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 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 2nd 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 z another along three axis. pz-orbitals.
y x

around

the

They are designated as px-, py- and

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 1s 22s22p2 . It may be shown in the form of a scheme:
1s 2s 2p

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:
1s 2s 2p

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:

+
s px

+
py

+
pz

4 hybrid orbitals

. Hybrid . . . orbitals are directed towards tetrahedron (the angle is 109o28’).

the corners of a

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.

+
s px

+
py

3 hybrid orbitals

These hybrid orbitals are directed towards the corners of an equilateral triangle (the angle is 120o).
pz

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 called “pyrrole type nitrogen”

in this case an atom is called “pyridine type nitrogen”

Two types of sp2-hybrid oxygen are known. Unhybrid pz-orbital can be occupied by one electron or by unshared electron pair:

. .

.. : or

. . .

. :

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.

+
s px

2 hybrid orbital

py- and pz-orbitals are placed perpendicular to the hybrid orbitals and perpendicular to each other.
pz p There is y

one electron at each orbital of carbon atom. unshared pair of nitrogen is always situated

The 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
.. Na * + . Cl: .. .. . .. Na *Cl :

Na+Cl-

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.
H* + . H . H* H

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

s s

s

p

p

p

hybrid orbitals

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 πbond. Triple bond (C C) 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.
δ−

Cl Cl

δ−

C

δ+

Cl Cl

δ−

δ−

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: H N: H + H+Cla proton is an acceptor H + H N ClH H

H N-atom is a donor

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:

H3 C Actual measurement .. shows that Htwo nitrogen-oxygen bonds of a nitro H3 C 3 C + .. H3 C N : + .. H3 C nitro or H CH -NO .. compound have exactly the O : length. InN : O : methane3 C N O for example, same 3 2,
3 3 two nitrogen-oxygen bonds length aretrimethylaminenm, as compared with a usual each 0.121

H3 C

HC

HC

length of 0.136 nm for a nitrogen-oxygen oxide bond and 0.118 nm for a nitrogensingle oxygen double bond. For this reason a better representation of O- nitro group is the + + O .. O or C6 H5 -N C6 H5 -N=O + O : C6 H5 -N . ..
-N nitrozobenzene O Onitrobenzene O

trimethylamine

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 and to the other - the hydrogen bond acceptor - by purely For example, water molecules are associated. There are
O intermolecular hydrogen bonds between them..

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

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:
CH3 -Cl + NaOH CH3 -OH + NaCl

Chlorine atom in chloromethane is replaced by hydroxyl group. Substitution reactions are designated by symbol S. 2. Addition reactions. For example:
CH2 =CH2 + HCl CH3 -CH2 -Cl

A molecule of hydrogen chloride is added to ethene. This type of the reactions is designated as A. 3. Elimination reactions. For example:
CH3 -CH2 -OH conc.H2 SO 4 t > 200o C CH2 = CH2 + H2 O

A molecule of water is eliminated from ethanol molecule. It is designated as E. 4. Oxidation reactions. For example:
CH3 -OH [O] H-C O H

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): A:B
. A + .B

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): A :B
A+ + B
-

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:
δ− The electronic density is displaced to the more electronegative O δ+ S O oxygen atoms. The big partial positive charge appears on sulfur. O

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.
radical

CH3. + HCl

Radical reaction (R) Nucleophilic reaction (N) Electrophilic reaction (E).

CH3-Cl + OHnucleophile

CH3-OH + ClCH3-CH2+

CH2=CH2 + H+
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.
. there is one electron on p-orbital

σ-bonds formation

..

there are two electrons on p-orbital

p-orbital is empty

methyl radical

methyl carbanion

methyl carbocation

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 C2H6 ethane C3H8 propane C4H10 butane C5H12 pentane C6H14 hexane C7H16 heptane C8H18 octane C9H20 nonane 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:
CH3-CH-CH 3 One hydrogen is replaced by CH 3-group CH3 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:

CH3-CH2-CH3
primary atom 1o secondary atom 2o primary atom 1o

Therefore propane can form two different radicals: CH3-CH2-CH2propyl

and

CH3-CH-CH3
isopropyl

3) The main chain is numbered in such a way that substituents receive the lowest possible number. For example:
2 3 5 6

CH3-CH-CH2-CH-CH2-CH3 CH3 CH3

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). CH3
2 3

CH3-C-CH 2-CH-CH 2-CH3 CH3 CH2 CH2 CH3
7 5

1

4

4-ethyl-2,2-dimethylheptane

Electronic structure of alkanes Carbon atoms are sp3-hybridized. Each carbon has four hybrid orbitals. The angle between them 109o28’.

109o 28'

ethane molecule

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:
CH4 + 2 O2 CO 2 + 2 H2 O + Q

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.
CH4 + Cl2 sun light (UV) CH3 -Cl + HCl chloromethane

If an excess of halogen is present, the reaction can be continued to give polyhalogenated products:
Cl2 , UV Cl2 , UV Cl2 , UV CH3 -Cl CH2 Cl2 CHCl3 CCl4 -HCl -HCl tetrachloro-HCl trichlorochlorodichloromethane methane methane methane (Chloroform)

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:
CH3 -CH3 + Br2 ethane sun light (UV) CH3 -CH2 -Br + HBr bromoethane

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):
Cl : Cl 2 Cl .

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.
H3 C : H + Cl . . H3 C + HCl methyl radical H3 C-Cl + Cl methyl chloride .

H3 C . + Cl : Cl

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:
Cl. + Cl. H3 C . + Cl . H3 C . + . CH3 Cl2 CH3 -Cl CH3 -CH3

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.
there is one electron on p-orbital H

H H

.

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 CH -CH -CH -Br + HBr products: can give two different
CH3 -CH2 -CH3 + Br2 UV 1-bromopropane
3 2 2

CH3 -CH-CH 3 + HBr Br 2-bromopropane

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.
Br2 UV 2 Br . . CH3 -CH 2 -CH 2 + HBr propyl radical . CH3 -CH-CH 3 + HBr isopropyl radical

. CH3 -CH 2 -CH 3 + Br

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.
CH3 . CH

The
CH3

secondary

radical

is

more

stable than primary

one, because two neighboring carbon atoms displace the In case of primary radical the electronic density is

electronic density to carbon with the unpaired electron. displaced from one neighboring carbon only. For this reason primary radical is lesser stable that secondary one.

CH3

CH2

. CH2

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.
. CH3 -CH-CH 3 + Br2 isopropyl . CH3 -CH-CH 3 + Br Br 2-bromopropane

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.
p, to NO 2 CH3 -C-CH 3 + H2 O CH3 2-methyl-2-nitropropane

CH3 -CH-CH3 + HNO3 CH3 2-methylpropane

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 carboncarbon 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:
CH2 =CH-CH-CH3 CH3
1 2 3 4

3-methyl-1-butene

The common names of radicals can be used: CH2=CH- vinyl (ethenyl by IUPAC), CH2=CH-CH2allyl (3-propenyl by IUPAC). Structure of the double bond of ethene
π-bond σ σ σ σ o 120 σ
π-bond formation

electronic structure 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.
pz- atomic orbitals overlapping

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 σbond 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 σbond therefore π-bonds are breaking more easily than σ-bonds. Every carbon atom in ethene is connected with hydrogen atom by the σbond. This σ-bond is formed due to overlapping sp2-hybrid orbital of carbon and sorbital 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:
CH3 H C=C H cisCH3 and H transCH3 C=C CH3 H

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).

cis-isomer of 2-butene

trans-isomer of 2-butene

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,transone. 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:
HCl CH2 =CH2 H2 O, H + Br2 , H2 O CH3 -CH2 -Cl CH3 -CH2 -OH CH2 -CH2 Br Br chloroethane ethanol 1,2-dibromoethane

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:
E+ + :Nu E : Nu

At the first step of the reaction an electrophile E+ comes up to the πelectronic cloud and they attract each other. So-called π-complex is produced:
CH2 =CH2 + E+ CH2 CH2

E+ π -complex

Then the electrophile forms a new σ-bond with carbon. Two electrons of πbond are used to form this σ-bond:
CH2 CH2 + CH2 -CH2 E σ-complex

E+ π -complex

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:
+ CH2 -CH2 + :Nu E σ-complex CH2 -CH2 E Nu

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:
CH2 =CH2 + H+Cl Cl -

CH2

CH2

+ CH3 -CH2 σ-complex

CH3 -CH2 -Cl chloroethane

H+ π -complex

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:
.. H2 O + H CH3 -CH2 -O H

CH2 =CH2 + H2 SO4

-HSO 4 -

CH2

CH2

+ CH3 -CH2 σ-complex

H+ π -complex

+ HSO4 -

CH3 -CH2 -OH + H2 SO4 ethanol

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.
CH2 =CH2 + Br2 H2 O CH2 -CH2 Br Br

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:
Br-Br H2 O δ+ Br δ− Br

Then this polarized molecule reacts with ethene:
δ+ CH2 =CH2 + Br δBr CH2 CH2 Br δ+ Brδ− π -complex - BrCH2 CH2 + CH2 -CH2 Br σ-complex

Br+ π -complex

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 Br electron pairs and the vacant
+ CH2 -CH2 : Br : .. σ-complex δ+ δ+ + Br CH2 -CH2 Br+ bromonium cation CH2 -CH2 Br trans-1,2-dibromoethane

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 150200oC in the presence of catalysts (such as nickel, platinum, palladium) alkenes combine with hydrogen to form alkanes:
CH2 =CH2 + H2 ethene Ni, to CH3 -CH3 ethane

The catalysts absorb hydrogen gas on their surface and activate the hydrogen-hydrogen bond to form hydrogen atoms (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:
CH3 -CH-CH 3 CH3 -CH=CH2 + HCl Cl 2-chloropropane

These radicals

CH3 -CH2 -CH2 -Cl 1-chloropropane

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).
CH3 δ+ δCH=CH2

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:
+ + CH3 -CH-CH3 secondary carbocation + CH3 -CH2 -CH2 primary carbocation

CH3 -CH=CH2 + H

CH3 -CH

CH2

H+ π-complex

The dynamic factor is the stability of intermediates (carbocations). Isopropyl cation is secondary and propyl cation is primary one. The stability of carbocations is decreased in the following order:
R R C+ > R + CH > R R 2o + + CH2 > CH3 1o the least stable

R 3o the most stable

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:
CH2 =CH2 + KMnO4 + H2 O CH2 -CH2 + MnO2 + KOH OH OH ethylene glycol

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:
CH3 -CH=CH-CH3 + KMnO4 + H2 SO4 2-butene to O 2 CH3 -C OH acetic acid + K 2 SO4 + MnSO4 + H2 O

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:
CH2 =C=CH2 cumulated diene 1,2-propadiene CH2 =C=CH2 cumulated diene 1,2-propadiene CH2 =CH-CH=CH2 conjugated diene 1,3-butadiene CH2 =CH-CH=CH2 conjugated diene 1,3-butadiene CH2 =CH-CH2 -CH=CH2 isolated diene 1,4-pentadiene CH2 =CH-CH2 -CH=CH2 isolated diene 1,4-pentadiene

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:
CH2 =CH-CH2 -CH=CH2 1,4-pentadiene HCl CH 3 -CH-CH 2 -CH=CH2 Cl 4-chloro-1-pentene HCl CH 3 -CH-CH 2 -CH-CH 3 Cl Cl 2,4-dichloropentane

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
H
1 2

H H H

All carbon atoms are sp2-hybridized. It means, all
H
4

3

H

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 σbonds.

pz-atomic orbitals overlapping in 1,3-butadiene molecule

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:
CH2 =CH-CH=CH2 or CH2....CH ....CH....CH2

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:
CH3 -CH-CH=CH 2 CH2 =CH-CH=CH2 HBr Br 3-bromo-1-butene

CH3 -CH=CH-CH 2 -Br 1-bromo-2-butene

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 1,2addition”. 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:
CH2 =CH-CH=CH2 H+ + CH3 -CH-CH=CH2 conjugated system

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 porbitals 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:
+ CH3 -CH-CH=CH 2 + CH3 -CH=CH-CH 2

These two structures are called resonance structures. In fact the carbocation
.... .... is a hybrid of two contributing resonance structures: [CH3 CH CH CH2 ]+

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:
+ CH3 -CH-CH=CH 2 + CH3 -CH=CH-CH 2 Br CH3 -CH-CH=CH 2 Br 3-bromo-1-butene

CH3 -CH=CH-CH 2 -Br 1-bromo-2-butene

The other addition reactions can occur as 1,2- or 1,4-addition too. For example:
Br2 , H2 O CH2 =CH-CH=CH2 H2 , Ni CH2 -CH-CH=CH 2 + CH2 -CH=CH-CH 2 Br Br Br Br

CH3 -CH2 -CH=CH2 + CH3 -CH=CH-CH 3

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.)

benzene

naphthalene

anthracene

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:

I

II

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 πelectrons 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.

pz-atomic orbitals overlapping

σ-bonds fornation in benzene molecule

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,πconjugated 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? 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, delocalization of π- electrons is possible; 3) The ring system must contain the Huckel's number of delocalized π-electrons. (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
CH3

What properties must all aromatic

because

only

in this case the ring

This number is (4n+2) electrons, where n must

be an integer

of

aromatic hydrocarbons are used and they are
CH3-CH-CH3 CH=CH2

accepted by IUPAC system, too. They are:

toluene (methylbenzene)

cumene (isopropylbenzene)

styrene (vinylbenzene)

These compounds may be also named as benzene derivatives.
CH3 CH3 CH3 orthometaxylenes (dimethylbenzenes) CH3 CH3

