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ORGANIC CHEMISTRY II
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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
Many of bifunctional molecules are used to
produce medicine, catalysts and also used in condensation
polymerization like polyester, polyamide etc.
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).
Organic Chemistry II arranged by Putri Nur Aulia 3
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
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H- NMR Spectroscopy Using D2O as Co-Solvent
1.3.1 Keto-enol Tautomerism
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Carbonyl Group Tautomer
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Enols and Enolates
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Implications of Enolisation
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Acid Catalysed Halogenations of Enols
The Hell-Volhard –Zelinsky Reaction
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The Aldol Reaction
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The Knoevenagel Condensation
The Claisen Condensation
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The Dieckman Reaction
β- Dicarbonyl Compounds
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Decarboxylation of β-Ketoacids
Aklylation of Dymethil Malonates
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ORGANIC CHEMISTRY II
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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.
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.
Organic Chemistry II arranged by Putri Nur Aulia 15
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
Ring Size 3 4 5 6 7 8 9 10
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.
Organic Chemistry II arranged by Putri Nur Aulia 16
• 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
• 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
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
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
Organic Chemistry II arranged by Putri Nur Aulia 17
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-
Other examples show similar addition reactions to thiiranes and
aziridines. The acid-catalyzed additions in examples 2 and 3, illustrate the
Organic Chemistry II arranged by Putri Nur Aulia 18
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
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
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.
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
Dipolar cycloaddition reactions often lead to more complex five-
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
Organic Chemistry II arranged by Putri Nur Aulia 22
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
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.
Organic Chemistry II arranged by Putri Nur Aulia 23
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).
Organic Chemistry II arranged by Putri Nur Aulia 24
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
Organic Chemistry II arranged by Putri Nur Aulia 25
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).
Organic Chemistry II arranged by Putri Nur Aulia 26
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
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 .
Organic Chemistry II arranged by Putri Nur Aulia 27
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
2.3.4 Six-Membered Rings
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
Organic Chemistry II arranged by Putri Nur Aulia 28
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
might appear to be the stronger base, but it should be remembered that
Organic Chemistry II arranged by Putri Nur Aulia 29
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
Organic Chemistry II arranged by Putri Nur Aulia 30
tribromide salt is a convenient source of bromine. Similarly, the reactive
compounds sulfur trioxide and diborane are conveniently and safely handled as
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
Organic Chemistry II arranged by Putri Nur Aulia 31
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
Organic Chemistry II arranged by Putri Nur Aulia 32
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.
Organic Chemistry II arranged by Putri Nur Aulia 33
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
Organic Chemistry II arranged by Putri Nur Aulia 34
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.
Organic Chemistry II arranged by Putri Nur Aulia 35
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.
Organic Chemistry II arranged by Putri Nur Aulia 36
ORGANIC CHEMISTRY II
Organic Chemistry II arranged by Putri Nur Aulia 37
Carbohydrates, along with lipids, proteins, nucleic acids, and other
compounds are known as biomolecules because they are closely associated with
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
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
Organic Chemistry II arranged by Putri Nur Aulia 38
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.,
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:
Organic Chemistry II arranged by Putri Nur Aulia 39
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
Organic Chemistry II arranged by Putri Nur Aulia 40
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
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
Organic Chemistry II arranged by Putri Nur Aulia 41
Examples : Number of Streoisomers
What is the maximum number of possible stereo-isomers of the following
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.
Organic Chemistry II arranged by Putri Nur Aulia 42
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
– 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
3.5.1 Classification of Monosaccharides
The monosaccharides are the simplest of the carbohydrates, since they
contain only one polyhydroxy aldehyde or ketone unit.
Organic Chemistry II arranged by Putri Nur Aulia 43
Monosaccharides are classified according to the number of carbon
atoms they contain:
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)
Organic Chemistry II arranged by Putri Nur Aulia 44
3.5.2 The Family of D-aldoses
Organic Chemistry II arranged by Putri Nur Aulia 45
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).
Organic Chemistry II arranged by Putri Nur Aulia 46
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.
Organic Chemistry II arranged by Putri Nur Aulia 47
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
B. Fructose Anomers
Fructose closes on itself to form a furanose ring:
Organic Chemistry II arranged by Putri Nur Aulia 48
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
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
Once the glycoside is formed, the ring can no longer open
up to the open-chain form. Glycosides,therefore, are not reducing
Organic Chemistry II arranged by Putri Nur Aulia 49
3.5.9 Important Monosaccharides
3.6 Disaccharides and Oligosaccharides
Two monosaccharides can be linked together through a glycosidic linkage
to form a disaccharide
Organic Chemistry II arranged by Putri Nur Aulia 50
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
3.6.2 Important Disaccharides
Organic Chemistry II arranged by Putri Nur Aulia 51
Oligosaccharides contain from 3 to 10 monosaccharide units.
