299
KURSK STATE MEDICAL UNIVERSITY ORGANIC CHEMISTRU DEPARTMENT NOTES OF LECTURES IN BIOORGANIC CHEMISTRY (Authors: I. Zubkova, G. Chalij)

Bio-Organic Chem Lectures

  • Upload
    -

  • View
    140

  • Download
    15

Embed Size (px)

Citation preview

Page 1: Bio-Organic Chem Lectures

KURSK STATE MEDICAL UNIVERSITY

ORGANIC CHEMISTRU DEPARTMENT

NOTES OF LECTURES

IN BIOORGANIC CHEMISTRY

(Authors: I. Zubkova, G. Chalij)

Page 2: Bio-Organic Chem Lectures

INTRODUCTION

Organic chemistry investigates a dependence of organic compounds

reactivity upon their chemical structures. Organic chemistry forms knowledge and

skills for biochemistry, pharmaceutical chemistry, toxicology and pharmacology

studying.

The main purpose of organic chemistry course is to familiarize you with

common principles of the electronic structure of chemical bonds, elementary idea

of electron displacement effects, stereo structures, and electronic mechanisms of

chemical reactions. Your main task is to get knowledge about functional groups

reactivity, because it is a base of the functional analysis. To consider the chemical

compatibility of drugs and for choosing correct methods of application, it is

necessary to study acid and basic properties of organic compounds, their ability for

hydrolysis and oxidation reactions, etc. Natural compounds, such as sugars, lipids,

proteins, studying is necessary for medical-biological preparation of medical

students.

Page 3: Bio-Organic Chem Lectures

ELECTRONIC STRUCTURE OF CARBON, NITROGEN AND OXYGEN

ATOMS. CHEMICAL BONDS

We need to discuss some basic questions of organic chemistry. They are:

atomic and molecular orbitals, electronic configuration of atoms, types of chemical

bonds and some other problems.

Chemical properties of organic compounds depend on their chemical

structure and mutual influence of atoms in the molecules. In means that chemical

properties of organic compounds depend on types of chemical bonds, the nature of

connected atoms and their mutual influence. Types of chemical bonds depend on

electronic structure of the atoms and their atomic orbitals interaction. For this

reason let us start from the electronic structure of carbon, nitrogen and oxygen

atoms discussing.

Atomic orbital is the region in space around the nucleus where the

electronic density is the greatest.

The other definition is following: it is the region in space around the

nucleus where the probability of the electron finding is the greatest.

There are different kinds of orbitals, which have different sizes and different

shapes, and which are disposed about the nucleus in special ways.

Hydrogen is an element of the 1-st period. Its atom has an electronic shell

consist of one s-orbital only. Carbon, nitrogen and oxygen are the elements of 2-

nd period. Their external electronic levels are represented by s- and p-orbitals.

s-Atomic orbital is spherically symmetrical around a nucleus and p-orbital has

a shape resembling a dumb-bell with two lobes disposed symmetrically about the

nucleus along a line. Two lobes of the orbital have a position concentric with

atomic nucleus where the probability of the electron finding is zero.

Because of carbon, nitrogen and oxygen are the elements of 2-nd period

their 2-ns shell consist of one s-orbital and three p-orbitals. These three p-orbitals

have the same shapes and energies and they are oriented perpendicular to one

another along three axis. They are designated as px-, py- and

pz-orbitals.

Page 4: Bio-Organic Chem Lectures

The energy of 2-p atomic orbital is greater than that of 2-s atomic orbital.

The electronic configuration of an atom is the distribution of electrons

in atomic orbitals. It take place in accordance with the following rules:

1) Not more than two electrons can present on each orbital.

2) These two electrons must have the opposite spins.

3) Each following sublevel can be completed only if the preceding sublevel

has been completed.

The electronic configuration of carbon atoms in the ground state is 1s22s22p2

. It may be shown in the form of a scheme:

We see that the carbon atom has two half-filled (half-completed) orbitals in

the ground state and according to the orbital theory carbon should be bivalent, but

this is not so. We know carbon to be always tetravalent in organic compounds.

This fact can be explained in such a way: under the conditions of the bond

formation the electrons of 2-s-atomic orbital become unpaired and one of them is

promoted to the empty 2-p-orbital. Therefore the electronic configuration of the

carbon atom becomes 1s22s2p3 (this is the configuration in the exited state). And

now carbon has four unpaired electrons:

s- and p-orbitals posess the different shapes and energies. How can the

equivalence of four valences of carbon be explained? To explain this fact we can

use the concept of hybridization of Pauling.

Hybridization is the process of the different orbitals of the same atom

mixing to form new equivalent orbitals. These new orbitals are called hybrid (or

hybridized) orbitals. They have the identical shapes, sizes, energies and orientation

in space.

Characteristics of hybrid orbitals are as follows:

1) The number of hybrid orbitals produced is equal to the number of atomic

orbitals taking part in hybridization.

Page 5: Bio-Organic Chem Lectures

2) A hybrid orbital can not possess more than two electrons with opposite

spins in it.

3) Hybrid orbitals are distributed in space in such a way that the distance

between one another is the greatest.

Hybridization is the profitable process, because hybrid orbitals make more

strong bonds due to the more great overlapping of the orbitals. Three types of

hybridization are characteristic for carbon and nitrogen: sp3-, sp2- and sp-one.

sp3- and sp2-hybridization only are characteristic for oxygen.

sp3-Hybridization of carbon is the process of one 2-s orbital and all three

p-orbitals (px, py and pz) mixing to form four new equivalent hybrid orbitals. The

shape of the hybrid orbital is like an irregular dumb-bell with one increased lobe.

We can describe this type of hybridization in form of a scheme:

Hybrid orbitals are directed towards the corners of a

tetrahedron (the angle is 109o28’). Each hybrid orbital of

carbon is occupied by one electron.

The electronic structure of sp3-hybridized nitrogen differs

from one's of carbon, because the nitrogen atom possess five

electrons in the 2-nd shell. It’s electronic formula is 1s22s22p3.

sp3-Hybridized nitrogen has only three unpaired electrons, which

occupy three sp3-orbitals. The fourth sp3-orbital of nitrogen contains a pair of

electrons. This pair is named an unshared or lone pair. The valent angle is equal

107o.

Page 6: Bio-Organic Chem Lectures

The electronic structure of oxygen is 1s22s22p4. It has two unshared electron

pairs at two sp3-orbitals. The valent angle is equal 104,5o.

s-Orbital and two p-orbitals take part in the process of sp2-

hybridization to form three sp2-hybrid orbitals.

These hybrid orbitals are directed towards the corners of an equilateral

triangle (the angle is 120o).

The pz-orbital is left in its original state and it is oriented perpendicular to

the plane of hybrid orbitals.

sp2-Hybrid carbon possess one electron in each orbital.

The electronic configuration of sp2-hybrid nitrogen can be different:

unshared pair can be situated at hybrid orbital or at unhybrid pz-orbital.

in this case an atom is in this case an atom called “pyrrole type nit- is called “pyridine rogen” type nitrogen”

Two types of sp2-hybrid oxygen are known. Unhybrid pz-orbital can be

occupied by one electron or by unshared electron pair:

Page 7: Bio-Organic Chem Lectures

These two types of oxygen do not have any special names.

In the process of sp-hybridization one s-orbital and only one px-orbital take

part. The result of their mixing is two sp-hybrid orbitals formation. Their axis are

placed in one plane and the angle between them is equal 180o. So, two sp-hybrid

orbitals are linear situated.

py- and pz-orbitals are placed perpendicular to the hybrid orbitals and

perpendicular to each other.

There is one electron at each orbital of carbon atom.

The unshared pair of nitrogen is always situated

at hybrid orbital:

Now when the types of hybridization of atoms have been discussed we can

pass to chemical bonds discussing.

A chemical bond is the attractive force which holds together atoms in a

molecule by their electrons. The reason of chemical bonds formation is the

atoms tendency to complete their external levels.

There are two main types of chemical bonds in organic compounds: ionic

bond (electrovalent) and covalent bond. The coordinate bond is the covalent bond

variety.

Ionic bonds. This type of chemical bonds is formed as a result of complete

transfer of one or more electrons from one atom to the other so that both the atoms

Page 8: Bio-Organic Chem Lectures

acquire inert gas electronic configuration. The atom that loses the electron

becomes positively charged and the atom that gains the electron becomes

negatively charged. For example in the formation of sodium chloride, sodium atom

loses its electron to acquire a stable octet and chlorine accepts the electron to

complete eight electrons.

Covalent bonds. This kind of bonds is formed by mutual sharing of electron

pairs between the atoms of the same or different elements. It is essential for sharing

that two electrons must have opposite spins.

For example the mutual sharing of the electron pair enable both hydrogen

atoms to acquire the stable configuration of helium gas.

The most important in organic molecules is the covalent bond. This fact

can be explained in such a way. Organic compounds are compounds of carbon.

Carbon is the element of fourth group of Mendeleev's Table, therefore carbon has

the same ability both to give and to accept four electrons to complete its external

level.

A covalent bond is formed as a result of combining orbitals overlapping. The

covalent bond is formed between two atoms when a half-filled valence orbital of

one atom overlaps a half-filled valence orbital of another atom. When this

happens, two atomic orbitals merge to form a molecular (or bond) orbital. So, the

atomic orbital always has one center only (this is the nucleus of the atom), but the

molecular orbital has two centers as minimum, and it can have three and more

centers (in so-called conjugated systems).

Covalent bonds are formed when electronegativities of the atoms are equal

or nearly equal. Electronegativity is the tendency of an atom in a molecule to

attract electrons.

Two types of the covalent bond are known. They are σ- and π-bonds.

σ-Bond is a single bond which is formed between two atoms by the linear

overlaping of orbitals along their axis. Therefore, σ-bond can be formed by the

Page 9: Bio-Organic Chem Lectures

linear overlaping of two s-orbitals, s-orbital and p-orbital, two p-orbitals or hybrid

orbitals. For example:

π-Bond is formed between two atoms by the lateral overlapping of

unhybrid p-orbitals. The greatest overlapping is above and below the axes

of σ-bond. The π-bond formation is impossible without σ-bond and

therefore π-bond is always formed when σ-bond already exist.

Because of the lesser overlapping π-bond is weaker than σ-bond.

The carbon-carbon double bond (C=C) is made up of one σ-bond and one π-

bond. Triple bond is one σ-bond and two π-bonds.

Properties of a covalent bond may be described by the following

characteristics: a length, energy (or strength), polarity and ability of the bonds to be

polarized.

Bond length is a distance between the nuclei of connected atoms.

Bond energy is the amount of the energy (per mole) that is given off when

a bond is formed (or it is the amount of the energy that must be put in to break the

bond). The bigger is the energy, the stronger is the bond. The shorter is the bond,

the bigger is the energy, because the orbitals overlapping is more full. For

example, C-H bond is stronger than C-C bond.

Because of lesser overlapping π-bond is weaker than σ-bond.

Polarity of the bond depends upon electronegativities of connected atoms.

Two atoms connected by a covalent bond share electrons; their nuclei are held

by the same electron cloud. But in most cases these two nuclei do not share the

electrons equally: the electron cloud can be displaced to one of the nuclei. One

end of the bond is thus relatively negative and the other is relatively positive. We

can indicate the polarity by using the symbols δ+ and δ-, which indicate partial

"+" and "-" charges.

Page 10: Bio-Organic Chem Lectures

The electron pair of the covalent bond is displaced toward the more

electronegative chlorine atom. It can be indicated by using an arrow. The greater is

the difference of electronegativities, the more polar is the bond.

The bond polarity is connected with both physical and chemical properties.

The polarity of the bond determines the kind of the reaction that can take place at

that bond and even affects reactivity of neighboring bonds.

Ability to be polarized. This characteristic shows easiness of the bond’s

electrons displacement with the action of any external factors (some other particles

- cations, anions, radicals, or an electric field). This characteristic influences on the

reactivity, too.

Coordinate bonds. The coordinate bonds are varieties covalent bonds. This

type of covalent bond id formed between two atoms in which one atom provides

both electrons for the share pair. These two electrons are named the unshared or

lone pair. The other atom provides an empty (vacant) orbital only. The 1-st atom is

called a donor and the 2-nd atom is called the acceptor. You have met this type of

the bond in inorganic chemistry. For example:

Coordinate covalent bond differs from the common covalent bond by the

mechanism of the formation only. They do not differ in their characteristics.

The so-called hemipolar bond is a particular example of the coordinate bond.

This bond is formed due to interaction between an atom with the lone electron pair

(a donor) and a neutral particle (an acceptor). In the result of hemi polar bond

formation the donor acquired a positive charge and the acceptor - a negative

charge. As a result a new bond between two atoms can be represented both as a

Page 11: Bio-Organic Chem Lectures

covalent bond (by the mechanism of its formation) and as an ionic bond (by the

positive and negative charges). The examples of hemi polar bonds are as follows:

Actual measurement shows that two nitrogen-oxygen bonds of a nitro

compound have exactly the same length. In nitro methane CH3-NO2, for example,

two nitrogen-oxygen bonds length are each 0.121 nm, as compared with a usual

length of 0.136 nm for a nitrogen-oxygen single bond and 0.118 nm for a nitrogen-

oxygen double bond. For this reason a better representation of the nitro group is

.

Hydrogen bonds. The hydrogen atom connected with a strong

electronegative element (such as nitrogen, oxygen, fluorine) has an ability for

interaction with an unshared electron pair of the other atom. In the case of this

interaction a so-called hydrogen bond is formed. It is a kind of the coordinate

bond. In the hydrogen bond hydrogen acts as a bridge between two

electronegative atoms (F,O,N); it is held to one - the hydrogen bond donor - by a

covalent bond, and to the other - the hydrogen bond acceptor - by purely

electronic attraction.

For example, water molecules are associated. There are

intermolecular hydrogen bonds between them..

The hydrogen bond energy is many times lesser than that of covalent

bond (10-40 kJ/mole in comparison with 340-360 kJ/mole).

Hydrogen bonds influence both physical (boiling points, melting points,

solubility) and chemical properties. Hydrogen bonds formation is a reason for

boiling and melting points increasing, for solubility increasing.

Hydrogen bonds play an important role in many biochemistry processes in

the living organism, for example, they take part in the stereo structure of proteins,

polysaccharides and DNA formation.

Page 12: Bio-Organic Chem Lectures

CLASSIFICATION OF ORGANIC REACTIONS. STRUCTURE OF

INTERMEDIATES. REACTIVITY OF ALKANES

Two types of organic reactions classification are known: 1) in accordance

with a final result of the reaction and 2) in accordance with a kind of bonds

cleavage.

In accordance with the final result all organic reactions may be classified as

follows:

1. Substitution reactions. For example:

Chlorine atom in chloromethane is replaced by hydroxyl group. Substitution

reactions are designated by symbol S.

2. Addition reactions. For example:

A molecule of hydrogen chloride is added to ethene. This type of the

reactions is designated as A.

3. Elimination reactions. For example:

A molecule of water is eliminated from ethanol molecule. It is designated as

E.

4. Oxidation reactions. For example:

Methanol is oxidized and formaldehyde is formed.

The other type of classification is that in accordance with the kind of bonds

cleavage (bonds breaking).

Let us tackle different types of the bonds breaking.

If in the result of the bond breaking each atom taking part in the covalent

bond receives one electron this type of bond breaking is known as homolysis (this

word is taken from the Greek homo, the same; lysis, cleavage):

Page 13: Bio-Organic Chem Lectures

Each atom is separated with one electron. In this case two free radicals are

obtained. For this reason the other name of this kind of bond cleavage is radical

type). The free radical is an atom or group of atoms possessing an unpaired

electron.

Non-polar bonds are broken in this way. Non-polar solvents promote this

type of bond cleavage (or absence of solvents – in gas phase). Cl ., HO., CH3., H.

are examples of radicals.

If in the result of bond cleavage one atom receives both electrons of the

bond this type is called heterolysis (from the Greek hetero, different):

The particle A has a positive charge, because it had lost its electron. The

particle B has a negative charge, because it had received the additional electron.

Thus, two ions are obtained: cation and anion. Therefore this type of bond breaking

is also called the ionic type.

Polar bonds are broken in this way. Polar solvents and acidic or basic

catalysts promote this type of bond breaking.

So, all reactions may be classified as radical and ionic reactions.

In accordance with a character of the active particle ionic reactions may be

divided into electrophilic and nucleophilic reactions.

Electrophilic reagents (or electrophiles) are electron loving in nature. The

electrophiles are positivly charged and they can accept a pair of electrons donated

by any other particle. For example, H+, NO2+, CH3

+, Cl+ are electrophiles.

Electrophiles are also neutral molecules having a partial positive charge on any

atom, for example, sulfur trioxide:

The electronic density is displaced to the more electronegative

oxygen atoms. The big partial positive charge appears on sulfur.

Nucleophilic reagents (or nucleophiles) are nucleous loving in nature. It

means, they love a positive charge. Nucleophiles are negatively charged particles

Page 14: Bio-Organic Chem Lectures

or neutral molecules having the unshared pair of electrons. For example: H-, Cl-,

H2Ö,:NH3, CH3ÖH.

In accordance with the type of bond breaking and the nature of the reagent

three types of chemical reactions are known: radical, electrophilic and nucleophilic

(two last types are ionic) reactions. E.g.:

CH4 + Cl. CH3. + HCl Radical reaction (R)

radical

CH3-Cl + OH- CH3-OH + Cl- Nucleophilic reaction (N) nucleophile CH2=CH2 + H+ CH3-CH2

+ Electrophilic reaction (E). electrophile

Chemical reactions may be classified in accordance with both types of

classification in the same time, for example: radical substitution reactions (SR),

electrophilic addition reactions (AE) and so on.

Electronic and stereo structures of intermediates.

You already know that different particles (radicals, cations, anions) can be

obtain as a result of bond breaking. Let us discuss their structures, taking methyl

radical (CH3.), methyl carbocation (CH3

+) and methyl carbanion (CH3-) as

examples.

Carbon atoms are sp2-hybridized in these particles. Due to three hybrid

orbitals three C-H σ-bonds are formed. They are situated in the same plane (an

angle is equal 120o).

Unhybrid pz-orbital is situated perpendicular to the plane of σ-bonds.

Page 15: Bio-Organic Chem Lectures

REACTIVITY OF ALKANES

Alkanes are saturated hydrocarbons. Their molecules contain carbon and

hydrogen atoms and single bonds only.

All alkanes fit the general molecular formula CnH2n+2. Names of the first ten

members of alkanes are as follows:

CH4 methane C6H14 hexane

C2H6 ethane C7H16 heptane

C3H8 propane C8H18 octane

C4H10 butane C9H20 nonane

C5H12 pentane C10H22 decane

If we examine the molecular formulas of the alkanes we can see that each

member differs from the previous and from the next member by a –CH2-group

(methylene group). A series of compounds of similar structure, in which the

members differ in composition from one another by –CH2-group is called the

homologous series. The individual members of this series are known as

homologous. Homologous have the similar physical and chemical properties.

Nomenclature of alkanes.

1) For alkanes naming it is necessary to choose the main chain. It is the

longest unbranched carbon chain. It gives a name of the parent hydrocarbon.

Alkanes with branched chains are considered as a derivatives of the parent

structures (the main chain). For example, isobutane is considered as a propane

derivative:

2) Groups, attached to the main chain are called substituents. Substituents

which are derived from alkanes by removing one of the hydrogen atoms are called

Page 16: Bio-Organic Chem Lectures

alkyls. To name alkyl we need to change the ending –ane in the name of the

corresponding alkane to –yl. For example, methane CH4 forms methyl –CH3.

Ethane CH3-CH3 forms one alkyl only (-C2H5 ethyl), because two carbon atoms in

ethane are equal. Three carbon atoms in propane structure are not equal:

Therefore propane can form two different radicals:

3) The main chain is numbered in such a way that substituents receive the

lowest possible number. For example:

4) The name of the compound is written out as one word. Substituents are

placed in alphabetical order. Each substituent is marked by its name and by the

number of carbon atom to which it is attached. When two or more identical groups

are attached prefixes such as di-, tri-, tetra- are used (but these prefixes are not

considered in alphabetizing).

Page 17: Bio-Organic Chem Lectures

Electronic structure of alkanes

Carbon atoms are sp3-hybridized. Each carbon has four hybrid orbitals. The

angle between them 109o28’.

sp3-hybrid orbital of first carbon overlaps sp3-hybrid orbital of second carbon

to form σ-bond. Each of other three sp3-hybrid orbitals of carbon overlaps s-orbital

of hydrogen to form σ-bond too. Thus there are σ-bonds only in the molecules of

alkanes.

The length of C-C-bond is equal 0.154nm, that of C-H-bond is 0.110nm.

Thus the energy of C-C-bond is smaller than that of C-H-bond.

All bonds in alkanes are single, covalent and nonpolar ones. Single bonds

are strong ones. Hence alkanes are relatively inert. Alkanes ordinary do not react

with common acids, bases or oxidizing and reducing agents.

Alkanes are known to be used as fuels. (Petroleum is a complex liquid

mixture of organic compounds, many of which are alkanes. Natural gas consists

mainly of methane and ethane). With excess of oxygen alkanes burn to form

carbon dioxide and water. This reaction is exothermic process:

Combustion is an oxidation reaction.

Halogenation reaction is characteristic for alkanes. When a mixture of

alkane and chlorine gas is stored at low temperature in dark place no reaction

occurs. This reaction is possible in sun light or at high temperature.

One or more hydrogen atoms in the alkane molecule are replaced by

chlorine atoms.

Page 18: Bio-Organic Chem Lectures

If an excess of halogen is present, the reaction can be continued to give

polyhalogenated products:

By controlling the conditions of chlorination reaction of methane we can

form one or another of the possible products. So, the product of the reaction

depends upon the conditions.

Bromine reacts with alkanes under similar conditions, forming similar

products:

When we are discussing halogenation of ethane it was not problem for us to

determine in what position the hydrogen atom is replaced by halogen atom. If we

shell examine halogenation of propane a problem of orientation occurs, because

carbon atoms in propane are not equal. It is a problem that we'll encounter again

and again, whenever we study a compound that has more than one reactive site to

attack by a reagent. It is an important problem, because orientation determines

what product can be obtained.

To dissolve this problem we need to discuss a mechanism of the

corresponding reaction. It is important for us to know not only what happens in a

chemical reaction, but also how it happens, that is, to know not only the facts, but

also the theory.

The detailed, step-by-step description of a chemical reaction is called a

mechanism of this reaction.

Let us discuss the mechanism of halogenation reactions.

Page 19: Bio-Organic Chem Lectures

All bonds in alkanes molecules are nonpolar, therefore the radical type of

bonds breaking is characteristic for them. Thus the radical substitution reactions

(SR) are characteristic for alkanes.

The first step of the halogenation reaction is a chain-initiating step. The

molecule of chlorine absorbs the sun light or heating energy and it is broken

homolytically into two chlorine atoms (radicals):

our The Cl-Cl bond is weaker than either C-H or C-C bond and therefore the

easiest bond to break. The light’s energy is enough to breake Cl-Cl bond only.

The next step is so-called chain-propagating one.

Chlorine radicals are very active particles, because they have an

uncompleted valence shell. When a chlorine radical collides with the alkane

molecule, the hydrogen atom (radical) is separated and the molecule of hydrogen

chloride is formed. Methyl radical is also formed. This formed methyl radical is

very active too. It attacks a molecule of chlorine to form methyl chloride and a new

chlorine radical. This chlorine radical can react to repeat the sequence.

In each chain-propagating step the radical is spent, but another radical is

formed and can continue the chain. Therefore this reaction is called a free radical

chain reaction. The mechanism of this reaction was studied by Russian scientist

Semenov.

Finally, there are chain-terminating steps. If any two radicals are combined,

the chain will be terminated. For example:

Page 20: Bio-Organic Chem Lectures

The radicals are spent, but no new radicals are formed, therefore the chain is

broken (terminated).

Structures of alkyl radicals

Let us discuss this problem on the example of methyl radical.

Carbon is sp2-hybridized. It means that the structure of the radical is flat. The

unpaired electron occupies the unhybrid pz-orbital, that is oriented perpendicular to

the plane of σ-bonds.

The halogenation reaction of propane can give two different products:

What product is predominated in the reaction? To answer this question we

need to discuss the mechanism of the reaction and compare stability of possible

radicals.

Page 21: Bio-Organic Chem Lectures

Two different radicals can be formed in this reaction: they are propyl and

isopropyl. The more stable is the radical the greater is the possibility of its

formation and then its interaction with the new bromine molecule. Thus, we need

to compare stability of these two radicals. You already know, that carbon with

unpaired electron in the radical is sp2-hybridized. It is more electronegative than

sp3-hybridized one.

The secondary radical is more stable than primary

one, because two neighboring carbon atoms displace the

electronic density to carbon with the unpaired electron.

In case of primary radical the electronic density is

displaced from one neighboring carbon only. For this reason

primary radical is lesser stable that secondary one.

