

of Plant Families, sometimes also referred to as the ‘Natural order’. A few

typical examples of plant families and the various species associated with them

are stated below, namely:

(i) Cannabinaceous Alkaloids e.g., Cannabis sativa Linn., (Hemp,

Marijuana).

(ii) Rubiaceous Alkaloids: e.g., Cinchona Sp. (Quinine); Mitragyna

speciosa Korth (Katum, Kratum, Kutum); Pausinystalia johimbe (K.

Schum) (Yohimbe).

(iii) Solanaceous Alkaloids: e.g., Atropa belladona L., (Deadly

Nightshade, Belladona); Brunfelsia uniflorus (Pohl) D. Don (Manaca,

Manacan); Capsicum annuumL., (Sweet Peppers, Paprika); Datura

candida (Pers.) Saff. (Borrachero, Floripondio);Duboisia myoporoides R.

Br. (Corkwood Tree, Pituri); Hyoscyamus niger L. (Henbane,

Henblain, Jusquaime); Mandragora officinarum L. (Mandrake,

Loveapple); Nicotiana glauca R. Grah. (Tree Tobacco); Seopolia

carniolica Jacq. (Scopolia); Solanum dulcamara L., (Bittersweet, Bitter

Nightshade, Felonwood); Withania somniferum (L.) Dunal

(Ashwagandha), etc.

Invariably, they are grouped together according to the name of

the genus wherein they belong to, such as: coca, cinchona, ephedra.

Some ‘phytochemists’ have even gone a step further and classified

the alkaloidsbased on their chemotaxonomic classification.


In the recent past, the alkaloids have been divided into two major

categories based on the analogy that one containing a non-heterocyclic nucleus,

while the other having theheterocyclic nucleus. These two classes of alkaloids

shall be discussed briefly as under.

(a) Non-heterocyclic Alkaloids A few typical alkaloids having non-heterocyclic

nucleus are erumerated below:

(b) Heterocyclic Alkaloids A large number of specific alkaloids possessing

heterocyclic nucleus are stated below:

http://1.bp.blogspot.com/-8LdrykOl7lo/T_f7Sds45jI/AAAAAAAAEcw/LPwVh738Vk0/s550/22-Non-heterocyclic-Alkaloi.jpg

http://3.bp.blogspot.com/-5scr2gsEXsc/T_f7W7VrwII/AAAAAAAAEc8/ZuqWFdEM59k/s550/23-Heterocyclic-Alkaloids.jpg


http://3.bp.blogspot.com/-1-WZKE2KI0g/T_f7ag1pppI/AAAAAAAAEdI/k1GKZFta5Fg/s512/24-Heterocyclic-Alkaloids.jpg

http://3.bp.blogspot.com/-1-WZKE2KI0g/T_f7ag1pppI/AAAAAAAAEdI/k1GKZFta5Fg/s512/24-Heterocyclic-Alkaloids.jpg


It is, however, pertinent to mention at this juncture that the enormous

volume of authentic information accumulated so far with regard to the isolation

of alkaloids from a variety of plant species and their subsequent characterization

by the help of latest analytical techniques they may be classified as follows:

A. Alkaloids derived from Amination Reactions

(i) Acetate-derived Alkaloids

(ii) Phenylalanine-derived Alkaloids

(iii) Terpenoid Alkaloids

(iv) Steroidal Alkaloids

B. Alkaloids derived from Anthranilic Acid

(i) Quinazoline Alkaloids

(ii) Quinoline Alkaloids

(iii) Acridine Alkaloids

C. Alkaloids derived from Histidine

http://3.bp.blogspot.com/-nqdqi2TrYo0/T_f7hP_px4I/AAAAAAAAEdg/YGD_bg5Z59U/s550/26-Heterocyclic-Alkaloids.jpg

http://3.bp.blogspot.com/-nqdqi2TrYo0/T_f7hP_px4I/AAAAAAAAEdg/YGD_bg5Z59U/s550/26-Heterocyclic-Alkaloids.jpg


Imidazole Alkaloids

D. Alkaloids derived from Lysine

(i) Piperidine Alkaloids

(ii) Quinolizidine Alkaloids

(iii) Indolizidine Alkaloids

E. Alkaloids derived from Nicotinic Acid

Pyridine Alkaloids

F. Alkaloids derived from Ornithine

(i) Pyrrolidine Alkaloids

(ii) Tropane Alkaloids

(iii) Pyrrolizidine Alkaloids

G. Alkaloids derived from Tyrosine

(i) Phenylethylamine Alkaloids

(ii) Simple Tetrahydro iso-quinoline Alkaloids

(iii) Modified Benzyl Tetrahydro iso-quinoline Alkaloids

H. Alkaloids derived from Tryptophan

(i) Simple Indole Alkaloids

(ii) Simple b-Carboline Alkaloids

(iii) Terpenoid Indole Alkaloids

(iv) Quinoline Alkaloids

(v) Pyrroloindole Alkaloids

(vi) Ergot Alkaloids

7.4 Principles of Alkaloid Biochemistry

There are 3 important reactions that occur many times in alkaloid

biosynthetic reactions, the oxidative coupling of phenols, Mannich-type reactions

and Schiff base formation. Oxidative coupling of phenols involves hydrogen


removal from the hydroxy group by one electron transfer oxidizing agents such as

ferric chloride creating a highly reactive phenolate free radical. These phenolate

radicals readily undergo coupling (dimerization) reactions:

The Mannich reaction involves a carbonyl compound (usually an

aldehyde), an amine and a compound that can provide a carbanion such as by loss

of an acidic hydrogen followed by condensation of these 3 reactants:

Compounds with primary amino groups can react with carbonyl groups to form

Schiff bases or azomethines the product being an imine:

http://www.uky.edu/~dhild/biochem/26/hidable.htm


7.4 A Deeper Look at the Synthesis of Selected Alkaloids

Only 3 relatively simple pathways of alkaloid biosynthetic routes that

include the synthesis of other important biochemical precursors will be covered.