CH3 para-

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

chlorobenzene

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:
Br CH3 Br m-dibromobenzene Br p-bromotoluene

If more than two groups are attached to the benzene ring, numbers are used to indicate their relative positions. For example:
Br
4 1 3 2

Br

Br 1,2,4-tribromobenzene

The radical of benzene C6H5- is named phenyl. Toluene can form four different radicals:
CH3 CH3 CH3 CH2-

o-tolyl

m-tolyl

p-tolyl

benzyl

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
Cl2 , AlCl are characteristic for benzene: 3 Cl

H + E+
CH3 Cl, AlCl 3

+ HCl

E
CH3 + HCl

halogenation reaction + H+ alkylation reaction

There are examples of electrophilic substitution reactions:
HNO3 , H2 SO4 NO 2 + H2 O SO3 H nitration reaction

SO3 ( H2 SO 4 )

sulfonation reaction

CH3 COCl, AlCl 3

C-CH 3 O

+ HCl acylation reaction

The mechanism of electrophilic substitution reactions in aromatic compounds Electrophilic substitution reactions proceed in such a way:
H + E+ H E+ H E E + H+

+

π -complex

σ -complex

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 πelectrons of the aromatic cloud to form σ-bond with a ring carbon atom (σcomplex is formed). This carbon atom becomes sp3-hybridized. Therefore σcomplex 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:
δ+ Cl δ+ δ− Cl Cl : + Fe Cl Cl Cl : ......FeCl3 week electrophile strong electrophile Cl Then this reaction proceeds by commonthe partial positive charge) (non-polar molecule) (there is mechanism of electrophilic

substitution:
H + Cl H Cl δ δ + − Cl : ......FeCl3 H δ π -complex + + FeCl4 Cl + HCl + FeCl 3 chlorobenzene Cl δ + − Cl : ......FeCl3 - FeCl4-

σ -complex

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:
CH3 -Cl + AlCl 3 + CH3 + AlCl 4

Then this reaction proceeds by common mechanism of electrophilic substitution:
H + + CH3 H + CH3 π -complex + H + AlCl 4 CH3 toluene CH3 + HCl + AlCl3

σ -complex

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:
.. H2 SO 4 + HO-NO 2 acid base H + O-NO 2 H protonated nitric acid + H2 O + NO 2 nitronium cation

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 H H + NO 2 H + NO 2 + HSO + substitution: 4 proceeds by + NO 2 mechanism NOelectrophilic common of 2 + H2SO 4
π -complex σ -complex nitrobenzene

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 δ+ O S O an electrophilic reagent. O
H + SO 3 Hδ π -complex O + S O O H + S O O O SO3H benzenesulfonic acid

σ -complex

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 200 oC. Cyclohexane is formed in this reaction:

+ 3 H2 benzene

to , p Ni cyclohexane

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:
CH3 KMnO4 to toluene benzoic acid COOH

If other homologous of benzene are oxidized the benzoic acid is obtained too:
CH2 -CH2 -CH3 KMnO4 to propylbenzene benzoic acid COOH + CH3 COOH

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:
α β β α β β

α α 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:
Br + Br2 naphthalene CH3 COOH + HBr α-bromonaphthalene

This reaction occurs without any catalyst in acetic acid medium. Nitration reaction of naphthalene gives α-nitronaphthalene:

NO 2 + HNO3 naphthalene H2 SO4 + H2 O α-nitronaphthalene

When naphthalene is heated with concentrated sulfuric acid both α- and βnaphthalenesulfonic 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 (2naphthalenesulfonic acid).
80o C SO3 H + H2 O α-naphthalenesulfonic acid

+ H2 SO4 160o C

SO3 H + H2 O β-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: mesomeric (or resonance) ones. they are inductive and

The inductive effect is the transference of the substituents influence through the molecular chain due to polarization of σ-bonds. For example: CH3
δ+''' δ+' δ+ δ−

CH 2

δ+''

CH 2

CH 2

Cl

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 σbond. 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. other part of the molecule. 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 . CH3 CH 2 OH -I OH CH3 CH 2 CH 2 CH 2 COOH -I COOH In our example chlorine exerts the The inductive effect is negative inductive effect, because it withdraws the electronic density from the (It is designated as -I). designated in the formula by arrow that is directed to the symbol of the most

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).

CH3

CH 2

O - Na+ +I O -

CH2=CH CH 3 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. 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 (1,3butadiene is the simplest example). Let us tackle its electronic structure: CH2=CH-CH=CH2.
H 1 2 H H 3 4 H

The result of the conjugation is the delocalization of the electronic

H H

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

CH2=CH-CH=CH 2

or

CH....CH .... .... 2 CH CH 2

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 porbitals 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 1,3butadiene 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. CH2=CH-NH2 molecule:
H H

For example, in vinyl amine

. C

. C
H

H

..

N

H H

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: .. CH2=CH-NH2

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 σbonds. Pay your attention: substituent can exert its mesomeric effect only in case if it is the part of the conjugated system. For example:
.. A CH2 =CH-CH=CH-NH2 mino-group is the part of the p,π-conjugated system.

p,π-conjugation
CH2 =CH-CH=CH-CH2 -NH2

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: .. CH2=CH-Cl
+M Cl

O CH2=CH-C
-M CHO

H

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). .. CH2=CH-O-CH 3 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) b)

substituents, having the full negative charge, for example, –O - ; 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: O C H , O C OH , S O O OH , N O O .

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. .. CH 2=CH NH 2
-I NH , +M NH ; |+M| > |-I | 2 2

Amino

group

is

electron

releasing substituent.

CH 3-CH2 NH 2

-I NH

2

Amino group exerts the negative inductive

effect only, because a molecule is not conjugated system. Amino group is electron withdrawing substituent. .. OH
-IOH , +MOH

Hydroxo

group

is

electron

; |+M| > |-I | releasing substituent.

Hydroxo group exerts the negative inductive effect CH2 OH OH-group does not
-IOH

only, because take part in the electron withdrawing

conjugated system. It is 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:
X E orthoX + E+ E X paraE meta-

X

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 orthoand 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:
:OH δ− δ− δ−

Hydroxyl group

in phenol

exerts

the

positive mesomeric takes

effect, because the unshared electron pair of oxygen

part

in p,π-conjugated system. OH-group

increases the electronic density para-positions. Therefore

of the ring (+M>-I), especially in ortho- and 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.
O C OH δ− δ− N O O

In benzoic the negative

acid

carboxyl

group and

exerts negative

inductive

mesomeric effects. The electronic density in the ring is decreased, but in meta positions it is relatively higher. In nitrobenzene nitrogroup exerts the negative inductive and

δ− benzoic acid

δ− nitrobenzene

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 SEreactions. 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.
O C OH FeCl3 δ− δ− benzoic acid to C OH + HCl Cl m-chlorobenzoic acid O

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 parapositions.
δ− :NH2 δ− + Br2 δ− aniline NH2 Br or o-bromoaniline NH2 + HBr Br p-bromoaniline

If bromination reaction is carried out in the presence of the excess of bromine water (waterNHa polar solvent) 2,4,6-tribromoaniline is obtained: is 2 NH2
+ 3 Br2 aniline H2 O Br Br + 3 HBr Br 2,4,6-tribromoaniline

Nitration of chlorobenzene occurs more slowly than that of benzene, because chlorin is ring deactivating substituent.
:Cl δ− δ− + HNO3 c.H2 SO4 to 1-chloro-2-nitrobenzene Cl NO 2 or Cl + H2 O NO 2 1-chloro-4-nitrobenzene

δ− chlorobenzene

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:

CH3 -CH2 -Cl chloroethane

Cl-CH2 -CHCl2 trichloroethane

b) as chloro-, bromo-, fluoro- and iodo-derivatives, for example:
CH3 -I iodomethane CH3 -CH2 -Br bromoethane

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.
CH3 CH3 -CH 2 -Cl (1o ) CH3 -CH-CH 3 Br (2o ) CH3 -C-CH 2 -CH3 I (3o )

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: 1) CH -CH -Cl 3 2
ethyl chloride 2) CH3 -CH-CH 3 Br isopropyl bromide

IUPAC names are the names of corresponding alkanes with a halogen attached as a side chain. For example: bromopropane. The other examples are as follows: 1) is chloroethane
CH3 CH3 -C-CH 2 -CH3 I 2-iodo-2-methylbutane CH2 -CH2 Cl Cl 1,2-dichloroethane

and

2) is 2-

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.
δ+ CH3 -CH2 δ− Cl

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:
R-NH2 + HCl primary amine R-NH-R' + HCl secondary amine R-N-R' + HCl R" tertiary amine R-SH + NaCl R-S-R' + NaCl thioether (disulfide) R + HCl alkylbenzene NH3 R'-NH2 R'-NH-R" R-Cl Na HS + R'-S Na C6 H6 + Na OH R-OH + NaCl this is so-called alcohol leaving group R-OH + HCl alcohol R-O-R' + NaCl ether R-C C-R' + NaCl alkyne

H2 O - + R'-O Na - + R'-C C Na K+CN

R-CN + KCl nitrile O R'-COO Na+ + NaCl R'-C OR ester

The general scheme of this reaction is as follows:
R :L substrate + :Nu nucleophile R : Nu + product :L leaving group

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), (thiolate) is better 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:
CH3 -CH 2 -Cl + NaOH chloroethane H2 O CH3 -CH2 -OH + NaCl (SN) ethanol

R-S -Na+

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

But if we use alcoholic solution of sodium hydroxide the other reaction can occur. It is elimination reaction (E):
CH3 -CH 2 -Cl + NaOH chloroethane alcohol CH 2 =CH2 + NaCl + H2 O (E) ethene

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).
H H H 3 2 δ'+ 1 δ+ H C C C Cl H H H

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.
CH3 -CH2 -CH2 -Cl + NaOH 1-chloropropane alcohol solution CH 3 -CH=CH2 + NaCl + H2 O propene

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
3 2 3 alkanes, alkenes, cycloalkanes. For 3example: o

CH -CH -OH ethanol (1 )

CH -CH-CH

OH 2-propanol (2 o )

CH2 =CH-CH2 -OH 2-propen-1-ol (1 o ) CH3

OH

CH3 -C-CH 3 OH 2-methyl-2-propanol (3 o )

o cyclohexanol (2 )

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:
CH3 -OH methyl alcohol CH3 -CH-CH 3 OH isopropyl alcohol

In the IUPAC system a suffix –ol is used to designate a hydroxyl group:
CH3 -CH-CH2 -OH CH3 2-methyl-1-propanol
3 2 1

CH2 -CH2 OH OH 1,2-ethanediol

Reactivity of alcohols. To determine what reactions are characteristic for alcohols let us tackle a distribution of the electronic density in their molecules.
electrophilic center H δ '+ δ R C CH 2 H CH-acid center basic and nucleophilic center δ..- δ + + O H OH-acid center

Due of

to

unshared oxygen

electron alcohols

pair are

nucleophiles. On the electrophilic center.

other hand is the Therefore

electron-deficient carbon

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:
CH3 -CH2 -OH + Na ethanol CH 3 -CH2 -O Na+ + H 2 sodium ethoxide

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: - + CH3-CH 2-O Na + H 2O
sodium ethoxide CH3-CH 2-OH + NaOH ethanol

Basic properties of alcohols. Alcohols are basic enough to accept a proton from strong acids like concentrated hydrochloric or sulfuric acid to form salts:
.. CH3 -CH2 -OH + H 2 SO 4 + H CH3 -CH2 -O H HSO 4

ethyloxonium hydrosulfate

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:
CH3 -CH2 -OH + HCl ethanol CH3 -CH2 -Cl + H2 O ethyl chloride

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.
HCl CH3 -CH 2 -OH -Cl ethanol + H CH 3 -CH 2 -O H -H2 O protonated alcohol + CH 3 -CH2 carbocation Cl CH 3 -CH2 -Cl ethyl chloride

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:
2 CH3 -CH 2 -OH ethanol c.H2 SO4 t=140o C CH 3 -CH 2 -O-CH 2 -CH3 + H2 O diethyl ether

The mechanism of this reaction is as follows:
CH3 -CH2 -OH ethanol .H2 SO4 -.HSO4+ H CH3 -CH2 -O H protonated alcohol .HSO4 .. + HO-CH2 -CH3 CH 3 -CH2 carbocation

-H2 O

+ CH3 -CH2 -O-CH 2 -CH3 H protonated ether

CH3 -CH2 -O-CH 2 -CH3 + H2 SO4 diethyl ether

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:
CH3 -CH2 -OH ethanol c.H2 SO4 t=200o C CH 2 =CH2 + H2 O ethene

Dehydration is an elimination reaction. The first two steps of this reaction are the same with that of the reaction of ethers formation:
CH3 -CH2 -OH ethanol .H2 SO4 -.HSO 4+ H CH 3 -CH2 -O H protonated alcohol + CH 3 -CH 2 carbocation

-H2 O

but then this carbocation reacts as CH-acid with sulfuric acid anion (a base) and gives up a proton:
+ CH3 -CH2 + HSO 4 carbocation a base CH 2 =CH2 + H2 SO 4 ethene

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:
CH3 -CH-CH 2 -CH3 OH 2-butanol c.H2 SO4 t=200o C CH 3 -CH=CH-CH3 + H2 O 2-butene

Reactions of esters formation. Alcohols can react as nucleophiles with carboxylic acids to form esters. This reaction is known as esterification reaction, for example:
δ+ O CH3 -C OH acetic acid + c.H2 SO4 .. HO-CH 3 to methanol O CH3 -C OCH3 methyl acetate + H2 O