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.
Organic Chemistry II arranged by Putri Nur Aulia 52
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.
Amylose consists of long, unbranched chains of glucose
(from 1000 to 2000 molecules) connected by (1 4) glycosidic
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
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.
Organic Chemistry II arranged by Putri Nur Aulia 53
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.
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.
Organic Chemistry II arranged by Putri Nur Aulia 54
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),
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
Organic Chemistry II arranged by Putri Nur Aulia 55
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.
Chitin is a polymer of N-acetylglucosamine, an amide derivative
Organic Chemistry II arranged by Putri Nur Aulia 56
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.
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ORGANIC CHEMISTRY II
AMINO ACIDS, PEPTIDES, AND
Organic Chemistry II arranged by Putri Nur Aulia 58
AMINO ACIDS, PEPTIDES, AND PROTEINS
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.
Organic Chemistry II arranged by Putri Nur Aulia 59
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
Organic Chemistry II arranged by Putri Nur Aulia 60
carbon atoms. For additional, all the standard amino acids are L-
Organic Chemistry II arranged by Putri Nur Aulia 61
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
arginine (Arg) valine (Val) methionine (Met)
leucine (Leu) threonine (Thr) phenylalanine (Phe)
histidine (His) isoleucine (Ile)
tryptophan (Trp) lysine (Lys)
Organic Chemistry II arranged by Putri Nur Aulia 62
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:
R + NaOH
O Na- + + H2O
In high pH, therefore, amino acids exist in anionic form:
Amino acids react with strong acids such as hydrochloric acid:
R + HCl
In low pH, therefore, amino acids exist in cationic form:
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:
Organic Chemistry II arranged by Putri Nur Aulia 63
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
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
Organic Chemistry II arranged by Putri Nur Aulia 64
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
Organic Chemistry II arranged by Putri Nur Aulia 65
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.
Organic Chemistry II arranged by Putri Nur Aulia 66
4.5.4 The Strecker Synthesis
Organic Chemistry II arranged by Putri Nur Aulia 67
In a separate step, hydrolysis of -amino nitrile gives an -amino
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
Organic Chemistry II arranged by Putri Nur Aulia 68
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
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
Organic Chemistry II arranged by Putri Nur Aulia 69
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
Or to make it more simple, we can write the abbreviated name:
Or using single letters, we symbolize by:
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
Organic Chemistry II arranged by Putri Nur Aulia 70
linkages) which can join two chains or link a single chain into a
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.
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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
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
Organic Chemistry II arranged by Putri Nur Aulia 72
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
Organic Chemistry II arranged by Putri Nur Aulia 73
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
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.
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ORGANIC CHEMISTRY II
LIPIDS AND FAT
Organic Chemistry II arranged by Putri Nur Aulia 75
LIPIDS AND FAT
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.
Organic Chemistry II arranged by Putri Nur Aulia 76
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
Organic Chemistry II arranged by Putri Nur Aulia 77
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.
Organic Chemistry II arranged by Putri Nur Aulia 78
Organic Chemistry II arranged by Putri Nur Aulia 79
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,
Organic Chemistry II arranged by Putri Nur Aulia 80
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
Organic Chemistry II arranged by Putri Nur Aulia 81
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.
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,
Organic Chemistry II arranged by Putri Nur Aulia 82
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
Organic Chemistry II arranged by Putri Nur Aulia 83
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
Organic Chemistry II arranged by Putri Nur Aulia 84
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
Organic Chemistry II arranged by Putri Nur Aulia 85
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
Organic Chemistry II arranged by Putri Nur Aulia 86
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.
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.
Organic Chemistry II arranged by Putri Nur Aulia 87
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
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.
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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
Organic Chemistry II arranged by Putri Nur Aulia 89
depends on whether the chain is even- or oddnumbered; the latter have higher
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).
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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
Organic Chemistry II arranged by Putri Nur Aulia 91
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.
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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-
Organic Chemistry II arranged by Putri Nur Aulia 93
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.
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ORGANIC CHEMISTRY II
Organic Chemistry II arranged by Putri Nur Aulia 95
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,
Organic Chemistry II arranged by Putri Nur Aulia 96
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
Organic Chemistry II arranged by Putri Nur Aulia 97
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
Organic Chemistry II arranged by Putri Nur Aulia 98
molecule are constructed of two or more isoprene units joined in a ‗head to
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
In applying isoprene rule we look only for the skeletal unit of
carbon. The carbon skeletons of open chain monotrpenoids and sesqui
Head head tail
Tail Tail tail
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,
Organic Chemistry II arranged by Putri Nur Aulia 99
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).
Organic Chemistry II arranged by Putri Nur Aulia 100
However, failing incoporations of 13
C-labeled acetate and successful ones
Clabeled 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
Organic Chemistry II arranged by Putri Nur Aulia 101
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-