Generally, tertiary radicals are the most stable and primary radicals are the

least stable.

If isopropyl radical is more stable, it can be formed faster and it can react

with bromine faster, too.

Therefore 2-bromopropane is the favorable product of bromination reaction

of propane.

Nitration reaction of alkanes

Nitration reactions of alkanes are radical substitution reactions too. When

alkanes are boiled with diluted nitric acid at high temperature and pressure

nitroalkanes are formed. This reaction is known as Konovalov’s reaction.

Page 22: Bio-Organic Chem Lectures

REACTIVITY OF ALKENES AND ALKADIENES

Alkenes are hydrocarbons that contain a carbon-carbon double bond. Their

general formula is CnH2n.

Nomenclature.

Common names are seldom used except for simple alkenes: CH2=CH2 –

ethylene and CH3-CH=CH2 – propylene.

Most alkenes are named by the IUPAC system. The rules of IUPAC system

are as follows:

1. Select as a parent structure the longest chain that contains the carbon-

carbon double bond. The name of the parent structure is derived by changing the

ending –ane in the corresponding alkane name for –ene (ethene, propene and so

on).

2. Number the chain from the end nearest the double bond (carbon atoms of

this bond must have the lowest possible numbers).

3. Indicate by a number a position of the double bond in the parent structure.

The position is designated by the number of the first doubly bonded carbon.

4. Branches are named in the usual way. For example:

The common names of radicals can be used:

CH2=CH- vinyl (ethenyl by IUPAC),

CH2=CH-CH2- allyl (3-propenyl by IUPAC).

Structure of the double bond of ethene

Page 23: Bio-Organic Chem Lectures

Carbon atoms are sp2-hybridized. A molecule is flat. Three hybrid orbitals of

each carbon atom are placed in the same plane; the angle between them is equal

120o. Axis of unhybrid pz-orbitals are oriented perpendicular to the plane.

The carbon-carbon double bond consists of one σ-bond and one π-bond.

σ-Bond is formed by the linear overlapping two sp2-hybrid orbitals and π-bond is

formed by the lateral overlapping two unhybrid pz-orbitals. Two electrons of σ-

bond lie along the internuclear axes. Two electrons of π-bond lie in the region of

space above and below the plane of σ-bonds. For this reason π-electrons are more

exposed than σ-electrons and can be attacked by various electron-seeking (electron

loving, electrophilic) reagents. The C-C π-bond energy is smaller than that of σ-

bond therefore π-bonds are breaking more easily than σ-bonds.

Every carbon atom in ethene is connected with hydrogen atom by the σ-

bond. This σ-bond is formed due to overlapping sp2-hybrid orbital of carbon and s-

orbital of hydrogen.

The carbon-carbon double bond is shorter than carbon-carbon single bond,

because two shared electron pairs draw the nuclei together stronger than a single

bond electron pair. The length of C=C bond is equal 0.134 nm.

Stereo isomerism of alkenes

If we examine the structure of 2-butene, we find that there are two different

ways, in which the atoms can be arranged:

Page 24: Bio-Organic Chem Lectures

In the first structure methyl groups lie on the same side of the molecule, and

in the second structure they lie on opposite sides of the molecule. These two

structures are stereo isomers (geometric isomers).

Stereo isomers are not readily interconverted by the rotation around the

double bond at room temperature. There is hindered rotation about double bond. It

is π-bond that "prevents" the rotation.

Geometric isomers can be separated from one another, for example, by

distillation, because they have different boiling points. These two structures are

differentiated in their names by the prefixes cis- (Latin: on this side) and trans-

(Latin: across), which indicate that methyl groups are on the same side or on

opposite sides of the molecule. The geometric isomerism is also called cis,trans-

one.

Cis-isomer is less stable than the trans-isomer. For cis,trans- isomerism in

alkenes each carbon of the double bond must have two different atoms or groups,

attached to it. For example, 1-butene CH2=CH-CH2-CH3 can not exist as cis- and

trans- isomers.

Chemical properties of alkenes

Alkenes are chemically more active than alkanes. The carbon-carbon double

bond determines the characteristic reactions that alkenes undergo. Addition

reactions are the most characteristic reactions of unsaturated hydrocarbons. For

example:

Page 25: Bio-Organic Chem Lectures

Three types of addition reactions are known: radical, electrophilic and

nucleophilic addition. What type of addition is characteristic for alkenes? We can

answer this question if remember an electronic structure of the double bond. We

already know that π-electrons are more exposed than σ-electrons and they can be

attacked by electron-loving reagents. These reagents are called electrophiles. Thus,

electrophilic addition reactions are characteristic for alkenes.

Electrophilic addition reactions mechanism

Each polar reagent may be represented as a product of the electrophile and

nucleophile interaction:

At the first step of the reaction an electrophile E+ comes up to the π-

electronic cloud and they attract each other. So-called π-complex is produced:

Then the electrophile forms a new σ-bond with carbon. Two electrons of π-

bond are used to form this σ-bond:

Because this σ-bond uses both π-electrons, other carbon atom acquires a

positive charge. Carbocation is formed (or σ-complex). Then σ-complex interacts

with the remaining nucleophile, that can supply two electrons for new σ-bond

formation:

The carbocation formation step is the slowest one. This step determines a

speed of all reaction.

Page 26: Bio-Organic Chem Lectures

Particular examples of AE-reactions

Addition of hydrogen halides. Alkenes react with hydrogen chloride,

bromide or iodide to form the corresponding alkyl halides:

Addition of water (hydration reaction). This reaction has some peculiarities.

The presence of an acid catalyst is necessary in this reaction. It is the result of the

low dissociation degree of water molecules and consequently the low

concentration of electrophilic reagent (H+). Therefore a proton of the strong acid

(catalyst) is the first that is added to the alkene to give the carbocation. This

carbocation reacts with water at the next step of the reaction:

Water molecule is the nucleophile due to unshared electron pair of oxygen.

New σ-bond C-O is formed due to this unshared electron pair, therefore oxygen

acquires a positive charge. Then this cation reacts with a remainder of sulfuric acid

and gives back the proton. Alcohol is obtained and sulfuric acid molecule (the

catalyst) is formed.

Addition of halogens (halogenation reaction). This reaction is carried out

simply by mixing together two reagents, usually in any inert solvent like carbon

tetrachloride. The aqueous solution of bromine – so-called bromine water is often

used too. The addition proceeds rapidly at room temperature.

Let us discuss the bromination reaction of ethene as an example.

Page 27: Bio-Organic Chem Lectures

The bromine molecule is non-polar, but in the presence of polar solvent

(water, for example) Br-Br bond is polarized and partial charges appear:

Then this polarized molecule reacts with ethene:

Br-Br bond becomes still more polar due to action of π-electrons and it can

be broken heterolytically. Cation Br+ adds to carbon using π-electrons to form a

new C-Br bond. Carbocation (σ-complex) is formed. The positively charged

carbon atom is sp2-hybridized, it has the vacant unhybrid pz-orbital. Bromine atom

has three unshared electron pairs. Due to one of these electron pairs and the vacant

orbital of carbon σ-bonds is formed (a mechanism of this bond formation is

coordinate one).

Then bromonium cation reacts with remaining bromide anion to yield

dibromoethane. There are partial positive charges on the carbon atoms, because the

electronic density is displaced to positive bromine. Bromide anion attacks carbon

atom and a new σ-bond is formed. But Br- can come up from the other side of the

molecule only. It is so-called trans-addition.

The reaction with bromine water can be used as a simple chemical test for

the qualitative detection of double bonds in organic compounds. The bromine

Page 28: Bio-Organic Chem Lectures

solution is dark reddish-brown. If bromine is added to alkene, the bromine color

disappears.

Addition of hydrogen (hydrogenation reaction). At a temperature of 150-

200oC in the presence of catalysts (such as nickel, platinum, palladium) alkenes

combine with hydrogen to form alkanes:

The catalysts absorb hydrogen gas on their surface and activate the

hydrogen-hydrogen bond to form hydrogen atoms (radicals). These radicals

combine with alkene.

Addition to unsymmetrical alkenes.

If a reagent H+X- (where X may be Cl, OH, Br) is added to unsymmetrical

alkene two products are possible:

Actually, only 2-chloropropane (isopropyl chloride) is formed.

On the examination of a large number of such additions, the Russian chemist

V. Markovnikov observed, that where two isomeric products are possible, one of

them usually predominates. He pointed out that the orientation of addition follows

the rule: In the addition of a reagent H+X- to the carbon-carbon double bond of an

alkene, hydrogen proton is attached to carbon that already holds the greater

number of hydrogens. This rule is known as Markovnikov's rule.

Markovnikov’s rule can be explained by the action of static and dynamic

factors. Static factor is the electronic density distribution in the initial molecule

(before the reaction).

Methyl group displaces the electronic density to sp2-hybridized

carbon. π-bond can be polarized more easily than σ-bond,

Page 29: Bio-Organic Chem Lectures

therefore electrons of π-bond are displaced to the neighboring sp2-hybridized

carbon. This carbon esquires a partial negative charge. Thus, H+ will be directed to

this (more hydrogenated) carbon.

The first step of the reaction is the proton addition to the double bond. This

step can occur in two ways, to give two possible products:

The dynamic factor is the stability of intermediates (carbocations). Iso-

propyl cation is secondary and propyl cation is primary one. The stability of

carbocations is decreased in the following order:

Their stability depends upon the delocalization of positive charge. In tertiary

cation the displacement of the electronic density from three radicals occurs. The

positive charge is delocalized and the stability is increased. There are two radicals

in the secondary carbocation, their influence is smaller than that in tertiary cation,

and therefore the secondary carbocation is less stable. And so on.

Thus iso-propyl cation is more stable than propyl. It means that iso-propyl

cation formation predominates, it is formed rather and then 2-chloropropane is

formed rather too.

Now we can reword Markovnikov’s rule as follows: electrophilic addition to

a carbon-carbon double bond involves the intermediate formation of the more

stable cation.

Oxidation reactions of alkenes

Page 30: Bio-Organic Chem Lectures

In general, alkenes are more easily oxidized than alkanes. Oxidizing agents

attack π-electrons of the double bond.

When alkenes are oxidized carefully by the aqueous solution of potassium

permanganate at room temperature glycols are formed:

This reaction is known as Wagner’s reaction. When this reaction occurs, the

purple color of potassium permanganate is replaced by the brown precipitate of

manganese dioxide. Because of this color change the reaction can be used as a

qualitative test of double (and triple) bonds. This reaction is used to distinguish

alkenes from alkanes.

More intense oxidation by acidic aqueous solution of potassium

permanganate at heating splits the molecule of alkene at the double bond:

In this case two molecules of the acid are formed.

ALKADIENES

Alkadienes (or dienes) are compounds with two double bonds. The location

of these two double bonds regarding each other may be different. If the double

bonds follow each other dienes are called cumulated. If two double bonds are

alternated with a single bond dienes are called conjugated. When more than one

single bond is situated between two double bonds dienes are named isolated. For

example:

Page 31: Bio-Organic Chem Lectures

To designate two double bonds in alkadienes the ending –diene is used.

Chemical properties of cumulated and isolated dienes are identical with

those of alkenes. The single difference: dienes can add two moles of reagents (HCl,

H2O, H2 and so on). For example:

Double bonds exert little effect on each other; hence they react

independently, as though they were in different molecules.

We shell concentrate our attention on the conjugated alkadienes, because

they differ from simple alkenes in their properties: they are more stable, they

undergo 1,4-addition reactions.

1,3-butadiene is the simplest conjugated diene. Let us revise its electronic

structure. CH2=CH-CH=CH2

All carbon atoms are sp2-hybridized. It means, all

atoms lie in the same plane and all σ-bonds are

situated in the same plane too. Each carbon atom

has also unhybrid pz-orbital. All pz-orbitals are

situated perpendicular to the plane of σ-bonds, therefore they are parallel to one

another. All four pz-orbitals overlap one another to form the common electron

cloud above and below the plane of σ-bonds.

Page 32: Bio-Organic Chem Lectures

Thus, 1,3-butadiene is a π,π-conjugated system. The electronic density is

delocalized between four carbon atoms. It can be shown as follows:

The conjugation makes a molecule more stable. It can be explained in such a

way: each pair of electrons attracts and is attracted by not just two carbon, but four.

During the conjugated system formation energy is released and therefore the

stability of molecules is increased too.

Electrophilic addition to conjugated dienes

When 1 mole of hydrogen bromide is added to 1 mole of 1,3-butadiene two

products are obtained:

In the first reaction HBr is added to one of two double bonds, and the other

double bond is still present in its original position. We call this “the product of 1,2-

addition”. In the second reaction hydrogen and bromine are added to C-1 and C-4

(at the ends of the conjugated system) and a new double bond has appeared

between C-2 and C-3. This process, called “1,4-addition”, is quite a general

reaction for electrophilic addition to conjugated systems. A lot of conjugated

dienes and reagents studying shows that such behavior is typical: in addition to

conjugated dienes a reagent may attach itself not only to a pair of neighboring

carbons (1,2-addition), but also to the carbon atoms at two ends of the conjugated

system (1,4-addition). Very often 1,4-addition product is the major one.

Page 33: Bio-Organic Chem Lectures

How can we explain the probability of 1,4-addition? We need to describe the

mechanism of electrophilic addition reaction.

In the first step the proton is added to the terminal carbon atom, according to

Markovnikov’s rule:

The resulting carbocation is the conjugated system too. Carbon atom with a

positive charge is sp2-hybridized. It has the unhybrid vacant pz-orbital. Three p-

orbitals overlap one another and the conjugated system is formed. Three carbon

atoms take part in the conjugation and only two electrons are delocalized between

them (the 3-rd orbital is empty). Therefore the positive charge is delocalized

between three carbon atoms of the conjugated system, and this carbocation is

stable. The structure of the carbocation may be represented by several formulas:

These two structures are called resonance structures. In fact the carbocation

is a hybrid of two contributing resonance structures:

The positive charge is delocalized.

In the next step, when the carbocation reacts with bromine anion, it can react

both at C-2 to give the product of 1,2-addition and at C-4 to give the product of

1,4-addition:

The other addition reactions can occur as 1,2- or 1,4-addition too. For example:

Page 34: Bio-Organic Chem Lectures

REACTIVITY OF AROMATIC COMPOUNDS

The term “aromatic compounds” was appeared, because the first compounds

of this series that were considered had a pleasant odor. Further investigations had

shown that there are compounds without odor or with disgusting odor among

aromatic compounds too.

The first aromatic compounds that were considered are benzene and its

derivatives and substances of similar structures (naphthalene, anthracene etc.)

They are hydrocarbons. Now a lot of compounds are known whose

structures are not like that of benzene (heterocyclic compounds are examples). But

we continue to use the terms “aromatic compounds” and “aromaticity” to signify

the characteristic physical and chemical behavior of benzene and the relative

compounds.

Aromaticity is a complex of properties of closed conjugated systems

reflecting their resistance to the addition and oxidation reactions.

A resonance is the phenomenon in which a molecule or ion can be

represented by two or more structures, having the same arrangement of atoms

nuclei, but the different distribution of electrons. These various structures are

called resonating structures or canonical forms while the actual structure is a

resonance hybrid of several canonical forms. The hybrid is the most stable form

with a minimum energy. Thus the molecule is stabilized by the resonance.

Page 35: Bio-Organic Chem Lectures

Let us take benzene as an example. Benzene molecule can be represented by

two Kekule’s structures:

These two structures differ by the distribution of electrons only. They are

canonical structures. Actually benzene molecule is a hybrid of two structures I and

II and it can be represented by the formula with the inscribed circle. Six π-

electrons of benzene are free to move through the system and thus do not belong to

any particular atom. It is more suitable to represent benzene ring as where the

circle corresponds to the so-called delocalized bond:

If benzene is really a resonance hybrid of structures I and II its molecule can

not have three single and three double bonds. In the case of resonance every

carbon-carbon bond in benzene will be an intermediate between a normal single

bond and a normal double bond. Each bond will be a hybrid bond. This fact has

been confirmed by the X-ray diffraction study of benzene. These investigations

show that the length of each carbon-carbon bond in benzene is 0.139 nm, which is

an intermediate between 0.154 nm (C-C-bond length) and 0.134 nm (C=C-bond

length). The lengths of all six carbon-carbon bonds in benzene are identical,

because all six bonds are identical: they are one-and-a-half bonds.

Thus, benzene has a symmetrical structure with no double bonds.

Electronic structure of benzene molecule.

There are six sp2-hybridized carbon atoms in the benzene molecule. The

angle between each two hybrid orbitals is 120o. The molecule is flat; all σ-bonds lie

in the same plane. It is very symmetrical molecule, each carbon lie at the angle of a

regular hexagon. Six unhybrid pz-orbitals are oriented perpendicular to the plane of

σ-bonds. Each pz-orbital is occupied by one electron.

Page 36: Bio-Organic Chem Lectures

As in the case of ethene, p-orbital of one carbon overlaps p-orbital of the

neighboring carbon atom and π-bond is formed. In the case of benzene p-orbital of

any one carbon atom overlaps p-orbitals of both carbon atoms to which it is

bonded. All six pz-orbitals are overlapped to form the common π-electronic cloud

that is situated above and below the plane of the cycle.

This cloud can be represented as two electronic

doughnuts, one lying above and the other below

the plane of the ring. Benzene molecule is π,π-

conjugated system; π-electrons delocalization

makes the molecule more stable.

So, two formulas of benzene can be used. One is the Kekule’s structure with

three double bonds, and other is a hexagon with inscribed circle, to represent the

idea of a delocalized π-electron cloud. The formula with the inscribed circle

emphasizes the fact of the distribution of electrons around the ring. The Kekule’s

formula reminds us very clearly that there are six π-electrons in benzene. But we

must keep in our mind that the double bonds are not fixed in the shown positions

and they are not really double bonds at all.

We already know that the closed conjugated systems are the most stable,

because when the conjugated system is formed energy is released. It is so-called

prize of energy. For benzene it is equal about 36 kcal/mole, or 151 kJ/mole.

Benzene and other aromatic compounds usually react in such a way as to preserve

their aromatic structure and therefore retain their resonance energy.

Page 37: Bio-Organic Chem Lectures

Aromatic compounds are not only benzene and its derivatives. Some

aromatic compounds structurally are not like benzene. How can we determine: is

the certain compound the aromatic one? What properties must all aromatic

compounds have at whole?

From the experimental standpoint, aromatic compounds are compounds

whose molecular formulas show a high degree of unsaturation, and yet which are

resistant to the addition and oxidation reactions. Substitution reactions are

characteristic for aromatic compounds.

But how can we determine: is any certain compound aromatic one, if we do

not know its chemical properties and know the chemical structure only?

On the bases of molecular orbitals calculations E. Huckel gave the basic

rules of the aromaticity. According to Huckel's rules three structural requirements

for aromaticity must be satisfied:

1) The molecule must be cyclic;

2) The ring system must be flat, because only in this case the ring

delocalization of π- electrons is possible;

3) The ring system must contain the Huckel's number of delocalized 

π-electrons. This number is (4n+2) electrons, where n must be an integer

(0,1,2,3 ... etc).

It means, that closed conjugated systems 2 (n=0), 6 (n=1), 10 (n=2), 14

(n=3) π-electrons satisfy the requirements of Huckel's rule and must exhibit the

aromaticity (aromatic properties). It does not depend upon whether they

contain a benzene ring or not. These π-electrons of the conjugated system are

regarded as common to all atoms of the system (they may be not carbon atoms

only) and they are considered to occupy common molecular orbitals (all electrons

belong to all atoms of the aromatic system).

Nomenclature of benzene derivatives

Some special names of aromatic hydrocarbons are used and they are

accepted by IUPAC system, too. They are:

Page 38: Bio-Organic Chem Lectures

These compounds may be also named as benzene derivatives.

xylenes (dimethylbenzenes)

Other compounds are named as derivatives of benzene only. For example,

When two substituents are present three isomeric structures are possible.

They are designated as by the prefixes ortho-, meta- and para-, which are usually

abbreviated as o-, m- and p-. If one of the groups that gives the special name is

present, we can name this compound as a derivative of this special name, for

example:

If more than two groups are attached to the benzene ring, numbers are used

to indicate their relative positions. For example:

Page 39: Bio-Organic Chem Lectures

The radical of benzene C6H5- is named phenyl. Toluene can form four

different radicals:

Chemical properties of benzene

Benzene is unsaturated compound, but we already know that there are no

single and double C-C bonds in its molecule. There is so-called aromatic bond

(the common electronic cloud) in its molecule. Benzene does not decolorize

bromine water as alkenes and it is not oxidized by the solution of potassium

permanganate. So it does not undergo the typical addition reactions of unsaturated

compounds. Typical for benzene are substitution reactions, because in these

reactions its aromatic structure is preserved. Three types of substitution are known:

radical, electrophilic and nucleophilic substitution. What type of substitution

reaction is characteristic for benzene? To answer this question let us remember the

electronic structure of benzene molecule. We know that the common π-electronic

cloud of benzene is situated above and below the plane of the ring. Therefore this

cloud may be attacked by electrophilic reagents. So, electrophilic

substitution reactions are characteristic for benzene:

There are examples of electrophilic substitution reactions:

Page 40: Bio-Organic Chem Lectures

The mechanism of electrophilic substitution reactions in aromatic compounds

Electrophilic substitution reactions proceed in such a way:

In the 1-st step an electrophile interacts with a total π-electronic cloud (they

are attracted to each other) and a π-complex is formed. Then the electrophile

attaches itself to one carbon atom of the benzene ring, using two of six π-

electrons of the aromatic cloud to form σ-bond with a ring carbon atom (σ-

complex is formed). This carbon atom becomes sp3-hybridized. Therefore σ-

complex is non-aromatic system (the ring is not flat, because one carbon atom

becomes sp3-hybridized; only five carbon atoms of the ring now take part in the

conjugation and only four electrons are delocalized in the conjugation system).

This positive charge is distributed over the five carbon atom (we show this

by non-closed ring with "plus" into it). The dispersal of the positive charge over

the molecule by resonance makes this ion more stable than an ion with a localized

positive charge. This ion is called benzenonium ion.

These two steps of reaction are similar to electrophilic addition reaction. But

attachment of a nucleophilic particle to the benzenonium ion to yield the addition

Page 41: Bio-Organic Chem Lectures

product would destroy the aromatic character of the ring. Instead, to reduce the

aromaticity σ-complex loses a proton. The pair of electrons of C-H σ-bond returns

to aromatic cloud. We can see that this step differs from addition reactions: the

intermediate carbocation does not add a nucleophile but detaches a proton.

It is the formation of the carbocation (step 2) that is the more difficult step;

once formed, the carbocation rapidly loses a proton (step 3) to form the final

product.

Particular examples of electrophilic substitution reactions

Halogenation reaction. The reaction of benzene with chlorine (or bromine)

proceeds slowly without a catalyst, but it occurs quite easily with one. Lewis acids

(such as FeCl3, FeBr3, AlCl3, AlBr3 and so on) are used in these reactions as a

catalyst. Lewis acid is a compound, which can except a pair of electrons.

The interaction of a halogen molecule with a Lewis acid converts chlorine

to a strong electrophile by the polarizing the Cl-Cl bond. Ferric chloride

combines with Cl2 using a lone pair of chlorine to form complex, from which

chlorine is transferred, without its electrons, directly to the ring:

Then this reaction proceeds by common mechanism of electrophilic

substitution:

Alkylation reaction.  Alkylation of aromatic compounds is known as a

Friedal-Crafts reaction, because the French scientist Friedel and the American

scientist Crafts were the first who discovered this reaction.

Page 42: Bio-Organic Chem Lectures

The electrophile is a carbocation, which is formed by removing halide ion

from an alkyl halide with a Lewis acid as a catalyst:

Then this reaction proceeds by common mechanism of electrophilic

substitution:

Nitration reaction.  Nitration reaction occurs in the presents of a mixture

of the nitric and sulfuric acids. Sulfuric acid is a catalyst of this reaction.

First of all the nitronium ion (NO2+)  which is electrophilic particle is

generated:

In this reaction sulfuric acid serves as an acid and the much weaker nitric

acid serves as a base. (By Bronsted-Lowry theory, an acid is a compound that

gives up a proton, and a base is a compound that accepts a proton). The protonated

nitric acid is formed. Then it loses a water molecule to generate the nitronium ion.

This is an electrophile that attacks the aromatic ring. And then this reaction

proceeds by common mechanism of electrophilic substitution:

So, concentrated sulfuric acid is a catalyst of this reaction. The other its role

is to take away water, which is formed in this reaction (to displace the equilibrium

of the reaction).

Page 43: Bio-Organic Chem Lectures

Sulfonation of benzene.  For sulfonation we usually use sulfuric acid

containing an excess of sulfur trioxide (it is so called fuming sulfuric acid).

There is a big partial positive charge in the sulfur atom; therefore it is

an electrophilic reagent.

