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