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:
CH3 -CH2 -OH ethanol [O] O H acetaldehyde CH3 -C [O] O CH 3 -C OH acetic acid

Then this aldehyde can be oxidized very easily to form the corresponding carboxylic acid. Secondary alcohols can be oxidized into ketones:
CH3 -CH-CH 3 OH 2-propanol [O] CH3 -C-CH 3 O propanone (acetone)

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.
CH2 -CH2 -OH + K 2 Cr2 O7 + H2 SO4 orange to O CH3 -C H + Cr 2 (SO4 )3 + K2 SO4 + H2 O blue-green

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.
CH2 -CH 2 -OH + I 2 + NaOH to O CHI 3 + iodoform ONa sodium formate H-C

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:

CH2 -CH2 OH OH 1,2-ethanediol (ethylene glycol)

CH2 -CH-CH 2 OH OH OH 1,2,3-propanetriol (glycerol)

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:
CH2 -CH2 OH OH ethylene glycol Na CH2 -CH2 OH ONa monosodium salt Na CH2 -CH2 ONa ONa disodium salt

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:
CH2 -OH CH2 -OH + HO Cu OH + HO-CH 2 HO-CH 2 CH2 -O CH2 -O H Cu H O-CH 2 O-CH 2 + 2 H2 O

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:
CH2 -OH CH -OH CH2 -OH glycerol + 3 HNO3 H2 SO4 CH2 -O-NO 2 CH -O-NO 2 + 3 H2 O

CH2 -O-NO 2 glyceryl trinitrate

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:
OH OH CH3 CH3 metacresols (methylphenols) OH OH Monophenols OH α-naphthol OH OH β-naphthol OH Polyphenols OH resorcinol OH hydroquinone OH OH Monophenols phenol orthoCH3 para-

catechol

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:
OH + NaOH ONa + HO

2 Phenols are lesser acids as carboxylic acids and carbonic acid. For this

reason phenols can not react with sodium bicarbonate. phenol sodium phenolate 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:
OH CH3 -C + phenol CH3 -C O O-C-CH 3 O O phenylacetate (ester) + CH3 -COOH

O acetanhydride

It is SN reaction. Phenols are converted into alkyl aryl ethers by reaction in alkaline solution with alkyl halides (it is Williamson synthesis):
OH + NaOH ONa + H2 O sodium phenolate ONa + C 2 H5 -I ethyl iodide sodium phenolate OC 2 H5 + NaI ethyl phenyl ether

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):
OH + HNO 3 phenol OH + NO 2 o-nitrophenol O2N p-nitrophenol OH

In the bromination reaction which is carried out in a solvent of low polarity, such as chloroform monobromoderivatives are obtained:
OH + Br2 phenol CHCl3 OH + Br o-bromophenol Br p-bromophenol OH

If bromination occurs in the presence of excess of bromine water 2,4,6tribromophenol is obtained:
Br OH + 3 Br2 phenol H2 O OH + 3 HBr Br Br 2,4,6-trinitrophenol

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:
OH K2 Cr2 O7 , H2 SO4 phenol O + O p-quinone o-quinone O O

Polyphenols are oxidized more easily than phenol:
OH OH [O] O O OH [O] O

catechol

o-quinone

OH hydroquinone

O p-quinone

Phenols form colored complexes with ferric chloride (this test is also given
OH OH FeCl3 FeCl3 OH phenol resorcinol violet color violet color catechol OH OH FeCl3 green color

by enols (enol group is =CH-OH). Phenol is also identified by bromination reaction: Br
OH + 3 Br2 orange solution H2 O Br white ppt OH + 3 HBr Br

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 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:
A-H + B acid base + A + B-H conjugated base acid

Lowry-

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

HCl + H2 O acid base

+ Cl + H3 O conjugated base acid

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:

CH3 -COOH + H 2 O acid O: CH3 -C base OH + H2 SO 4 acid base

+ CH 3 -COO + H 3 O + O-H CH3 -C OH + HSO 4 -

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 acid base A- + H3O+

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 2 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:
CH3 -OH + NaOH CH3 -SH + NaOH no reaction CH3 -S Na+ + H2 O

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.
OH O- + H + phenolate anion CH O - + H + alcoholate anion
3

CH3 -OH

Phenols can react with alkali, but alcohols can not, they react with alkaline metals only.
OH + NaOH ONa + H2 O sodium phenolate CH3 -OH + NaOH CH3 -OH + Na no reaction CH3 -ONa + H2 sodium methanolate

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 4aminophenol (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.
O O -

O

N O O -I NO , -M NO
2

: NH2 +M NH > -I NH
2 2

2

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:
no reaction

OH + Na 2 CO 3

ONa + H2 CO 3 stronger acid weaker acid

OH + NaHCO 3

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 socalled 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.
O CH3 -C OH CH3 -C O

O acetate anion

+ - + H

OH

O- + H + phenolate anion

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:
O CH3 -C OH + NaOH CH3 -C O ONa + H2 O

O O + NaCl CH3 -C + HCl CH3are stronger than carbonic acid; therefore carboxylic acids -C Carboxylic acids OH ONa

liberate carbonic acid from its salts:
CH3 -COOH + NaHCO 3 CH3 -COONa + CO 2 + H2 O

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 base 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. A- + BH+ a conjugated acid

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:
R-NH2 R-NH-R' R-N-R' R''

Classification Amines may be classified as primary, secondary and tertiary, according to the number of groups, attached to the nitrogen atom. For example:
CH3 -NH2 primary amine (1o ) CH3 -NH-C 2 H5 secondary amine (2o ) CH3 -N-CH 3 CH3 tertiary amine (3o )

We can also classify amines in accordance with a nature of radicals into aliphatic, aromatic and mixed amines. For example:

CH3 -NH 2 aliphatic amine

NH2 aromatic amine

NH-CH3 mixed amine

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,Ndiethylamino-, etc.) to the name of the parent chain. For example:
CH3 -NH2 methylamine CH3 -NH-C 2 H5 ethylmethylamine CH3 -N-CH 3 CH3 trimethylamine CH3 -CH-CH 3 NH2 isopropylamine CH2 -CH2 NH2 OH 2-aminoethanol
2 1

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:
NH2 Br Br NH-CH3 Br 2,4,6-tribromoaniline N-methylaniline CH3 p-toluidine NH2

Salts of amines are generally named by replacing –amine by –ammonium (or –aniline by –anilinium), and adding the name of the anion. For example:
(CH3 )3 NH+Cl trimethylammonium + [CH3 -NH2 -C 2 H5 ] HSO4 ethylmethylammonium + NH3 Cl

anilinium basic Due chloride to unshared electron pair of nitrogen amines show chloride and hydrosulfate

nucleophilic properties. Basic properties. Amines can react with mineral and carboxylic acids to form salts:
CH3 -NH2 + HCl methylamine CH3 -NH3+ Cl methylammonium chloride

O CH3 -NH2 + CH3 -COOH methylamine CH 3 -C -+ O NH 3 -CH3

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.
CH3 -NH2 + H2 O methylamine + CH3 -NH3 OH methylammonium hydroxide

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 electronreleasing alkyl groups increase the electronic density of the nitrogen atom:
.. NH3 ammonia .. CH3 NH2 methylamine .. CH3 NH CH3 dimethylamine

Dimethylamine has the highest basicity, because two methyl groups displace the electronic density to the nitrogen atom.
CH3 .. N CH3

We can suppose that tertiary amines are more basic than
CH3

secondary, but it is not so. nitrogen

The electronic density higher than

of the in the

atom in the tertiary amines is

secondary amines. But the to this nitrogen atom.

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

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
.. NH2

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:
NH2 + HCl + NH3 Cl anilinium chloride (phenylammonium chloride)

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:
.. NH2 .. NH2 .. NH2

<
N O O -I NO , -M NO 2 2

<
CH3 +I CH
3

Nucleophilic properties of amines. Amines are nucleophilic reagents due to their unshared electron pair. They can react with alkyl halides:
δ+ .. C2 H5 -NH 2 + CH 3 Cl C2 H5 -NH-CH 3 + HCl ethylamine methyl chloride ethylmethylamine

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.
NH2 + CH3 -Cl aniline NH-CH3 + HCl N-methylaniline (methylphenylamine)

As nucleophiles both aliphatic and aromatic amines can react with acid chlorides and anhydrides to form substituted amides:
O O

δ CH3 -C CH3 -C

.. + H2 N-CH 3

+

O CH 3 -C NH-CH 3 N-methylamide of acetic acid + CH 3 -COOH acetic acid

O acetanhydride O CH3 -C Cl + H2 N

O CH 3 -C NH + HCl

acetyl chloride

N-phenylamide of acetic acid (acetanilide)

Aniline and its N-methyl derivatives can be identified by the reaction with bromine water (it is a reaction for activated aromatic ring):
NH2 + 3 Br2 H2 O Br NH2 Br + 3 HBr

Br 2,4,6-tribromoaniline (white ppt.)

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:
R-C O H this is a general formula of aldehydes R-C-R' O this is a general formula of ketones

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:
O H-C H O CH3 -C H O CH3 -CH2 -C H O CH3 -CH2 -CH2 -C H O CH3 -CH2 -CH2 -CH2 -C valeraldehyde H pentanal butyraldehyde butanal propionaldehyde propanal acetaldehyde ethanal common name formaldehyde IUPAC name methanal

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. letters, The common names of substituted aldehydes are derived from the α-, β-, γ -, etc., are used. The α-carbon is the one bearing the -CHO corresponding common names. To indicate a position of a substituent the Greek group. For example:
β CH3 -CH-CH 2 -C CH3
3

α
2

1

O H 3-methylbutanal (IUPAC) β-methylbutyraldehyde O C

The simplest aromatic aldehyde is benzaldehyde:

H

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:
CH3 -C-CH 3 O acetone dimethylketone propanone CH3 -C-CH 2 -CH2 -CH3 O methylpropylketone 2-pentanone
1 2 3 4 5

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
electrophilic center δ+ δ− C O: nucleophilic and basic center

Carbonyl other

carbon by

is

joined to

three

atoms

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 porbital 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.
δ+ H-C O CH3 δ+ C O CH3 δ+ C CH3

H formaldehyde

H acetaldehyde

O acetone

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 electrondeficiency 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
δ+ O + E+Nu R-C H (R') O R-C Nu H (R') E+ OE R-C Nu H (R')

-E +

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 σbond 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.

CH3

δ

O: C H

dry HCl + -Cl

+ OH CH3 C H CH3

+ C

OH H

.. HO-CH3

CH3

OH + C O CH3 H H

Cl -

CH3

OH C O CH3 H

hemiacetal

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:
OH dry HCl CH3-C-O-CH 3 + CH 3-OH H hemiacetal OCH 3 CH3-C-O-CH 3 + H2O H acetal (dimethylacetal of acetaldehyde)

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:
OC 2 H5 CH3 -C-O-C 2 H5 + H2 O H diethylacetal of acetaldehyde H+ O CH3 C H + 2 C2 H5 OH ethanol

acetaldehyde

Addition of cyanide. The elements of HCN add to the carbonyl group of aldehydes and ketones to yield compounds known as cyanohydrins or hydroxynitriles:
CH3 -C-CH 3 + HCN O acetone OH CH 3 -C-CH 3 HO CN cyanohydrin

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: mechanism of AN-reactions:
CH3 -C-CH 3 O CN CH3 -C-CH 3 O - CN H2 O CH3 -C-CH 3 + OH HO CN HCN + OH CN - + H 2 O

Then cyanide ion react with the carbonyl compound by the general

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:
O + .. δ CH3 -C + NH3 H acetaldehyde O+ CH3 -C-NH 3 H OH CH3 -C-NH 2 H addition reaction product (unstable)

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:
OH CH3 -CH-NH 2 CH3 -CH=NH + H2 O imine (acetimine)

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 NH2-R NH2-OH NH2-NH2 amines hydroxylamine hydrazine Product R-CH=N-R substituted imine R-CH=N-OH oxime R-CH=N-NH2 hydrazone R-CH=N-NH-C6H5 phenylhydrazone R-CH=N-NH-CO-NH2 semicarbazone

C6H5-NH-NH2 phenylhydrazine H2N-NH-CO-NH2 semicarbazide

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. condensation reaction. This reaction is called the aldol

H O α δ+ CH3 -C C H H

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:

O CH3 -CH2 -C H

OH -

O + H2 O CH3 -CH-C H

The anion is formed, which is the nucleophilic reagent and can react with other molecule of the aldehyde. It is a nucleophilic addition reaction:
δ+ O CH3 -CH2 -C + H CH-C CH3 O H O CH3 -CH2 -C-CH-C H CH3 O H H2 O

OH CH3 -CH2 -CH-CH-C CH3 aldol

O H + OH

-

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:
OH H CH3 -CH2 -CH-C-C CH3 aldol O H dil. HCl warm O CH3 -CH2 -CH=C-C CH3 H

2-methyl-2-pentenal

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 αhydrogens 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.
O 2 H-C 50% NaOH O CH 3 -OH + H-C ONa methanol sodium formate
O CH2 -OH + benzyl alcohol C ONa sodium benzoate

H formaldehyde
O 2 C H benzaldehyde 50% NaOH

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:
O H formaldehyde 2 H-C H2 O O CH 3 -OH + H-C OH methanol formic acid

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.
O CH3 -C H + Ag(NH3 )2 OH to O CH3 -C ONH4 + Ag + H2 O silver mirror

Aldehydes reduces copper (II) hydroxide into copper (I) oxide:
O CH3 -C + Cu(OH)2 H blue ppt. CuOH to O CH3 -C OH + CuOH yellow ppt.