SO3 molecule attacks the common electronic cloud of the benzene to form

a π-complex. Then the sulfur atom uses two electrons of the aromatic ring to form

a new σ-bond. σ-Complex is non-aromatic system, therefore a proton is lost and

this proton is added to the oxygen atom. The product of this reaction is named

benzenesulfonic acid.

Reactions with breach of the aromaticity

It is difficult to carry out reactions which result is the breach of the

aromaticity. For example the hydrogenation reaction occurs on passing the vapor

of benzene and hydrogen over Ni at temperature of 200oC. Cyclohexane is formed

in this reaction:

Oxidation reactions

Benzene may be oxidized only with very strong oxidizing reagents (V2O5 at

temperature of 500oC). Aromatic ring is broken in these conditions. But oxidation

of side chains of benzene homologues occurs easily. They may be oxidized with

solution of potassium permanganate (with prolonged treatment) to form benzoic

acid:

Page 44: Bio-Organic Chem Lectures

If other homologous of benzene are oxidized the benzoic acid is obtained

too:

Reactivity of naphthalene

Naphthalene is an aromatic compound, because it satisfies all Huckel’s

rules. The bonds lengths in naphthalene are not all identical, but they all

approximate the bond length in benzene. Although it has two six-membered rings,

naphthalene has resonance energy somewhat less, than twice that of benzene

(about 60 kcal/mole, but not 2x36=72 kcal/mole). Because of its symmetry

naphthalene has two sets of equivalent carbon atoms. They are designated as α-

and β-positions:

Like benzene naphthalene undergoes electrophilic substitution reactions

(halogenation, nitration and so on). But these reactions usually occur under

somewhat milder conditions than benzene reactions.

The electronic density in α-positions is greater than that in β-positions. For

this reason electrophilic substitution reactions occur in α-positions first of all. For

example, naphthalene can be brominated with α-bromonaphthalene formation:

This reaction occurs without any catalyst in acetic acid medium.

Page 45: Bio-Organic Chem Lectures

Nitration reaction of naphthalene gives α-nitronaphthalene:

When naphthalene is heated with concentrated sulfuric acid both α- and β-

naphthalenesulfonic acids can be obtained. The result of the reaction depends upon

its conditions.

If sulfonation reaction occurs at temperature about 50-80oC, the principal

product is α-naphthalenesulfonic acid (1-naphthalenesulfonic acid ). At the higher

temperature (about 160oC) the main product is β-naphthalenesulfonic acid (2-

naphthalenesulfonic acid).

MUTUAL INFLUENCE OF ATOMS IN THE MOLECULES.

ELECTROPHILIC SUBSTITUTION REACTIONS IN BENZENE DERIVATIVES

You already know, that atoms and groups of atoms of a molecule influence

one another. The mutual influence of atoms is the main factor that determines the

reactivity of the molecule.

We shell talk about so-called electronic displacement effects. Electronic

effect of the atom or atomic group (or substituent) is the transference of its

influence in the molecule.

Two types of electronic effects are known: they are inductive and

mesomeric (or resonance) ones.

Page 46: Bio-Organic Chem Lectures

The inductive effect is the transference of the substituents influence through

the molecular chain due to polarization of  σ-bonds. For example:

We know, that C-Cl bond is a polar one, because chlorine is more

electrenegative element than carbon. The C-C bond is nonpolar. But chlorine

exerts its influence not only on its "own" bond, but on the next bonds too. It can

be obtained in such a way: When chlorine withdraws electronic pair of σ-bond

from carbon the partial negative charge (δ-) appears at the chlorine atom and the

partial positive charge appears at the carbon atom. To decrease its electronic

deficiency this electron-deficient carbon withdraws electronic pair of the next σ-

bond. The partial positive charge (δ+) appears at the next carbon atom. And so on.

This effect weakens steadily with increasing a distance from the substituent,

because the ability of σ-bonds to be polarized is small. For this reason the value

of δ+ is greater than that of δ+` and so on. The inductive effect is transferred only

at three or four σ-bonds only. In our example chlorine exerts the

negative inductive effect, because it withdraws the electronic density from the

other part of the molecule. (It is designated as -I). The inductive effect is

designated in the formula by arrow that is directed to the symbol of the most

electronegative element.

Most elements likely to be substituted for hydrogen in an organic molecule

are more electronegative than hydrogen (the inductive effect of hydrogen is

considered as zero), so that most substituents exert the electron-withdrawing

inductive effect (or negative inductive effect), for example: -F, -Cl, -Br, -I, -OH, -

NH2, -NO2, -COOH, >C=O .

Page 47: Bio-Organic Chem Lectures

If a substituent displaces the electronic density from itself to the carbon

atom of the chain, this substituent exerts the  positive inductive effect (it is

electron-releasing inductive effect). It is designated as +I.

Oxygen with full negative charge exerts the positive

inductive effect (+I).

Carbon atom of methyl group is sp3-hybridized and the neighboring atom is sp2-

hybridized. sp2-Hybridized carbon is more electronegative than sp3-one. Therefore

methyl group exerts the positive inductive effect.

So, the inductive effect is exerted in any molecules where the atoms with

different electronegativity are present.

The other type of the electronic effects (the mesomeric effect) can be

displayed in conjugated systems only.

Conjugation is the phenomenon of the extra interaction of p-electronic

orbitals. The result of the conjugation is the delocalization of the electronic

density.

To overlapping p-orbitals they must be situated perpendicular to the same

plane. So, all atoms of the conjugated system must lie in the same plane (the

conjugated system is flat). Therefore the conjugated system is the system with

alternated single and double bonds. It is so-called π,π-conjugated system (1,3-

butadiene is the simplest example).

Let us tackle its electronic structure: CH2=CH-CH=CH2.

All carbon atoms are sp2-hybridized, therefore all atoms lie in the same plane

and all σ-bonds are situated in the same plane too. Each carbon atom has also

unhybrid pz-orbital, that is oriented perpendicular to the plane of σ-bonds. We can

suppose that one π-bond is formed by the p-orbitals of C1 and C2 overlapping and

Page 48: Bio-Organic Chem Lectures

the other – by that of C3 and C4. But really in this molecule p-orbital of C2

overlaps p-orbital of C3 too. So, in this molecule the overlapping of all four p-

orbitals occurs to form a common electronic cloud. Four electrons belong to four

carbon atoms. The electronic density is delocalized between these four carbon

atoms. It can be shown as:

The electron cloud is situated above and below the plane of σ-bonds.

This kind of conjugation is called π,π-conjugation (and molecules are named

π,π-conjugated systems), because the electrons of π-bonds take part in this process.

Conjugation gives a certain double bond character to the C2-C3 bond and a certain

single bond character to the C1-C2 and C3-C4 bonds (C2-C3 bond length in 1,3-

butadiene is 0.148 nm, but not 0.154 nm as that of single bonds in alkanes).

The conjugation makes the molecule more stable, because each pair of

electrons attracts and is attracted by not just two nuclei, but four (in our example)

or more. During a conjugated system formation an energy is released and therefore

stability of the molecule is increased. The longer is the conjugated chain, the

higher is the releasing energy, the more stable is the system (molecule).

1,3-Butadiene is the open-chain π,π-conjugated system. Benzene molecule

is the example of closed π,π-conjugated systems.

All carbon atoms in benzene are sp2-hybridized, therefore all σ-bonds lie in

the same plane, the molecule is flat. Each carbon has unhybrid pz-orbital, situated

perpendicular a plane of σ-bonds. The overlapping all six pz-orbitals occurs and the

common electron cloud is formed. It is situated abow and below the plane. This

delocalization is more complete. The energy of the closed conjugated systems is

lesser than that of opened conjugated systems. So, closed conjugated systems are

more stable, than opened conjugated systems.

Page 49: Bio-Organic Chem Lectures

The other kind of conjugated systems is so called p,π -conjugated system. In

this case orbitals of π-bonds interact with p-orbitals, containing one electron or

unshared electron pair or with vacant p-orbital. For example, in vinyl amine

CH2=CH-NH2 molecule:

Carbon and nitrogen atoms are sp2-hybridized. The molecule is flat. All

three p-orbitals overlap one another, and p,π-conjugation occurs. There are three

centers and four delocalized electrons in this system.

The conjugation can be shown by curved arrow that is directed as the

displacement of the electronic density:

In allyl cation CH2=CH-CH2+ all carbon atoms are sp2-hybridized. Carbon

with full positive charge has a vacant pz-orbital. The common electronic cloud is

formed as a result of the p,π-conjugation. There are three centers in this conjugated

system and only two delocalized electrons.

Thus, the mesomeric effect is exerted in conjugated systems only.

Mesomeric (or resonance) effect is the transference of the substituents

influence through the conjugated system due to polarization of  π-bonds.

Mesomeric effect does not weaken with increasing a distance from the

substituents, because the ability of π-bonds to be polarized is higher than that of σ-

bonds.

Pay your attention: substituent can exert its mesomeric effect only in

case if it is the part of the conjugated system. For example:

A mino-group is the part of the p,π-conjugated system. p,π-conjugation

Amino-group does not take part in the conjugation. Mesomeric effect is impossible.

π,π-conjugation

Page 50: Bio-Organic Chem Lectures

Mesomeric effect can be both positive and negative one. It is designated

+M and -M. For example:

Clorine exerts the positive mesomeric effect (+M), because its atom gives

two electrons into p,π-conjugated system (its unshared electron pair). Aldehyde

group exerts negative mesomeric effect (-M), because oxygen atom gives only one

electron into π,π-conjugation (it has one electron on the unhybrid orbital). Each

carbon atom gives one electron too. But oxygen is more electronegative than

carbon; therefore the electronic density is displaced to the oxygen atom. At whole

aldehyde group withdraws electronic density and therefore exerts the negative

resonance effect (-M).

In the methylvynyl ether molecule methoxy group exerts the

positive mesomeric effect, because oxygen gives two

electrons (its unshared electron pair) into the conjugated system.

Summary:

1. Substituents giving two electrons into the conjugated system exert the

positive mesomeric effect. They are:

a) substituents, having the full negative charge, for example, –O - ;

b) substituents, having atoms with unshared electron pair in pz-orbital, for

example: –NH2, -OH, -F, -Cl, -Br-, -I, -OR (-OCH3, -OC2H5).

2. Substituents attracting the electronic density from the conjugated system

exert the negative mesomeric effect. They are substituents including more

electronegative atoms, connected by double bonds, for example:

Page 51: Bio-Organic Chem Lectures

Now you can see, that a substituent can exert both inductive and mesomeric

effects at the same time. These two effects can be identical by their direction

(+I, +M; -I, -M), but they can be non-identical, too (for example, -I, +M). How

can we determine the general influence of the substituent for the other part of the

molecule (by the other words: is this substituent electron withdrawing or electron

releasing at whole)?

To answer this question we need to compare values of these two effects.

The positive effect is predominated - the substituent is electron releasing. The

negative effect is predominated - the substituent is electron withdrawing. As usual

the mesomeric effect is exerted stronger than the inductive effect. Halogens are

exceptions; their negative inductive effect is always stronger than the positive

mesomeric one because of their high electronegativity.

Let us tackle some examples.

Amino group is electron

releasing substituent.

Amino group exerts the negative inductive

effect only, because a molecule is not conjugated system. Amino group is electron

withdrawing substituent.

Hydroxo group is electron

releasing substituent.

Hydroxo group exerts the negative inductive effect only, because

OH-group does not take part in the

conjugated system. It is electron withdrawing

substituent.

Thus, electron releasing substituents increase an electronic density of the

molecule and electron withdrawing substituents decrease it. We can determine

Page 52: Bio-Organic Chem Lectures

the influence of the certain substituent in the certain molecule only! The

substituent can exert the different influence in different molecules.

When we discussed electrophilic substitution reactions in benzene it was not

a problem for us to determine the direction of substitution in the molecule, because

all positions in the benzene molecule are the equal.

If there is already a substituent in the benzene ring three different isomers

can be obtained:

Substituents, that are already present in the aromatic ring, determine a

position taken by a new substituent.

Two types of substituents are known. Substituents of the 1-st type are ortho-

and para-directing substituents. Substituents of the 2-nd type are meta-directing

groups. The directing action depends upon the nature of the substituent which is

already present in the molecule.

Ortho- and para-directing substituents are as follows: -OH, -O-, -NH2, alkyl

groups (methyl, ethyl etc.) and halogens. You can see: they are groups, which exert

a positive inductive or positive mesomeric effect. These substituents are the cause

of the electronic density in the benzene ring redistribution in such a way, that the

greatest electronic density is in ortho- and para-positions. For example:

Hydroxyl group in phenol exerts the positive mesomeric

effect, because the unshared electron pair of oxygen takes

Page 53: Bio-Organic Chem Lectures

part in p,π-conjugated system. OH-group increases the electronic density

of the ring (+M>-I), especially in ortho- and para-positions. Therefore

electrophilic reagents are directed in these positions.

Substituents of the 2-nd type are meta-directing substituents. They are as

follows: -NH3+, -COOH, -CHO (aldehyde group), -NO2, -SO3H. All these

substituents exert the negative inductive or negative mesomeric effect. They attract

the electronic cloud and decrease the electronic density in the ring, especially in

ortho- and para-positions. The electronic density in meta-positions is therefore

relatively higher than that in ortho- and para-positions. For this reason electrophilic

reagents are directed towards atoms in meta-positions.

In benzoic acid carboxyl group exerts

the negative inductive and negative

mesomeric effects. The electronic density

in the ring is decreased, but in meta positions

it is relatively higher. In nitrobenzene nitro-

group exerts the negative inductive and

negative mesomeric effects.

Substituents affect the speed of the electrophilic substitution reaction,

whether it will occur more slowly or faster than for benzene.

Substituents of the 1-st type increase the electronic density of the aromatic

ring. Therefore they are ring-activating groups. Electrophilic substitution reactions

occur more easily than that in benzene. Halogens are exceptions. Because of their

high electronegativity they are strong electron-withdrawing substituents (-I>+M)

and they are ring-deactivating substituents. They decrease the speed of SE-

reactions. But you need to remember that due to the conjugation of the unshared

electron pair of halogen with the aromatic cloud they are o-,p-directing

substituents.

All meta-directing groups (or substituents of the 2-nd type) withdraw

electrons from the ring. They decrease the electronic density of the aromatic ring.

Page 54: Bio-Organic Chem Lectures

Therefore all meta-directing groups are ring deactivating substituents in

electrophilic substitution reactions. They decrease the speed of these reactions.

Summary:

- Ring-activating substituents are all ortho- and para-directing substituents,

except halogens.

- Ring-deactivating substituents are all meta-directing substituents and

halogens.

Let us discuss some particular examples of SE-reactions in benzene

derivatives.

Chlorination reaction of benzoic acid occur more slowly than chlorination of

benzene, because carboxyl group is ring-deactivating substituent (carboxyl group

exerts both negative inductive and mesomeric effects). Chlorine replaces hydrogen

in meta-position, because carboxyl group is meta-directing substituent.

Bromination of aniline (aminobenzene) occurs very easily without any

catalyst, at room temperature, because amino-group is a strong electron-releasing,

ring-activating substituent. Substitution reaction can occur in ortho- or para-

positions.

If bromination reaction is carried out in the presence of the excess of

bromine water (water is a polar solvent) 2,4,6-tribromoaniline is obtained:

Page 55: Bio-Organic Chem Lectures

Nitration of chlorobenzene occurs more slowly than that of benzene, because

chlorin is ring deactivating substituent.

Nitro-group is directed in ortho- and para-positions, because chlorine is the

1-st type substituent.

Thus, to determine how readily does the electrophilic substitution reaction

occur and where does it occur we need to examine the electronic influence of the

substituents in the ring.

REACTIVITY OF HALOGEN DERIVATIVES OF HYDROCARBONS,

ALCOHOLS AND PHENOLS

We start chemical properties of organic compounds classes study. Each class

of compounds has its own functional group. The functional group is an atom or

atomic group that defines a structure of the particular family of organic

compounds and, at the same time/ determines their properties.

The halogen atom is the functional group of halogen derivatives of

hydrocarbons.

Classification and nomenclature of halogen derivatives of hydrocarbons

They can be classified:

a) as mono-, di-, tri- etc. derivatives, for example:

Page 56: Bio-Organic Chem Lectures

b) as chloro-, bromo-, fluoro- and iodo-derivatives, for example:

c) as derivatives of alkanes, alkenes, alkynes and aromatic compounds.

Monohalogen derivatives of alkanes are called alkyl halides. They are

classified as primary (1o), secondary (2o) and tertiary (3o) alkyl halides, according

to the kind of carbon that bears a halogen atom.

Two types of nomenclature can be used for alkyl halides naming. Common

names can be given for the simplest alkyl halides. The common name is that of the

corresponding radical, following by the name of halogen, where ending –ine is

changed into –ide. For example:

IUPAC names are the names of corresponding alkanes with a halogen

attached as a side chain. For example: 1) is chloroethane and 2) is 2-

bromopropane.

The other examples are as follows:

Chemical properties of alkyl halides

To determine what type of reactions is characteristic for alkyl halides we

need to consider the distribution of the electronic density in their molecules.

The electronic density is displaced to the more electronegative

halogen atom. A partial positive charge appears on the carbon atom

Page 57: Bio-Organic Chem Lectures

which is bonded with halogen. This electron-deficient carbon is an electrophilic

center (it is a place for attack of a nucleophile). Therefore nucleophilic

substitution reactions (SN) are characteristic for alkyl halides. The examples of SN

reactions are as follows:

The general scheme of this reaction is as follows:

Carbon-halogen bond is broken heterolytically. A nucleophile supplies its

electron pair for a new σ-bond formation. The nucleophile replaces halogen in the

molecule of alkyl halide. X- is a leaving group, it leaves the molecule of alkyl

halide and takes away the pair of the electrons.

Nucleophilic substitution reactions can be the reversible process, because

each leaving group is the nucleophile too (it has the unshared electron pair, which

can be supplied for σ-bond formation). We can use various methods to force the

reaction to go in the forward direction. For example, we can choose the

Page 58: Bio-Organic Chem Lectures

nucleophile that is stronger than a living group. Or we can use a large excess of the

reagent or remove one of the products of the reaction.

SN- reaction occurs easily if there is a good nucleophile and a good living

group in this reaction. What is the good nucleophile? It is the strong (active)

nucleophile. How can we compare different nucleophiles activity?

1) Negative ions are more active nucleophiles than the corresponding neutral

molecules, because anions can supply an electron pair more easily. Thus, OH- is

better than H2O, R-O-Na+ (alcoholate) is better than R-OH (alcohol), R-S-Na+

(thiolate) is better than R-SH (thiol), R-COO-Na+ (salt of carboxylic acid –

carboxylate) is better than R-COOH (carboxylic acid).

2) The low is the electronegativity of the atom of nucleophilic center; the

higher is its activity, because this atom can supply the electron pair more easily

than an atom of higher electronegativity. For example, NH3 is more active

nucleophile than H2O, because electronegativity of oxygen is higher than that of

nitrogen.

A good leaving group is the weak nucleophile. For example, a neutral

molecule of water is better as a living group than OH- anion.

Elimination reactions (E) in alkyl halides

If alkyl halide is heated with an aqueous solution of sodium hydroxide a

corresponding alcohol is obtained. This is nucleophilic substitution reaction, for

example:

But if we use alcoholic solution of sodium hydroxide the other reaction can

occur. It is elimination reaction (E):

Page 59: Bio-Organic Chem Lectures

To explain a possibility of elimination reactions we need to discuss the

distribution of the electronic density in the alkyl halide molecule (1-chloropropane

is an example).

Chlorine displaces the electronic density to itself.

C1 becomes partially positively charged. The inductive

effect is transferred father through the chain and the

neighboring carbon becomes partially positively charged too. The result of the

carbon electron deficiency is C-H bonds polarization. Thus C2 is weak CH-acid

center. Weak CH-acids can react with a strong base only. Sodium hydroxide in

aqueous solution is not enough basic to this acid center, but NaOH in alcoholic

solution is stronger base, it can eliminate hydrogen proton from CH-acid center.

SN and E-reactions compete with each other. The mechanism of the reactions

depends on the conditions.

ALCOHOLS

Alcohols are compounds of the general formula R-OH, where R is any alkyl

or substituted alkyl group.

Classification and nomenclature

Alcohols can be classified as primary, secondary and tertiary one in

accordance with the kind of carbon that bears a hydroxyl group. Alcohols can be

classified also in accordance with the nature of the radical as derivatives of

alkanes, alkenes, cycloalkanes. For example:

Page 60: Bio-Organic Chem Lectures

Alcohols are named by two principal systems. For the simplest alcohols

common names are most often used. The common name consists simply of the

alkyl group name followed by the word alcohol, for example:

In the IUPAC system a suffix –ol is used to designate a hydroxyl group:

Reactivity of alcohols.

To determine what reactions are characteristic for alcohols let us tackle a

distribution of the electronic density in their molecules.

Due to unshared electron pair

of oxygen alcohols are

nucleophiles. On the other hand

electron-deficient carbon is the

electrophilic center. Therefore

alcohols can react with nucleophilic reagents. Alcohols are both acids and bases.

Hydrogen is bonded to the very electronegative oxygen. OH-bond is polar one and

hydrogen can be lost as a proton (it is acidity). On the other hand oxygen with its

unshared pair makes an alcohol basic.

Page 61: Bio-Organic Chem Lectures

Thus, there are acid, basic, nucleophilic and electrophilic centers in the

alcohols molecules.

Acid properties of alcohols are proved by their reactions with active metals

such as sodium and potassium to liberate hydrogen gas:

The general name of this kind of salts is alkoxides. Alcohols are weaker

acids than water. When water is added to an alkoxide sodium hydroxide and a

parent alcohol are formed:

Basic properties of alcohols. Alcohols are basic enough to accept a proton

from strong acids like concentrated hydrochloric or sulfuric acid to form salts:

Properties of alcohols as electrophiles. There is a partial positive charge on

the α-carbon atom. It is an electrophilic center due to which an alcohol can react

with nucleophilic reagents. A reaction of alcohols with hydrogen halides is the

example:

It is the nucleophilic substitution reaction (SN). Chloride anion is the

nucleophile. But you already know that alkyl halides can react with water to form

alcohol. This reaction is reversible one. To increase the activity of the alcohol in

this reaction an acid catalyst can be used.

Page 62: Bio-Organic Chem Lectures

At the first step of the reaction an alcohol reacts with the acid proton, the

protonated alcohol is formed. Then it dissociates into water and a carbocation.

There is a full positive charge on the carbon atom in the carbocation. It is more

active electrophilic center than that in the parent alcohol. Then carbocation

combines with a halide ion to form alkyl halide.

Ethers formation (intermolecular dehydration reaction) . If an alcohol is

heated in the presence of concentrated sulfuric acid an ether is obtained:

The mechanism of this reaction is as follows:

At the first step of the reaction an alcohol accepts a proton and protonated

alcohol is formed. Then a molecule of water is lost and a carbocation is obtained.

This carbocation reacts with the other molecule of the alcohol as with the

nucleophilic reagent. The protonated ether is formed that then gives out a proton.

Alcohol molecules play two roles in this reaction: the protonated alcohol is a

substrate and the second molecule is the nucleophile. Concentrated sulfuric acid

plays two roles also: it is a catalyst, that increase electrophilic center activity

(partial positive charge on α-carbon atom is converted into full positive charge)

and it is a water removing agent.

Intramolecular dehydration reaction. If an alcohol is heated with the

concentrated sulfuric acid at temperature about 180-200oC dehydration reaction

occurs:

Page 63: Bio-Organic Chem Lectures

Dehydration is an elimination reaction. The first two steps of this reaction

are the same with that of the reaction of ethers formation:

but then this carbocation reacts as CH-acid with sulfuric acid anion (a base) and

gives up a proton:

Dehydration reaction competes with the reaction of ether formation. The

way of the reaction depends upon its conditions.

Dehydration reaction occurs in accordance with Zaytzeff’s rule, for example:

Reactions of esters formation. Alcohols can react as nucleophiles with

carboxylic acids to form esters. This reaction is known as esterification reaction,

for example:

This reaction occurs when an alcohol is heated with the carboxylic acid in

the presence of any mineral acid, usually concentrated sulfuric acid. It is a

nucleophilic substitution reaction.

Oxidation of alcohols. Different products can be obtained when alcohols are

oxidized. They depend upon whether the alcohol is primary, secondary or tertiary.

The oxidation reaction of the primary alcohol gives an aldehyde:

Page 64: Bio-Organic Chem Lectures

Then this aldehyde can be oxidized very easily to form the corresponding

carboxylic acid.

Secondary alcohols can be oxidized into ketones:

Tertiary alcohols can be oxidized in more hard conditions only.

Potassium permanganate and acidic aqueous solution of potassium

dichromate are often used for oxidation reactions of alcohols.

Qualitative tests of ethanol. Two reactions may be used for ethanol

distinguishing:

1. Oxidation reaction by potassium dichromate.

When a mixture of ethanol, potassium dichromate and diluted sulfuric acid

is heated the orange color disappears and opaque blue-green solution is obtained.