The formation of isoquinoline alkaloids can be illustrated by biosynthesis

of peyote alkaloids by the peyote cactus involving at least 7 steps. The principal

biosynthetic precursor is tyrosine, which is hydroxylated to

dihydroxyphenylalanine (DOPA) which is decarboxylated to dopamine. One of

the hydroxyl groups of dopamine is methylated, another hydroxyl added and a 2nd

hydroxyl group methylated forming 3-hydroxy-4, 5-

dimethoxyphenylethylamine. This condenses with glyoxylate forming peyoxylic

acid that can be converted into various other peyote alkaloids:



CHAPTER VIII

FLAVONOIDS


CHAPTER VIII

FLAVONOIDS

8.1 Introduction

Flavonoids (or bioflavonoids) (from the Latin

word flavus meaning yellow, their colour in nature) are a class of plant secondary

metabolites. Flavonoids were referred to as Vitamin P (probably because of the

effect they had on the permeability of vascular capillaries) from the mid-1930s to

early 50s, but the term has since fallen out of use.

Flavonoids are secondary plant metabolites, which together with other plant

phenols share a common origin: the amino acid phenylalanine (Parr & Bolwell,

2000). As a result, these phenols are derived from a common building block in

their carbon skeleton: the phenylpropanoid unit, C6-C3. Biosynthesis according to

this pathway produces the large variety of plant phenols: cinnamic acids (C6-C3),

benzoic acids (C6-C3, or C6-C1), flavonoids (C6-C3-C6), proanthocyanidins (C6-

C3-C6)n, stilbenes (C6-C2-C6), coumarins (C6-C3), lignans (C6-C3- C3-C6), and

lignins (C6-C3)n.

8.2 Classification

According to the IUPAC nomenclature, they can be classified into:

flavones, derived from 2-phenylchromen-4-one (2-phenyl-1,4-

benzopyrone) structure (examples:quercetin, rutin).

Molecular structure of theflavone backbone (2-phenyl-1,4-benzopyrone)

isoflavonoids, derived from 3-phenylchromen-4-one (3-phenyl-1,4-

benzopyrone) structure.

https://en.wikipedia.org/wiki/Flavus

https://en.wikipedia.org/wiki/Yellow

https://en.wikipedia.org/wiki/Plant

https://en.wikipedia.org/wiki/Secondary_metabolite



https://en.wikipedia.org/wiki/IUPAC

https://en.wikipedia.org/wiki/Flavones

https://en.wikipedia.org/wiki/Chromone

https://en.wikipedia.org/wiki/Phenyl

https://en.wikipedia.org/wiki/Benzopyran

https://en.wikipedia.org/wiki/Quercetin

https://en.wikipedia.org/wiki/Rutin

https://en.wikipedia.org/wiki/Flavone

https://en.wikipedia.org/wiki/Isoflavonoid

https://en.wikipedia.org/wiki/Chromone


https://en.wikipedia.org/wiki/File:Flavon.svg


Isoflavan structure

neoflavonoids, derived from 4-phenylcoumarine (4-phenyl-1,2-

benzopyrone) structure.

Neoflavonoids structure

The three flavonoid classes above are all ketone-containing compounds,

and as such, are flavonoids and flavonols. This class was the first to be termed

"bioflavonoids." The terms flavonoid and bioflavonoid have also been more

loosely used to describe non-ketone polyhydroxy polyphenol compounds which

are more specifically termed flavanoids, flavan-3-ols (or catechins).

The three cycle or heterocycles in the flavonoid backbone are generally

called ring A, B and C. Ring A usually shows a phloroglucinol substitution

pattern.

Flavonoids occur as aglycones, glycosides and methylated derivatives. The

flavonoid aglycone consists of a benzene ring (A) condensed with a sixmembered

ring (C), which in the 2-position carries a phenyl ring (B) as a substituent. Six-

member ring condensed with the benzene ring is either a a-pyrone (flavonols and

flavonones) or its dihydroderivative (flavanols and flavanones). The position of

the benzenoid substituent divides the flavonoid class into flavonoids (2-position)

and isoflavonoids (3-position). Flavonols differ from flavonones by hydroxyl

group the 3-position and a C2-C3 double bonds. Flavonoids are often

https://en.wikipedia.org/wiki/Neoflavonoids

https://en.wikipedia.org/wiki/Coumarine


https://en.wikipedia.org/wiki/Ketone

https://en.wikipedia.org/wiki/Flavan-3-ol

https://en.wikipedia.org/wiki/Phloroglucinol

https://en.wikipedia.org/wiki/File:Isoflavan.PNG

https://en.wikipedia.org/wiki/File:4-phenylcoumarin.PNG


hydroxylated in position 3,5,7,2',3',4',5'. Methylethers and acetylesters of the

alcohol group are known to occur

in nature. When glycosides are formed, the glycosidic linkage is normally located

in positions 3 or 7 and the carbohydrate can be L-rhamnose, D-glucose, glucor-

hamnose, galactose or arabinose.

Nomenclature of the subclasses of flavonoids based on the position of their substituents.


8.3 Functions of Flavonoids in Plants

Flavonoids are widely distributed in plants fulfilling many functions.

Flavonoids are the most important plant pigments for flower coloration producing

yellow or red/blue pigmentation in petals designed to attract pollinator animals.

In higher plants, Flavonoids are involved in UV filtration, symbiotic

nitrogen fixation and floral pigmentation. They may act as a chemical messenger

or physiological regulator, they can also act as cell cycle inhibitors.

Flavonoids secreted by the root of their host plant help Rhizobia in the

infection stage of their symbiotic relationship with legumes like peas, beans,

clover, and soy. Rhizobia living in soil are able to sense the flavonoids and this

triggers the secretion of Nod factors, which in turn are recognized by the host

plant and can lead to root hair deformation and several cellular responses such as

ion fluxes and the formation of a root nodule.

In addition, some flavonoids have inhibitory activity against organisms

that cause plant disease e.g. Fusarium oxysporum.

8.4 Flavonoids and Human health

Flavonoids (specifically flavanoids such as the catechins) are "the most

common group of polyphenolic compounds in the human diet and are found

ubiquitously in plants". Flavonols, the original bioflavonoids such as quercetin,

are also found ubiquitously, but in lesser quantities.