Cu2 O + H2 O reddishbrown ppt.

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.
O H acetaldehyde CH3 -C-CH 3 O acetone [H] CH3 -C [H] CH 3 -CH2 -OH ethanol

CH3 -CH-CH 3 OH 2-propanol

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
CH3 -C-CH 3 + I2 O acetone NaOH CI 3 -C-CH 3 NaOH O CHI3 + CH3 -C ONa iodoform sodium acetate

O 1,1,1-triiodopropanone

characteristic iodoform smell (hospital smell). This reaction involves halogenation and cleavage:
CH3 -C-CH 3 + I2 O acetone NaOH CI3 -C-CH 3 NaOH O CHI3 + CH3 -C ONa iodoform sodium acetate

O 1,1,1-triiodopropanone

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.
O 6 H-C H + 4 NH3 to H2C N CH2 C H2

N CH2 CH2 N N CH2 Urotropine

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 group.
C O OH

is known as carboxyl

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:
O H-C OH O CH3 -C OH O CH3 -CH2 -C OH O CH3 -CH2 -CH2 -C OH O CH3 -CH2 -CH2 -CH2 -C valeric acid OH pentanoic acid butyric acid butanoic acid common name formic acid acetic acid IUPAC name methanoic acid ethanoic acid

propionic acid

propanoic acid

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:
CH3 -CH2 -CH-COOH CH3 2-methylbutanoic acid (IUPAC name) α-methylbutyric acid (common name) CH2 =CH-COOH 2-propenoic acid (IUPAC name) acrylic acid (common name)

Aromatic acids are usually named as derivatives of the parent acid, benzoic acid:
COOH

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:
O ONH 4 ammonium formate H-C (CH 3 COO) 2 Ca calcium acetate O C ONa

sodium benzoate

Electronic structure of the carboxyl group Carboxyl group is a p,π-conjugated

H R-C

electrophilic center basic center δ O: C .. O H OH-acid center +

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.

H CH-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:
O R-C R-C OO R-C O O

O resonance structures

a hybrid structure

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:
CH3 -COOH + Zn acetic acid (CH3 -COO) 2 Zn + H2 zinc acetate CH 3 -CH2 -CH2 -COONa + H 2 O sodium butyrate C 6 H5 -COONa + CO 2 + H2 O sodium benzoate

CH3 -CH2 -CH2 -COOH + NaOH butyric acid C6 H5 -COOH + NaHCO 3 benzoic acid

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:
OH O R-C OH O -E + E+ substitution addition R-C-Nu OH O R-C Nu this way is not characteristic + E+OH

+ E+Nu

R-C-Nu OH

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.
O: R-C OH OH R-C O CH 3 + - H2 O O-H H H2 SO 4 + O-H R-C OH + R-C + R-C OH OH HSO4 .. HO-CH 3 OH + R-C O CH 3 OH H O R-C OCH 3 + H2 SO 4

OH OCH 3

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:

O O R-C Cl R-C O R-C O acid anhydride R-C

O O-R' ester R-C

O NH2 R-C

O NH-NH2

acid chloride

amide

hydrazide

Last derivative can be considered as substituted amide. O All functional derivatives contain acyl group R-C

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. (PCl5) or trichloride (PCl3):
SOCl2 O R-C Cl O R-C Cl O R-C Cl + H3 PO 4 + HCl + POCl3 + HCl + SO 2 + HCl

A carboxylic acid can be converted into the

acid chloride by the action of thionyl chloride (SOCl2), phosphorus pentachloride

O R-C OH

PCl5

PCl3

For example:
O CH3 -C OH acetic acid + SOCl2 CH3 -C O Cl acetyl chloride + SO 2 + HCl

O C OH benzoic acid + PCl5 C

O Cl + POCl3 + HCl

benzoyl chloride

Acid anhydrides can be obtained by the acid heating with phosphorus oxide. The molecule of water is lost. ("anhydride" means "without water").
O CH3 -C + CH3 -C OH OH O P2 O5 , to CH3 -C CH3 -C O O + H2 O O

acetanhydride

Amides can be prepared by the ammonium salts of carboxylic acids heating:
O CH3 -CH2 -C ONH4 to O CH3 -CH2 -C NH2 + H2 O

ammonium propionate

propionamide

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.
δ+ R-C R-C O acid anhydride -I < +M O O: δ+ R-C O .. NH2 amide
2 2

O δ+ R-C .. Cl acid chloride -I Cl > +M
Cl

O R-Cδ+ .. O-R' ester -I OR'< +M OR'

O δ+ R-C .. OH acid -I OH< +M OH

-I NH << +M NH

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.
R'-COO Na+ O R-C O R'-C O .. H2 O O R-C + HCl OH O R-C + HCl OR' O R-C NH2 .. H2 O O R-C .. R'-OH + HCl O 2 R-C OH + HCl O + R-COOH OR' aminolysis ammonolysis alcoholysis hydrolysis + HCl Name of the reaction acylolysis

O R-C Cl

.. R'-OH

.. NH3

.. R'-NH2

NH-R' R-C

O O

R-C On the other hand, all these reactions are acylation reactions. The R'-C O mechanism of these reactions is the nucleophilic substitution. NH O
3 2

..

Anhydrides can be converted into acids, R-C NH amides: esters and
.. R'-NH2 O R-C

+ R-COOH

+ R-COOH NH-R'

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:
CH3 -C O OCH3 methyl acetate + H2 O H+ O CH3 -C + CH3 OH OH methanol acetic acid

In reaction of the alkaline hydrolysis of esters the salt of the carboxylic acid and the alcohol are obtained. For example:
O C ethyl benzoate + NaOH OC 2 H5 H2 O O C + C 2 H5 OH ONa ethanol

sodium benzoate

Esters can take part in ammonolysis and aminolysis reactions also:
O R-C NH2 amide O R-C + R'-OH

NH3 O R-C OR' .. R'-NH2

+ R'-OH

NH-R' substituted amide

Amides are hydrolyzed when are heated with aqueous acids or aqueous bases, but these reactions occur more slowly than that of esters. For example:
O CH3 -CH 2 -CH2 -C butyramide + NaOH NH2 H2 O to O CH3 -CH 2 -CH 2 -C sodium butyrate + NH4 OH ONa

O CH3 -C NH2 acetamide + H2 O + HCl

to

O CH3 -C + NH4 Cl OH

acetic acid

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 HellVolhard-Zelinsky reaction.
CH3 -CH2 -COOH + Br2 propionic acid P CH3 -CH-COOH + HBr Br α-bromopropionic acid

Reactions of unsaturated carboxylic acids. The electrophilic addition reactions are characteristic for unsaturated aliphatic acids. Bromination reaction is the example:
CH2 =CH-COOH + Br2 propenoic acid (acrylic acid) H2 O CH2 -CH-COOH Br Br 2,3-dibromopropanoic acid (α,β-dibromopropionic acid)

The addition of hydrogen bromide (chloride) or water is anti-Markovnikov’s addition:
O δ− δ+ δ+ + HCl CH2 =CH C OH propenoic acid O CH2 -CH2 -C Cl β-chloropropionic acid OH

It can be explain by the distribution of the electronic density in the π,πconjugated 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 βcarbon. 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 aromatic carboxylic acids. These reactions (bromination, nitration, for example) occur more slowly then reactions of benzene, because the carboxyl group is the electron-withdrawing substituent.
COOH + Br2 benzoic acid FeBr3 to Br m-bromobenzoic acid COOH + HBr

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:
common name HOOC-COOH HOOC-CH 2 -COOH HOOC-CH 2 -CH2 -COOH HOOC-CH 2 -CH2 -CH2 -COOH HOOC-CH 2 -CH2 -CH2 -CH2 -COOH oxalic acid malonic acid succinic acid glutaric acid adipic acid IUPAC name ethanedioic acid propanedioic acid butanedioic acid pentanedioic acid hexanedioic acid

Isomerism Cis-trans-isomerism is possible for unsaturated dicarboxylic acids:
HOOC H C=C COOH H HOOC H C=C H COOH

maleic acid (cis-butenedioic acid)

fumaric acid (trans-butenedioic acid)

Three structural isomers of aromatic dicarboxylic acids are possible:
COOH COOH COOH phthalic acid isophthalic acid COOH terephthalic acid COOH COOH

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.

O C-C

O

NaOH

O C-C

O

NaOH

O C-C NaO

O ONa

OH HO oxalic acid

ONa HO monosodium salt

disodium salt (sodium oxalate)

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:
O C-C HO OH O CaCl2 O C-C O O Ca calcium oxalate O + HCl

Dicarboxylic acids can form two types of esters, amides and other functional derivatives, for example:
O C-CH 2 -C HO O OH malonic acid CH3 OH O C-CH 2 -C O CH3 OH O H3 CO C-CH 2 -C O OCH3

OCH3 HO monomethyl malonate

dimethyl malonate

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:
O C-C OH HO oxalic acid O to O + CO 2 OH formic acid H-C

O C-CH 2 -C

O

to

O CH3 -C OH acetic acid + CO 2

OH HO malonic acid

When succinic and glutaric acids are heated cyclic anhydrides formation occurs. It is possible, because these acids chains are not linear (sp 3-hybridized carbon atoms valent angle is equal 109o28’) and they can exist in the claw conformation:
H2 C H2 C C O succinic acid C OH OH to O H2C H2C C O + H2 O C O

O succinanhydride

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:
CH2 -CH2 OH NH2

As an amine 2-aminoethanol forms salts with acids:
CH2 -CH2 + HCl OH NH2 cholamine CH2 -CH2 + OH NH3 Cl -

cholamine hydrochloride

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:
CH2 -CH2 OH NH2 3 CH3 -I OH CH3 + CH2 -CH2 -N-CH 3 OH choline CH3

Both cholamine and choline are structural components of phospholipids molecules. Due to alcohol hydroxyl group choline can be acylated to form acetylcholine:
CH3 + CH2 -CH2 -N-CH 3 OH choline CH3 (CH3 CO)2 O CH3 + CH2 -CH2 -N-CH 3 O-C-CH 3 O CH3

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:
HO HO CH-CH2 -NH2 OH noradrenalin CH3 -I HO HO CH-CH2 -NH-CH 3 + HI OH adrenalin

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:
CH3 -CH-COOH OH 2-hydroxypropanoic acid α-hydroxypropionic acid lactic acid CH3 -CH-CH 2 -COOH OH 3-hydroxybutanoic acid β-hydroxybutyric acid

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:
NaOH CH3 -CH-COONa + H 2 O OH sodium salt CH3 OH H+

CH3 -CH-COOH OH lactic acid

CH3 -CH-COOCH 3 + H2 O OH methyl ester

Hydroxy acids exhibit properties of alcohols: they can take part in acylation and oxidation reactions. For example:
[O] CH3-C-COOH O 2-oxopropanoic (pyruvic) acid (CH3CO)2O CH3-CH-COOH + CH3COOH O-C-CH3 O O-acetyl derivative of lactic acid

CH3-CH-COOH OH 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:
CH3 -CH-COOH OH lactic acid c.H2 SO 4 to O + H-COOH H formic acid acetaldehyde CH3 -C

CH3 -CH 2 -CH-COOH OH α -hydroxybutyric acid

c.H2 SO 4 to

O CH3 -CH 2 -C H propionaldehyde + H-COOH formic acid

At heating two molecules of α-hydroxy acid take part in cyclization reaction. The cyclic ester (lactide) is formed:
O CH3 -CH-C OH HO + OH HO C-CH-CH 3 O lactic acid to CH3 -HC O C O lactide of lactic acid C O CH-CH3 + 2 H2 O O

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:
H α CH3 -CH-C-COOH OH H β-hydroxybutyric acid to CH3 -CH=CH-COOH + H 2 O crotonic acid

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:
O α C to OH H2 C β OH H2 C γ CH CH3 γ-hydroxyvaleric acid H2C H2C O C O + H2 O CH CH3

γ-valerolacton

γ-Lactons are obtained in this kind of reactions. Lactons are esters and they can be hydrolyzed.
O C H2C H2C O C H2 NaOH, H2 O HO-CH2 -CH2 -CH2 -COONa sodium salt of γ-hydroxybutyric acid H2 O, H+ HO-CH2 -CH2 -CH2 -COOH γ-hydroxybutyric acid

γ-butyrolacton

Examples of hydroxy acids containing two or three carboxyl groups are following:
COOH HOOC-CH-CH-COOH OH OH tartaric acid (2,3-dihydroxybutanedioic acid) HOOC-CH 2 -C-CH 2 -COOH OH citric acid (2-hydroxypropane-1,2,3-tricarboxylic acid)

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:
HOOC-CH-CH-COOH OH OH tartaric acid KOH HOOC-CH-CH-COOK KOH KOOC-CH-CH-COOK OH OH dipotassium salt (it is soluble in water)

OH OH monopotassium salt (it is insoluble in water, white precipitate is formed)

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:
COOH COOH COOH CH-O CH-O H COOH Cu COOH H O-CH O-CH COOH + 2 H2 O

CH-OH HO HO-CH + Cu + CH-OH OH HO-CH COOH tartaric acid COOH

coordinate complex 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:
CH3 -CH-COOH NH2 2-aminopropanoic acid α-aminopropionic acid CH2 -CH2 -CH2 -COOH NH2 4-aminobutanoic acid γ-aminobutyric acid

As all carboxylic acids amino acids can form salts , esters, acid chloride, amides. For example:
NaOH CH3 -CH-COONa + H 2 O NH2 CH3 OH, H + sodium salt O CH3 -CH-C + H2 O OCH 3 H2 O NH 2 ester O CH3 -CH-C + SO 2 + HCl Cl H2 O NH
2