The characteristic “apple” smell of acetaldehyde appears.

2. Iodoform reaction.

When ethanol is heated feebly with iodine in the presence of an alkali,

iodoform is formed. The yellowish precipitate of iodoform is formed. Iodoform

also has the characteristic smell (“hospital” smell).

Polyalcohols

Polyalcohols molecules contain two or more hydroxyl groups. For example:

Page 65: Bio-Organic Chem Lectures

All properties of alcohols are characteristic for polyalcohols too, but

polyalcohols can react by one hydroxyl group or by more than one group. For

example:

Polyalcohols are stronger acids than monoalcohols, because one hydroxyl

group places an electron withdrawing role in regard to another. Polyalcohols can

react with copper (II) hydroxide:

A blue precipitate of copper hydroxide is dissolved and the dark-blue

solution of the complex salt is formed. It is the qualitative test of all polyalcohols.

We can not distinguish glycerol and ethelene glycol using this reaction.

As all alcohols polyalcohols can form esters. Glyceryl trinitrate (the ester of

glycerol and nitric acid) is the most important of them:

Glyceryl trinitrate is very powerful explosive; it is used in the dynamites

manufacture. Glyceryl trinitrate (nitroglycerol) is used in medicine to give relief

from chest pain in angina.

PHENOLS

Page 66: Bio-Organic Chem Lectures

Phenols are compounds containing hydroxyl group or groups attached

directly to the aromatic ring. Phenols are classified as mono- and polyphenols.

Their examples are following:

Chemical properties of phenols

Phenols exhibit acid properties. The acidity of phenols is stronger than that

of alcohols, because of higher stability of phenolate anion (it is p,π-conjugated

system). Phenols can react with sodium hydroxide to form salts – phenolates:

Phenols are lesser acids as carboxylic acids and carbonic acid. For this

reason phenols can not react with sodium bicarbonate.

Basic and nucleophilic properties of phenols are decreased in comparison

with that of alcohols. Phenols do not form salts with mineral acids. They do not

react with carboxylic acids to form esters. To ester formation the more active

derivatives of carboxylic acids must be used: they are anhydrides and acids

chlorides. For example:

Page 67: Bio-Organic Chem Lectures

It is SN reaction.

Phenols are converted into alkyl aryl ethers by reaction in alkaline solution

with alkyl halides (it is Williamson synthesis):

The electrophilic substitution reactions are characteristic for phenols as for

aromatic compounds. SN reactions in phenols occur more easily as in benzene,

because hydroxyl group is ring activating substituent. For example, nitration

reaction of phenol occurs in the presence of dilute nitric acid at room temperature

(compare, nitration reaction of benzene occurs at high temperature by the mixture

of concentrated nitric and sulfuric acids):

In the bromination reaction which is carried out in a solvent of low polarity,

such as chloroform monobromoderivatives are obtained:

Page 68: Bio-Organic Chem Lectures

If bromination occurs in the presence of excess of bromine water 2,4,6-

tribromophenol is obtained:

Oxidation reactions of phenols. Phenols can be oxidized very easily, even in

the presence of oxygen of the air. A mixture of different products can be obtained

as a result of these reactions.

If potassium dichromate K2Cr2O7 in acidic medium is used for oxidation

quinones are formed:

Polyphenols are oxidized more easily than phenol:

Phenols form colored complexes with ferric chloride (this test is also given

by enols (enol group is =CH-OH).

Phenol is also identified by bromination reaction:

Page 69: Bio-Organic Chem Lectures

White precipitate of 2,4,6-tribromophenol is formed in this reaction.

ACID AND BASIC PROPERTIES OF ORGANIC COMPOUNDS.

REACTIVITY OF AMINES

Acidity and basicity of organic compounds are important aspects of their

reactivity.

There are some different theories of acids and bases in the organic

chemistry. You already know about Arrenius theory, but it can be used for

electrolites only. The most important for organic compounds are Lowry-

Bronsted and  Lewis theories.

According to the Lowry-Bronsted theory,  an acid is a neutral molecule or

ion that gives up a proton, and a base is a neutral molecule or ion that accepts

a proton.

An interaction between an acid and a base may be expressed in form of a

scheme:

The acid A-H loses a proton and forms the anion A-. This anion can accept a

proton, therefore it is a base (it is so-called conjugated base of the acid A-H). On

the contrary the base B accepts a proton and it is converted into the conjugated acid

B+-H.

The important detail exists in this acid-base interaction: the stronger is the

acid – the weaker is the corresponding conjugated base.

Acid and basic properties are connected with one another: acid properties

are exhibited in the presence of bases only and vice versa. For example, hydrogen

Page 70: Bio-Organic Chem Lectures

chloride gas does not exhibit the acid properties. But in presence of water as a base

it is a strong acid:

Many compounds can display both acid and basic properties. It depends

upon conditions. For example:

Usually water is a solvent in biochemical reactions; therefore we'll talk about

acidity and basicity of the organic compounds in regard to water.

Bronsted acids

In aqueous solutions an acid exists in equilibrium with the corresponding

anion (conjugated base) and hydronium ion H3O+:

A-H + H2O A- + H3O+

acid base

As for any equilibrium, the concentrations of the components can be

expressed by the following formula:

[A-][H3O+] Keq = [AH][H2O] .

The acidity constant (Ka) is equal to equilibrium constant multiplied on

water concentration: Ka=Keq[H2O]. We can combine this equilibrium with the

previous to obtain the following expression:

Page 71: Bio-Organic Chem Lectures

[A-][H3O+] Ka = [A-H] .

So, the acidity constant is the ratio of the concentrations of ionized

molecules to un-ionized molecules.

Every Bronsted acid has its characteristic K a, which indicates the strength of

the acid. Since the acidity constant is the ratio of ionized to un-ionized molecules,

the larger the Ka, the stronger is the acid. But the values of Ka are very small (for

example, Ka of acetic acid is 1.75x10-5) and it is uncomfortable to use this constant.

We can use so-called index of acidity constant pKa that is the negative logarithm of

acidity constant: pKa=-lgKa. For example, pKa of acetic acid is 4.76. The lesser is

pKa, the stronger is the acid.

In accordance with the nature of the acidic center the acids are classified as:

OH-acids (water, alcohols, phenols, carboxylic acids);

SH-acids (thiols, thiophenols);

NH-acids (amines, amides of acids);

CH-acids (hydrocarbons).

The strength of the acid depends upon the stability of its anion. The more

stable is the anion, the stronger is the acid.

Factors, which influence on the stability of anions, are as follows:

1) a nature of the acid center;

2) an influence of substituents;

3) solvents influence.

First of all the acidity degree is determined by the kind of the atom that

holds the hydrogen and, in particular, by that atom's ability to accommodate the

electron pair left behind by the departing hydrogen ion.

This ability to accommodate the electron pair depends on two factors: 1) the

atom's electronegativity and 2) its size. The higher is electronegativity (the ability

to attract electrons) – the higher is the acidity. Thus, within a given row of the

periodic Table acidity increases as electronegativity increases. For this reason,

Page 72: Bio-Organic Chem Lectures

acidity OH > NH > CH. And within a given family, acidity increases as a size

increases: acidity SH > OH.

For example: alcohols don't react with sodium hydroxide, but thiols react

with it:

OH-acids are the most important for us (they are alcohols, phenols,

carboxylic acids), therefore we’ll discuss the other factors on the examples of

different OH-acids.

Phenols are stronger acids than alcohols. It may be explained in such a way:

you already know that acidity depends on the stability of the corresponding anion.

Anion of phenol (phenolate) is the p,π-conjugated system and the negative charge

is delocalized between all atoms of this conjugated system. The negative charge in

the alcoholate anion is delocalized not so strong, due to weak inductive effect only.

Phenols can react with alkali, but alcohols can not, they react with alkaline

metals only.

Substituents in the aromatic ring of phenol influence on the acidity too.

Electron withdrawing substituents promotes a delocalization of the negative

Page 73: Bio-Organic Chem Lectures

charge, therefore they increase the acidity. On the contrary, electron releasing

substituents prevent the delocalization, therefore they decrease the acidity.

For example, let us compare acid properties of phenol, 4-nitrophenol and 4-

aminophenol (stability of their anions):

Nitro group is the strong electron withdrawing substituent, it increases stability of

the anion and acid properties. Amino group is the electron releasing substituent, it

decreases the anion stability and acid properties.

Phenols are stronger acids than alcohols, but an acidity of phenols is not so

high. Most phenols acid properties are weaker than that of carbonic acid. For this

reason phenols don't react with aqueous bicarbonate solutions. Indeed, phenols are

liberated from their salts by the action of carbonic acid:

Carboxylic acids are stronger acids than phenols. To explain this fact we

need to discuss not the radical influence only, but also the next factor: a solvent

influence.

Anion stability depends upon its interaction with solvent molecules (the so-

called solvatation of ions occurs). Solvatation of ions means the hydrogen bonds

formation with the solvent molecules. The higher is a solvatation degree, the

Page 74: Bio-Organic Chem Lectures

higher is the anion stability. Hydration (the interaction with water molecules0 is

the particular case of the solvatation).

The ability of ions to be hydrated depends upon their sizes. The lesser is the

size of the anion, the higher is its ability to be hydrated.

Now we can compare phenols and carboxylic acids acid properties from the

position of this factor.

Both these anions are conjugated systems, therefore we can not determine

what of them is more stable. A size of phenolate anion is bigger size than that of

acetate-anion; therefore acetate anion can be hydrated better. Acetate anion is more

stable – acetic acid is stronger than phenol.

So, carboxylic acids are stronger acids than phenols, although much weaker

than the strong mineral acids (sulfuric, hydrochloric). Aqueous hydroxides readily

convert carboxylic acids into their salts, but aqueous mineral acids readily convert

the salts back into the carboxylic acids:

Carboxylic acids are stronger than carbonic acid; therefore carboxylic acids

liberate carbonic acid from its salts:

Summary:

1. The row of acidity decreasing is following: SH > OH > NH > CH-acids.

Page 75: Bio-Organic Chem Lectures

2. The row of OH-acids acidity decreasing is following: carboxylic acids >

carbonic acid > phenols > alcohols.

3. Electron withdrawing substituents increase the acidity, electron releasing

substituents decrease it.

Bronsted bases

Bases are compounds that can accept a proton. For bond formation with a

proton bases can used either unshared electron pair (so-called n-bases) or electrons

of  π-bonds (π-bases).

n-Bases are molecules with an unshared pair or anions. They are classified

in accordance with the nature of the base center:

1. Oxonium bases – oxygen is the basic center (for example, alcohols,

aldehydes, ketones, carboxylic acids, ethers).

2. Ammonium bases – nitrogen is the basic center (for example, amines,

some heterocyclic compounds).

3. Sulfonium bases – sulfur is the basic center (for example, thiols,

thioethers).

Alkenes, benzene and their derivatives are π-bases examples. They are weak

bases, because electrons of π-bonds are not free.

A value of pKBH+ is used for the base strength characteristic. pKBH+ is pKa of

the corresponding conjugated acid:

A-H + B: A- + BH+

a base a conjugated acid

The greater is pKBH+ the stronger is the base.

To be a base a molecule must have an electron pair that can be shared. An

ability of the electron pair sharing depends upon the nature of the basic center

(from its electronegativity and size). The stronger an atom accommodates the

electron pair, the lesser is the ability of the pair to be shared.

Page 76: Bio-Organic Chem Lectures

Nitrogen electronegativity is lesser than that of oxygen; therefore nitrogen

ability to give up the electron pair is higher, than that of oxygen. Ammonium bases

are stronger than oxonium ones. (The operation of these factors here is necessarily

opposite to that we observed for acidity).

A size of sulfur atom is bigger, than that of oxygen, therefore an electron

pair is delocalized in the greater volume and sulfur ability to give up the electron

pair is lesser, than that of oxygen.

The row of the basicity decreasing is the opposite of the row of the acidity:

ammonium bases > oxonium bases > sulfonium bases.

Let us be digress from basicity now and discuss chemical properties of

amines (including basic properties).

AMINES

All classes of organic compounds that we have studied early are considered

as hydrocarbons derivatives, in which molecules one or more hydrogen atoms are

replaced by functional groups. Amines are considered as ammonia derivatives, in

which molecule one, two or three hydrogen atoms are replaced by any alkyl or aryl

radicals. So, general formulas of amines are as follows:

Classification

Amines may be classified as primary, secondary and tertiary, according to

the number of groups, attached to the nitrogen atom. For example:

We can also classify amines in accordance with a nature of radicals into

aliphatic, aromatic and mixed amines. For example:

Page 77: Bio-Organic Chem Lectures

Nomenclature

Alipatic amines are named by naming the alkyl group or groups attached to

nitrogen (in alphabetical order), and following these by the word –amine. More

complicated ones are often named by prefixing amino- (or N-methylamino-, N,N-

diethylamino-, etc.) to the name of the parent chain. For example:

Aromatic amines – those in which nitrogen is attached directly to an

aromatic ring – are generally named as derivatives of the simplest aromatic amine,

aniline. And aminotoluene is given the special name of toluidine. For example:

Salts of amines are generally named by replacing –amine by –ammonium (or

–aniline by –anilinium), and adding the name of the anion. For example:

Due to unshared electron pair of nitrogen amines show basic and

nucleophilic properties.

Basic properties. Amines can react with mineral and carboxylic acids to

form salts:

Page 78: Bio-Organic Chem Lectures

Aliphatic amines can react with water too. It shows that amines are the

strong bases, because only strong bases can react with so weak acid as water.

For this reason the aqueous solutions of amines change the color of the

litmus (red) and phenolphthalein paper.

Let us discuss how basicity of amines is related to structure.

Aliphatic amines are more basic than ammonia, because the electron-

releasing alkyl groups increase the electronic density of the nitrogen atom:

Dimethylamine has the highest basicity, because two methyl groups displace

the electronic density to the nitrogen atom.

We can suppose that tertiary amines are more basic than

secondary, but it is not so. The electronic density of the

nitrogen atom in the tertiary amines is higher than in the

secondary amines. But the unshared electron pair of nitrogen in the tertiary

amine is eclipsed by three big methyl groups. It is difficult to a proton to be added

to this nitrogen atom.

Thus the row of decreasing basicity of the aliphatic amines is as follows:

secondary amine > primary amine > tertiary amine > ammonia .

Page 79: Bio-Organic Chem Lectures

Let us compare the basicity of the aliphatic and aromatic amines.

The unshared electron pair of nitrogen takes part in the p,π-conjugated

system. For this reason the basicity of aromatic

amines is lower than that of aliphatic amines.

Aromatic amines react with strong mineral acid only. For example:

Aniline and other aromatic amines can not react with water, because water is

the weak acid.

The electron-releasing substituents in the aromatic ring increase basicity and

electron-withdrawing substituents decrease basicity. For example:

Nucleophilic properties of amines. Amines are nucleophilic reagents due to

their unshared electron pair. They can react with alkyl halides:

It is nucleophilic substitution reaction.

Nucleophilic properties of aromatic amines are lower than that of aliphatic

amines (due to unshared electron pair conjugation), but alkylation reactions are

characteristic for the aromatic amines too.

Page 80: Bio-Organic Chem Lectures

As nucleophiles both aliphatic and aromatic amines can react with acid

chlorides and anhydrides to form substituted amides:

Aniline and its N-methyl derivatives can be identified by the reaction with

bromine water (it is a reaction for activated aromatic ring):

White precipitate of tribromoaniline is formed.

REACTIVITY OF ALDEHYDES AND KETONES.

Both aldehydes and ketones are so-called oxo-compounds or carbonyl

compouns, because they contain oxo- or carbonyl group (>C=O) in their structures.

Page 81: Bio-Organic Chem Lectures

In aldehydes molecules this group is connected with a radical and hydrogen atom,

in ketones – with two radicals:

Nomenclature

The common names of aldehydes are derived from the names of the corresponding

carboxylic acids by replacing -ic acid by -aldehyde. The names of the firsts

members of the aldehydes are:

The IUPAC names of aldehydes follow the usual pattern: the longest

chain carrying the aldehyde group is considered the parent structure and is named

by replacing the –e in the corresponding alkane by –al. The position of a

substituent is indicated by a number, the carbonyl carbon always being considered

as C-1. The common names of substituted aldehydes are derived from the

corresponding common names. To indicate a position of a substituent the Greek

letters, α-, β-, γ -, etc., are used. The α-carbon is the one bearing the -CHO

group. For example:

Page 82: Bio-Organic Chem Lectures

The simplest aromatic aldehyde is benzaldehyde:

The simplest aliphatic ketone has the common name of acetone. For most

other aliphatic ketones we name two radicals that are attached to carbonyl carbon,

and follow these names by the word ketone. For example:

According to the IUPAC system, the longest chain carrying the carbonyl

group is considered the parent structure, and is named by replacing the -e of the

corresponding alkane with -one.

Electronic structure of the carbonyl group

Carbonyl carbon is joined to three

other atoms by σ-bonds. It is sp2-

hybridized atom. The angle between s-bonds

is 120o, they lie in the same plane. The remaining p-orbitals of carbon overlaps a p-

orbital of oxygen to form a π-bond. So, oxygen, carbonyl carbon and two atoms

directly attached to carbonyl group lie in the same plane (this part of a molecule is

flat).

The electrons of the carbonyl double bond hold together atoms of quite

different electronegativity, and hence the electrons are not equally shared; in

particular, the mobile π-cloud is pulled strongly toward the more electronegative

oxygen atom. The partial positive charge appears on the carbon atom and the

partial negative charge - on the oxygen atom. Carbonyl carbon is electron-deficient

and carbonyl oxygen is electron-rich one.

Page 83: Bio-Organic Chem Lectures

What kind of reagents will attack such a group? Since the important step in

these reactions is the formation of a bond to the electron-deficient carbonyl carbon,

the carbonyl group can be attacked by electron-rich, or nucleophilic reagents. A

typical reaction of aldehydes and ketones is the nucleophilic addition reaction.

Let us compare the activities of different aldehydes and ketones in the

nucleophilic addition reactions, giving formaldehyde, acetaldehyde and acetone

as examples.

The activity in AN-reactions depends on the value of the partial positive charge on

carbonyl carbon. The bigger is this charge, the higher is activity. You already

know that methyl group exerts the positive inductive effect. For this reason methyl

group in the acetaldehyde molecule decreases the electron-deficiency of carbonyl

carbon. And two methyl groups in the acetone molecule decrease the electron-

deficiency stronger. Thus the row of the decreasing activity is: formaldehyde >

acetaldehyde > acetone. Generally, aldehydes are more active than ketones.

The general mechanism of nucleophilic addition reactions

When a nucleophile attacks carbonyl carbon both electrons of the π-bond go

away to the oxygen atom. Oxygen becomes negative charged atom. The new σ-

bond of carbonyl carbon with the nucleophile are formed due to two electrons of

the nucleophile. And then the remaining electrophile is added to the negative

oxygen.

Many compounds can be nucleophilic reagents in this reaction: alcohols

R-OH, cyanide K+CN-, ammonia NH3, amines R-NH2 and their derivatives.

Page 84: Bio-Organic Chem Lectures

Particular examples of AN-reactions

Addition of alcohols. Acetal formation.

Alcohols add to the carbonyl group of aldehydes in presence of anhydrous

acids (usually hydrogen chloride) to yield acetals.

At the first step of the reaction a proton of the catalyst adds to the unshared

electron pair of oxygen. The protonated aldehyde is formed. This cation can be

represented by two resonance structures. In the second structure the full positive

charge appears on the carbon atom, which then is attacked by the nucleophilic

molecule of the alcohol. The new σ-bond is formed due to the unshared electron

pair of oxygen. For this reason the positive charge appears on this oxygen atom.

Then chloride anion takes a proton and hemiacetal and a molecule of the catalyst

are obtained.

So, the role of the acidic catalyst in this reaction is the increasing positive

charge on the carbonyl carbon atom.

This reaction is not characteristic for ketones.

Hemiacetals are too unstable to be isolated. But in the presence of the

excess of the alcohol hemiacetals can react to form acetals:

Page 85: Bio-Organic Chem Lectures

The mechanism of this reaction is the nucleophilic addition, too. Acetals

undergo acidic cleavage very easily. They are rapidly converted even at room

temperature into a corresponding aldehyde and alcohol by dilute mineral acids:

Addition of cyanide.

The elements of HCN add to the carbonyl group of aldehydes and ketones to

yield compounds known as cyanohydrins or hydroxynitriles:

This reaction is carried out in the presence of an alkali.

Cyanide ion is the nucleophilic reagent in this reaction, but cyanic acid is

very weak acid and it is a poor source of the cyanide ion. When cyanic acid reacts

with the alkali the cyanide ion is formed:

Then cyanide ion react with the carbonyl compound by the general

mechanism of AN-reactions:

Cyanohydrins can undergo hydrolysis in the organism with carbonyl

compounds and cyanic acid formation. Some cyanohydrins are found in nature;

they are synthesized by the plants. For example, a derivative of cyanohydrin of

benzaldehyde presents in the stones of the cherry, plum, and almond. The using

stones of this plants as a food can be the cause of the poisoning, because the

forming as a result of the hydrolysis HCN is the strongest poisonous.

Page 86: Bio-Organic Chem Lectures

Reactions with ammonia and its derivatives

Ammonia and its derivatives can add to the carbonyl group of aldehydes and

ketones. It is the nucleophilic addition reaction:

But the product of this reaction is unstable and then the elimination of a

molecule of water from the initial addition product occurs and imine is formed:

The mechanism of this reaction is called nucleophilic addition-elimination.

If the carbonyl compound reacts with derivatives of ammonia the other

substanses can be obtain:

Reagent Product

NH2-R amines R-CH=N-R substituted imine

NH2-OH hydroxylamine R-CH=N-OH oxime

NH2-NH2 hydrazine R-CH=N-NH2 hydrazone

C6H5-NH-NH2 phenylhydrazine R-CH=N-NH-C6H5 phenylhydrazone

H2N-NH-CO-NH2 semicarbazide R-CH=N-NH-CO-NH2 semicarbazone

These derivatives are important chiefly for the characterization and

identification of aldehydes and ketones.

Aldol condensation reaction

Under the influence of dilute bases, two molecules of an aldehyde er a

ketone may combine to form an aldol. This reaction is called the aldol

condensation reaction.

Page 87: Bio-Organic Chem Lectures

Due to a negative inductive effect of aldehyde group there is a

partial positive charge on α-carbon atom. It becomes a weak

CH-acid center.

Under the influence of a strong base α-carbon gives up a proton:

The anion is formed, which is the nucleophilic reagent and can react with

other molecule of the aldehyde. It is a nucleophilic addition reaction:

The product of this reaction is aldehydoalcohol (there are aldehyde and

hydroxyl groups in its molecule) or briefly aldol.

Ketones take part in this reaction more difficulty.

The obtained aldol is very easily dehydrated; the major product have the

carbon-carbon double bond between α- and β-carbon atoms. For example:

Thus the aldol condensation reaction is characteristic only for those carbonyl

compounds in which α-hydrogen atom is present. No α-hydrogen atoms, no

Page 88: Bio-Organic Chem Lectures

reaction. For example, formaldehyde and benzaldehyde can not take part in this

reaction.

Cannizzaro reaction

In the presence of the concentrated alkali, aldehydes containing no α-

hydrogens undergo self-oxidation-and-reduction to yield a mixture of an alcohol

and a salt of a carboxylic acid. This reaction is known as the Cannizzaro reaction.

You know formaldehyde as an active compound in nucleophilic addition

reactions. Therefore formaldehyde can undergo the Cannizzaro reaction without

alkali. methanol and formic acid are obtained in this reaction:

It is arbitrary reaction. For this reason the aqueous solutions of

formaldehyde have the acidic medium.

Oxidation reactions

Aldehydes are easily oxidized to carboxylic acids, ketones are not.

Aldehydes are oxidized not only by the potassium permanganate and

dichromate but also by the very mild oxidizing agents: the ammonia solution of

silver hydroxide or copper hydroxide. Both these reactions occur in an alkaline

medium.

The reaction with ammonia solution of silver hydroxide is called Tollens'

reaction. Oxidation of the aldehyde is accompanied by reduction of silver ion to

Page 89: Bio-Organic Chem Lectures

free silver in the form of a mirror. Therefore the other name of this reaction is the

silver mirror reaction.

Aldehydes reduces copper (II) hydroxide into copper (I) oxide:

When an aldehyde is heated with the blue copper (II) hydroxide the yellow

precipitate of copper (I) hydroxide is obtained. Then it is converted into reddish

brown precipitate of copper (I) oxide.

These two oxidation reactions are used for aldehydes distinguishing.

Reduction reactions

Aldehydes can be reduced to primary alcohols, and ketones to secondary

alcohohols. Hydrogen in presence of catalyst (Ni or Pt) or lithium aluminium

hydride (LiAlH4) can be used as reducing reagents.