The widespread distribution of flavonoids, their variety and their relatively

low toxicity compared to other active plant compounds (for instance alkaloids)

mean that many animals, including humans, ingest significant quantities in their

diet. Preliminary research indicates that flavonoids may modify allergens, viruses,

and carcinogens, and so may be biological "response modifiers". In vitro studies

show that flavonoids also have anti-allergic, anti-inflammatory, anti-

microbial, anti-cancer, and anti-diarrheal activities. In vitro, flavonoids have

antiviral activity against several viruses, among them poliovirus.

https://en.wikipedia.org/wiki/Biological_pigment

https://en.wikipedia.org/wiki/Pollinator

https://en.wikipedia.org/wiki/Rhizobia

https://en.wikipedia.org/wiki/Symbiosis

https://en.wikipedia.org/wiki/Root_nodule

https://en.wikipedia.org/wiki/Polyphenol


https://en.wikipedia.org/wiki/Toxicity

https://en.wikipedia.org/wiki/Chemical_compound

https://en.wikipedia.org/wiki/Alkaloids

https://en.wikipedia.org/wiki/Human_nutrition

https://en.wikipedia.org/wiki/Allergen

https://en.wikipedia.org/wiki/Virus

https://en.wikipedia.org/wiki/Carcinogen

https://en.wikipedia.org/wiki/In_vitro

https://en.wikipedia.org/wiki/Allergy

https://en.wikipedia.org/wiki/Anti-inflammatory

https://en.wikipedia.org/wiki/Cancer


8.4.1 Antioxidant activity in vitro

Flavonoids (both flavonols and flavanols) are most commonly

known for their antioxidant activity in vitro. At high experimental

concentrations that would not exist in vivo, the antioxidant abilities of

flavonoids in vitro may be stronger than those of vitamin C and E,

depending on concentrations tested.

Consumers and food manufacturers have become interested in

flavonoids for their possible medicinal properties, especially their putative

role in inhibiting cancer or cardiovascular disease. Although physiological

evidence is not yet established, the beneficial effects of fruits, vegetables,

tea, and red wine have sometimes been attributed to flavonoid compounds.

8.4.2 Negligible antioxidant properties of flavonoids in vivo

A research team at the Linus Pauling Institute and the European

Food Safety Authority state that flavonoids, inside the human body, are of

little or no direct antioxidant value. Body conditions are unlike controlled

test tube conditions, and the flavonoids are poorly absorbed (less than 5%),

with most of what is absorbed being quickly metabolized and excreted.

The increase in antioxidant capacity of blood seen after the

consumption of flavonoid-rich foods may not be caused directly by the

flavonoids themselves, but is probably because of increased production

of uric acid resulting from excretion of flavonoids from the

body. According to Frei, "we can now follow the activity of flavonoids in

the body, and one thing that is clear is that the body sees them as foreign

compounds and is trying to get rid of them."

8.4.3 Cancer

Flavonoids might induce mechanisms that affect cancer cells and

inhibit tumor invasion. In preliminary studies, UCLA cancer researchers

proposed that smokers who ate foods containing certain flavonoids, such

as the flavan-3-ols (catechins) found in strawberries and green and black

https://en.wikipedia.org/wiki/Antioxidant

https://en.wikipedia.org/wiki/In_vivo

https://en.wikipedia.org/wiki/In_vitro

https://en.wikipedia.org/wiki/Cardiovascular_disease

https://en.wikipedia.org/wiki/Linus_Pauling_Institute

https://en.wikipedia.org/wiki/European_Food_Safety_Authority



https://en.wikipedia.org/wiki/Uric_acid

https://en.wikipedia.org/wiki/UCLA



teas, kaempferol from brussel sprouts and apples, and quercetin from

beans, onions and apples, may have reduced risk of developing lung

cancer.

8.4.5 Carcinogenic potential

Flavonoids were found to be strong topoisomerase inhibitors and

induce DNA mutations in the MLL gene, which are common findings in

neonatal acute leukemia. The DNA changes were increased by treatment

with flavonoids in cultured blood stem cells.[20] In one study, a high

flavonoid-content diet in mothers seemed to increase risk of MLL+ acute

myeloid leukemia in neonates. This result was not statistically significant

though, and when the data on all types of leukemia in the study were taken

together, a beneficial effect of the high-flavonoid diet was seen.

Natural phenols (flavonoids in one set of experiments

and delphinidin in another) were found to be strong topoisomerase

inhibitors, similar to some chemotherapeutic anticancer drugs,

including etoposide and doxorubicin. This property may be responsible for

both an anticarcinogenic-proapoptotic effect and a carcinogenic, DNA

damaging potential of the substances.

8.5 Common Flavonoids

8.5.1 Quercetin

Quercetin, a flavonoid and more specifically a flavonol, is the

aglycone form of other flavonoid glycosides, such as rutin and quercitrin,

found in citrus fruit, buckwheat and onions. Quercetin forms the

https://en.wikipedia.org/wiki/Kaempferol

https://en.wikipedia.org/wiki/Brussel_sprouts


https://en.wikipedia.org/wiki/Lung_cancer



https://en.wikipedia.org/wiki/Topoisomerase_inhibitor

https://en.wikipedia.org/wiki/DNA

https://en.wikipedia.org/wiki/Mutations

https://en.wikipedia.org/wiki/MLL_(gene)

https://en.wikipedia.org/wiki/Acute_leukemia

https://en.wikipedia.org/wiki/Flavonoid#cite_note-pmid17468513-20

https://en.wikipedia.org/wiki/Acute_myeloid_leukemia



https://en.wikipedia.org/wiki/Delphinidin




https://en.wikipedia.org/wiki/Etoposide

https://en.wikipedia.org/wiki/Doxorubicin

https://en.wikipedia.org/wiki/Proapoptotic


https://en.wikipedia.org/wiki/File:Quercetin.svg


glycosides, quercitrin and rutin, together with rhamnose and rutinose,

respectively.

Although there is preliminary evidence that asthma, lung cancer

and breast cancer are lower among people consuming higher dietary levels

of quercetin, the U.S. Food and Drug Administration (FDA), EFSA and

the American Cancer Society have concluded that no physiological role

exists. The American Cancer Society states that dietary quercetin "is

unlikely to cause any major problems or benefits."

8.5.2 Epicatechin

Epicatechin (EC)

Epicatechin may improve blood flow and has potential

for cardiac health. Cocoa, the major ingredient of dark chocolate, contains

relatively high amounts of epicatechin and has been found to have nearly

twice the antioxidant content of red wine and up to three times that

of green teain vitro. In the test outlined above, it appears the potential

antioxidant effects in vivo are minimal as the antioxidants are rapidly

excreted from the body.