CH3 -CH-COOH NH2

SOCl2

acid chloride

On the other hand amino acids exhibit all properties of amines (basic properties, acylation and alkylation reactions):

HCl

CH3 -CH-COOH + NH3 Cl hydrochloride of α -aminopropionic acid CH3 -CH-COOH + HI H2 O NH-CH
3

CH3 -CH-COOH NH2

CH3 I

α -N-methylaminopropionic acid (CH3 CO) 2 O CH3 -CH-COOH + CH3 COOH H2 O NH-C-CH
3

O α -N-acetylaminopropionic acid

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:
CH3 -CH-COOH + Ba(OH) 2 NH2 to CH3 -CH 2 -NH 2 + BaCO3 + H2 O ethylamine

Two molecules of α-amino acid can take part in intermolecular cyclic amide formation at heating:
O CH3 -CH-C OH H2 N NH2 HO C-CH-CH 3 O α-aminopropionic acid CH3 -CH-C HN O O NH C-CH-CH 3 + 2 H2 O

to

diketopyperazine

The special reaction of β-amino acids is intramolecular elimination of ammonia:
β CH3-CH α CH COOH to CH3-CH=CH-COOH + NH 3 2-butenoic acid (crotonic acid)

NH2 H β -aminobutyric acid

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:
O C H2 C H2 C OH NH2 CH2 to H2C O C NH + H2 O CH2 H2C γ-butyrolactam

γ-aminobutyric acid

Because of amide bond lactams can be hydrolyzed both in acid and basic medium:
O C H2C H2C NH CH CH3 NaOH H2 O, to H2 O
o HCl, t

CH3 -CH-CH2 -CH2 -COOH + NH3 Cl γ -aminovaleric acid hydrochloride 2 CH3 -CH-CH2 -CH2 -COONa NH2 sodium salt of -aminovaleric acid γ

γ -valerolactam

Keto acids Some keto acids take an important part in biochemical processes. They are for example:
CH3 -C-COOH O 2-oxopropanoic acid α-ketopropionic acid pyruvic acid CH3 -C-CH 2 -COOH O 3-oxobutanoic acid β-ketobutyric acid acetoacetic aid HOOC-C-CH 2 -COOH O 2-oxobutanedioic acid ketosuccinic acid oxaloacetic acid

These keto acids are formed in the organism as a result of the oxidation reactions of corresponding hydroxy acids. For example:
CH3 -CH-COOH OH lactic acid [O] CH3 -C-COOH O pyruvic acid

CH3 -CH-CH 2 -COOH OH β-hydroxybutyric acid

[O]

CH3 -C-CH 2 -COOH O acetoacetic acid

Keto acids give all reactions of carboxylic acids and ketones. For example:
NaOH CH3 -C-COONa + H 2 O O sodium pyruvate (salt) CH3 -C-COOCH 3 + H2 O O methyl pyruvate (ester) NH2 OH CH3 -C-COOH + H 2 O N-OH oxime of pyruvic acid

CH3 -C-COOH O pyruvic acid

CH3 OH, H+

Decarboxylation reaction is a special reaction of β-keto acids only. For example, acetoacetic acid is decarboxylated at heating to give acetone:
CH3 -C-CH 2 -COOH O acetoacetic acid to CH3 -C-CH 3 O 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):
H CH3 -C C O H C OC 2 H5 O CH3 -C=CH-C OH O OC 2 H5

keto tautomer (92.5%)

enol tautomer (7.5%)

The electronic density is displaced from α-carbon atom to two electronwithdrawing 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:
CH3 -C-CH 2 -COOC 2 H5 O [H] HCN (OH ) Br2 (H2 O) CH3 -C=CH-COOC 2 H5 OH FeCl3 violet color Br CH3 -C-CH-COOC 2 H5 HO Br decolorization of bromine water is observed

CH3 -C-CH 2 -COOC 2 H5 HO CN CH3 -CH-CH 2 -COOC 2 H5 cyanohydrin OH β -hydroxybutyric acid ethyl ester

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:

H5 C2 OOC-C-CH 2 -COOC 2 H5 O keto tautomer (15%)

H5 C2 OOC-C=CH-COOC 2 H5 OH enol tautomer (85%)

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,transisomerism. 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 all
a b

waves

vibrating in of

possible light

planes

perpendicular

to its path (a).

If this

beam is passed through certain types

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

light α hold the substance that is being examined for optical activity. These are arranged source α polarizer so that the light passes through one of the lenses (polarizer), then the tube, then the second lens (analyzer), and finally reaches our eye. analyzer 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. 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.
H * CH3 -C-COOH OH

(Such achiral

molecule always contains more than one chiral center; if there is only one chiral

There is one chiral carbon in the lactic acid molecule (it is isomers by the formula N=2n, where N is the number of acid isomers; n is the number of chiral centers. So, lactic

can exist as two optical isomers. They are similar as an object and its mirror image:
COOH C H 1 OH CH3 HO H3 C mirror COOH C H 2

We need to use Fisher’s projections to show structures of these isomers:
COOH H CH3 1 mirror HO CH3 2 COOH H

We

draw a cross

and attach to four ends attached to the chiral lines cross. Chemists

four groups that are located where the

OH

center. The chiral center is understood to be 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.
CHO H OH CH2 OH I D-glyceraldehyde HO CHO H CH2 OH II 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:
CHO H OH CH2OH D(+)-glyceraldehyde Br2 H2O H COOH OH CH2OH D(-)-glyceric acid PBr3 H COOH OH CH2Br D(-)-3-bromo-2hydroxypropanoic acid Zn,H+ H CH3 D(-)-lactic acid COOH OH

To indicate the relationship thus established, compounds related to Dglyceraldehyde are given the designation D, and compounds related to Lglyceraldehyde 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,Lsystem 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 Lstereoisomers. For example:
H CH3 D-lactic acid COOH OH H CH3 D-α -aminopropionic acid COOH NH2 H2 N CH3 L-α -aminopropionic acid COOH H

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, 2,3dibromobutanoic acid has two chiral carbons:
* * CH3 -CH-CH-COOH Br Br

The number of stereoisomers is calculated as N=2n=22=4.

Let us draw Fisher’s formulas of stereoisomers.
COOH H H CH3 I Br Br Br Br CH3 II COOH H H H Br CH3 III COOH Br H Br H CH3 IV COOH H Br

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:
* * HOOC-CH-CH-COOH OH OH

Does this compound, too, exist in four stereo someric forms?

Fisher’s formulas of four supposed stereoisomers are folowing:
COOH H HO I OH HO H H COOH II COOH H OH COOH H H III COOH OH HO OH HO COOH IV COOH H H COOH

Not superimposable Enantiomers

Superimposable 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. only! The molecule has a plane of symmetry, and cannot be chiral. Optical activity is a property of chiral molecules

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:
ONa NaOH OH NH2 OH NH2 HCl + - p-aminophenol hydrochloride NH3 Cl + H2 O sodium salt of p-aminophenol

As phenol p-aminophenol can form ethers, but this reaction occurs through sodium p-aminophenolate formation:
OH NaOH NH2 sodium p-aminophenolate ONa C2 H5 -Cl OC 2 H5

NH2 p-aminophenol

NH2 phenetidine

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:
OC 2 H5 (CH3 -CO) 2 O OC 2 H5 + CH3 -COOH NH-C-CH 3 O phenacetine

NH2 phenetidine

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):
OH (CH3 -CO) 2 O OH + CH3 -COOH NH-C-CH 3 O paracetamol

NH2 p-aminophenol

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:
COONa NaOH COOH NH2 + H2 O sodium salt of p-aminobenzoic acid

COOH NH2 HCl + - p-aminobenzoic acid hydrochloride NH3 Cl

As carboxylic acid p-aminobenzoic acid can form acid chloride in the interaction with PCl5 or thionyl chloride:
COOH SOCl2 NH2 C O Cl + SO 2 + HCl NH2 acid 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:
COOH C2 H5 OH NH2 C O OC 2 H5 + H2 O NH2 ethyl ester of p-aminobenzoic acid

Novocain is the other example of drugs – p-aminobenzoic acid derivatives. Chemically it is N,N-diethylaminoethyl ester of p-aminobenzoic acid:
COOH + NH2 HO-CH2 -CH 2 -N C2 H5 C2 H5 NH2 Novocain C O O-CH 2 -CH2 -N + H2 O C2 H5 C2 H5

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:

C

O O-CH 2 -CH 2 -N

C2 H5 C2 H5 + HCl

C

C2 H5 + O-CH 2 -CH2 -NH Cl C2 H5

O

NH2 Novocaine

NH2 Novocain hydrochloride

COOH

p-Aminosalicylic acid (PAS) is one of the earlier drugs used to

OH treat tuberculosis infections.

NH2

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:
NH2 H2 SO4 + NH3 HSO4 180-200o C anilinium hydrosulfate NH2

aniline

SO 3 H sulfanilic acid

As a sulfonic acid sulfanilic acid exhibits strong acidity, it can form salts with alkali:
NH2 + NaOH SO3 H sulfanilic acid NH2 + H2 O SO3 Na sulfanilic acid sodium salt

Salts are soluble in water.

Basic properties of sulfanilic acid are very decreased, because of electronwithdrawing 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:
NH2 + NH3

SO3 H

SO3 dipolar ion

The amide of sulfanilic acid (sulfanilamide) and certain related substituted amides are of considerable medical importance as the sulfa drugs.
NH2 NH2

SO2 NH2 sulfanilamide

SO2 NH-R general structure of 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:
NH2

N SO2 NHN Sulfamerazine CH3

Derivatives of salicylic acid
COOH

Salicylic acid (o-hydroxybenzoic acid) behaves as phenol and

OH as carboxylic acid.

The acidity of salicylic acid is higher than that of benzoic acid, because of higher stability of salicylate anion.
O COOH OH H2 O C O H + H3 O+ hydrogen bond

O

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:
COONa OH NaOH COOH OH NaHCO 3 COONa OH

sodium salicylate

salicylic acid

sodium salicylate

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 αhydroxy acids):
COOH OH to phenol OH + CO 2

salicylic acid

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:
COOH OH + CH3 OH salicylic acid H+ COOCH 3 OH + H2 O

methyl salicylate

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).
COOH OH PCl5 COCl OH C6 H5 OH COOC 6 H5 OH

salicylic acid

salicyl chloride

phenyl salicylate

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:
COOH OH + (CH3 CO)2 O acetanhydride salicylic acid COOH O-C-CH 3 O acetylalicylic acid + CH3 COOH

Aspirin is used as febrifugal drug (antipyretic). Acetylsalicylic acid is an ester. It can be hydrolyzed if stored in the moist place:
COOH O-C-CH 3 O acetylalicylic acid + H2 O COOH OH + CH3 COOH

salicylic acid

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 FeCl 3. 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:
α β β N H pyrrole α O furan S thiophene

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.

.
H H

.
H

All atoms are sp2-hybridized. The cycle is flat. Nitrogen

. ..
N H

has the unshared electron pair on the unhybrid pz-orbital.
H 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.
N H

..

α + Br2

N H α-bromopyrrole

..

Br

+ HBr

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:
polymerization H

N H

..

+ HNO3

H H

+ N

NO 3 -

+ N

H

n

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:
O O + CH3 -C O-NO 2 acetylnitrate NO 2 + CH3 -COOH O α-nitrofuran acetic acid

Pyridine sulfotrioxide is used for sulfonation reactions of acidophobic compounds:

N H

..

+

N . SO3 pyridine sulfotrioxide

SO3 H N H α-pyrrolesulfonic acid

..

+ N pyridine

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:

K N H

..

- H2

N K+ potassium salt of pyrrole

H2 O

N H

..

+ KOH

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.
Zn + CH3 COOH N H pyrroline pyrrolidine

..

H2 , Pt

N H N H

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:
N H proline COOH HO COOH N H hydroxyproline

Pyrrolidone can be considered both as oxo-derivative of pyrrolidine and γbutyrolactam. A reaction of pyrrolidone with acetylene gives vinylpyrrolidone, that may be polymerized into polyvinylpyrrolidone:
HC CH O N H pyrrolidone N O N O CH=CH2 vinylpyrrolidone -CH-CH 2 polyvinylpyrrolidone n

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
N H N H N N

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+).
β N H α

Indol is pyrrole derivative also. It is benzopyrrol. Indole is an aromatic compound with ten electrons in the aromatic cloud.

indole

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:
Br + Br2 indole N H N H β -bromoindole + HBr

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:
K N H N K+ potassium salt of indole

The most important derivatives of indole are as follows: α-amino acid thryptophane, nerve mediator serotonin, indomethacin (an anti-inflammatory drug).
CH2 -CH-COOH NH2 N H tryptophane CH3 O N O=C indomethacin N H serotonin CH2 -COOH CH3 Cl HO CH2 -CH2 -NH2

Two ways of trypthophane metabolism in the organism are possible: oxidative and non-oxidative types of decarboxylation.

enzimes CH2 -CH-COOH NH2 N H tryptophane [O] enzimes HO N H N H tryptamine

CH2 -CH2 NH2 + CO 2

CH2 -CH-COOH NH2

5-hydroxytryptophane enzimes HO N H 5-hydroxytryptamine (serotonin) CH2 -CH2 NH2 + CO 2

Properties of furan derivatives
4 5 3 1 2

O

C

O H

Furfuraldehyde furan derivatives.

or

furfural is one of the most important

All properties of aldehydes are characteristic for furfural, for example, the silver mirror reaction, Cannizzaro reaction, nucleophilic addition and additionelimination reactions. Silver mirror reaction gives furoic acid:
O H + Ag(NH3 )2 OH to O + Ag + NH3 + H2 O

O

C

O OH furoic acid

C

In Cannizzaro reaction furfuril alcohol and sodium salt of furoic acid are formed:

2 O furfural

C

O H

NaOH O C

O

+ O

ONa sodium salt of furoic acid

CH2 OH

furfuril alcohol

Some antibacterial drugs may be prepared from furfural, Furacin (5-nitro-2furaldehyde semicarbazone) is an example:
O O C O H HNO 3 (CH3 CO) 2 O O2 N C O H 5-nitrofurfural
5

O

H2 N-NH-C-NH 2 semicarbazide

O2 N

O

CH=N-NH-C-NH

2

O 5-nitro-2-furaldehyde semicarbazone

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:
4 5 1 3 3 4 2 5 3

N
2 5

4

3 5

4

N S
1

N O
1 2

N H imidazole

1 N2 N H pyrazole

thiazole

oxazole

All these compounds are aromatic ones. Let us explain it giving imidazole as an example.
N: N1 H pyrrole type nitrogen
3

..

pyridine type nitrogen

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,πconjugation. 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.
N: N H acid center N H HCl N K N H N N K+ potassium salt of imidazole + NH Cl imidazolium chloride

..