Iodoform test

Acetaldehyde and all methyl ketones (dimethylketone, ethylmethylketone

and so on) give the iodoform test. If these compounds are treated with iodine and

Page 90: Bio-Organic Chem Lectures

sodium hydroxide a yellow precipitate of iodoform appears. If a concentration of

iodoform is low we can not observe the precipitate formation, but we can feel very

characteristic iodoform smell (hospital smell). This reaction involves halogenation

and cleavage:

This reaction is possible due to CH-acid center existence.

This reaction can be used for acetone distinguishing in the urea of diabetes

patients.

Using of aldehydes and ketones

Formalin (40% aqueous solution of formaldehyde) is used for oreservation

of anatomic preparation and for disinfection.

Acetone is used as a solvent in drugs synthesis.

Acetaldehyde and acetone are used in the synthesis of iodoform. Iodoform is

used as an antiseptic for dressing wounds.

Formaldehyde reacts with ammonia to form hexamethylene tetramine or

Urotropine used as an antiseptic drug.

This drug is used as uroantiseptic for treatment of diseases of the urinary

system. The hydrolysis of Urotropine in the organism forms formaldehyde which

exerts an antiseptic action.

Page 91: Bio-Organic Chem Lectures

REACTIVITY OF CARBOXYLIC ACIDS.

FUNCTIONAL DERIVATIVES OF CARBOXYLIC ACIDS

The functional group of carboxylic acids is known as carboxyl

group.

Carboxylic acids are classified as aliphatic (saturated and unsaturated) and

aromatic.

Nomenclature

The names of the firsts members of saturated aliphatic acids are as follows:

In the common names to indicate a position of a substituent the Greek

letters, α-, β-, γ-, etc., are used. The α-carbon is the one bearing the -COOH group.

The IUPAC names of carboxylic acids follow the usual pattern. The longest

chain carrying the -COOH group is considered the parent structure and is named

by replacing the -e of the corresponding alkane by -oic acid. The position of a

substituent is indicated by a number, the carbon of the carboxyl group always

being considered as C-1. For example:

Page 92: Bio-Organic Chem Lectures

Aromatic acids are usually named as derivatives of the parent acid, benzoic

acid:

The name of a salt of a carboxylic acid consist of the name of the cation

(sodium, potassium,etc.) followed by the name of the acid with the ending -ic acid

changed to -ate. For example:

Electronic structure of the carboxyl group

Carboxyl group is a p,π-conjugated

system: an unshared electron pair of

singly bonded oxygen takes part in the

conjugation with π-electronic cloud of

the double bond. O-H-bond is polarized

and this is a strong OH-acid center.

There is a partial positive charge on the doubly bonded carbon atom;

therefore it is an electrophilic center. The unshared electron pair of the doubly

bonded oxygen does not take part in the conjugation, so it is a reason of the

basicity. Carboxyl group at whole displaces an electronic density to itself to make

the neighboring carbon an electron deficient, C-H bonds of α-carbon becomes

polarized and α-carbon is a weak acid center.

Acid properties

The most characteristic property of the carboxylic acids is their acidity. The

acidity of carboxylic acids is higher than that of phenols or alcohols. You already

know that acidity is higher when the anion of the acid is more stable. The structure

of the carboxylate anion can be represented as a hybrid of two resonance

structures:

Page 93: Bio-Organic Chem Lectures

The negative charge is distributed over between both oxygen atoms.

Carbon is joined with each oxygen atom by "one-and-a-half" bond. The lengths

of these two bonds are the equals. These bonds are shorter that the usual single

bond, but they are longer than the usual double bond.

Thus the carboxylate anion is a conjugated system and the negative charge

is delocalized in this system.

Carboxylic acids can form salts in reactions with metals, hydroxides and

sodium bicarbonate:

You already know that electron-withdrawing substituents increase the

acidity and electron-releasing substituents decrease it.

Nucleophilic substitution reactions

Nucleophilic reactions are characteristic for carboxylic acids due to

electrophilic center (electron deficient carbon atom). Let us discuss why

nucleophilic substitution reactions are characteristic for carboxylic acids but not

nucleophilic addition (as for aldehydes for example).

They are characteristic because the carboxyl group is the conjugated system

and the acid has the tendency to keep the conjugation.

The general mechanism of the reaction is following:

Page 94: Bio-Organic Chem Lectures

The first step of this reaction is the identical with that of nucleophilic

addition reaction in aldehydes. But if this intermediate then adds the electrophile

(as in aldehydes reactions) the non-conjugated system is formed. The result of

substitution reaction is the conjugated system formation.

Esterification reaction. Carboxylic acids are converted directly into esters

when are heated with alcohols in the presence of a little mineral acid, usually

concentrated sulfuric acid or dry hydrogen chloride. The acidic catalyst is

necessary because alcohols are weak nucleophiles.

The first step of this reaction is the addition of a proton of the acid to

unshared electron pair of oxygen. The positive charge appears on the oxygen atom.

This cation can be represented by two resonance structures. Second structure has

the positive charge on the carbon atom. It is the center which can be attacked by

the nucleophile (the molecule of the alcohol). Then a proton goes to oxygen of

OH-group and a molecule of water is lost. The cation gives up the proton to the

anion of the catalyst and a conjugated molecule of ester is obtained.

So, roles of concentrated sulfuric acid are: 1) increasing the positive charge

on carbon atom; 2) water removing.

Page 95: Bio-Organic Chem Lectures

Esters are called the functional derivatives of carboxylic acids. These

derivatives are compounds in which molecules the OH-group of carboxyl group

has been replaced by -Cl, -O-CO-R, NH2- or OR'. They are as follows:

Last derivative can be considered as substituted amide.

All functional derivatives contain acyl group in their structures.

Functional derivatives can be prepared from carboxylic acids and one from

another. Let us examine the preparation of different functional derivatives from the

carboxylic acids.

Acid chlorides preparation. A carboxylic acid can be converted into the

acid chloride by the action of thionyl chloride (SOCl2), phosphorus pentachloride

(PCl5) or trichloride (PCl3):

For example:

Page 96: Bio-Organic Chem Lectures

Acid anhydrides can be obtained by the acid heating with phosphorus oxide.

The molecule of water is lost. ("anhydride" means "without water").

Amides can be prepared by the ammonium salts of carboxylic acids heating:

The nucleophilic substitution reactions are characteristic for all functional

derivatives of carboxylic acids. Let us compare their activities in SN reactions.

Their activity depends upon the value of the partial positive charge on the carbon

atom of the substituted carboxyl group.

The value of the partial positive charge depends upon the influence of the

substituent. Chlorine is the electron-withdrawing substituent, it increase the

electron-deficiency of carbon (-ICl >+MCl).

Page 97: Bio-Organic Chem Lectures

OH- and OR'-groups are electron-releasing ones, because their positive

mesomeric effect is higher than the negative inductive effect. The partial positive

charges on carbon in the acid and ester molecules are approximately equal.

The partial positive charge on the carbon atom of the anhydride is higher

than that in the carboxylic acid or ester, because the electron-releasing influence of

oxygen is distributed between two carbon atoms.

NH2-group is very strong electron-releasing substituent (-I<<+M). For this

reason the partial positive charge on the carbon atom of the amide is lesser than

that in the acid or ester.

Thus, the row of the activity decreasing is folowing:

Acid chloride > Anhydride > Ester ~ Acid > Amide

The less active functional derivatives can be easily prepared from the more

active derivatives. For example acids chlorides can be converted easily into

anhydrides, acids, esters and amides. But acids chlorides preparation from amides,

for example, is impossible.

Page 98: Bio-Organic Chem Lectures

On the other hand, all these reactions are acylation reactions. The

mechanism of these reactions is the nucleophilic substitution.

Anhydrides can be converted into acids, esters and amides:

These reactions occur a little slowly than that of acid chlorides.

Esters are hydrolyzed in the presence of the acid or alkali as a catalyst. The

acidic hydrolysis of esters is the reversible reaction, the alkaline hydrolysis is not.

The result of the acidic hydrolysis is the mixture of the carboxylic acid and

alcohol. For example:

In reaction of the alkaline hydrolysis of esters the salt of the carboxylic acid

and the alcohol are obtained. For example:

Esters can take part in ammonolysis and aminolysis reactions also:

Page 99: Bio-Organic Chem Lectures

Amides are hydrolyzed when are heated with aqueous acids or aqueous

bases, but these reactions occur more slowly than that of esters. For example:

Reactions of carboxylic acids radicals

Halogenation reactions of aliphatic acids. In the presence of a small amount

of phosphorus aliphatic carboxylic acids react with chlorine or bromine to yield a

compound in which a hydrogen has been replaced by halogen. This is Hell-

Volhard-Zelinsky reaction.

Reactions of unsaturated carboxylic acids. The electrophilic addition

reactions are characteristic for unsaturated aliphatic acids. Bromination reaction is

the example:

Page 100: Bio-Organic Chem Lectures

The addition of hydrogen bromide (chloride) or water is anti-Markovnikov’s addition:

It can be explain by the distribution of the electronic density in the π,π-

conjugated system. The partial negative charge appears on the α-carbon atom. It is

the place for the attack of a proton. Chloride anion adds to electron-deficient β-

carbon.

These addition reactions occur more slowly than addition to alkenes,

because the carboxyl group is the electron-withdrawing substituent.

Electrophilic substitution reactions are characteristic for aro matic carboxylic

acids. These reactions (bromination, nitration, for example) occur more slowly

then reactions of benzene, because the carboxyl group is the electron-withdrawing

substituent.

REACTIVITY OF DICARBOXYLIC ACIDS

There are two carboxyl groups in dicarboxylic acids structures. Dicarboxylic

acids may be aliphatic (saturated and unsaturated) and aromatic.

Nomenclature

The names of the first members of saturated aliphatic dicarboxylic acids are

as follows:

Page 101: Bio-Organic Chem Lectures

Isomerism

Cis-trans-isomerism is possible for unsaturated dicarboxylic acids:

Three structural isomers of aromatic dicarboxylic acids are possible:

Chemical properties

All chemical properties of carboxylic acids are characteristic for

dicarboxylic acids too. It is possible to prepare compounds in which only one of

the carboxyl groups has been converted into a derivative; it is possible to prepare

compounds in which two carboxyl groups have been converted into

derivatives. For example, dicarboxylic acids can form two types of salts: mono-

(acidic salts) and di- (neutral salts), mono- and diesters etc.

Page 102: Bio-Organic Chem Lectures

Acid properties of dicarboxylic acids are higher than that of monocarboxylic

acids, because second carboxyl group is electron-withdrawing substituent as

regards the first carboxyl group. Oxalic acid has the highest acidity, which is

decreased in the homologous series. The father are two carboxyl groups from each

other, the lesser is the acidity (an influence of one carboxyl group on the other is

decreased).

If oxalic acid reacts with solution of calcium chloride white crystals of

calcium salt of oxalic acid (calcium oxalate) are obtained:

Dicarboxylic acids can form two types of esters, amides and other functional

derivatives, for example:

So, all properties of carboxylic acids are characteristic for dicarboxylic acids

too. In addition, some dicarboxylic acids undergo certain special reactions that are

possible only because two carboxyl groups are located in a particular way with

respect to each other.

Page 103: Bio-Organic Chem Lectures

Decarboxylation reaction is characteristic for oxalic and malonic acids only.

This reaction occurs at heating. Corresponding carboxylic acids are formed:

When succinic and glutaric acids are heated cyclic anhydrides formation

occurs. It is possible, because these acids chains are not linear (sp3-hybridized

carbon atoms valent angle is equal 109o28’) and they can exist in the claw

conformation:

HETEROFUNCTIONAL ALIPHATIC COMPOUNDS

Heterofunctional compounds molecules include several different functional

groups. Most of organic compounds, which take part in the metabolism, are

heterofunctional ones. They are amino alcohols, amino acids, hydroxy acids and

keto acids, for example.

The chemical properties of heterofunctional compounds must not be

considered as a sum of properties of each functional group. Functional groups

influence one another. For this reason heterofunctional compounds exhibit special

chemical properties also.

Amino alcohols

2-aminoethanol or cholamine is the simplest amino alcohol:

Page 104: Bio-Organic Chem Lectures

As an amine 2-aminoethanol forms salts with acids:

The basic properties of 2-aminoethanol are decreased in comparison with that

of ethylamine, because hydroxyl group is the electron-withdrawing substituent.

As all amines 2-aminoethanol is a nucleophile and it takes part in the

alkylation and acylation reactions. For example, in the alkylation reaction with the

excess of methyl iodide in the alkaline medium cholamine is converted into

choline:

Both cholamine and choline are structural components of phospholipids

molecules.

Due to alcohol hydroxyl group choline can be acylated to form

acetylcholine:

Acylation reaction of cholamine occurs in the organism by the similar way,

under the action of acetyl coenzyme A. Acetylcholine is a neurotransmitter.

Noradrenalin and adrenalin can be considered as amino alcohols and amino

phenols at the same time. Adrenalin is synthesized in the organism by the

alkylation reaction of noradrenalin:

Page 105: Bio-Organic Chem Lectures

Adrenalin is a central nervous system neurotransmitter. Noradrenalin and

adrenalin are known as catecholamine hormones, because there is catecholamine

fragment in their structures.

Hydroxy acids

The examples of hydroxy acids are as follows:

Hydroxy acids exhibit all properties of carboxylic acids (their acidity is

higher than that of corresponding carboxylic acids). Hydroxy acids can form salts,

esters and other functional derivatives:

Hydroxy acids exhibit properties of alcohols: they can take part in acylation

and oxidation reactions. For example:

CH3-CH-COOH

OH CH3-CH-COOH + CH3COOH

(CH3CO)2O

CH3-C-COOH

O

O-C-CH3

2-oxopropanoic (pyruvic) acid

lactic acid

[O]

OO-acetyl derivative of lactic acid

Page 106: Bio-Organic Chem Lectures

The special properties of hydroxy acids

If α-hydroxy acids are heated in the presence of concentrated sulfuric acid

the corresponding carbonyl compound and formic acid are obtained. For

example:

At heating two molecules of α-hydroxy acid take part in cyclization reaction.

The cyclic ester (lactide) is formed:

Lactides are esters and they can be hydrolyzed in the presence of acids or

alkali.

β-Hydroxy acids can eliminate a molecule of water, when are heated. It is

intramolecular elimination reaction:

Page 107: Bio-Organic Chem Lectures

α-Carbon becomes a CH-acid center due to electron withdrawing action of

two functional groups: carboxyl and hydroxyl groups. It eliminates a hydrogen

proton and a neighboring carbon – hydroxyl group to form a molecule of water. A

corresponding unsaturated carboxylic acid is formed.

γ-Hydroxy acids undergo an intermolecular esterification reaction at heating.

For example:

γ-Lactons are obtained in this kind of reactions. Lactons are esters and

they can be hydrolyzed.

Examples of hydroxy acids containing two or three carboxyl groups are

following:

Page 108: Bio-Organic Chem Lectures

Tartaric acid is dicarboxylic acid and polyalcohol at the same time. For this

reason this compound can form two series of salts and functional derivatives. For

example:

It is the qualitative test of tartaric acid.

As a polyalcohol tartaric acid reacts with copper hydroxide to form the blue

solution of the salt:

Salts of tartaric acids are used as laxative (anti-constipation) drugs. Lactic

acid is a product of glucose utilization in the organism.

Amino acids

Amino acids are heterofunctional compounds, containing carboxyl and

amino groups. In accordance with a regard position of amino and carboxyl groups

they can be classified into α-, β-, γ- , etc. amino acids:

As all carboxylic acids amino acids can form salts , esters, acid chloride,

amides. For example:

Page 109: Bio-Organic Chem Lectures

On the other hand amino acids exhibit all properties of amines (basic

properties, acylation and alkylation reactions):

Special properties of amino acids depend upon the mutual disposition of two

functional groups.

If α-amino acids are heated in the presence of Ba(OH)2 decarboxylation

reaction occurs and corresponding amines are formed, for example:

Two molecules of α-amino acid can take part in intermolecular cyclic amide

formation at heating:

Page 110: Bio-Organic Chem Lectures

The special reaction of β-amino acids is intramolecular elimination of

ammonia:

An influence of two electron-withdrawing groups is a reason of CH-acid

properties.

The special reaction of γ-amino acids is the intramolecular amide (lactam)

formation:

Because of amide bond lactams can be hydrolyzed both in acid and basic

medium:

Keto acidsSome keto acids take an important part in biochemical processes. They are

for example:

Page 111: Bio-Organic Chem Lectures

These keto acids are formed in the organism as a result of the oxidation

reactions of corresponding hydroxy acids. For example:

Keto acids give all reactions of carboxylic acids and ketones. For example:

Decarboxylation reaction is a special reaction of β-keto acids only. For

example, acetoacetic acid is decarboxylated at heating to give acetone:

The same reaction occurs in the living organisms under enzymes action.

Acetoacetic acid, acetone and β-hydroxybutyric acid, which precedes of

acetoacetic acid, appear in the blood and urine during diabetes. They are known as

“ketone bodies”.

Page 112: Bio-Organic Chem Lectures

The other special property of β-keto acids is their tautomerism.

Tautomerism is a kind structural isomerism Tautomers are compounds

whose structures differ in the arrangement of atoms, but which exist in easy and

rapid equilibrium.

The most common kind of tautomerism involves structures that differ in the

point of hydrogen attachment.

Keto-enol tautomerism is characteristic for β-keto acids esters. Let us

examine it on the example of ethyl ester of acetoacetic acid (it is known also as

acetoacetic ester):

The electronic density is displaced from α-carbon atom to two electron-

withdrawing groups. α-Carbon atom is CH-acid center – it can give up a proton.

Oxygen of keto group has an unshared electron pair and can take this proton (it is a

basic center). If the proton goes from α-carbon to oxygen, keto tautomer is

converted into enol tautomer. There is an equilibrium between these two forms, but

the keto tautomer is favor (92.5% of acetoacetic ester exist as keto tautomer). All

reactions of both tautomeric structures are characteristic for acetoacetic ester. For

example:

Page 113: Bio-Organic Chem Lectures

Usually, keto tautomer is more stable, but sometimes enol tautomer becomes

more stable than keto one. For example, enol tautomer is favor in the keto-enol

equilibrium of diethyl ester of oxaloacetic acid:

In this case enol tautomer is more stable, because it is a common conjugated

system.

OPTICAL ISOMERISM AS A TYPE OF STEREOISOMERISM

Stereo isomerism is a particular kind of isomerism. Stereo isomers have

the same order of attachment of the atoms, but they differ from each other by

their atoms orientation in space.

You already know one type of stereo-isomerism - it is  cis,trans-

isomerism. Today we shell talk about so-called optical isomerism. 

The name "optical" is connected with the special property of these isomers:

they can be optically active. The optical activity is the ability of the compound

to rotate the plane of polarized light.

An ordinary light beam consist of waves vibrating in

all possible planes perpendicular to its path (a).

If this light beam is passed through certain types of

substances, the transmitted beam will have all of its waves

vibrating in parallel planes (b).This light beam is called plane-polarized. The way

to polarize light is to pass it through a device composed of Iceland spar

(crystalline calcium carbonate) called a Nicol prism (proposed in 1828 by the

Page 114: Bio-Organic Chem Lectures

British physicist W. Nicol).When polarized light, vibrating in a certain plane, is

passed through an optically active substance, it emerges vibrating in a different

plane.How can this rotation of the plane of polarized light (the optical activity) be

detected? It is both detected and measured by an instrument called the polarimeter.

It consists of a light source, two Nicol lenses, and between the lenses a tube to

hold the substance that is being examined for optical activity. These are arranged

so that the light passes through one of the lenses (polarizer), then the tube, then

the second lens (analyzer), and finally reaches our eye.

Shematic representation of a polarimeter. Solid lines: before rotation. Broken lines: after rotation. α is the angle of rotation.

When the tube is empty, we find that the maximum amount of light reaches

our eye when the two lenses are so arranged that they pass light vibrating in the

same plane.

Now let us place the sample to be tested in the tube. If the substance does

not affect a plane of polarization, light transmission is still at a maximum and the

substance is said to be optically inactive. If, on the other hand, the substance

rotates the plane of polarization, then the lens nearer our eye must be rotated to

conform with this new plane if light transmission is again to be a maximum, and

the substance is said to be optically active. If the rotation of the plane, and hence

our rotation of the lens, is to the right (clockwise), the substance is dextrorotatory

(Latin: dexter, right); if the rotation is to the left (counterclockwise), the

substance is levorotatory (Latin: laevus, left).

Page 115: Bio-Organic Chem Lectures

We can determine not only that the substance has rotated the plane, and in

which direction, but also by how much. The amount of rotation is simply the

number of degrees that we must rotate the lens to conform to the light. The

symbols «+» and «-» are used to indicate rotations to the right and to the left,

respectively.

Most compounds do not rotate the plane of polarized light.

Optically active compounds not belong to particular chemical family, since

optically active compounds are found in all families.

How can we determine: is any particular compound optically active or not

without polarimeter?

The optical activity is characteristic for so-called chiral molecules only.

Chirality is a property of the object (not only molecule) to be not

superimposable with its mirror image. The word "chiral" comes from the Greek:

cheir, hand. Our left and right hands are similar each other as in the mirror. But

our hands are not superimposable one on the other.

Molecules that are not superimposable on their mirror images are chiral. To

determine is the molecule chiral or not we can make its model and the model of the

"mirror image" and then we can see hether these two models are not

superimposable or not.

We can determine that also on the other way. If a molecule has chiral

centers it may be chiral itself.  Chiral center is a carbon atom with four different

groups attached to it. The other name of this carbon is asymmetric carbon atom. 

Many - but not all-molecules that contain a chiral center are chiral. There

are molecules that contain chiral centers and yet are achiral. (Such achiral

molecule always contains more than one  chiral center; if there is only one chiral

center in a molecule, we can be certain that the molecule is chiral).

Thus, if we find a chiral center, then we should consider the possibility that

the molecule is chiral too.

Let us examine the the particular examples.

Page 116: Bio-Organic Chem Lectures

There is one chiral carbon in the lactic acid molecule (it is

isomers by the formula N=2n, where N is the number of

isomers; n is the number of chiral centers. So, lactic acid

can exist as two optical isomers. They are similar as an object and its mirror

image:

We need to use Fisher’s projections to show structures of these isomers:

We draw a cross and attach to four ends

four groups that are attached to the chiral

center. The chiral center is understood to be

located where the lines cross. Chemists

have agreed that such a diagram stands for a

particular structure: the horizontal lines represent bonds coming toward us out of

the plane of the paper, whereas the vertical lines represent bonds going away from

us behind the plane of the paper.

Isomers that are mirror images of each other and are not

superimposable are called enantiomers. 

Enantiomers have identical physical properties except for the direction of

rotation of the plane of polarized light.

Enantiomers possess identical chemical properties except toward optically

active reagents.

Because of enzymes are optically active the interaction of enantiomers with

them may be different. For this reason one isomer of the pair may serve as a drug,

and the other isomer may be useless. So, enantiomers have the different biological

properties.

The arrangement of atoms that characterized a particular stereoisomer is

called its configuration.

Using the test of superimposability we conclude, for example, that there are

two stereoisomers of lactic acid. We find that one of them rotates the plane of

Page 117: Bio-Organic Chem Lectures

polarized light to the right, and the other to the left. We have drawn two Fisher

formulas and we have, for example, isolated two stereoisomers. Now the question

arises, which configuration does each isomer have? This question (the

determination the absolute configuration) could not be answered until 1951. Only

in this year the special kind of X-ray analysis was applied for determine of actual

arrangement in space of the atoms of an optically active compound.

Thus, absolute configuration is the actual arrangement of atoms. 

Most applications of stereochemistry are based upon the relative

configuration of different compounds, not upon their absolute configuration. We

are chiefly interested in whether the configurations of a reactant and its product are

the same or different, not in what either configuration actually is.

The compound  glyceraldehyde  was selected as a standart of refrence.

(+)-Glyceraldehyde was arbitrarily assigned configuration I, and was designated

D-glyceraldehyde; (-)-Glyceraldehyde was arbitrarily assigned configuration II,

and was designated L-glyceraldehyde.

Configurations were assigned to the glyceraldehyde purely for convenience.

But then, when the absolute configurations were determined the relative

configuration coincided with the absoluty configuration.

Other compounds could be related configurationally to one or the other of

glyceraldehydes by means of chain of chemical reactions. On the basis of the

assumed configuration of the glyceraldehyde, these related compounds could be

assigned configurations, too. As it has turned out, these configurations are the

correct absolute one. For example:

Page 118: Bio-Organic Chem Lectures

To indicate the relationship thus established, compounds related to D-

glyceraldehyde are given the designation D, and compounds related to L-

glyceraldehyde are given the designation L. The symbols D and L thus refer to

configuration, not to sign of rotation. Rotation can be determined with polarimeter

only!

The other system (R-,S-) is more universal for specification of configuration.

But in biochemistry D,L-system is often used. For this reason we shell study D,L-

system only.