8.6 Dietary sources

Good sources of flavonoids include all citrus fruits, berries, ginkgo

biloba, onions (particularly red onion), parsley,

pulses,tea (especially white and green tea), red wine, seabuckthorn, and dark

chocolate (with a cocoa content of seventy percent or greater).

https://en.wikipedia.org/wiki/Food_and_Drug_Administration

https://en.wikipedia.org/wiki/EFSA

https://en.wikipedia.org/wiki/American_Cancer_Society

https://en.wikipedia.org/wiki/Epicatechin

https://en.wikipedia.org/wiki/Cardiac

https://en.wikipedia.org/wiki/Cocoa_mass

https://en.wikipedia.org/wiki/Chocolate

https://en.wikipedia.org/wiki/Red_wine

https://en.wikipedia.org/wiki/Green_tea

https://en.wikipedia.org/wiki/In_vivo

https://en.wikipedia.org/wiki/Citrus

https://en.wikipedia.org/wiki/Ginkgo_biloba



https://en.wikipedia.org/wiki/Onion

https://en.wikipedia.org/wiki/Red_onion

https://en.wikipedia.org/wiki/Parsley

https://en.wikipedia.org/wiki/Pulses

https://en.wikipedia.org/wiki/Tea

https://en.wikipedia.org/wiki/White_tea

https://en.wikipedia.org/wiki/Green_tea

https://en.wikipedia.org/wiki/Red_wine

https://en.wikipedia.org/wiki/Seabuckthorn

https://en.wikipedia.org/wiki/Dark_chocolate



https://en.wikipedia.org/wiki/Cocoa_solids

https://en.wikipedia.org/wiki/File:Epicatechin.png


8.6.1 Citrus

A variety of flavonoids are found in citrusfruits, including grapefruit.

The citrus bioflavonoids include hesperidin (a glycoside of the

flavanone hesperetin),quercitrin, rutin (two glycosides of the

flavonol quercetin), and the flavone tangeritin. In addition to possessing in

vitro antioxidant activity and an ability to increase intracellular levels

of vitamin C, rutin and hesperidin may have beneficial effects

on capillary permeability and blood flow. They also exhibit anti-allergy

and anti-inflammatory benefits of quercetin from in vitro studies.

Quercetin can also inhibit reverse transcriptase, part of the replication

process of retroviruses.[35] The therapeutic relevance of this inhibition has

not been established.

8.6.2 Tea

8.6.3 Wine

8.6.4 Dark chocolate

Flavonoids exist naturally in cacao, but because they can be bitter,

they are often removed from chocolate, even dark chocolate. Although

flavonoids are present in milk chocolate, milk may interfere with their

absorption.

https://en.wikipedia.org/wiki/Citrus

https://en.wikipedia.org/wiki/Grapefruit

https://en.wikipedia.org/wiki/Hesperidin

https://en.wikipedia.org/wiki/Hesperetin

https://en.wikipedia.org/wiki/Quercitrin

https://en.wikipedia.org/wiki/Rutin

https://en.wikipedia.org/wiki/Glycoside


https://en.wikipedia.org/wiki/Tangeritin

https://en.wikipedia.org/wiki/Vitamin_C

https://en.wikipedia.org/wiki/Hesperidin

https://en.wikipedia.org/wiki/Capillary

https://en.wikipedia.org/wiki/Blood_flow

https://en.wikipedia.org/wiki/Reverse_transcriptase

https://en.wikipedia.org/wiki/Retrovirus

https://en.wikipedia.org/wiki/Flavonoid#cite_note-35

https://en.wikipedia.org/wiki/Cacao_bean

https://en.wikipedia.org/wiki/Chocolate


https://en.wikipedia.org/wiki/File:Grapefruit_Schnitt_2008-3-3.JPG


8.7 Subgroups

Over 5000 naturally occurring flavonoids have been characterized from

various plants. They have been classified according to their chemical structure,

and are usually subdivided into the following subgroups:

8.7.1 Flavones

Flavones are divided into four groups:

Group

Skeleton

Examples Description

Functional groups

Structural formula 3-hydroxyl 2,3-dihydro

Flavone

2-phenylchromen-4-

one ✗ ✗

Luteolin, Apigeni

n, Tangeritin

Flavonol

or

3-

hydroxyflavon

e

3-hydroxy-2-

phenylchromen-4-one ✓ ✗

Quercetin, Kaemp

ferol,Myricetin, Fi

setin,Isorhamnetin

, Pachypodol,Rha

mnazin

Flavanone

2,3-dihydro-2-

phenylchromen-4-one ✗ ✓

Hesperetin, Narin

genin,Eriodictyol,

Homoeriodictyol

Flavanonol

or

3-

Hydroxyflava

none

or

2,3-

dihydroflavon

ol

3-hydroxy-2,3-

dihydro-2-

phenylchromen-4-one

✓ ✓

Taxifolin (or Dihy

droquercetin),Dih

ydrokaempferol

https://en.wikipedia.org/wiki/Flavone

https://en.wikipedia.org/wiki/Flavones

https://en.wikipedia.org/wiki/Luteolin

https://en.wikipedia.org/wiki/Apigenin



https://en.wikipedia.org/wiki/Tangeritin

https://en.wikipedia.org/wiki/Flavonols








https://en.wikipedia.org/wiki/Myricetin

https://en.wikipedia.org/wiki/Fisetin



https://en.wikipedia.org/wiki/Isorhamnetin



https://en.wikipedia.org/wiki/Pachypodol

https://en.wikipedia.org/wiki/Rhamnazin



https://en.wikipedia.org/wiki/Flavanones

https://en.wikipedia.org/wiki/Hesperetin

https://en.wikipedia.org/wiki/Naringenin



https://en.wikipedia.org/wiki/Eriodictyol

https://en.wikipedia.org/wiki/Homoeriodictyol

https://en.wikipedia.org/wiki/Flavanonols

https://en.wikipedia.org/wiki/Taxifolin

https://en.wikipedia.org/wiki/Dihydroquercetin



https://en.wikipedia.org/wiki/Dihydrokaempferol



https://en.wikipedia.org/wiki/File:Flavone_skeleton_colored.svg

https://en.wikipedia.org/wiki/File:Flavonol_skeleton_colored.svg

https://en.wikipedia.org/wiki/File:Flavanone_skeleton_colored.svg

https://en.wikipedia.org/wiki/File:Flavanonol_skeleton_colored.svg


8.7.2 Isoflavones

Isoflavones use the 3-phenylchromen-4-one skeleton (with no

hydroxyl group substitution on carbon at position 2).

Examples: Genistein, Daidzein, Glycitein

8.7.3 Flavan-3-ols, Flavan-4-ols, Flavan-3,4-diols, and

proanthocyanidins

Flavan structure

Derivatives of flavan.