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:
4 5

N: N H
1 2 4

3

5

NH N
3 2 5

1

4

3

4 2 3

5 1

N H

1

N:

N
2

NH

tautomerism in imidazole

tautomerism in pyrazole

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:
[H] H2 , Ni

C2 H5 OH + Na N H pyrazole

N

N H pyrazoline

N

NH N H pyrazolidine

Pyrazolone is the most important derivative of pyrazoline. It can exist in different tautomeric forms:
O
4 5 3 2 4 3 5 1 1 N 2 NH O N N H H pyrazolone tautomerism

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.
CH3 O N N CH3 H3 C H3 C N O N CH3 N CH3

C6 H5 Phenazone

C6 H5 Amidopyrine

NaSO 3 - H2 C H3 C

N O N

CH3 N CH3

H9 C4 O N

O N C6 H5

C6 H5 Analgine

C6 H5 Phenylbutazone

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.
N N H CH2 -CH-COOH NH2 - CO 2 N N H CH2 -CH2 -NH2

histidine

histamine

Benzimidazole is a condensed ring system consist of benzene and imidazole rings. Benzimidazole is a part of vitamin B12 structure.
N H N benzimidazole

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.
R-CO-NH O N S CH3 CH3

COOH a general structure of Penicillines

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
N pyridine N quinoline

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:
β N β

Examples of electrophilic substitution reactions in pyridine are as follows:
KNO 3 ,H2 SO 4 γ β α N 300o β α H2 SO4 350o Br2 , 300o N N Br β-bromopyridine N SO3 H β-pyridinesulfonic acid NO 2 β-nitropyridine

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:
5 6 7 8 4 3

NO 2 HNO 3 H2 SO 4 N 5-nitroquiniline NO 2
2

N

1

+ N 8-nitroquiniline

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:
NaNH ++NaNH2 2 tot -H -H2 2
o

NH NH3 3 NHNa NHNa NN sodium salt of sodium salt of 2-aminopyridine 2-aminopyridine

NN

NH NH2 2 NN 2-aminopyridine 2-aminopyridine

NaNH ++NaNH2 2

+ KOH N

300o N OK

HCl potassium salt of 2-hydroxopyridine

+ KCl OH N 2-hydroxopyridine

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:
+ HCl N ..

+ N H

Cl pyridinium chloride

Pyridine is enough strong base to react with so weak acid as water:

+ H2 O N

+ N H

OH pyridinium hydroxide

Pyridine can react with sulfur trioxide, which is a Lewis acid:
O δ+ + S O N O

N . SO3 pyridine sulfotrioxide

Due to unshared electron pair pyridine exhibits nucleophilic properties. It can react with alkyl halides to form quaternary salts:
+ δ+ CH3 I δ− + N I-

N ..

CH3 N-methylpyridinium iodide

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:
H H+ N CH3 [O] N CH3 H

A product of this reaction is nonaromatic 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:
N [H] (C2 H5 OH + Na)

N H pyperidine

Quinoline undergoes reduction reactions also. These reactions occur due to pyridine ring. Oxidation of quinoline occurs due to benzene ring:
[H] N H N [O] HOOC HOOC N quinolinic acid (2,3-pyridinedicarboxylic acid) tetrahydroquinoline

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 βpicoline) with potassium permanganate:
CH3 N β-picoline COOH [O] N nicotinic acid

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):
COOH N nicotinic acid SOCl2 COCl N acid chloride NH3 N nicotinamide CONH 2

Nicotinamide is used in medicine as vitamin PP, too. Pyridoxine (one of the vitamin B6 forms) is pyridine derivative also:
HO H3 C CH2 OH CH2 OH N

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:
CH3 [O] N γ-picoline N isonicotinic acid COOH SOCl2 COCl NH2 -NH2 N acid chloride N hydrazide of isonicotinic acid CONH-NH 2

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.
N OH 8-hydroxyquinoline (Oxine)

Oxine has antibacterial properties which are connected with its ability to increase the toxical action of Fe2+ and these ions, for example: Complexes with Fe2+ are toxic for all bacteria, with Cu2+
O N Fe N O

Cu2+ ions. Oxine forms complexes with

- for fungus.

Some 8-hydroxyquinoline derivatives are used as antibacterial drugs, too. For example, Clioquinol is 5-chloro-8-hydroxy-7-iodoquinoline:
Cl

I OH

N

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:
4 5 6 3 1 N2 5 6 1 4

N3
2

5 6

N
1

4

3 2

N pyridazine

N pyrimidine

N pyrazine

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:
N: N .. pyrimidine N + N

+ H2 SO4

HSO4 -

H pyrimidinium hydrosulfate

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
NH2 N N 4-aminopyrimidine

electronic density is especially decreased:
N N pyrimidine NaNH2

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 2,4,6trihydroxypyrimidine. 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).
O H 4 lactam H N3 5 H fragments 2 1 6 O N O H I lactam-lactim tautomerism keto fragment keto-enol tautomerism H N O N H O H OH II lactam-lactim tautomerism enol fragment

OH lactim fragments HO N N H H O III

OH keto-enol tautomerism HO N N OH IV

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:

O H N O N H + NaOH OH H N O

O H N ONa + H2 O

H barbituric acid

H sodium salt of barbituric acid

Barbiturates are alkyl or aryl derivatives of barbituric acid (for 5-th position). There general formula is as follows:
2

O R 4 H N3 5 R' O N
1 6

O

H

For example, Barbital is 5,5-diethylbarbituric acid; 5-ethyl-5-phenyl-barbituric acid.

Phenobarbital

is

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.
O R 4 H N3 5 R'
2

O H N R R' NaOH H N Na O

O R R'

O

N

1 6

O

H lactam tautomer

O N HO lactim tautomer acid center

O N sodium salt

Condensed ring systems. Purine is the most important condensed heterocyclic system.
N
2 3 1 6 5 7 9

N
8

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

N 4 N H

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:
N N .. N N H basic center acid center

Purine reacts with acid and bases to form corresponding salts:
Na N N N H HCl N N N N N N N Na sodium salt of purine

+ NH N H Cl - purinium chloride

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.
N
2 3 1 6 5

N
9 8

7

N N

H N N
7 9

N 4 N H

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:

O HN 6

O H N HN 6
2

H N N

O HN
2 6

H N
8

O

N N hypoxanthine 6-hydroxypurine

O

N H xanthine 2,6-dihydroxypurine

N H uric acid 2,6,8-trihydroxypurine O

N H

Lactam-lactim tautomerism is characteristic for all these compounds. Lactam tautomers are more stable.
O HN O H N HO OH N N H N N

N N H lactam tautomer of xanthine

lactim tautomer

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):
O CH3 N O N
3 1

H N N

O HN O N
3

N N

7

CH3

O CH3 N O N
3 1

N N

7

CH3

CH3 theophilline 1,3-dimethylxanthine

CH3 theobromine 3,7-dimethylxanthine

CH3 caffeine 1,3,7-trimethylxanthine

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.
O : ..... H HN O N H N O N H NaOH HN O N H O : ..... H N ONa N NaO N NaOH N O : ..... H N ONa N

uric acid

monosodium salt

disodium salt

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. carbohydrates and their derivatives are drugs. Carbohydrates are polyhydroxy aldehydes, polyhydroxy ketones, or compounds that can be hydrolyzed to them. Carbohydrates that cannot be Some

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:
O H (CH-OH)n CH2 OH aldoses C CH2 OH C=O (CH-OH)n CH2 OH ketoses

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. 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.
* * * * CH2 -CH-CH-CH-CH-C OH OH OH OH OH O H

Most

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.
C H HO H H
1

O

The

relative

configuration

of

monosaccharides

H 2 OH 3 H 4 OH 5 OH 6 CH2 OH

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. most of natural monosaccharides have D-configuration. The

D-glucose

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. different properties and different names. For example:
O C H HO H H H OH H OH OH CH2 OH C HO H HO HO O H H OH H H CH2 OH HO HO H H O C H H H OH OH CH2 OH C O H OH H HO H H HO H OH CH2 OH D-galactose

Diastereomers have the

D-glucose enantiomers

L-glucose

D-mannose

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 Dgalactose are epimers. Some other examples of monosaccharides (hydrogen atoms in Fisher’s formulas can be not designated) are:
O C H OH OH OH C O H OH OH CH2 OH D-deoxyribose aldopentoses HO H O C H OH OH CH2 OH D-xylose CH2 OH C=O HO OH OH CH2 OH D-fructose ketohexose

CH2 OH D-ribose

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:
H CH2 OH .. CH OH O C OH H C C C H OH H OH

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:
O C HO H OH HO OH 5 OH CH2 OH H

* 1C
2 3 4 5 6

OH OH OH O

hemiacetal hydroxyl group or

CH2 OH O 4 1 OH 2 OH HO 3 OH
5

6

hemiacetal hydroxyl group

D-glucose

CH2 OH α -D-glucopyranose (Tollens formula)

α -D-glucopyranose (Haworth formula)

"On the right" in Tollens formula means "down" in the Haworth formula. If the aldehyde group reacts with hydroxyl group of 5-position the sixmembered 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.
CH2OH O OH HO α CH2OH β O OH OH HO OH β -D-glucopyranose

OH D-glucopyranose −

α OH

When the aldehyde group reacts with hydroxy group of 4-position the fivemembered cycle is formed . It is called furanose cycle.
O C HO H OH HO H

* 1C
2 3 4 5 6

OH OH

hemiacetal hydroxyl group O or

4

OH OH CH2 OH

D-glucose

OH CH2 OH α-D-glucofuranose (Tollens formula)

OH 2 3 OH α-D-glucofuranose (Haworth formula)

CH2 OH 5 O HO 4 OH

6

hemiacetal hydroxyl group
1

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:

CH2 OH O HO OH

OH OH α -D-glucofuranose (32%) HO

O C H OH

HO α

OH OH D-glucopyranose −

CH2 OH O OH

CH2 OH O OH HO OH OH β -D-glucofuranose (64%)

OH OH CH2 OH HO β < 0.5%

D-glucose

CH2 OH O OH OH OH D-glucopyranose −

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).
CH2 OH O HO β-D-glucopyranose CH2 OH O HO

HO HO

OH (equatorial)

HO HO

OH (axial) α-D-glucopyranose

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:

CH2 OH O OH OH HO β OH D-glucopyranose −

CH3 OH, HCl dry HO

CH2 OH O OCH3 OH OH

O-methyl - β -D-glucopyranoside

Glycosides are acetals In the monosaccharides reaction with amines N-glycosides are formed. For example:
CH2 OH O OH CH2 OH O OH

C2 H5 NH2 HO

HO α

OH OH D-glucopyranose −

NH-C2 H5 OH N-ethyl α - -D-glucopyranoside

Glycosides are hydrolyzed very easily in acidic medium:
HO CH2 OH O OC 2 H5 OH CH2 OH O OH HO OH + C2 H5 OH OH -D-galactopyranose − β

H2 O, H

+

O-ethyl-

OH D-galactopyranoside β

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:
ether bonds CH2OH O OH (CH3)2SO4, NaOH OH HO excess OH β -D-glucopyranose glycoside bond CH2OCH3 O OCH3 OCH3 OCH3

H3CO

β -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:
CH2 OCH3 O OCH3 OCH3 OCH3 H2 O, H+ H3 CO CH2 OCH3 O OH OCH3 OCH3 + CH3 OH

H3 CO

2,3,4,6-tetramethyl- β -D-glucopyranose

Monosaccharides treatment with carboxylic acids anhydrides yields esters:
CH2 OH O OH HO OH O CH2 OAc O O-C-CH 3 OAc AcO OCOCH 3

(CH3 CO) 2 O excess

OH β -D-glucopyranose

Ac pentaacetylglucose

Esters are hydrolyzed both in the acidic and alkaline medium:
NaOH, H2 O O CH2 OAc O O-C-CH 3 OAc AcO OCOCH 3 pentaacetylglucose H2 O, H+ CH2 OH O OH OH + 5 CH3 COONa HO sodium acetate OH glucose CH2 OH O OH OH + 5 CH3 COOH HO acetic acid OH

Esters of phosphoric acid are very important compounds. They are a methabolism of carbohydrates result in the organism. For example:
HO O=P-O-CH 2 HO O OH

OH OH

β -D-ribofuranose 5-phosphate

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:
C HO O H OH CH2 OH OH C O C HO O H OH HO O HO H C O CH2 OH OH

OH + Cu(OH) HO 2 OH HO CH2 OH HO D-glucose H

O Cu OH CH2 OH

Reduction reactions. As all aldehydes and ketones monosaccharides can be reduced in the corresponding polyalcohols. For example:
C HO O H OH [H] HO CH2 OH OH OH OH CH2 OH glucitol (sorbitol)
HO O H OH OH [H]

C

CH2 OH OH HO OH CH2 OH xylitol

OH OH CH2 OH D-glucose

CH2 OH D-xylose

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. 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: The result of oxidation depends upon the

C HO

O H OH Ag(NH3 )2 OH , to products of oxidation + Ag + NH3 + H2 O silver mirror Cu(OH)2 , to products of oxidation + Cu2 O + H2 O redish-brown ppt.