Thus, all stereoisomers that have the configuration the same with

configuration of D-glyceraldehyde are D-stereoisomers. And stereoisomers that

have the configuration the same with configuration of L-glyceraldehyde are L-

stereoisomers. For example:

A mixture of equal parts of enantiomers is called a racemic modification. A

racemic modification is optically inactive: when enantiomers are mixed together,

the rotation caused by a molecule of one isomer is exactly canceled by an equal

and opposite retation by a molecule of its enantiomer.

Compounds with more than one chiral center.

Diastereomers

Compounds may have more than one chiral center. For example, 2,3-

dibromobutanoic acid has two chiral carbons:

Page 119: Bio-Organic Chem Lectures

The number of stereoisomers is calculated as N=2n=22=4.

Let us draw Fisher’s formulas of stereoisomers.

Because II is mirror image of I they are enantiomers; and III and IV are

enantiomers too. I and III are stereoisomers but not enantiomers. Stereoisomers

that are not mirror images of each other are called diastereomers. Compound

III is a diastereomer of I and II.

Diastereomers possess similar chemical properties, but not identical.

Diastereomers have different physical properties: different melting points, boiling

points, solubility. They differ in the rotation.

Meso-structures

Let us look at tartaric acid, which also has two chiral centers:

Does this compound, too, exist in four stereo someric

forms?

Fisher’s formulas of four supposed stereoisomers are folowing:

Not superimposable Superimposable

Enantiomers A meso-compound

I and II are enantiomers and each should be capable of optical activity. III is

a diastereomer of I and II. If we take IV, the mirror image of III, we find the two

to be superimposable; turned end-for-end, III coincides in every respect with IV.

Page 120: Bio-Organic Chem Lectures

In spite of its chiral centers, III is not chiral (it has a plane of symmetry). It cannot

be optically active. It is called a meso-compound. A meso-conpound is one whose

molecules are superimposable on their mirror images even though they contain

chiral centers.

A meso-compound is optically inactive. The molecule has a plane of

symmetry, and cannot be chiral. Optical activity is a property of chiral molecules

only!

HETEROFUNCTIONAL DERIVATIVES OF BENZENE,

WHICH ARE USED IN MEDICINE

There are many compounds, which are used as drugs among the

heterofunctional derivatives of benzene. They are derivatives of p-aminophenol,

p-aminobenzoic acid, sulphanilic acid, salicylic acid for example.

Derivatives of p-aminophenol

p-Aminophenol exhibits all properties of aromatic amines and phenols. It is

an amphoteric compound. As an amine p-aminophenol can react with mineral

acids and as phenol - with alkali:

Page 121: Bio-Organic Chem Lectures

As phenol p-aminophenol can form ethers, but this reaction occurs through

sodium p-aminophenolate formation:

Sodium salt formation reaction is necessary to increase nucleophilic

properties of p-aminophenol.

Phenetidine has free amino group and can take part in acylation reaction, for

example, with acetanhydride. Phenacetine is formed in this reaction:

Phenacetine is used as febrifugal and anodyne drug (antipyretic and

analgetic).

In acylation reaction of p-aminophenol the other drug can be prepared. It is

Paracetamol (Acetaminophen):

Paracetamol is used as antipyretic.

Derivatives of p-aminobenzoic acid

Page 122: Bio-Organic Chem Lectures

p-Aminobenzoic acid exhibits all properties of carboxylic acid and primary

aromatic amines. It is an amphoteric compound: as the carboxylic acid it exhibits

an acidity, as the amine – a basicity:

As carboxylic acid p-aminobenzoic acid can form acid chloride in the

interaction with PCl5 or thionyl chloride:

Acid chloride can be used as an intermediate in reactions of other functional

derivatives preparation.

As carboxylic acid p-aminobenzoic acid can form esters. Some of them are

used in medicine as local anaesthetics, for example, ethyl ester of p-aminobenzoic

acid is known as Anaesthesine, or Benzocaine:

Novocain is the other example of drugs – p-aminobenzoic acid derivatives.

Chemically it is N,N-diethylaminoethyl ester of p-aminobenzoic acid:

Page 123: Bio-Organic Chem Lectures

Novocain (Procaine) is used in medicine as hydrochloride. Hydrochloride is

soluble in water and can be injected by a parenteral way. The most basic nitrogen

takes part in the salt formation:

p-Aminosalicylic acid (PAS) is one of the earlier drugs used to

treat tuberculosis infections.

Sulfanilic acid derivatives

Sulfanilic acid is obtained by aniline sulfonation reaction. By the action of

concentrates sulfuric acid a salt– anilinium hydrosulfate is formed. By the

«baking» of this salt at 180-200oC p-aminobenzenesulfonic acid (sulfanilic acid )

is formed:

Page 124: Bio-Organic Chem Lectures

As a sulfonic acid sulfanilic acid exhibits strong acidity, it can form salts

with alkali:

Salts are soluble in water.

Basic properties of sulfanilic acid are very decreased, because of electron-

withdrawing action of sulfo-group. That is why sulfanilic acid is not soluble in

aqueous acids.

Sulfanilic acid melting point is abnormally high. That so, because it exists as

dipolar ion, or intramolecular salt:

The amide of sulfanilic acid (sulfanilamide) and certain related substituted

amides are of considerable medical importance as the sulfa drugs.

The antibacterial activity of sulfanilamide stems from a rather simple fact:

enzymes in the bacteria “confuse” it for p-aminobenzoic acid, which is an essential

metabolite. In what is known as metabolite antagonism, the sulfanilamide

Page 125: Bio-Organic Chem Lectures

competes with p-aminobenzoic acid for reactive sites on the enzymes; without this

essential metabolite microorganisms fail to reproduce and die.

Sulfanilamides action (their activity and toxicity) depends upon the nature of

the group R attached to amido hydrogen. In nearly all these effective compounds

the group R contains a heterocyclic ring, for example:

Derivatives of salicylic acid

Salicylic acid (o-hydroxybenzoic acid) behaves as phenol and

as carboxylic acid.

The acidity of salicylic acid is higher than that of benzoic acid, because of

higher stability of salicylate anion.

Salicylate anion is stabilized by the hydrogen bond formation between

negatively charged oxygen and partially positively charged hydrogen of hydroxyl

group.

As carboxylic acid salicylic acid forms salts in reactions with alkali or

sodium bicarbonate:

Page 126: Bio-Organic Chem Lectures

Sodium salicylate is used in medicine as antirheumatic drug.

Aqueous solutions of salicylic acid give a violet color with ferric chloride

(as all phenols).

When salicylic acid is heated, it undergoes decarboxylation reaction (as α-

hydroxy acids):

As carboxylic acid salicylic acid can form esters. Some of them are used in

medicine; methyl salicylate and phenyl salicylate are examples.

Methyl salicylate is used for rheumatism treatment and in perfumary. It is

obtained by the esterification reaction of salicylic acid with methanol:

Phenyl salicylate can not be prepared by the esterification reaction of

salicylic acid with phenol (if you remember, phenols are bad nucleophiles and can

not be acylated by carboxylic acids). We need to activate salicylic acid converting

it in salicyl chloride (acid chlorides are the strongest acylating agents).

Phenyl salicylate (salol) is used as an intestinal antiseptic.

As phenol salicylic acid can be acylated, for example it can react with

acetanhydride to give acetylsalicylic acid:

Page 127: Bio-Organic Chem Lectures

Aspirin is used as febrifugal drug (antipyretic).

Acetylsalicylic acid is an ester. It can be hydrolyzed if stored in the moist

place:

The admixture of free salicylic acid appears in this case and Aspirin can not

be used as a drug, because salicylic acid irritates a stomach. To indicate the

admixture of salicylic acid we can carкy out a reaction with FeCl3. Aspirin has not

free phenol hydroxyl group and can not react with FeCl3. If the admixture of

salicylic acid appeared the result of this reaction is violet color.

HETEROCYCLIC COMPOUNDS.

FIVE-MEMBERED HETEROCYCLES WITH ONE AND TWO

HETEROATOMS.

Heterocyclic compounds are cyclic compounds with the ring, containing

carbon and other elements, the commonest being oxygen, nitrogen and sulfur.

Heterocyclic compounds are wide-spread in nature. They are the base of

many vitamins, alkaloids, drugs.

Heterocyclic compounds may be three-membered, four-membered, five- and

six-membered ones. The most important are five- and six-membered heterocyclic

compounds.

Heterocyclic compounds may contain one, two or more heteroatoms.

Five-membered heterocycles with one heteroatom

They are as follows:

Page 128: Bio-Organic Chem Lectures

There are two kinds of positions in these molecules: carbon, neighboring to

heteroatom, is designated as α-position and the next – as β-position.

All this compounds are aromatic ones.

All atoms are sp2-hybridized. The cycle is flat. Nitrogen

has the unshared electron pair on the unhybrid pz-orbital.

This unshared electron pair takes part in the conjugation

(p,π-conjugated system). For this reason there are six

electrons in the common electron cloud. 4n+2=6, n=1.

The Huckel's rule is satisfied. Thus pyrrole is the aromatic compound.

Furan and thiophene have the same electronic structures (their heteroatoms

unshared electron pairs take part in p,π-conjugation).

Electrophilic substitution reactions are characteristic for pyrrole, furan

and thiophene. The electronic density in the molecules of these compounds is

increased, because six electrons of the aromatic cloud are delocalized between only

five atoms of the ring. Therefore these compounds are named π-surplus systems.

The SE reactions occur more easily in comparison with that in benzene. For

example, the bromination reaction of pyrrole occurs without any catalyst, at low

temperature. This reaction occurs in α-position, because the highest electronic

density there.

Page 129: Bio-Organic Chem Lectures

Due to the increased electronic density in the ring furan and pyrrole

should undergo sulfonation and nitration reactions more easily than benzene. But

these reactions occur in special conditions only.

If you remember, we use the concentrated sulfuric acid for sulfonation and a

mixture of concentrated nitric and sulfuric acids for nitration. Pyrrole and furan

form polymers (resins) in these conditions. How can this fact be explained? Let us

discuss that on the example of pyrrole. The unshared electron pair of nitrogen

takes part in the p,π-conjugation. For this reason pyrrole has not basic properties

in usual conditions and does not react with dilute acids. But if we add a

concentrated strong acid, such as sulfuric or nitric, the proton of the acid pulls out

the electron pair of nitrogen from the conjugated system and adds itself to it. The

salt is formed:

This salt is not aromatic compound, because nitrogen does not take part in

the conjugation. Then this salt can undergo polymerization and a resin is formed.

For this reason pyrrole is called the acidophobic compound (phobos means fear) -

it is afraid of acids. Furan is the acidophobic compound too.

Thus, it is necessary to use for nitration and sulfonation reactions of pyrrole

and furan those reagents that are not strong acids.

Acetylnitrate is used for nitration of acidophobic compounds. Acetylnitrate

is the mixed anhydride of acetic and nitric acids. It has not acid properties:

Pyridine sulfotrioxide is used for sulfonation reactions of acidophobic

compounds:

Page 130: Bio-Organic Chem Lectures

Properties of pyrrole derivatives

Acid and basic properties. You already know that pyrrole does not exhibit

basic properties, because the unshared electron pair takes part in the conjugated

system.

Pyrrole is a weak NH-acid. It forms salts in reactions with potassium and

sodium. For example:

The hydrogenation reaction of pyrrole is the difficult process, because the

aromaticity will be lost in this reaction. In reduction reaction in the presence of

zinc in acetic acid pyrroline is formed. In hydrogenation reaction by hydrogen in

the presence of platinum catalyst pyrrolidine is obtained.

Pyrrolidine is a typical secondary amine; it is a strong base, because the

unshared electron pair of nitrogen does not take part in the conjugation.

Amino acids proline and hydroxyproline are important derivatives of

pyrrolidine:

Page 131: Bio-Organic Chem Lectures

Pyrrolidone can be considered both as oxo-derivative of pyrrolidine and γ-

butyrolactam. A reaction of pyrrolidone with acetylene gives vinylpyrrolidone, that

may be polymerized into polyvinylpyrrolidone:

Polyvinylpyrrolidone (povidone) is used in medicine as extender of plasma

volume and in pharmacy – as a dispersing and suspending agent.

Pyrrole rings take part in the structure formation of very important natural

products such as chlorophyll (the green plant pigment, catalyst of photosynthesis);

heme (the prostetic part of hemoglobine (which carry oxygen from the lungs to

tissues). The base of both chlorophyll and heme is so-called tetrapyrrole system of

porphin.

Porphine is a stable system, because it is the aromatic

structure: all aromaticity rules are satisfied (a molecule

is flat, it is closed p,π-congugated system, 26 electrons

are delocalized in it - 4n+2=26, when n=6).

Porphirins are compounds containing the porphin structure to which a

variety of side chains are attached. Heme and chlorophyll are porphirins,

complexed with metal iond (Fe2+ and Mg2+).

Indol is pyrrole derivative also. It is benzopyrrol. Indole is an

aromatic compound with ten electrons in the aromatic cloud.

Page 132: Bio-Organic Chem Lectures

As for aromatic compounds electrophilic substitution reactions are

characteristic for indole. These reactions occur in β-position (in this case the more

stable intermediate is formed). For example, β-bromoindole is formed in

bromination reaction of indole:

Indole is an acidophobic conpound, thus its nitration and sulfonation

reactions must be carried out in the special conditions (using acetylnitrate and

pyridine sulfotrioxide).

Acid and basic properties of indole are the same with that of pyrrole: it does

not exhibit basic properties. It is a weak NH-acid:

The most important derivatives of indole are as follows: α-amino acid

thryptophane, nerve mediator serotonin, indomethacin (an anti-inflammatory

drug).

Page 133: Bio-Organic Chem Lectures

Two ways of trypthophane metabolism in the organism are possible:

oxidative and non-oxidative types of decarboxylation.

Properties of furan derivatives

Furfuraldehyde or furfural is one of the most important

furan derivatives.

All properties of aldehydes are characteristic for furfural, for example, the

silver mirror reaction, Cannizzaro reaction, nucleophilic addition and addition-

elimination reactions.

Page 134: Bio-Organic Chem Lectures

Silver mirror reaction gives furoic acid:

In Cannizzaro reaction furfuril alcohol and sodium salt of furoic acid are

formed:

Some antibacterial drugs may be prepared from furfural, Furacin (5-nitro-2-

furaldehyde semicarbazone) is an example:

Furacin is an antibacterial drug for external using.

Five-membered heterocycles with two heteroatoms

Nitrogen-containing five-membered heterocycles with two heteroatoms are

known as azoles. The examples of azoles are as follows:

All these compounds are aromatic ones. Let us explain it giving imidazole as

an example.

Page 135: Bio-Organic Chem Lectures

There are two different nitrogen atoms in the

imidazol structure. Nitrogen in the 1-st position is

pyrrole type, its unshared electron pair is situated at

unhybrid pz-orbital and takes part in the p,π-

conjugation. Pyridine type of nitrogen (in the 3-rd

position) has only one electron at pz-orbital that can take part in the conjugation. Its

unshared electron pair occupies a hybrid orbital, it is not a part of the conjugation

system. All aromaticity rules are satisfied: imidazol is a flat cyclic molecule, it is

closed p,π-conjugated system, six electrons are delocalized in it (4n+2=6, n=1).

Imidazole and pyrazole exhibit both weak acid and strong basic properties,

thiazole and oxazole – basic only.

Pyrrole type of nitrogen is an acid center, pyridine type – a basic center.

Because of strong basic properties they are not acidophobic (aromaticity is

not broken; becaude an unshared electron pair of pyridine type nitrogen did not

take part in the conjugation).

Because imidazole and pyrazole are acids and basis at the same time a

tautomerism is characteristic for them, this ability is connected with a hydrogen

proton transference from the acid to the basic center:

For this reason 4-th and 5-th positions in imidazole and 3-rd and 5-th

positions in pyrazole are equal.

Page 136: Bio-Organic Chem Lectures

Electrophilic substitution reactions are characteristic for imidazole and

pyrazole. They occur in 4-th positions of their molecules.

Pyrazole derivatives

Pyrazole reduction reactions give pyrazoline and then - pyrazolidine:

Pyrazolone is the most important derivative of pyrazoline. It can exist in

different tautomeric forms:

We can name it both 3-pyrazolone and 5-pyrazolone, because 3-rd and 5-th

positions are equal. We can name it 3(5)-pyrazolone, too.

3(5)-pyrazolone is a base of some drugs structures: Antipyrine (Phenazone)

and Amidopyrine are used as antipyretics, Analgine – as analgetic, Butadione

(Phenylbutazone) – as anti-inflammatory drug.

Page 137: Bio-Organic Chem Lectures

Imidazole derivatives

α-Amino acid histidine and amine histamine are imidazole derivatives.

Histamine decreases a blood pressure, increases the gastric secretion. The excess of

histamine in the blood may be a cause of allergic reactions.

Benzimidazole is a condensed ring system consist of benzene and imidazole

rings. Benzimidazole is a part of vitamin B12 structure.

Thiazole derivatives

Thiazole ring is a structural fragment of some sulfa drugs and vitamin B1.

Reduced thiazole – thiazolidine is a part of Penicillines molecules structures.

SIX-MEMBERED HETEROCYCLES WITH ONE HETEROATOM.

Pyridine and quinoline (benzopyridine) are examples of six-membered

heterocycles with one nitrogen heteroatom.

They are aromatic compounds. All atoms are

sp2-hybridized. Their molecules are flat. An

electronic configuration of pyridine type of

nitrogen differs that of pyrrole type. There is

only one electron at unhybrid pz-orbital of nitrogen in pyridine. Thus one electron

of nitrogen can take part in π,π-conjugated system. An unshared electron pair

Page 138: Bio-Organic Chem Lectures

occupies sp2-hybridized orbital, which is oriented on the plane of the molecule.

And can not take part in the conjugation. So, there are six electrons in the

common electron cloud of pyridine and ten electrons – in quinoline: 4n+2=6

(n=1), 4n+2=10 (n=2). All Huckel’s rules are satisfied.

Electrophilic substitution reactions are characteristic for pyridine and

quinoline as for aromatic compounds. These reactions occur with difficulties,

because the electronic density in the aromatic ring is decreased. (Nitrogen gives

one electron in the conjugation, as each carbon atom, but due to higher

electronegativity nitrogen displaces the electronic density to itself). Both pyridine

and quinoline are so-called electron-deficient systems.

Pyridine undergoes nitration, sulfonation and halogenation reactions under

very vigorous conditions only. These reactions occur more slowly than of

benzene. Pyridine and quinoline do not undergo acylation reactions at all.

Substitution reactions occur chiefly at the 3- (or β-) position in pyridine ring,

because the electronic density is the highest in these positions:

Examples of electrophilic substitution reactions in pyridine are as follows:

All these reactions occur at hard conditions. The pyridine ring resembles a

benzene ring that contains strongly electron-withdrawing groups.

Page 139: Bio-Organic Chem Lectures

Quinoline undergoes electrophilic substitution reactions more slowly than

benzene, but more easily than pyridine. These reactions occur in benzene ring, in

5-th and 8-th positions:

Due to electron withdrawing properties of nitrogen the electronic density of

the pyridine ring is decreased. For this reason nucleophilic substitution reactions

are characteristic for pyridine. The nucleophilic substitution take place readily,

particularly at the 2-nd and 4-th positions (or α- and γ-). Amination by sodium

amide (Chichibabin's reaction) and hydroxylation reaction with potassium

hydroxide are the important examples of nucleophilic substitution reactions:

Quinoline undergoes these reactions, too.

Pyridine and quinoline exhibit basic properties. The unshared electron pair

of nitrogen dies not take part in the conjugation. Due to this unshared electron pair

both pyridine and quinoline are bases.

As a base pyridine (and quinoline) can react with mineral acids to form salts:

Page 140: Bio-Organic Chem Lectures

Pyridine is enough strong base to react with so weak acid as water:

Pyridine can react with sulfur trioxide, which is a Lewis acid:

Due to unshared electron pair pyridine exhibits nucleophilic properties. It

can react with alkyl halides to form quaternary salts:

An electronic density of the ring in this salt is more decreased that that in

pyridine. N-methylpyridinium cation can actively react with a nucleophile, for

example with hydride anion:

A product of this reaction is non-

aromatic one, and its molecule is not as

stable as the initial cation. The molecule

can get back the aromaticity due to

oxidation reaction. This reversible process is the base of co-enzyme NAD+ action

(NAD+ takes part in oxidative-reducing processes in the organism).

Pyridine can be reduced by the action of sodium in ethanol. This kind of

reduction reactions is impossible for benzene:

Page 141: Bio-Organic Chem Lectures

Quinoline undergoes reduction reactions also. These reactions occur due to

pyridine ring. Oxidation of quinoline occurs due to benzene ring:

Quinoline is oxidized by potassium permanganate in the alkaline medium

with the benzene ring destruction to form 2,3-pyridinedicarboxylic acid.

Some pyridine and quinoline derivatives are used in medicine as drugs.

Nicotinic acid and its derivatives. Nicotinic acid is β-pyridine carboxylic

acid. It can be obtained by the oxidation reaction of β-methylpyridine (or β-

picoline) with potassium permanganate:

Nicotinic acid is anti-pellagra

complex (vitamin PP, Niacin).

As carboxylic acid nicotinic acid forms acid chloride and then all other

functional derivatives (amides, for example):

Nicotinamide is used in medicine as vitamin PP, too.

Pyridoxine (one of the vitamin B6 forms) is pyridine derivative also:

Page 142: Bio-Organic Chem Lectures

Isonicotinic acid and its derivatives. Isonicotinic acid (γ-pyridine carboxylic

acid) can be obtained by the oxidation reaction of γ-picoline. Acid chloride and

then hydrazide are prepared from isonicotinic acid:

Hydrazide of isonicotinic acid is used in the treatment of tuberculosis

(Isoniazid).

Quinoline derivatives. Derivatives of 8-hydroxiquinoline are the most

interesting as antibacterial drugs.

Oxine has antibacterial properties which are connected with its ability to

increase the toxical action of Fe2+ and Cu2+ ions. Oxine forms complexes with

these ions, for example:

Complexes with Fe2+ are toxic for all bacteria, with

Cu2+ - for fungus.

Some 8-hydroxyquinoline derivatives are used as antibacterial drugs, too.

For example, Clioquinol is 5-chloro-8-hydroxy-7-iodoquinoline:

Page 143: Bio-Organic Chem Lectures

SIX-MEMBERED HETEROCYCLES WITH TWO HETEROATOMS

Heterocycles with two nitrogen atoms (so-called diazines) are the most

investigated. Three structural isomers of diazines are possible, they are:

All these compounds are aromatic (molecules are flat, there are two pyridine

nitrogen atoms in there structures, they are closed π,π-conjugates structures,

4n+2=6 electrons are delocalized in the aromatic cloud). Pyridazine, pyrimidine

and pyrazine are electron deficient systems. The electronic density is decreased by

the electron-withdrawing action of both pyridine nitrogen atoms. You know, that

even pyridine with one heterocyclic nitrogen can take part in electrophilic

substitution reactions in very hard conditions. SE reactions are impossible for

diazines. Derivatives of diazines with strong electron-releasing groups (such as -

NH2 and -OH) can take part in electrophilic substitution reactions.

Diazines are weak bases. Two nitrogen atoms in their structures decrease a

basicity of each other. Diazines are weaker bases as pyridine (pKBH+ of pyridine =

5.3, pKBH+ of pyrimidine =1.3) . There are two basic centers in diazines molecules,

but they form salts with one equivalent of strong mineral acid. For example:

Page 144: Bio-Organic Chem Lectures

Because an electronic density of the aromatic rings of diazines are decreased

nucleophilic substitution reactions (for example, Chichibabin’s reactions) are

possible for them. These reactions occur in positions 2,4 and 6, where the

electronic density is especially decreased:

Pyrimidine derivatives that are used in medicine. There are very important

compounds among pyrimidine derivatives. They are nucleic bases (uracil, thymine

and cytosine), vitamin B1 and so-called barbiturates.

Barbiturates are barbituric acid derivatives. Barbituric acid is 2,4,6-

trihydroxypyrimidine. Two kinds of tautomerism are characteristic for it; they are

keto-enol and lactam-lactim tautomerism.

Carbon atom in the 5-th position is CH-acid center (C-H bonds are polarized

under the action of two electron-withdrawing C=O groups). CH-acid center gives

up a proton, oxygen in 6-th position accepts it due to an unshared electron pair.

Keto tautomer (I) is converted into enol tautomer (II).

N-H bonds are polarized also under the action of the neighboring C=O

groups. NH-acid centers give protons; oxygen atoms in 2-nd and 4-th positions

accept them. Lactam tautomer (I) is converted into lactim tautomer (III).

Page 145: Bio-Organic Chem Lectures

The most stable tautomer of barbituric acid is I.