Skeleton Name

Flavan-3-ol

Flavan-4-ol

Flavan-3,4-diol (leucoanthocyanidin)

a) Flavan-3-ols (also known as flavanols) and Proanthocyanidins

Flavan-3-ols use the 2-phenyl-3,4-dihydro-2H-chromen-3-ol skeleton.

Catechin (C), Gallocatechin (GC), Catechin 3-gallate (Cg), Gallocatechin

3-

https://en.wikipedia.org/wiki/Genistein

https://en.wikipedia.org/wiki/Daidzein

https://en.wikipedia.org/wiki/Glycitein

https://en.wikipedia.org/wiki/Flavan



https://en.wikipedia.org/wiki/Flavan-3,4-diol

https://en.wikipedia.org/wiki/Flavan-3-ols

https://en.wikipedia.org/wiki/Catechin

https://en.wikipedia.org/wiki/Gallocatechin

https://en.wikipedia.org/w/index.php?title=Catechin_3-gallate&action=edit&redlink=1

https://en.wikipedia.org/w/index.php?title=Gallocatechin_3-gallate&action=edit&redlink=1



https://en.wikipedia.org/wiki/File:Flavan_acsv.svg

https://en.wikipedia.org/wiki/File:Flavan-3-ol.svg

https://en.wikipedia.org/wiki/File:Flavan-4-ol.svg

https://en.wikipedia.org/wiki/File:Flavan-3,4-diol.svg


gallate (GCg)), Epicatechins (Epicatechin (EC)),Epigallocatechin (EGC),

Epicatechin 3-gallate (ECg), Epigallocatechin 3-gallate (EGCg)

Proanthocyanidins are dimers, trimers, oligomers, or polymers of the

flavanols.

b) Anthocyanidins

Flavylium skeleton of anthocyanidins

Anthocyanidins are the aglycones of anthocyanins. Anthocyanidins use

theflavylium (2-phenylchromenylium) ion skeleton

Examples: Cyanidin, Delphinidin, Malvidin, Pelargonidin, Peonidin, and

Petunidin



https://en.wikipedia.org/wiki/Epigallocatechin

https://en.wikipedia.org/wiki/Epicatechin_3-gallate

https://en.wikipedia.org/wiki/Epigallocatechin_3-gallate

https://en.wikipedia.org/wiki/Proanthocyanidins

https://en.wikipedia.org/wiki/Anthocyanidin

https://en.wikipedia.org/wiki/Aglycone

https://en.wikipedia.org/wiki/Anthocyanin

https://en.wikipedia.org/wiki/Flavylium

https://en.wikipedia.org/wiki/Cyanidin

https://en.wikipedia.org/wiki/Delphinidin

https://en.wikipedia.org/wiki/Malvidin

https://en.wikipedia.org/wiki/Pelargonidin

https://en.wikipedia.org/wiki/Peonidin

https://en.wikipedia.org/wiki/Petunidin

https://en.wikipedia.org/wiki/File:Flavylium_cation.svg



CHAPTER IX

STEROIDS


CHAPTER IX

STEROIDS

9.1 Introduction

Steroids form an important group of compounds based on the fundamental

saturated tetracyclic hydrocarbon : 1,2-cyclopentanoperhydrophenanthrene

(sterane orgonane).

This nucleus, partially or completely hydrogenated, is generally

substituted by methyl groups at C10 and C13. A chemical group (ketone,

hydroxyl...) or an alkyl side-chain may also be present at C17. Steroids may

possess a nucleus derived from sterane by one or more C-C bond scissions or ring

expansions or contractions.

The term "steroids" was coined by Callow RK et al. (Proc Royal Soc

London series A 1936, 157, 194) "for the group of compounds comprising the

sterols, bile acids, heart poisons, saponins, and sex hormones".

As natural steroids are derived from squalene by cyclization, unsaturation

and substitution, they may be considered as modified triterpenes. Fatty acid esters

of steroids are found mainly in the blood but their exact role is not known to date.

An efficient analytical method for the simultaneous determination of 12 esters in

serum has been desscribed.

There is a close connection between modern-day biosynthesis of particular

triterpenoid biomarkers and presence of molecular oxygen in the environment.

Thus, the detection of steroid and triterpenoid hydrocarbons far back in Earth

history has been used to infer the antiquity of oxygenic photosynthesis.

http://www.journals.royalsoc.ac.uk/(dswcf2uktkr5djf0vbeoh2zo)/app/home/contribution.asp?referrer=parent&backto=issue,13,14;journal,988,1018;linkingpublicationresults,1:120148,1


9.2 Classification

According to their chemical structure, the wide array of steroid molecules

may be divided into several groups :

9.2.1 Brassinosteroids

They are derivatives of cholestane with two vicinal diols (C-2, C-3

and C-22, C-23) and a 6-keto group.

They are a unique class of plant growth regulators with structural

similarity to animal steroid hormones, and ecdysteroids from insects and

crustacea. Many of them may be considered as sterols. The first

biologically active compound isolated from the pollen of Brassica

napus in 1979 is brassinolide (Grove MD et al., Nature 1979, 281,

216). Over 60 analog compounds have been isolated but brassinolide

exhibits the highest biological activity of the known brassinosteroids.

As it was shown that these compounds could be potent plant growth and

development regulators, dozens of compounds of similar structure were

isolated from plant sources (algae, ferns, gymnosperms, and angiosperms,

but not bacteria) or synthesized. It was shown that they interact with

jasmonates in the formation of anti-herbivory traits in tomato.

Extensive reviews on brassinosteroids released by Zullo

MAT and Clouse SD may be consulted with interest. The complex role of

brassinosteroids in plant developmental and physiological responses has

been reviewed.

http://members.tripod.com/~mzullo/mainpage.htm

http://www.bioone.org/bioone/?request=get-document&issn=1543-8120&volume=026&issue=01&page=0001



http://www.bioone.org/pdfserv/i1543-8120-026-01-0001.pdf


9.2.2 Bufadienolides

They are typically polyhydroxy C24 steroids with a pentadienolide

ring at C-17. The structure of hellebrigenin is given below as a typical

example of bufadienolides.

They have been isolated from plants and animals. More than 250

compounds have been identified. In plants, thay are mostly glycosides

with one to three sugars in a chain linked to the 3-hydroxyl group.