OH OH CH2 OH D-glucose

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:
C HO O H OH C Br2 , H2 O (HOBr) HO O OH OH

OH OH CH2 OH D-glucose

OH OH CH2 OH D-gluconic acid

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:

C HO

O OH OH Ca(OH)2

C HO

O OOH

OH OH CH2 OH D-gluconic acid

OH OH CH2 OH 2 calcium gluconate

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:
C HO O H OH HNO3 COOH OH HO OH OH COOH

OH OH CH2 OH D-glucose

glucaric acid

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 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 monosaccharide.

first molecule and alcohol hydroxyl group in 4-th position of the second molecule interaction.
CH2 OH O OH CH2 OH O 4 OH OH HO OH α -D-glucopyranose hemiacetal hydroxyl group group

1

+

OH OH α -D-glucopyranose HO

HO

O OH α -1,4OH OH linkage -maltose ( -D-glucopyranosyl-1,4- α -D-glucopyranose) α

CH2 OH O OH

CH2 OH O OH

CH2 OH O 1 OH HO OH

O β -1,4linkage

CH2 OH O 4 OH OH

Cellobiose
OH

contains

two

glucopyranose units, too, but they are joined by β-glycoside linkage.

-cellobiose ( -D-glucopyranosyl-1,4- -D-glucopyranose) β β

O β -1,4OH linkage OH -lactose (β -D-galactopyranosyl-1,4- β -D-glucopyranose) β -D-glucopyranose -D-glucopyranose) β

CH2 OH HO O 1 OH

CH2 OH O 4 OH

OH

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:
CH2 OH CH2 OH O HO O 1 OH O 4 OH OH -lactose CH2 OH CH2 OH O OH O OH OH H O,H+ 2 + OH OH HO OH OH OH β -D-galactopyranose β -D-glucopyranose HO

β -D-glucopyranose -D-glucopyranose) β

Cyclo-oxo tautomerism is characteristic for reducing disaccharides, because they have free hemiacetal hydroxyl group. For example:
CH2 OH O OH HO OH CH2 OH O OH OH hemiacetal hydroxyl group OH reducing fragment CH2 OH O OH OH OH O C H

O -maltose

CH2 OH O OH HO

OH open tautomer

CH2 OH O OH HO OH

O -maltose

hemiacetal CH2 OH hydroxyl group OH O OH OH

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:
CH2 OH O OH CH2 OH O OH Ag(NH3 )2 OH to products of + Ag + NH3 +H2 O oxidation silver mirror

OH

O C

H Cu(OH)2 OH OH products of + Cu2 O + H2 O open tautomer OH CH2 to oxidation reddishCH2 OH of cellobiose O brown ppt O OH C OH OH O H Br2 , H2 O HO OH by bromineOH Oxidation water gives bionic acids (maltobionic, lactobionic HO

acids are examples):

maltose CH2 OH O OH HO OH maltobionic acid CH2 OH O OH OH O C OH

OH

Reducing disaccharides can react with alcohols in dry HCl presence to yield glycosides due to free hemiacetal hydroxyl group:
CH2 OH O OH HO CH2 OH O OH CH3 OH OH HCl dry OH CH2 OH O OH HO CH2 OH O OCH3 OH OH

O

O

OH β -cellobiose

OH O-methyl--cellobioside β

Disaccharides can be alkylated and acylated due to all hydroxyl groups:
CH2 OH O OH HO CH2 OH O OH OH OH

O

(CH3 )2 SO 4 NaOH

OH maltose

H3 CO

CH2 OCH3 O OCH3

O

CH2 OCH 3 O OCH3 OCH 3

OCH 3 OCH3 octamethylmaltose

H3 CO

CH2 OCH3 O OCH3

+ HO

CH2 OCH3 O OH OCH3 OCH3

H2 O, H

+

OH OCH3

2,3,4,6-tetramethylα -D-glucopyranose

2,3,6-trimethylβ -D-glucopyranose

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.
CH2 OH O OH HO OH maltose CH2 OH O OH OH OH

O

(CH3 CO) 2 O CH2 OAc O OCOCH 3 OAc Ac O OAc OAc octaacetylmaltose

CH2 OAc O OAc AcO

+ 8 CH3 COOH OH OH glucose CH2 OH CH2 OH H2 O, NaOH O OH O + 8 CH3 COONa O HO OH OH OH OH maltose 2 HO

H2 O, H+

CH2 OH O OH

Sucrose (our common table sugar) is an example of non-reducing sugars. Sucrose contains α-glucopyranose and β-fructofuranose units, joined by 1,2glycoside 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.

CH2 OH O OH HO

OH HO

1

OH α -D-glucopyranose + CH2 OH O OH HO 2 CH2 OH OH β -D-fructofuranose
1

CH2 OH O OH

1

OH O 1,2-glycoside bond CH2 OH O HO 2 CH2 OH OH sucrose
1

As glycoside sucrose can be hydrolyzed in acidic medium:
H2 O, H + HO CH2 OH O OH CH2 OH O OH HO CH2 OH OH β -D-fructofuranose

Sucrose

OH

+

OH α -D-glucopyranose

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 homoand 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.
CH2 OH O OH HO OH CH2 OH O OH CH2 OH O OH OH CH2 OH O OH OH

O

OH Amylose

O α -1,4

O
n

OH

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 α1,6-glycoside bonds. Amylopectin has a highly branched structure. There are 2025 glucose units between each two branches.
CH2OH O OH OH O α -1,6 CH2OH O OH OH CH2 O OH O O α -1,4 CH2OH O OH OH CH2OH O OH OH

O

O

OH Amylopectin

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.
CH2 α -1,6 O HO O α -1,3 O HO OH Dextran OH CH2 O HO OH CH2 OH CH2 OH O α -1,4 O

O HO

O

O

O OH CH2 OH

O

O OH

OH CH2 OH HO

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 nonreducing carbohydrate. Cellulose is made up of chains of D-glucose units, each unit joined by βglycoside bond to C-4 of the next unit:
CH2 OH O OH HO OH CH2 OH O OH OH CH2 OH O OH OH CH2 OH O OH OH OH

O

O β -1,4

O
n

Cellulose

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
R-CH-COOH NH2

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:
CH2 -COOH NH2 CH3 -CH-COOH NH2 CH3 CH3 Glycine CH3 CH3 CH-CH2 -CH-COOH Leucine * NH
2

Alanine

CH3 -CH2 -CH-CH-COOH CH3 NH2 Isoleucine*

CH-CH-COOH NH2 Valine *

CH2 -CH-COOH OH NH2

Serine

CH3 -CH-CH-COOH OH NH2

Threonine*

CH2 -CH-COOH SH NH2 Cysteine

CH3 -S-CH 2 -CH2 -CH-COOH NH2 Methionine

CH2 -CH-COOH S S NH2 NH2 Cystine ( ys-Cys) C

HOOC-CH 2 -CH-COOH NH2 Aspartic acid

CH2 -CH-COOH

HOOC-CH 2 -CH2 -CH-COOH NH2 Glutamic acid

H2 N-CH 2 -CH2 -CH2 -CH 2 -CH-COOH NH2 Lysine *

H2 N-C-NH-CH 2 -CH2 -CH2 -CH-COOH NH NH2 Arginine

Examples of aromatic α-amino acids are as follows:

CH2 -CH-COOH NH2 Phenylalanine*

HO

CH2 -CH-COOH NH2 Tyrosine

Heterocyclic α-amino acids are as follows:
CH2 -CH-COOH N H NH2 Tryptophane* N N H CH2 -CH-COOH NH2 Histidine

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:
* CH3 -CH-COOH NH2 Alanine H COOH NH2 CH3 D-alanine H2 N CH3 L-alanine COOH H

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:
R-CH-COOH NH2 R-CH-COO + NH3
-

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:
H2 N-CH-COO R pH>7 anion
-

OH H+

+ H3 N-CH-COO R pH=7 dipolar ion

-

H+ OH -

+ H3 N-CH-COOH R pH<7 cation

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:
R-CH-COOH + NH3 Cl α -amino acid hydrochloride NaOH R-CH-COONa + H 2 O NH2 sodium salt of α -amino acid HCl

R-CH-COOH NH2

As carboxylic acids α-amino acids can form esters and acid chlorides:
CH3 OH, H + R-CH-COOH NH2 SOCl2 R-CH-COOCH 3 NH2 methyl ester R-CH-COCl NH acid chloride
2

As amines α-amino acids can react with acids anhydrides, aldehydes and nitrous acid:
R-CH-COOH NH2 HNO2 R-CH-COOH + N 2 + H2 O OH α -hydroxy 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:
(CH3 CO) 2 O R-CH-COOH NH2 O H-C-H R-CH-COOH NH-CO-CH 3 N-acetyl derivative R-CH-COOH NH-CH2 OH N-methylol derivative

A special reaction of all α-amino acids is their interaction with Cu2+ ions to form coordinate salts:
O C R-CH OH + Cu 2+ + HO H2 N CH-R C R-CH C O O Cu H2 N O CH-R C

NH2

NH2

O

O deep dark blue color

The other special reaction of α-amino acids is decarboxylation reaction:
R-CH-COOH NH2 to Ba(OH)2 R-CH2-NH 2 amine

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:
HO CH2 -CH-COOH NH2 Tyrosine HNO3 , to HO O2 N CH2 -CH-COOH NH2 yellow color NaOH orange color

Sulfur containing α-amino acids react with lead acetate in alkaline medium to form black precipitate:

CH2 -CH-COOH SH NH2 Cysteine

1) NaOH, to 2) (CH3 COO) 2 Pb

PbS black ppt

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:
N N H CH2 -CH-COOH NH2 histidine enzymes enzymes N N H CH2 -CH2 -NH2 + CO 2 histamine

CH2 -CH-COOH OH NH2 serine

CH2 -CH2 -OH + CO 2 NH2 cholamine

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:
HOOC-CH2 -CH-COOH NH2 aspartic acid enzymes HOOC-CH=CH-COOH 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.
CH3 -CH-COOH NH2 alanine [O] enzymes CH3 -C-COOH NH imino acid H2 O enzymes CH3 -C-COOH O pyruvic acid

Transamination reaction occurs between amino acid and keto acid, for example:
HOOC-CH 2-CH-COOH + NH2 aspartic acid CH3-C-COOH O pyruvic acid enzymes

HOOC-CH 2-C-COOH + CH3-CH-COOH O oxaloacetic acid NH2 alanine

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 is often referred to as the peptide linkage.
-C-NH- in such compounds O

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).
N-end O O C-end H2 N-CH-C-NH-CH-C-NH-CH-COOH R R R general formula of polypeptides

For example:

O

O

H2 N-CH-C-NH-CH 2 -C-NH-CH-COOH CH3 CH2

alanylglyc ylphenylalanine (Ala-Gly-Phe) H2 N-CH 2 -CO-NH-CH-COOH CH3 glyc ylalanine (Gly-Ala) + H3 N-CH 2 -CO-NH-CH-COO dipolar ion CH3

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
O R N C .. C C .. N H O H H

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: of p,π-conjugation.
O C N H

It is a result

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:
H2 O,HCl H2 N-CH 2 -CO-NH-CH-COOH Gly-Ala CH3 + + H3 N-CH 2 -COOH + H3 N-CH-COOH ClClCH
3

H2 O,NaOH

H2 N-CH 2 -COONa + H2 N-CH-COONa CH3

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 -CONH-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 βconformation. 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 αamino 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:
Base Base

-Sugar-O-P-O-Sugar-OO OH

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.
O NH O N H Uracil (U) H3 C O NH O N H Thymine (T) NH2 N O N H Cytosine (C)
NH2 N N N O NH NH2 N N H Guanine (G)

N N H Adenine (A)

The lactam-lactim tautomerism is characteristic for all heterocyclic bases except adenine:
O NH OH N N N H N O NH NH2 N N H N OH N NH2

O OH N N H lactam tautomer lactim tautomer Uracil

lactam tautomer lactim tautomer Guanine

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:
F O
4 5 3NH 6 1 2

SH N7
8 9 5 4 6

O N H 5-fluorouracil (uracil antagonist)

N N H 6-mercaptopurine (adenine antagonist)

N 1 2 3

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:
O Uracil
4 NH 5 3 6 1 2

O
4 NH 5 3 6 1 2

N H

O HO-CH2
5'

HO-CH 2 O

+ OH

N

O + H2 O

4' 3'

O
2'

1'

OH OH β-D-ribofuranose

OH

OH

Uridine

Ribose and deoxyribose are present in the β-furanose tautomeric forms. Carbon atoms of sugar are numbered by figures with a touch.
NH2 Adenine N N H HO-CH2 O + OH N HO-CH2
4' 3' 5'