Barbituric acid is a strong acid (it is stronger than acetic acid). Enol tautomer

is responsible for its acidity:

Barbiturates are alkyl or aryl derivatives of barbituric acid (for 5-th

position). There general formula is as follows:

For example, Barbital is 5,5-diethylbarbituric acid; Phenobarbital is

5-ethyl-5-phenyl-barbituric acid.

Barbiturates are drugs of sedative and hypnotic action. Barbiturates are bad

soluble in water, but their sodium salts are soluble. Sodium salts may be formed

due to acid properties of lactim tautomer form. Lactam-lactim tautomerism is

possible for barbiturates, but not keto-enol, because there are not hydrogen atoms

in 5-th position of barbiturates. Barbiturates are weaker acids than barbituric acid.

Page 146: Bio-Organic Chem Lectures

Condensed ring systems.

Purine is the most important condensed heterocyclic system.

Purine molecule consists of pyrimidine and imidazole rings.

It is an aromatic compound, because all aromaticity rules

are satisfied: it is a flat molecule, all atoms take part in the

conjugation, ten electrons are delocalized in the conjugated system (1-st, 3-rd and

5-th nitrogen atoms are that of pyridine type and 9-th nitrogen – pyrrol type).

There are both acid and basic centers in purine molecule:

Purine reacts with acid and bases to form corresponding salts:

Tautomerism is characteristic for purine. Acid center gives up a proton,

basic center – accepts it. 7-th nitrogen becomes an acid center, 9-th nitrogen –

basic center. For his reason 7-th and 9-h positions in purine are equal.

Page 147: Bio-Organic Chem Lectures

Some purine derivatives are important compounds, for example, purine

nucleic bases (adenine and guanine), xanthine, uric acid.

Hydroxypurines.

Hypoxanthine, xanthine and uric acid are hydroxypurines:

Lactam-lactim tautomerism is characteristic for all these compounds.

Lactam tautomers are more stable.

Lactim tautomers are responsible for acid properties.

Three important methylated xanthines that occur naturally are caffeine,

theobromine and theophilline (they occur in tea and coffee):

Page 148: Bio-Organic Chem Lectures

All these compounds are weak bases (due to unshared electron pair of 9-th

nitrogen), theophilline and theobromine are also acids (due to lactim tautomers).

Lactam-lactim tautomerism is impossible for caffeine, thus it can not exhibit

acidity.

Acid properties of theophiline and theobromine are used for their qualitative

analysis. They form insoluble colorized salts with hard metals ions (Co2+, Cu2+).

Theophilline and theobromine are diuretics. Caffeine and theobromine are

central nerve system stimulators.

Uric acid is 2,6,8-trihydroxypurine. Lactam-lactim tautomerism is

characteristic for it. Lactim tautomer is responsible for acid properties. Uric acid

can form two types of salts, but not three as we could suppose. Salts of uric acid

are called urates.

Acidic hydrohyl group in 6-th position can not be formed, because an

unshared electron pair of oxygen takes part in the intramolecular hydrogen bond

formation.

Monourates are insoluble in water (litium salts are exceptions). Urates can

be deposited in the organism as stones in kidney or in joints.

Murexide test is the qualitative reaction of uric acid and other purine

derivatives. After a heating with concentrated nitric acid ammonium hydroxide is

added and purple color is formed.

Page 149: Bio-Organic Chem Lectures

CARBOHYDRATES. MONOSACCHARIDES.

Carbohydrates (sugars) are very wide-spread in nature. They are the source

of the energy, the base if the framework of the plants. They take part in the

molecules of nucleic acids, some enzymes and vitamins building. Some

carbohydrates and their derivatives are drugs.

Carbohydrates are polyhydroxy aldehydes, polyhydroxy ketones, or

compounds that can be hydrolyzed to them. Carbohydrates that cannot be

hydrolyzed to simpler compounds are called monosaccharides. Carbohydrates that

can be hydrolyzed to two monosaccharide molecules are called disaccharides.

Carbohydrates that can be hydrolyzed to many monosaccharide molecules are

called polysaccharides.

Monosaccharides

Classification. If a monosaccharide contains an aldehyde group, it is known

as an aldose; if it contains a keto group, it is known as a ketose. Their general

formulas are:

Depending upon the number of carbon atoms they contain, monosaccharides

are known as trioses, tetroses, pentoses, hexoses, and so on. An aldohexose, for

example, is a six-carbon monosaccharide containing an aldehyde group;

ketopentose is a five-carbon monosaccharide containing a keto group. Most

naturally occurring monosaccharides are pentoses and hexoses.

Stereo isomerism. The molecules of monosaccharides contain several chiral

centers, for this reason stereo isomerism is characteristic for them.

Page 150: Bio-Organic Chem Lectures

For example, there are four chiral centers in the

molecule of aldohexose. Therefore 24 =16 stereo

isomers can exist. Glucose is the most important of

them.

The relative configuration of monosaccharides

is determined by the configuration of the chiral center, which

is the farthest of aldehyde or keto group. In case of glucose it

is the fifth carbon atom. Glyceraldehyde is a standard. The

most of natural monosaccharides have D-configuration.

Thus among 16 stereo isomers there are 8 pairs of enantiomers. Enantiomers

have the same names (for example, D-glucose and L-glucose). In regarding to

them the other 14 stereo isomers are diastereomers. Diastereomers have the

different properties and different names. For example:

D-glucose, D-mannose and D-galactose are diastereomers.

Diastereomers that differ by configuration of one carbon atom only are

named epimers. For example, D-glucose and D-mannose, D-glucose and D-

galactose are epimers.

Some other examples of monosaccharides (hydrogen atoms in Fisher’s

formulas can be not designated) are:

Page 151: Bio-Organic Chem Lectures

Chemical properties of monosaccharides

You already know that monosaccharides are polyhydroxy aldehydes or

polyhydroxy ketones, therefore they must undergo all reactions of polyalcohols

and aldehydes or ketones. Actually, glucose, for example, gives the silver mirror

reaction (as an aldehyde) and dissolves the blue precipitate of Cu(OH)2 to form

dark blue solution (as a polyalcohol). But some properties are characteristic for

glucose and other monosaccharides, which can not be explained due to its

structure. For example:

1) We know that each stereo isomer has the certain optical activity. But if

we determine the optical activity of glucose solution, this activity is changed

during some time. The change in rotation is called mutarotation.

2) Glucose can react with one mole of the alcohol to form a product, which

has properties resembling those of a full acetal. This product can be hydrolyzed by

aqueous acids.

What is the reason of these facts? It is cyclo-oxo tautomerism. The idea

about cyclic structure of monosaccharides appears in 1895 due to researches by

Fisher and Tollens.

Monosaccharides can form the cyclic hemiacetals, because their aldehyde

(or keto) group and hydroxy groups are near one another in space and can react one

another. Let us tackle it on the example of glucose:

Page 152: Bio-Organic Chem Lectures

Actually, the aldehyde group of glucose is near with hydroxy group of 4-th

and 5-th carbon atoms. When an aldehyde reacts with alcohol the hemiacetal is

formed. In this case the cyclic hemiacetal will be formed. There are four cyclic

structures of D-glucose:

"On the right" in Tollens formula means "down" in the Haworth

formula.

If the aldehyde group reacts with hydroxyl group of 5-position the six-

membered cycle is formed. It is called pyranose cycle. A new chiral center and

new hydroxyl group appear. This hydroxyl group is known as hemiacetal

hydroxyl. The configuration of C-1 may be different; therefore there are two stereo

isomers of D-glucopyranose: they are α- and β-glucopyranoses. If the hemiacetal

hydroxyl is on the right side it is α-isomer; if the hemiacetal hydroxyl is on the left

side - it is β-isomer.

α-D-glucopyranose and β-D-glucopyranose are diastereomers. Such a pair

of diastereomers is called anomers.

Page 153: Bio-Organic Chem Lectures

When the aldehyde group reacts with hydroxy group of 4-position the five-

membered cycle is formed . It is called furanose cycle.

Thus, there are five tautomeric structures of D-glucose in its solution: the

open-chain structure, α-D-glucopyranose, β-D-glucopyranose, α-D-glucofuranose

and β-D-glucofuranose. They exist in the equilibrium:

About 64% in this equilibrium is β-D-glucopyranose. It is the most stable

form. It can be explain as follows. Pyranose ring is not flat. It exists in chair

conformation. In β-D-glucopyranose a hemiacetal hydroxyl group is situated in

equatorial position (the energy is lesser that that of axial position).

Page 154: Bio-Organic Chem Lectures

Each tautomer has the certain optical activity. Before the equilibrium is

established the optical activity of the solution is changed. It is the reason for

mutarotation.

Due to the equilibrium of tautomeric structures monosaccharides can react

as aldehydes or ketones, as alcohols, as cyclic hemiacetals. It depends upon a

nature of the reagent.

Glycosides formation. A treatment of a monosaccharide with an alcohol and

dry hydrogen chloride yields the glycoside. For example:

Glycosides are acetals

In the monosaccharides reaction with amines N-glycosides are formed. For

example:

Glycosides are hydrolyzed very easily in acidic medium:

Page 155: Bio-Organic Chem Lectures

Cyclo-oxo tautomerism is not characteristic for glycosides, because they

have not free hemiacetal hydroxyl group and can not form an open-chain structure

and other cyclic structures.

Esters and ethers formation. As polyalcohols monosaccharides can form

ethers and esters.

For example, glucose treatment with dimethyl sulfate and sodium

hydroxide yields O-methyl-2,3,4,6-tetramethylglucopyranoside:

There are two types of bonds in this molecule: glycoside bond, which was

formed by hemiacetal hydroxyl group, and ether bonds, that were formed by

alcohol groups. Glycoside bonds only can be hydrolyzed in the acidic medium.

Ether bonds can not be hydrolyzed:

Monosaccharides treatment with carboxylic acids anhydrides yields esters:

Page 156: Bio-Organic Chem Lectures

Esters are hydrolyzed both in the acidic and alkaline medium:

Esters of phosphoric acid are very important compounds. They are a

methabolism of carbohydrates result in the organism. For example:

Reactions of the open-chain form.

Reactions of monosaccharides as polyalcohols. Monosaccharides can react

with Cu(OH)2 to form dark-blue solution of coordinate salt:

Reduction reactions. As all aldehydes and ketones monosaccharides can be

reduced in the corresponding polyalcohols. For example:

Page 157: Bio-Organic Chem Lectures

Glucitol and xylitol are used instead of sucrose as sugar in case of diabetes.

Oxidation reactions of monosaccharides. Monosaccharides can be oxidized

under the different conditions. The result of oxidation depends upon the

conditions.

Oxidation by ammonia solution of silver hydroxide or copper (II) hydroxide

does not give the corresponding carboxylic acid as oxidation of all aldehydes.

Both these reagents (Ag(NH3)2OH and Cu(OH)2 ) are the alkaline ones, and the

treatment of sugars with alkali can be a cause of decomposition of the chain. For

this reason the different products of oxidation may be obtained:

These reactions cannot be used to differentiate aldoses and ketoses (for

example, glucose and fructose). Ketoses, too, reduce these reagents, because on

alkaline medium aldoses and ketoses can convert one into another. We can use

Selivanoff's test for fructose distinguishing. When a solution of polyphenol

resorcinol in concentrated hydrochloric or sulfuric acid is boiled with the fructose

solution, a red color is obtained.

So, all monosaccharides are reducing compounds (they can reduce other

compounds). But these reactions occur due to open-chain tautomers only.

Page 158: Bio-Organic Chem Lectures

Therefore glycosides are non-reducing compounds, because they can not be

transformed into open-chain structures (they have not free hemiacetal hydroxyl

groups).

Oxidation reactions by bromine water is characteristic for aldoses but not

for ketoses.

The result of this oxidation reaction is the corresponding aldonic acid

(gluconic, mannonic) formation:

Gluconic acid is a monocarboxylic acid and it can form salts. Its calcium salt

is a drug. It is used as a source of calcium ions:

The treatment of an aldose with the more strong oxidising agent - nitric acid

- brings about oxidation not only of the aldehyde group but also if the primary

alcohol group, and leads to the formation of the aldaric acid (dicarboxylic acid).

For example:

Page 159: Bio-Organic Chem Lectures

CARBOHYDRATES. DISACHCRIDES AND POLYSACCHRIDES

Disaccharides are carbohydrates that are made up of two monosaccharide

units. On hydrolysis a molecule of disaccharide yields two molecules of

monosaccharide.

Principle of disaccharide molecules building may be different. All

disaccharides are acetals. If the acetal bond is formed due to hemiacetal hydroxyl

of one monosaccharide and alcohol hydroxyl of other monosaccharide disaccharide

will be reducing one. If the acetal bond is formed due to two hemiacetal hydroxyl

groups of both monosaccharides disaccharide will be non-reducing one.

The examples of reducing disaccharides are as follows: maltose, cellobiose

and lactose.

Two α-D-glucopyranose molecules take part in the molecule of α-maltose

building. α-1,4-glycoside bond is formed due to hemiacetal hydroxyl group of the

first molecule and alcohol hydroxyl group in 4-th position of the second molecule

interaction.

Page 160: Bio-Organic Chem Lectures

Cellobiose contains two

glucopyranose units, too, but they are

joined by β-glycoside linkage.

Lactose contains galactopyranose

and glucopyranose units, joined by

β-glycoside linkage.

All disaccharides are O-glycosides, therefore hydrolysis reaction in the

acidic medium is characteristic for them. For example:

Cyclo-oxo tautomerism is characteristic for reducing disaccharides, because

they have free hemiacetal hydroxyl group. For example:

Page 161: Bio-Organic Chem Lectures

So, cyclic tautomers of reducing disaccharides can be converted into open

tautomers and the aldehyde group appears. The aldehyde group is the reducing

group, because it can be oxidized very easily. Then other cyclic form can be

formed. Both α- and β-tautomers of reducing disaccharides exist in nature.

The reducing properties of disaccharides can be confirmed by "silver mirror

reaction" or reaction with copper (II) hydroxide at heating:

Oxidation by bromine water gives bionic acids (maltobionic, lactobionic

acids are examples):

Reducing disaccharides can react with alcohols in dry HCl presence to yield

glycosides due to free hemiacetal hydroxyl group:

Page 162: Bio-Organic Chem Lectures

Disaccharides can be alkylated and acylated due to all hydroxyl groups:

Pay your attention: only glycoside bonds are hydrolyzed, ether bonds can

not be hydrolyzed!

Esters are formed in acylation reactions. Both glycoside and ester bonds can

be hydrolyzed in the acidic medium; ester bonds can be hydrolyzed in alkaline

medium also.

Page 163: Bio-Organic Chem Lectures

Sucrose (our common table sugar) is an example of non-reducing sugars.

Sucrose contains α-glucopyranose and β-fructofuranose units, joined by 1,2-

glycoside bond. Two hemiacetal hydroxyl groups take part in this bond formation.

So, this bond blocks both carbonyl groups of both monosaccharides. There is not

free hemiacetal hydroxyl group in sucrose molecule. No hemiacetal group – no

cyclo-oxo tautomerism, carbonyl group can not appear. No carbonyl group – no

reducing properties.

As glycoside sucrose can be hydrolyzed in acidic medium:

Page 164: Bio-Organic Chem Lectures

Products of sucrose hydrolysis exhibit reducing properties.

Sucrose can be acylated and alkylated also.

Polysaccharides.

Polysaccharides are compounds made up of many - hundreds or even

thousands - monosaccharide units per molecule. These units are held together by

glycoside linkages, which can be broken by acid hydrolysis.

Polysaccharides are naturally occurring polymers, which can be considered

as derived from aldoses or ketoses by polymerization with loss of water.

Polysaccharides may be homo- and heteropolysaccharides.

Homopolysaccharides molecules contain the same units. Heteropolysaccharides

molecules contain the different units. We'll discuss homopolysaccharides only.

Starch. Starch occurs as granules whose size and shape are characteristic of

the plant from which the starch is obtained. Starch is insoluble in cold water; in

hot water a gel is formed.

In general, starch contains about 20% of water-soluble fraction called

amylose and 80% of water-insoluble fraction called amylopectin.

Upon treatment with acid or under the influence of enzymes the components

if starch are hydrolyzed progressively to dextrin (a mixture of low-molecular-weigt

polysaccharides), then to maltose, and finally to D-glucose. Both amylose and

amylopectin are made up of D-glucose units, but differ in structure.

Amylose is made up of chains of many D-glucose units, each unit joined by

α-glycoside linkage to C-4 of the next one. The chain of amylose is not branched.

Amylose gives the intense blue color with iodine. X-ray analysis shows that

the chain is coiled, inside which is just enough space to accommodate an iodine

molecule; blue color is obtained due to entrapped iodine molecules.

Page 165: Bio-Organic Chem Lectures

Amylopectin is made up of many D-glucose unites joined by α-1,4- and α-

1,6-glycoside bonds. Amylopectin has a highly branched structure. There are 20-

25 glucose units between each two branches.

Glycogen is a compound in form of which carbohydrates are stored in

animals to be released upon metabolic demand. It has a structure very similar to

that of amylopectin, but its molecules are more highly branched. There are only

12-18 glucose units between each two branches.

Dextrans are polysaccharides which are made by the action of certain

bacteria. Dextrans have been used as substituents for blood plasma in transfusion

(as a plasma volume extender). Dextrans are made of D-glucose, too. Their

molecules are very highly branched. The main type of linkages is α-1,6-glycoside

one, in places of branches - α-1,4- and α-1,3-glycoside bonds.

Page 166: Bio-Organic Chem Lectures

Cellulose is the chief component of wood and plant fibers; cotton, for

instance, is nearly pure cellulose. It is insoluble in water and tasteless, it is a non-

reducing carbohydrate.

Cellulose is made up of chains of D-glucose units, each unit joined by β-

glycoside bond to C-4 of the next unit:

This chain is non-branched. As polyglycoside cellulose can be hydrolyzed.

As polyalcohol cellulose forms ethers and esters. For example, a treatment

of cellulose be a mixture of concentrated nitric and sulfuric acid gives nitrates

(mono-, di- and trinitrates). There solution in diethyl ether and ethanol mixture is

so-called collodion. Its a syrupy liquid, which dries to a transparent, tenacious

film; used as a topical protectant, applied to the skin to close small wounds and

cuts, to holt surgical dressing in place and to keep medications in contact with the

skin.

NATURAL α-AMINO ACIDS AND PROTEINS

Proteins are substances of life. They make up a large part of animals bodies,

they are found in all living cells. They are a principal material of skin, muscle,

nerves and blood; of enzymes and many hormones.

Chemically, proteins are high polymers. They are polyamides, and

monomers from which they are derived are α-amino acids. A single protein

molecule contains hundreds or even thousands of amino acids units.

Structure and classification of α-amino acids

It is a general formula of α-amino acids. They differ by the

radicals structures. In accordance with the nature of the

Page 167: Bio-Organic Chem Lectures

radical α-amino acids may be classified as aliphatic, aromatic and heterocyclic

amino acids. Aliphatic α-amino acids can also contain hydroxy- or thiol groups in

their structures.

Examples of aliphatic α-amino acids and are as follows:

Examples of aromatic α-amino acids are as follows:

Page 168: Bio-Organic Chem Lectures

Heterocyclic α-amino acids are as follows:

In accordance with the number of amino and carboxyl groups α-amino acids

are classified as:

1) Neutral α-amino acids (one amino and one carboxyl group in their

structures). Glycine, alanine are examples.

2) Basic α-amino acids (two amino and one carboxyl group in their

structures). Lysine, arginine are examples.

3) Acidic α-amino acids (one amino and two carboxyl groups in their

structures). Aspartic and glutamic acids are examples.

Some α-amino acids cannot be synthesized in the organism from the other

materials, they must be entered into the organism with food. They are called

essential amino acids (their formulas are designated by *).

Stereo isomerism

All α-amino acids except glycine have chiral centers in their structures and

can exist as enatiomers pairs. For example:

All natural α-amino acids have L-configurations.

Chemical properties of α-amino acids

Page 169: Bio-Organic Chem Lectures

α-Amino acids as dipolar ions. α-Amino acids exist in form of

intramolecular salts, or dipolar ions:

For this reason α-amino acids have the high melting points, they are

insoluble in non-polar solvents, like ether, benzene, and they are soluble in water.

Actually, there is equilibrium of dipolar ions, cations and anions in aqueous

solutions of α-amino acids. This equilibrium depends upon pH of the solution. In

quite alkaline solution there is the excess of anions, in quite acidic solution there is

the excess of cations:

Thus, in acidic medium α-amino acid can migrate towards the cathode and

in alkaline medium - towards the anode.

The hydrogen ions concentration (pH) of the solution in which a particular

α-amino acid does not migrate under the influence of an electric field is called the

isoelectric point of that α-amino acid.

So, the isoelectric point is pH of the solution in which all molecules of

certain α-amino acid exist as dipolar ions. The isoelectric point (IEP) depends upon

the type of α-amino acid. IEP of acidic α-amino acids are situated in pH<7, IEP of

basic α-amino acids - in pH>7.

Acid and basic properties. Amino acids exhibit both acid and basic

properties, therefore they can react with alkali and with acids:

Page 170: Bio-Organic Chem Lectures

As carboxylic acids α-amino acids can form esters and acid chlorides:

As amines α-amino acids can react with acids anhydrides, aldehydes and nitrous

acid:

This reaction is used in quantitative analysis.

The reaction with nitrous acid is known as deamination reaction in vitro. It

is used in the quantitative analysis of α-amino acids. It is a base of Van Slyke

determination of amino nitrogen. It is possible to determine the quantity of amino

acid by the volume of nitrogen gas.

As amines α-amino acids can be acylated, can react with oxo-compounds:

A special reaction of all α-amino acids is their interaction with Cu2+ ions to

form coordinate salts:

Page 171: Bio-Organic Chem Lectures

The other special reaction of α-amino acids is decarboxylation reaction:

Special reactions of particular groups of α-amino acids

Aromatic α-amino acids react with concentrated nitric acid at heating to

form a yellow color that becomes orange when a solution made alkaline:

Sulfur containing α-amino acids react with lead acetate in alkaline medium

to form black precipitate:

Reactions of α-amino acids in vivo

The main reactions of α-amino acids in the organism are following:

decarboxylation, deamination and transamination reactions. All these reactions

occur in the presence of corresponding enzymes.

Decarboxylation reactions of α-amino acids give the corresponding amines,

for example:

Page 172: Bio-Organic Chem Lectures

There are two types of deamination reactions in vivo: non-oxidative and

oxidative deamination.

In non-oxidative deamination reaction ammonia molecule is eliminated.

This reaction is characteristic for fungus and some microorganisms. For example,

aspartic acid is deaminated in fumaric acid:

Oxidative deamination is characteristic for animals and humans. This

reaction occurs in two steps: amine oxidation into imine and then its hydrolysis

into keto acid.

Transamination reaction occurs between amino acid and keto acid, for

example:

The most important property of α-amino acids is peptides formation.

PEPTIDES

Peptides are amides formed by the interaction between amino groups and

carboxyl groups of α-amino acids. The amide group in such compounds

is often referred to as the peptide linkage.

Page 173: Bio-Organic Chem Lectures

Depending upon the number of α-amino acids residues per molecule, they

are known as dipeptides, tripeptides, and so on, and finally polypeptides. (By

convention, peptides of molecular weight up to 10 000 are known as polypeptides

and above that are proteins).

For example:

According to convention, the N-terminal α-amino acid residue (having the

free amino group) is written at the left end and the C-terminal α-amino acid residue

(having the free carboxyl group) - at the right end.

Geometry of peptide linkage

X-ray studies of dipeptides indicate that amide

group is flat: carbonyl carbon, nitrogen and

four atoms attached to them all lie in a same

plane.

The short carbon-nitrogen distance (0.132 nm as compared with 0.147 nm

for the usual carbon-nitrogen single bond) indicates that the carbon-nitrogen

bond has considerable double bond character: It is a result

of p,π-conjugation.

Page 174: Bio-Organic Chem Lectures

Peptides are amides, therefore they can be hydrolyzed both in alkaline and

acidic medium (the corresponding salts are obtained) and in the presence of

enzymes. For example:

Qualitative test of peptide linkage is biuret reaction. Addition of a very

dilute solution of copper sulfate to an alkaline solution of a protein produces a red

or violet color. This reaction is possible due to the presence of the grouping -CO-

NH-CHR-CO-NH-. At least two peptide linkages must be present (dipeptides do

not give this test).

The primary structure of a peptide (or protein) is the sequence of α-amino

acids residues in the molecule.

The secondary structure of proteins is the arrangement of a polypeptide

chain in space. There are two types of the secondary structure: α-helix and β-

conformation.

The α-helix model for the conformation of proteins was proposed by Pauling

et al. in 1951. It is a right- handed helix with 3.6 α-amino acids residues per tern.

Hydrogen bonds occurs between different parts of the same chain, between oxygen

of C=O group of each first peptide linkage and hydrogen of N-H group of each

fifth peptide linkage.

β-Conformation or pleated sheet. In this conformation the polypeptide chain

is extended and chains are held together by intermolecular hydrogen bonds.