They are important for their cardiotonic activity. Furthermore, they

possess insecticidal and antimicrobial properties, those produced by the

toad skin are strongly poisonous. An extensive review on bufadienolides

released by Steyn may be consulted with interest.

9.2.3 Cardenolides

Their structure is closely related to bufadienolides but these C23

steroids possess a butenolide ring located at C-17. The structure of

digitoxigenin is given below as a typical example of cardenolides.

http://pubs.rsc.org/ej/NP/1998/Y9815397.pdf


They are widely distributed in plants mainly as glycosides and are

either toxic or insect deterrents. As potent cardiotonics, through their

inhibition of Na/K- ATPases, these steroids were largely studied (digoxin

and its derivative ouabain...). Monarch butterfly is well known to be

highly toxic to birds because of cardenolides which come from the

milkweed leaves eaten by its caterpillar. Experimentally, the larvae of the

lepidopteran Trichoplusia ni were poisoned by feeding on the

milkweedAsclepias curassavica, which contains cardenolides in its latex

(Dussourd DE et al. Chemoecology 2000, 10, 11).

9.2.4 Cucurbitacins

They are the most oxygenated C30 triterpenoids with a dimethyl

group at C-4 and methylated at C-9 and C-14. Strictly, they are not steroid

since they are not methylated at C-10. The structure of cucurbitacin D is

shown below as a typical example of cucurbitacins.

These steroids which are commonly combined in glycosides, are

mainly associated with cucurbitaceae species but they have also been

detected in other families. About 50 species have been identified.

Mammals perceived these toxic molecules as some of the bitterest

substances known. They have protective effects against herbivores but are

feeding stimulants for some beetles. Cucurbitacins have been shown to act

as ecdysteroid receptor antagonists.

9.2.5 Ecdysteroids

These C27 steroids have in common a 7-en-6-one chromophore,

sometimes a methyl group at C-24 and several hydroxyl groups increasing


their polarity. The first ecdysteroid was isolated as a molting hormone

(ecdysone) in 1954 by Butenandt and Karlson. The structure of ecdysone

is given below as an example of these steroids. Its structure was first

elucidated from a hormonal fraction extracted from silk worm pupae .

Ecdysteroids are present both in animals (arthropods) and plants.

About 400 species have been identified.

In plants, they are named "phytoecdysteroids" and they seem to

protect plants against most insects. Most phytoecdysteroids possess a

cholest-7-en-6-one carbon skeleton and a hydroxyl group on the C14. The

carbon number can vary between C19-C29 (sometimes C30). The most

common phytoecdysteroid in plants is ecdysone (20Ehydroxyecdysone).

Among many structures, we noticed the presence of ajugalactone jn Ajuga

reptans (Labiatae), ajugasterone C in Vitex madiensis(Verbenaceae),

cyasterone in Ajuga chamaepitys (Labiatae), inokosterone in Achyranthes

fauriei (Amaranthaceae), makisterone B in Ajuga chamaepitys (Labiatae),

ponasterone A in Podocarpus nakaii (Podocarpaceae), polypodine B

in Polypodium vulgare (Polypodiaceae) and poststerone in Cyathula

capitata (Amaranthaceae). Insects that ingest phytoecdysteroids and are

not adapted to this defense are subject to serious adverse effects, including

reduced weight, molting disruption, and/or mortality.

In insects, precursors are produced by prothoracic glands and

metabolites are known to trigger a cascade of morphological changes

through specific receptors (molting hormones). The most efficient is 20-

hydroxyecdysone. Relationships between plants and insects have been

hypothesized. It appears that all arthropods employ essentially the same

http://www.rrreading.com/files/ecdysteroids_rklein.pdf


compound as the molting hormone. An extensive data base may be

consulted with interest.

9.2.6 Sapogenins

They form the aglycon part of saponins which have well known

detergent properties. They are oxygenated C27 steroids with an hydroxyl

group in C-3. The structure of diosgenin is given below as an example of

these compounds.

These steroids can mimic or regulate steroid hormones. Thus,

diosgenin can be chemically converted into corticosteroids, estrogens and

progesterone. They are externally distributed in plants. They are extremely

distributed in plants since they occur in over 90 plant families. They are

used in nutrition, as herbal medicine, and in cosmetics.

9.2.7 Steroid alkaloids

They form a large group of molecules where a nitrogen atom is

integrated into a ring or in a substituent. The steroid nucleus can contain

double bonds and hydroxyls in various positions. The structure of

solasodine is given below as an example of these compounds.

http://ecdybase.org/


These alkaloids are only distributed in Solanaceae (potato, tomato,

eggplant ...). Fortunately, their toxic properties disappear by structural

transformation during ripening. Solasodine is the most common species

in Solanum.

9.2.8 Withasteroids

They typically C28 ergostane-type steroids with a 22,26-

lactone.They are also characterized by a large number of oxygenated

functions (hydroxyls, ketones, epoxides ...). 90% of withasteroids (or

withanolides) possess a 1-oxo-group as shown below in withaferin.

Over than 200 species are known, some of them as glycosides.

They are predominantly associated with Solanaceae but are also found in

other families (Taccacceae, Leguminosae, Labiatae). Withanolides are

known to have important pharmacological properties (anti-tumor,

immunosuppressive) but they are also antimicrobial, insect deterrent or

ecdysteroid receptor antagonists.

9.2.9 Bile acids

The end products of cholesterol utilization are the bile acids,

synthesized in the liver. In mammals, the most common bile acids are C24

steroids with a carboxyl group at C-24 and up to three hydroxyl groups on

the steroid nucleus, one being at C-3. The most abundant bile acids in

human bile are chenodeoxycholic acid (45%) and cholic acid (31%).


These are referred to as the primary bile acids. Within the intestines the

primary bile acids are converted by bacteria into the secondary bile acids,

identified as deoxycholate (from cholate) and lithocholate (from

chenodeoxycholate). These compounds are reabsorbed by the intestines

and delivered back to the liver via the portal circulation. Within the liver

the carboxyl group of primary and secondary bile acids is conjugated via

an amide bond to either glycine or taurine before their secretion into the

bile. These conjugation reactions yield glycoconjugates and

tauroconjugates, respectively. They are hydrolized in the intestine.

Glycoconjugates are present among eukaryotes only in mammals, but they

were also detected (with deoxycholic acid) in a marine

bacterium, Myroides sp.