The tertiary structure is the arrangement of α-helix in space. Pauling has

suggested that each α-helix can itself be coiled into a super helix which has one

tern for every 35 turns of the α-helix. The tertiary structure is stabilized by

hydrogen bonds; ionic bonds between COOH groups of the residues of acidic α-

Page 175: Bio-Organic Chem Lectures

amino acids and NH2 group of the residues of basic α-amino acids; covalent

bonds (disulfide bridges) between two cysteine residues.

NUCLEIC ACIDS

Nucleic acids are substances of heredity. Nucleic acids are high polymers;

their molecular weight may be greater than one million. The monomers of nucleic

acids are nucleotides, so nucleic acids are polynucleotides. Nucleotides consist of

heterocyclic bases, monosaccharides (ribose or deoxyribose) and phosphoric acid

remainder. The general structure of nucleic acids is as follows:

Heterocyclic bases

Two types of heterocyclic bases are known. They are purines and

pyrimidines. Purine heterocyclic bases are adenine (A) and guanine (G), which

contain the purine ring system. Cytosine (C), uracil (U) and thymine (T) contain

the pyrimidine ring system.

The lactam-lactim tautomerism is characteristic for all heterocyclic bases

except adenine:

Page 176: Bio-Organic Chem Lectures

Lactam tautomers are more stable, because of higher ability to form

hydrogen bonds. Lactam tautomers take part in nucleic acids molecules building.

There are two types of nucleic acids in the organism: ribonucleic acids

(RNA) and deoxyribonucleic acids (DNA). They differ not only in the sugar

remainder, but in the heterocyclic bases set also. RNA contains adenine, guanine,

cytosine and uracil. DNA contains adenine, guanine and cytosine too, but thymine

instead of uracil.

Some derivatives of purine and pyrimidine are used in medicine as

antineoplastic drugs. Their structures are like the structures of heterocyclic bases

therefore they can take part in DNA and RNA of swelling cells building instead of

"real" bases. It breaks the synthesis of swelling cell proteins. The examples of the

drugs are:

Nucleosides

Combination of a base (either a purine or pyrimidine) with a sugar (ribose in

RNA or deoxyribose in DNA) gives a nucleoside. Nucleosides are N-glycosides.

The glycoside bond is formed due to hemiacetal hydroxyl of ribose or deoxyribose

and hydrogen of N-1 of pyrimidines or N-9 of purines. For example:

Page 177: Bio-Organic Chem Lectures

Ribose and deoxyribose are present in the β-furanose tautomeric forms.

Carbon atoms of sugar are numbered by figures with a touch.

Names of nucleosides

Base Sugar Name of nucleoside

Uracil (RNA only)

Thymine (DNA only)

cytosine

cytosine

adenine

adenine

guanine

guanine

ribose

deoxyribose

ribose

deoxyribose

ribose

deoxyribose

ribose

deoxyribose

uridine

thymidine

cytidine

deoxycytidine

adenosine

deoxyadenosine

guanosine

deoxyguanosine

Nucleosides are glycosides; therefore they can be hydrolyzed in the acidic

medium only. For example:

Page 178: Bio-Organic Chem Lectures

Nucleosides are interesting not only as compounds, which take part in the nucleic

acids building. Some of nucleosides are present in the living cells in the free state.

They exhibit antibiotic and antiswelling activity. Some of

them are used as drugs, for example azidothymidine, that

decreases a speed of AIDS (acquired

immunodeficiency syndrome) virus reproduction.

Nucleotides

Nucleotides are phosphates of nucleosides (the esters). Esterification

reaction can occur due to hydroxyl group in 3' or 5'-position of the sugar.

Page 179: Bio-Organic Chem Lectures

There are two types of bonds in the nucleotides molecules: N-glycoside

bonds and ester bonds. Ester bonds can be hydrolyzed both in acidic and alkaline

medium; N-glycoside bond - in acidic medium only. For example:

Phosphoric acid can take part in esterification reaction with two hydroxyl

groups at the same time. In this case so-called cyclophosphates are formed. For

example:

Page 180: Bio-Organic Chem Lectures

Nucleotides are known as monomers of the nucleic acids. But not only is

this role characteristic for them. For example, ATP (adenosine triphosphate) is

present in all tissues of the organism. Its role is as supplier of the energy in all

living cells. When ATP is synthesized the energy is stored, when ATP is

hydrolyzed the energy is evolved.

The energy of anhydride bonds is great (32 kJ/mole), therefore they are

called macroergic bonds. Their hydrolysis gives a lot of energy.

Page 181: Bio-Organic Chem Lectures

ATP also takes part in the biosynthesis of peptides, it activates α-amino

acids molecules to form a mixed anhydrides:

Nucleic acids

Nucleic acids are polynucleotides. DNAs are present in nuclei of cells,

RNAs - in ribosomes and protoplasma. The main role of DNAs is to preserve the

hereditary information and control of protein synthesis. RNAs take part in the

protein synthesis.

The primary structure of nucleic acids

is the certain sequence of nucleotides in

the chain. Nucleotides are connected due

to phosphate groups.

Page 182: Bio-Organic Chem Lectures

This is a structure of RNA

fragment

(U-A-C)

A secondary structure of nucleic acids is the arrangement of a

polynucleotide chain in space.

Watson and Crick proposed the model of DNA molecule as a double helix.

DNA is made up of two polynucleotide chains wound about each other to form a

double helix 20 A in diameter. Each helix is right-handed and has ten

nucleotide units for each completed coil. The chains are held together by hydrogen

bonds. There are two linear hydrogen bonds between adenine and thymine and

three ones between guanine and cytosine. These bases are called complementary

ones.

In the secondary structure of RNA helixes are again involved, but this time

nearly always single-strand helixes.

DNA must both preserve the hereditary information and use it: a) DNA

molecules can duplicate themselves, that is, can bring about the synthesis of

other DNA molecules identical with the original (this process takes place in

accordance with the principle of complementarity); b) DNA molecules can

Page 183: Bio-Organic Chem Lectures

control the synthesis of the proteins that are characteristic of each kind of

organisms.

The information is rewritten from DNA to messenger RNA and then is

carried to the ribosomes, where protein synthesis actually takes place.

LIPIDS

Lipids are natural compounds, insoluble in water, that can be extracted from

cells by organic non-polar solvents (like ether, benzene). Lipids include

compounds of many different kinds. Lipids are classified as hydrolyzing and non-

hydrolyzing ones. Hydrolyzing lipids are fats and oils, waxes and phospholipids.

Non-hydrolyzing lipids are terpenes and steroids.

Fats

Fats are the main constituents of the storage fat cells in animals and plants,

and are one of the important food reserves of the organism.

Fats may be solid or liquid. Liquid fats are often named as oils. Chemically,

fats are carboxylic esters derived from the glycerol. They are known as glycerides

(triacylglycerols).

The general formula of fats is as follows:

Each fat is made up of glycerides derived from many different carboxylic

acids. The proportions of the various acids vary from fat to fat; each fat has its

characteristic composition which does not differ very much from sample to

sample.

Fatty acids are all straight chain compounds, and almost always contain an

even number of carbon atoms. The fatty acids may be saturated and unsaturated

ones. The chief saturated acids are palmitic and stearic acids:

Page 184: Bio-Organic Chem Lectures

The chief unsaturated acids are oleic, linoleic and linolenic acids:

Cis-trans isomerism is characteristic for unsaturated fatty acids, they

usually exist in cis-form. Saturated parts of their radicals exist in zigzag

conformations. To designate cis configuration and zigzag conformation we can use

following formulas of fatty acids:

There is a relationship between the structure of fatty acids and fats

consistence. The remainders of saturated acids are favorable - the fat is solid one

(it is a fat). The remainders of unsaturated acids are favorable - the fat is liquid

one (it is the oil). As usually, animal fats are solid and plants fats are liquid (they

are called oils).

Glycerides are named according to the nature of the acids present, the suffix

-ic of the common name of the acid being changed to -in. Glycerides are said to be

"simple" when all acids are the same and "mixed" when the acids are different. For

example:

Page 185: Bio-Organic Chem Lectures

To determine of unsaturation degree of fats the special test is used: it is

iodine value. It is a number of iodine grams that combine with 100 grams of oil or

fat. The bigger is iodine value – the more unsaturated are fatty acids remainders.

An addition reaction is a base of this test:

Fats are the esters; therefore the hydrolysis reaction is characteristic for

them. Hydrolysis can occur both in acidic and alkaline medium:

An acidic hydrolysis is a reversible process.

Salts of long-chain fatty acids are soaps. A soap molecule has a polar end –

COO- Na+ , and a non-polar end, the long carbon chain. They are often named as a

polar head and non-polar tail:

Sodium salts are solid, potassium soaps are liquid (soft soaps).

The polar end is water-soluble, and is thus hydrophylic. The non-polar end

is water-insoluble, and is thus hydrophobic (or lipophilic); it is soluble in non-polar

solvents. Molecules like these are called amphipathic: they have both polar and

Page 186: Bio-Organic Chem Lectures

non-polar ends. In line with the rule of «like dissolves like", each non-polar end

seeks a non-polar environment.

How does soap clean? The problem in cleansing is the fat and grease that

make up and contain the dirt. Water alone cannot dissolve these hydrophobic

substances; oil droplets in contact with water tend to coalesce so that there is a

water layer and an oil layer. But the presence of soap changes this. The non-polar

ends of soap molecules dissolve the oil droplet, leaving the carboxylate ends

projecting into the surrounded water layer. Repulsion between similar charges

keeps the oil droplets from coalescing; a stable emulsion of oil and water forms,

and can be removed from the surface being cleaned.

Soap micelle.

Hard water contains calcium and magnesium salts, which

react with soap to form insoluble calcium and magnesium soaps. Therefore soaps

have the bad cleaning ability in hard water.

The next property of fats is hydrogenation reaction. It is characteristic for

unsaturated fats only. For example:

It is very important reaction, because it converts liquid fats (oils) into solid

fats. Oils (plants fats) are not so expensive than animal solid fats. This reaction

allows to prepare solid fats from cheap cottonseed oil, corn oil or soybean oil.

Hardering of oils is the basis of an important industry that produced cooking fats

and oleomargarine.

Phosphoglycerides (phospholipids)

Phospholipids are complecated lipids. Their hydrolysis gives not only

glycerol and carboxylic acids, but phosphoric acid also.

Page 187: Bio-Organic Chem Lectures

Phospholipids are derivatives of phosphatidic acid (or diacylglycerol

phosphate).

Phosphatidic acid can react with alcohols to form esters. In the reaction with

aminoethanol (cholamine) so-called kephalin is formed:

In the organism kephalin can exist as dipolar ion.

In the reaction with choline phosphatidic acid gives phosphatidyl choline, or

lecithin:

Lecithin exists in form of the dipolar ion too.

The hydrolysis reaction in acidic and alkaline medium is characteristic for

phospholipids. For example:

Page 188: Bio-Organic Chem Lectures

Phospholipids are found in the membranes of cells and they are the basic

structural element of living organisms. This vital function depends on their

physical properties. Phosphoglyceride molecules are amphipathic structures. The

lipophilic part is the long fatty acid chain. The hydrophilic part is the dipolar ionic

end: the substituted phosphate group with its positive and negative charges.

Phospholipids form bilayers: two rows of molecules are lined up, back to back,

with their polar ends projecting into water on two surfaces of the bilayer.

Non-polar molecules can therefore be

dissolved in this mostly hydrocarbon

wall and pass through it, but it is an

effective barrier to polar molecules

and ions.

Phospholipids constitute walls that not only enclose the cell but also very

selectively control the passage, in and out, of the various substances. But many of

these substances that enter and leave the cells are highly polar molecules like

carbohydrates and amino acids, or ions like sodium and potassium. How can these

molecules pass through cell membranes when they cannot pass through simple

bilayer? The answer to this question seems to involve the proteins that are also

found in cell membranes: embedded in the bilayer, and even extending clear

through it. A protein molecule, coiled up to tern its lipophilic parts outward, is

dissolved in the bilayer, forming a part of the cell wall. Particular ions and polar

molecules can smuggle through the particular protein part of the membrane.

NON-HYDROLYZING LIPIDS (TERPENES)

Non-hydrolyzing lipids are those lipids that can not be hydrolyzed. They are

terpenes, carotenoids and steroids. Terpenes and carotenoids are known also as

isoprenoids.

Page 189: Bio-Organic Chem Lectures

Many plants contain volatile oils in their leaves, blossoms, and fruits. The

essential oils are obtained by steam distillation and have been used in perfumery

and pharmacy. These oils are called not because they are absolutely necessary but

because they are volatile essences.

Terpenes are unsaturated hydrocarbons of general formula (C5H8)n and their

oxygen containing derivatives (alcohols, aldehydes and ketones). Because C5H8 is

isoprene unit they are known as isoprenoides. The terpenes are of great scientific

and industrial importance, being characteristic products of many varieties of

vegetable life and important constituents of most odorants, natural and synthetic,

employed in perfumery. Many of them, e.g. constituents of many eucalyptus oils,

menthol and camphor, are of pharmaceutical importance. Terpenes are chemically

unsaturated, very reactive compounds. Most of them have highly characteristic and

usually pleasant odors.

In accordance with chemical classification terpenes are different classes of

organic compounds, but they are collected together because they can be considered

as isoprene (2-methyl-1,3-butadiene) polymers. Isoprene units are joined in a

regular, head-to-tail way (isoprene rule).

This rule can be illustrated by some examples:

In accordance with a number of isoprene units terpenes (C5H8)n are classified

into following groups: - monoterpenes (n=2)

Page 190: Bio-Organic Chem Lectures

- sesquiterpenes (n=3)

- diterpenes (n=4)

- triterpenes (n=6) etc.

In accordance with a number of cycles in the structures terpenes are

classified into acyclic (without a cycle) monocyclic and bicyclic terpenes.

Acyclic terpenes

Geraniol is an example of acyclic terpenes. It is an alcohol. It can be

oxidized into corresponding aldehyde – geranial:

Both geraniol and geranial (citral) found in rose oil and in lemongrass oil.

As an aldehyde geranial gives silver mirror reaction, it reacts with

hydroxylamine and hydrazine.

Geranial is used in medicine as anti-inflammatory drug, usually in

ophthalmology.

Monocyclic terpenes

Limonene is an example of monocyclic terpenes. It found in orange, lemon

and grapefruit peel. Hydrogenation reaction of limonene gives menthane:

Menthane can be considered as a structural base of several important

terpenes. For example, menthol is its hydroxyl derivative:

Menthol is a constituent of many

oils. It is used externally as an analgetic

Page 191: Bio-Organic Chem Lectures

in rheumatism treatment and by inhalation in the alleviation

of nasal congestion and sinusitis and other respiratory

tract disorders.

Menthol can be synthesized from m-cresol. Its alkylation reaction by

isopropyl chloride gives thymol that then is hydrogenated into menthol:

Hydration reaction of limonene gives terpene that is used in medicine in

form of hydrate in the cough treatment. Hydration reaction occurs in accordance

with Markovnikov’s rule:

Bicyclic terpenes

Pinane and camphane (bornylane) are examples of bicyclic terpenes.

α-Pinene is unsaturated pinane derivative. It is a constituent of turpentene

oil. As all unsaturated hydrocarbon it can decolorize bromine water and react with

potassium permanganate:

Page 192: Bio-Organic Chem Lectures

Camphor is a derivative of camphane. It is synthesized from pinene into

several steps:

At the first step bornyl acetate is formed – it is an ester of the alcohol

borneol and acetic acid. Then this ester is hydrolyzed to form free borneol. As a

secondary alcohol borneol can be oxidized into corresponding ketone – it is

camphor.

Synthetic camphor is used topically as anti-infective drug and in rheumatism

treatment. Natural camphor (from the Asian tree Cinnamomium camphora) is used

as a hart activity stimulator (in oil solutions).

Bromination reaction of camphor gives α-bromocamphor:

Bromocamphor is used in medicine as a hart activity stimulator.

As ketone camphor can take part in the nucleophilic addition and addition-

elimination reactions, for example it can react with hydroxylamine to form oxime:

Page 193: Bio-Organic Chem Lectures

This reaction is used in the quantitative analysis of camphor (gravimetric

analysis).

Carotenoids

Carotenoids are a special group of isoprenoids. Carotenoids are pigments

which occur in plants and in certain animal tissues. They include hydrocarbons

carotene and lycopene and their related hydroxyl compounds, xanthophylls.

β-Carotene is a precursor of vitamin A (the trasformation occurs in the

liver). Two molcules of vitamin A are formed from one molecule of β-carotene:

Vitamin A is the original fat-soluble vitamin. Its absence from the diet leads

to a loss in weight and failure of growth in children, to the eye diseases

xerophthalmia and night blindness, and to a general susceptibility to infections.

The most fundamental effect of its deficiency is a keratinization of epithelial

tissues. Vitamin A is present in animal fats, butter, eggs, in fish-liver oils. Its

precursor – carotene is present in vegetables.

STEROIDS

Steroids form a group of structurally related compounds which are widelly

destributed in animals and plants. About 20 thousands of different steroids are

known today. More than 100 of them are used in medicine.

Cyclopentaneperhydrophenanthrene structure is a base of all steroids (the

other names of this compound are sterane and gonane):

Page 194: Bio-Organic Chem Lectures

Rings are usually indicated as A, B, C and D.

All cyclohexane rings in sterane structure are not flat, they exist in chair

conformation:

A fusion of the rings to each other may be cis- or trans-one. Trans-fusion is

more advantageous. B and C rings are always trans-fused. A and B rings can be

fused both cis- and trans-.

Let us discuss different types of the rings fusion on the simpler example of

decalin (perhydronaphthalene):

It is cis-fusion

(both hydrogens are situated

at the same side)

It is trans-fusion

(hydrogen atoms are situated

on the opposite sides).

Page 195: Bio-Organic Chem Lectures

Steroids include the following groups of compounds: sterols, bile acids, sex

hormones, adrenal cortex hormones, cardiac glycosides.

The trivial names are used for basic structures of different steroids, because

their IUPAC names are very complicated.

Sterols

Sterol occurs in animal and plants oils and fats. A hydrocarbon cholestane is

a base of their structures:

Cholestane molecule has two so-called

angular methyl groups at C-10 and

C-13 and a side chain at C-17 (it

consists of eight carbon atoms).

Cholesterol is the sterol of higher animals, occurring free or as fatty acids

esters in all animal cells, particularly in the brain and spinal cord. Cholesterol is an

intermediate in the other steroids biogenesis. Cholesterol can be deposited on the

Page 196: Bio-Organic Chem Lectures

walls of arteries; it is a reason of atherosclerosis. Cholesterol is the chief

constituent of gall stones.

Chemically cholesterol is 5-cholestene-3-ol.

It can form esters with fatty acids due to

alcohol hydroxyl group.

Ergosterol is the other example of sterols. It occurs in yeast.

Ergosterol is 24-methyl-5,7,22-

cholestatriene-3-ol).

Ergosterol is a precursor of vitamin D2 (ergocalciferol). Vitamin D is the

antirikets vitamin, it is essential compound for bone formation, its function being

the control of calcium and phosphorous metabolism. Vitamin D2 is formed from

ergosterol (by the ultraviolet irradiation):

Vitamin D is used in the treatment of rickets.

Bile acids

Page 197: Bio-Organic Chem Lectures

The bile acids occur in the bile (a secretion of the liver which is stored in the

gall bladder) of the most animals. Their function is as emulsifying agents in the

intestinal tract).

Cholane is a structural base of all bile acids.

In bile acids

molecules A and B rings are cis-

fused.

About twenty natural bile acids are known. One of them is cholic acid:

C

h olic acid is 3,7,12-trihydroxy-5-β-

cholanic acid. A and B rings are

cis-fused.

The bile acids are combined as amides with either glycine or taurine:

Page 198: Bio-Organic Chem Lectures

hydrophilic part

lipophilic part

The bile acids are present as sodium salts in the bile and intestine. They are

the amphipathic molecules. Their molecules have both the lipophilic part and

hydrophilic part. For this reason the bile acids are emulsifying agents (e.g., fats,

which are insoluble in water, are rendered “soluble”, and so may be absorbed in

the intestine).

Adrenocortical hormones

These hormones are produced by the cortex of the adrenal glands. The other

name of adrenocortical hormones is corticoids. Corticoids have many

physiological functions, but their main roles are: carbohyrates and protein

metabolism control (glucocorticoids) and water and electrolytes balance control

(mineralocorticoids).

Pregnane is a structural base of all corticoids:

Page 199: Bio-Organic Chem Lectures

The examples of corticoids are as follows:

Corticosterone is 11,21-dihydroxy-4-

pregnene-3,20-dion. It is insulin

antagonist. Insulin decreases glucose

level in the blood, corticosterone

increases it.

Deoxycorticosterone is 21-hydroxy-4-

pregnene-3,20-dione. It is a mineralo-

corticoid, it controls water and mineral

salts balances.

Page 200: Bio-Organic Chem Lectures

Cortisone and hydrocortisone are used for the treatment of rheumatoid

arthritis and rheumatic fever, because of their anti-inflammatory and anti-allergic

action. But it is necessary to know that these compounds increase sugar degree in

the blood.

Sex hormones

The sex hormones are of two types: the androgens (male hormones) and the

estrogens (female hormones). The sex hormones are responsible for the sexual

processes, and for the secondary characteristics which differentiate males from

females.

Androgens

Androstane is the base of all androgens:

Androsterone was the first androgen isolated from the male urine:

Androsterone – (3-hydroxy-17-androstanone).

Page 201: Bio-Organic Chem Lectures

The other male hormone is testosterone

(17-hydroxy-4-androsten-3-one):

Testosterone is used as a drug in form of the ester with propionic acid;

testosterone propionate:

The action of this ester is prolonged in comparison with testosterone. In the

organism the hydrolysis reaction of the ester occurs and testosterone is released.

Estrogens

The hydrocarbon estrane is the base of all estrogens:

Estrone was the first female hormone which was isolated from the urine of

pregnant women. Then two other hormones were isolated – estradiol and estriol:

Page 202: Bio-Organic Chem Lectures

Estrone can be reduces in estradiol by catalytic hydrogenation:

Steroidal glycosides

There are many plant steroids which occur as glycosides and have the

property of stimulating heart muscle. They are named cardiotonic glycosides.

Digitoxigenin is the example:

Rings

A/B and C/D are cis-fused.

The unsaturated lactone cycle is

present at C-17.

A sugar in the glycoside generally consists of several hexose residues and

glycoside bond is formed due to hydroxyl group at C-3.

ALKALOIDS

Alkaloids are nitrogen containing natural organic compounds, existing in

great variety in many plants. Most of alkaloids are heterocyclic compounds. Many

alkaloids are use in medicine. Alkaloids are very poisonous, and even in minute

doses produce characteristic physiological effects.

Page 203: Bio-Organic Chem Lectures

All alkaloids are bases and in plants they exist in form of salts with organic

(such as oxalic, succinic, acetic, citric acids) and mineral (sulfuric, phosphoric)

acids.

Alkaloids occur chiefly in flowering plants, especially in the

Ranunculaceae, Papaveraceae and Solanaceae.

Alkaloids include a number of important drugs, e.g. morphine, caffeine,

quinine.

Alkaloids are classified by the nature of the basic heterocycle (pyridine

derivatives, indol derivatives, quinoline derivatives etc.).

Nicotine molecule consists of pyridine and pyrrolidine

rings. It is a base, it can form salts with two molecules of

the acid. Nicotine is used as incecticide and usually

manufactured from tobacco.

Nicotine is oxidized into nicotinic acid:

Quinine molecule contains quinoline

and quinoclidine rings.Quinine and its

salts are used for the treatment of

malaria. It also possess analgetic,

antipyretic, cardiac depressant properties.

Papaverine is

isoquinoline derivative. It is

obtained from opium or prepared

synthetically. Its hydrochloride is used as a

Page 204: Bio-Organic Chem Lectures

smooth muscle relaxant, for example in

hypertension treatment..

Synthetic analogous of papaverine that is used as smooth muscle relaxant is

no-spa:

Alkaloid morphine can be considered as isoquinoline derivative also:

Morphine molecule contains two hydroxyl groups;

one of them is alcohol, the other – phenol

hydroxyl. As phenol morphine reacts with FeCl3.

Morphine exhibits both basic properties (due to

nitrogen atom) and acid properties (due to

phenol hydroxyl group). It is soluble both in the

aqueous solutions of alkali and acids.

Morphine and its salts are used in medicine as analgetics but are highly

addictive.

Methyl ether of morphine – codeine is used in the treatment of coughs and

as analgetic:

Diacetyl derivative of morphine is heroine.

Alkaloid reserpine is indol derivative:

Page 205: Bio-Organic Chem Lectures

Reserpine is the alkaloid from various species of Rauwolfia. It is used as an

antihypertensive and tranquilizer.

Because reserpine is an ester, it can be hydrolyzed.

Caffeine, theophilline and theobromine are purine derivatives.