Cholic acid : R1 = OH, R2 = H

Chenodeoxycholic acid : R1 = R2 = H

Glycocholic acid : R1 = OH, R2 = NH-CH2-COOH

Taurocholic acid : R1 = OH, R2 = NH-CH2-CH2-SO3H

Bile acids have long been known to be essential in dietary lipid

absorption and cholesterol catabolism. Furthermore, an important role for

bile acids as signaling molecules has emerged. They were shown to

activate mitogen-activated protein kinase pathways, to be ligands for the

G-protein-coupled receptor TGR5 and to activate nuclear hormone

receptors. Bile acids have been discovered to activate specific nuclear


receptors (FXR, PXR, Vitamin D receptor), a cell surface receptor

(TGR5), and cell signaling pathways (JNK 1/2, AKT and ERK 1/2) in

cells in the liver and gastrointestinal tract. Several works provide

evidences of bile acid signaling in regulation of glucose and lipid

metabolism.

Several 3-keto-cholestenoic acids (dafachronic acids) were shown

to be involved in the control of dauer formation and reproduction in the

nematode Caenorhabditis elegans. Investigations revealed that the nuclear

hormone receptor DAF-12 from that worm was optimally activated by two

isomers, (25S)-D7- and (25S)-D4-dafachronic acid with EC50 values of

23 and 33 nM, respectively. One of these isomers is shown below.

(25S)-D7-Dafachronic acid

It has been shown that bile acids were able to function as nutrient

signaling molecules primarily during the feed/fast cycle as there is a flux

of these molecules returning from the intestines to the liver following a

meal induce. They regulate the increase in energy expenditure in brown

adipose tissue, preventing obesity and resistance to insulin. This novel

metabolic effect is dependent on induction of the cyclic-AMP-dependent

thyroid hormone activating enzyme type 2 iodothyronine deiodinase.

A simple and rapid procedure for the isolation of bile acid fraction

using a solid-phase extraction on a C18 column has been described .

Conjugates of fatty acid with bile acids are a new class of

molecules synthesized with the aim of reducing cholesterol crystallization

in bile. Among them, arachidyl amido cholic acid (Aramchol) was shown

to be the most active to retard that process and may be of potential use in

cholesterol gall stone disease in humans (Gilat T et al., Gut 2001, 48, 75).

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11115826&dopt=Abstract


A documented review on bile acids, present in all vertebrates

except fish and bile alcohol present in fish, may be consulted.

Bile acids determination : As early as 1974, an almost complete

separation of bile acids was done by TLC. Analyses using HPLC coupled

with refractive index detector or with ultraviolet detection were proposed,

but their low sensitivity limited their applications. More recently, it has

been shown that evaporative light-scattering detection improved both

selectivity and sensitivity. A further improvement was observed using an

isocratic HPLC charged aerosol detector which enabled the determination

of individual bile acids in human gastric and duodenal aspirates.

9.2.10 Vertebrate hormonal steroids

This large group can be divided into three major families, mainly

on the basis of their physiological function or their tissue origin : the

sexual hormones, the corticosteroids, and the neurosteroids.

Steroidogenesis pathway

http://www.cyberlipid.org/images/Steroidogenesis.svg.png


While best known in vertebrates, the presence of several steroids in

aquatic invertebrates (echinoderms, molluscs, and crustaceans) have been

already reported. However, these results obtained by immunoassay

methods should be regarded with caution, because of possible cross-

reactivity and interferences.

A - Sexual hormones

This important group may be again divided into estrogens,

progestagens, and androgens. It must be noticed that

androstenedione, produced in the adrenal glands and the gonads (ovary

and testicles), is the common precursor of all sexual hormones (see

Steroidogenesis pathway). In females, androstenedione is produced by

theca cells and exported in granulosa cells for estrogen production. This

steroid has a fuunction of sexual pheromone in fish.

Andostenedione

This compound was also detected in the pollen of a pine species

(Pinus sylvestris). It has been also reported inNicotiana tabacum and Inula

helenium at a level of 8 to 11 pmol/g. Its presence is also documented in

waters and bottom sediments of rivers which receive paper mill effluent.

Estrogens : They are C18 steroids generally with a phenolic function at C-

3 (the first ring A being aromatic), without methyl group at C-10, and with

always an oxygenated function at C-17. 17b-estradiol is the model

molecule.


Estrone (or folliculin) is a compound similar to 17b-estradiol but

with a ketone group on the C-17. Secreted by the ovary, it has estrogenic

activity but is also present in plants (pollen and seeds of date palm, seeds

of pomegranate). This hormone was discovered by Butenandt A.

The glucuronide derivative of estradiol has been found in high

concentrations in seawater around spawning Euphyllia ancora (a stony

coral) seawater, and has therefore been implicated as a candidate signaling

molecule in spawn synchronisation. It seems thus evident that Corals

already evolved the vertebrate-type hormone system in their sexual

reproduction.

Progestagens : They are C21 steroids with a en-4-one-3 group and a

ketone function at C-20. Progesterone is the model molecule. In 1934,

Butenandt A (Nobel Prizein chemistry, 1939) and Westphal U succeeded

in producing this hormone in a chemically pure form.

http://nobelprize.org/nobel_prizes/chemistry/laureates/1939/press.html


High levels of progesterone have been reported in plants, Nicotiana

tabacum and Digitalis purpurea (55 to 59 pmol/g).

Guggulsterone is an analogue of progesterone. That sterol is found in the

resin of the guggul tree (Commiphora mukul).

Guggulsterone

Guggul tree extract has been suggested to lower low-density

lipoprotein levels in animal models, it has been successfully used in

Ayurveda medicine since at least 600 BC to treat obesity and lipid

disorders (Satyavati GV et al., Indian J Med Res 1988, 87, 327; Singh V et

al., Pharmacol Res 1990, 22, 37). It has been also shown that

guggulsterone is an efficacious antagonist of the liver X receptor (FXR)

and the bile acid receptor (Urizar NL et al., Science 2002, 296, 1703); Wu

J et al., Mol Endocrinol 2002, 16, 1590). It has been proposed that

inhibition of FXR activation is the basis for the cholesterol-lowering

activity of guggulsterone. Sulfate and ester derivatives of guggulsterone

have been proposed as component of nanosomes or liposomes for drug

delivery.

Androgens : They are C19 steroids. The major androgen is testosterone

which is a 17b-hydroxysteroid with a en-4-one-3 group. This steroid was

also detected in the pollen of Scots pine (Pinus sylvestris).

http://www.ncbi.nlm.nih.gov/pubmed/2330337





Several testosterone derivatives are present in human male

secretions such as sweat, saliva, and semen and have been implicated as

putative human pheromones. Among them, the most studied is

androstadienone. It was shown that smelling androstadienone was able to

maintain higher levels of cortisol in women.

Androstenol and androstenone were also characterized in human sebum.

Androstadienone

Androstenone

Androstenol

B – Corticosteroids

Theoretically, these compounds, named also corticoids, should be

formed in the adrenal cortex. Furthermore, they must be C21 steroids and

three or more oxygen atoms. They have all a en-4-one-3 group and an

oxygenated function at C-20. The major corticosteroids in vertebrates are

cortisol which has an hydroxyl group at C-11, C-17, and C-21

(glucocorticoid hormone) and aldosterone which has only one hydroxyl

group at C-11 and one aldehyde function at C-18 (mineralocorticoid

hormone).


Corticosteroid hormones in vertebrates are critical for metabolism,

growth, reproduction, immunity, and ion homeostasis, and are an

important part of the coping mechanisms involved in the stress responses.

In tetrapod groups, there are at least two active glucocorticoid hormones,

either cortisol or corticosterone, and one mineralocorticoid hormone,

aldosterone, which regulates ion balance. In contrast, in teleosts, cortisol

apparently has both activities, whereas aldosterone is not present. It has

been clearly determined that 11-deoxycortisol (one of the precursors of

cortisol) is the only corticosteroid hormone present in the earliest

vertebrates, the agnathans (the lamprey) (Close DA et al., PNAS 2010,

107, 13942).

C – Neurosteroids

Recent discoveries have revealed that brain is a site of extensive

steroid metabolism and also a target of steroid hormones. These hormones

play an important role in the development, growth, maturation and

differentiation of the brain (Baulieu EE, Psychoneuroendocrinol 1998, 23,

963). The term "neurosteroid", proposed by EE Baulieu in 1981, applies to

steroids which are accumulated in the brain independently of supply by

peripheral endocrine glands and which are synthesized from cholesterol in

the nervous system. Several steroids have been described in the brain since

the first report in 1981 of dehydoepiandrosterone (DHEA) and its sulfated

derivative in the rat brain (Corpechot C et al., PNAS 1981, 78, 4704).

Among the best known are pregnenolone, progesterone, allopregnanolone

and DHEA. A review of the pleiotropic and protective abilities of


http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=9924747&ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=6458035&ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum


neurosteroids and hormonal steroids may be consulted (Melcangi RC et

al., Cell Mol Life Sci 2008, 65, 777).

Pregnenolone is the product of cholesterol conversion by a P450 oxydase

complex (cholesterol side-chain cleavage enzyme, P450scc) and is the

immediate precursor of progesterone. This steroid is found in free form or

as a sulfated derivative. Its function is mainly a negative modulation of

GAGA-A receptor activity and a positive modulation of NMDA receptors.

Several studies suggest that pregnenolone plays an important role in the

control of neural development and in the improvement of neuron

plasticity.

Progesterone, as described above is a progestagen, but also is

active at the brain level. That important steroid is formed directly from

pregnenolone in neurons and glial cells by a 3b-

hydroxysteroid dehydrogenase. Its sedative and anesthetic properties have

been described as soon as 1941 by H. Selye. Among its numerous

functions, it can be noticed that progesterone has important consequences

for myelinisation, neuronal development, survival and regeneration of the

nervous system.

Allopregnanolone (3a-hydroxy-5a-pregnan-20-one) is formed from

progesterone by the action of 5a-reductase and 3b-

hydroxysteroid dehydrogenase. It acts mainly in modulating the GABA-A

receptor activity and its physiological role is important in neurogenesis,

survival and migration of neurons. Furthermore, its involvement in the

http://www.ncbi.nlm.nih.gov/pubmed/18038216?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum




stress reaction suggests that this neurosteroid could have implications in

depressive disorders.

Dehydroepiandrosterone (DHEA) is the first neurosteroid

discovered in a mammalian brain and, thus, is the most actively studied.

DHEA is a direct metabolite of pregnenolone and is found in free form or

as a sulfated derivative. The great interest in this neurosteroid is the

observation of its abundance in human brain and blood and its

concentration lowering during stress situations and aging. Recent studies

amphasize its role in neurogenesis, survival and protection of neuronal

cells.


References

McMurry, John. Organic Chemistry 8th Edition. 2012. Brooks/Cole : USA

http://bilder.buecher.de/zusatz/20/20836/20836067_lese_1.pdf

http://en.wikipedia.org/wiki/Bifunctional

http://en.wikipedia.org/wiki/Alkaloid

http://en.wikipedia.org/wiki/Flavonoid

https://www2.chemistry.msu.edu/faculty/reusch/VirtTxtJml/heterocy.htm

http://www.angelo.edu/faculty/kboudrea/index_2353/Notes_Chapter_07.pdf

http://www.chem.canterbury.ac.nz/

http://www.health-mall.in/files_hl/bioflavonoids_therapeutic_potential.pdf

http://www.hull.ac.uk/php/chsanb/Bifunc/Bifunctional.pdf

http://www.mdpi.com/journal/molecules/

http://www.pearsonhighered.com/showtell/wade_032159231X/assets/pdf/Wade

_Chapter24.pdf

http://www.srmuniv.ac.in/sites/default/files/files/unit-1.pdf

http://bilder.buecher.de/zusatz/20/20836/20836067_lese_1.pdf

http://en.wikipedia.org/wiki/Bifunctional

http://en.wikipedia.org/wiki/Alkaloid

http://en.wikipedia.org/wiki/Flavonoid

https://www2.chemistry.msu.edu/faculty/reusch/VirtTxtJml/heterocy.htm

http://www.angelo.edu/faculty/kboudrea/index_2353/Notes_Chapter_07.pdf

http://www.chem.canterbury.ac.nz/

http://www.health-mall.in/files_hl/bioflavonoids_therapeutic_potential.pdf

http://www.hull.ac.uk/php/chsanb/Bifunc/Bifunctional.pdf

http://www.mdpi.com/journal/molecules

http://www.pearsonhighered.com/showtell/wade_032159231X/assets/pdf/Wade_Chapter24.pdf

http://www.pearsonhighered.com/showtell/wade_032159231X/assets/pdf/Wade_Chapter24.pdf

http://www.srmuniv.ac.in/sites/default/files/files/unit-1.pdf

Organic chemistry ii

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