N N
8 9 7

NH2
5 6 3 N 4 N 1' 2' 1N 2

O OH

OH β-D-deoxyribofuranose

Deoxyadenosine

Names of nucleosides Base Uracil (RNA only) Thymine (DNA only) cytosine cytosine adenine adenine guanine guanine Sugar ribose deoxyribose ribose deoxyribose ribose deoxyribose ribose deoxyribose Name of nucleoside uridine thymidine cytidine deoxycytidine adenosine deoxyadenosine guanosine deoxyguanosine

Nucleosides are glycosides; therefore they can be hydrolyzed in the acidic medium only. For example:
O H3 C HO-CH2 O OH Thymidine N NH O H2 O, H+ O H3 C NH + O N H thymine OH deoxyribose HO-CH2 O OH

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.
O H3 C HO-CH2 O N NH

They exhibit antibiotic and antiswelling activity. Some of them are used as drugs, for example azidothymidine, that a speed of AIDS (acquired immunodeficiency syndrome) virus reproduction.
O decreases

N3 Azidothymidine

Nucleotides

Nucleotides are phosphates of nucleosides (the esters). Esterification reaction can occur due to hydroxyl group in 3' or 5'-position of the sugar.
O
4 NH 5 3 6 1 2

O ester bond HO H3 PO 4 HO O
5' 4 NH 5 3 6 1 2

HO-CH2
4' 3'

5'

N

O

O
2'

P-O-CH 2
4' 3'

N

O

1'

O
2'

N-glycoside bond

1'

OH

OH

OH

OH

uridine

uridine-5'-phosphate (or 5'-uridylic acid)

NH2 N HO HO O
5' 8 9 7 5 6 3 1N 2

NH2 N HO-CH2
5'

P-O-CH 2
4' 3'

N 4 N
1'

N O
1' 2'

O

O
2'

4' 3'

OH deoxyadenosine-5'-phosphate (5'-deoxyadenylic acid)

O O=P HO OH

OH cytidine-3'-phosphate 3'-cytidylic acid

There are two types of bonds in the nucleotides molecules: N-glycoside
O bonds and ester bonds. Ester bonds can be hydrolyzed both in acidic and alkaline
3 medium; N-glycoside bond - in acidic medium only. For example: O NH O

HC

HOCH2

H3 C HO HO P-O-CH 2 O O N

H2 O, H+

OH + H3 PO 4

NH O

N H thymine H3 C

O

+

OH deoxyribose O

NaOH, H2 O OH 5'-thymidylic acid

NH N O + H3 PO 4

HOCH2

O

OH thymidine

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:
N
5' 8 9 7 5

NH2
6 3 N 4 N 1' 2' 1N 2

O-CH 2 HO
4'

O
3'

P O NH2

O

OH
NH2 N

OH

N

N N Nucleotides N N HO-P-O-CH 2 are known as monomers of the nucleic acids. But not only is HO-P-O- P-O-CH 2 H3 PO 4 H3 PO 4 O this roleOcharacteristic for them. For example, ATP (adenosine triphosphate) is O O O

adenosine-3',5'-cyclophosphate N N OH OH

present in all tissues of the organism. Its role is as supplier of the energy in all living AMP (adenosineATP is synthesized the energyOH diphosphate) cells. When monophosphate) is OH ADP (adenosine stored, when ATP is hydrolyzed the energy is evolved. NH2
ester bond OH OH OH HO-P- O-P-O- P-O-CH 2 O O O O N N N N-glycoside bond N OH OH

anhydride bonds

OH OH ATP (adenosine triphosphate)

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:
OH OH OH CH3 -CH-COOH + HO-P- O-P-O- P-O-CH 2 NH2 alanine O O O ATP O OH OH NH2 OH CH3 -CH-C-O- P-O-CH 2 NH2 O O O N N N N OH OH + HO-P-O-P-OH O OH OH aminoacyladenylate O N N N NH2 N

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.
O
4 NH 5 3 6 1 2

-O-CH 2 O O

N

O

U NH2

OH

N N O OH N

N A

HO-P-O-CH 2 O

NH2 N N O O OH O C A-C)

This (U-

O

is a structure of RNA fragment

HO-P-O-CH 2 O

HO-P-OO

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.
NH2 N N H A N N HN O N H T O CH3 N N H G N O NH NH2 O H2 N N N H C

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); 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 nonhydrolyzing 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. b) DNA molecules can control the synthesis of the proteins that are characteristic of each kind of

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:
O CH2 -O-C-R O CH -O-C-R' O CH2 -O-C-R'' acyl

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:
O C15 H31 -C OH palmitic acid C17 H35 -C O OH stearic acid

The chief unsaturated acids are oleic, linoleic and linolenic acids:
CH3 -(CH2 )7 -CH=CH-(CH2 )7 -COOH oleic acid C17 H33 -COOH linoleic acid C H31 -COOH 17

CH3 -(CH2 )4 -CH=CH-CH 2 -CH=CH-(CH2 )7 -COOH

CH3 -CH2 -CH=CH-CH 2 -CH=CH-CH 2 -CH=CH-(CH2 )7 -COOH

linolenic acid C17 H29 -COOH

Cis-trans isomerism is characteristic for usually exist in cis-form.

unsaturated

fatty acids, they

Saturated parts of their radicals exist in zigzag

conformations. To designate cis configuration and zigzag conformation we can use following formulas of fatty acids:
H3 C
10 13 12 10 9 9

COOH COOH

oleic acid linoleic acid

H3 C H3 C
16 15 13 12 10 9

COOH

linolenic acid

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:
CH2 -O-CO-C 17 H35 CH -O-CO-C 17 H35 CH2 -O-CO-C 17 H35 tristearin (simple gliceride) solid CH2 -O-CO-C 15 H31 CH -O-CO-C 17 H33 CH2 -O-CO-C 17 H31 α-palmito- -oleo-α'-linolein β (mixed glyceride) liquid

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:
CH2 -O-CO-(CH 2 )7 -CH=CH-(CH2 )7 -CH3 CH -O-CO-C 17 H35 CH2 -O-CO-C 17 H35 α -oleo-α ', -distearin β + I2 CH2 -O-CO-(CH 2 )7 -CH-CH-(CH2 )7 -CH3 CH -O-CO-C 17 H35 I CH2 -O-CO-C 17 H35 I

Fats are the esters; therefore the hydrolysis reaction is characteristic for them. Hydrolysis can occur both in acidic and alkaline medium:
CH2 -O-CO-C 17 H35 CH -O-CO-C 17 H35 CH2 -O-CO-C 17 H35 tristearin H2 O, H + CH2 -OH CH -OH + 3 C17 H35 -COOH stearic acid CH2 -OH glycerol

An acidic hydrolysis is a reversible process.
CH2 -O-CO-C 17 H33 CH -O-CO-C 17 H33 CH2 -O-CO-C 17 H33 triolein H2 O, NaOH CH2 -OH CH -OH + 3 C17 H35 -COONa sodium oleate CH2 -OH glycerol

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.

head

tail

-

-

- -

-

-

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:
CH2 -O-CO-C 17 H33 CH -O-CO-C 17 H33 CH2 -O-CO-C 17 H33 triolein H2 , Ni p, to CH2 -O-CO-C 17 H35 CH -O-CO-C 17 H35 CH2 -O-CO-C 17 H35 tristearin

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).
O CH2 -O-C-R O CH -O-C-R' O CH2 -O-P-OH OH phosphatidic acid

Phosphatidic acid can react with alcohols to form esters. In the reaction with aminoethanol (cholamine) so-called kephalin is formed:
CH2 -O-CO-R CH -O-CO-R' CH2 -O-P-OH OH phosphatidic acid O + HO-CH2 -CH2 NH2 cholamine CH2 -O-CO-R CH -O-CO-R' CH2 -O-P-O -CH2 -CH2 O CH2 -O-CO-R CH -O-CO-R' CH2 -O-P-O -CH 2 -CH2 O ONH3 dipolar ion
+

OH NH2 phosphatidyl cholamine (kephalin)

In the organism kephalin can exist as dipolar ion. In the reaction with choline phosphatidic acid gives phosphatidyl choline, or lecithin:
CH2 -O-CO-R CH -O-CO-R' CH2 -O-P-OH O OH phosphatidic acid + HO-CH2 -CH2
+

CH2 -O-CO-R CH -O-CO-R' CH2 -O-P-O -CH 2 -CH2 O O+

N(CH3 )3

N(CH3 )3

choline

phosphatidyl choline (lecithin)

Lecithin exists in form of the dipolar ion too. The hydrolysis reaction in acidic and alkaline medium is characteristic for phospholipids. For example:
CH2 -O-CO-C 17 H35 CH -O-CO-C 17 H33 CH2 -O-P-O -CH 2 -CH2 OH kephalin O NH2 CH2 -OH CH -OH CH2 -OH glycerol + C 17 H35 -COOH + C 17 H33 -COOH stearic acid oleic acid

H2 O, H+

+ H3 PO 4 + HO-CH 2 -CH2 NH2 cholamine

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.
Water

Non-polar molecules can
hydrophilic part lipophilic part

therefore be

dissolved in this mostly hydrocarbon wall and pass through it, but it is an

Water

effective and ions.

barrier

to

polar

molecules

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).

head CH2 =C-CH=CH2 CH3

tail

it is a brief formula of isoprene

This rule can be illustrated by some examples:
head tail head

limonene (citrene)

. .

tail

. .

CH2 OH

geraniol

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:
O CH2 OH [O] C H

geraniol

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:
H2 , Ni

limonene

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 in the
menthol OH rheumatism treatment and by

externally as an analgetic inhalation in congestion and of nasal

alleviation

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:
CH3 Cl CH3 -CH-CH3 OH m-cresol AlCl3 OH CH3 -CH-CH3 thymol CH3 [H] OH 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:
2 H2 O, H
+

OH

limonene

Bicyclic terpenes

terpene

Pinane and camphane (bornylane) are examples of bicyclic terpenes.

pinane

camphane

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:
Br2 , H2 O Br Br

α-pinene

KMnO4 , H2 O

HO HO + MnO 2 + KOH

Camphor is a derivative of camphane. It is synthesized from pinene into several steps:
CH3 COOH O-CO-CH 3 H2 O borneol OH [O] O

α-pinene

bornyl acetate

camphor

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:
O Br2 O Br camphor bromocamphor

Bromocamphor is used in medicine as a hart activity stimulator. As ketone camphor can take part in the nucleophilic addition and additionelimination reactions, for example it can react with hydroxylamine to form oxime:
O NH2 OH N-OH

camphor

camphor 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

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:
CH2 OH 2 vitamin A

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):
12 11 1 2 3 10 9 13 17

Rings are usually indicated as A, B, C and D.
16 15

C
8 7 14

D

A
5 4

B
6

Sterane

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):

H H H

H

It is cis-fusion (both hydrogens are situated at the same side)
cis-decalin

H

It is trans-fusion (hydrogen atoms are situated on the opposite sides).

H

H

H trans-decalin

H

H

H

H

It is 5-β-sterane (A/B-cis). β-Bonds come out of the plane of paper. We indicate these bonds by solid lines.

It is 5-α-sterane (A/B-trans). α-Bonds, going behind the plane of paper. We indicate these bonds by broken lines.

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:

21 12 11 1 2 3 4 19 10 5 6 9 8 7 14 18 13

22 20 23 17 16 15

24

26 25 27

Cholestane angular C-13 and

molecule methyl a side

has chain

two at

so-called C-17 (it

groups

at C-10 and

consists of eight carbon atoms).

Cholestane

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
1 2 3 10 5 4 6 9 8 7

alcohol hydroxyl group.

HO

Cholesterol

Ergosterol is the other example of sterols. It occurs in yeast.
21 12 11 1 2 3 19 10 5 4 6 9 8 7 14 18 13 17 22 20 23 16 15 24 26 25 27

Ergosterol

is

24-methyl-5,7,22-

cholestatriene-3-ol).

HO

Ergosterol

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):

UV

CH2

HO Ergosterol

HO Vitamin D2

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.
21 12 11 1 2 3 4 19 10 5 6 9 8 7 14 18 13 17 22 20 23 16 15 24

In bile acids molecules fused. A and B rings are cis-

Cholane

About twenty natural bile acids are known. One of them is cholic acid:

OH
12

21 18

22 20 23 17 16 15

24

COOH

Ch lic acid is cholanic cis-fused. acid. 3,7,12-trihydroxy-5-βA and B rings are

o
1 2 3 19

11 9 8 7 4 5 6

13 14

10

HO

OH

Cholic acid

The bile acids are combined as amides with either glycine or taurine:
OH COOH + H2 N-CH 2 -COOH glycine HO OH cholic acid HO OH glycocholic acid OH C O NH CH2 COOH

OH

COOH

OH

C

O NH CH2

+ H2 N-CH 2 -CH2 -SO 3 H HO OH cholic acid NaOH O NH CH2 CH2 HO OH SO3 Na hydrophilic part taurine HO OH taurocholic acid

CH2 SO3 H

OH

C

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:
11 1 2 3 4 19 10 5 6 9 8 7 14 20 12 18 13 17 16 15 21

The examples of corticoids are as follows:
O HO
1 2 3 19 10 5 4 6 9 8 7 14 11 12 18 13 20

pregnane

CH2 OH

21

C
16 15

Corticosterone antagonist. level in increases it.

is Insulin

11,21-dihydroxy-4It is insulin corticosterone decreases glucose

17

pregnene-3,20-dion. the blood,

O

corticosterone CH2 OH
21

O
11 1 2 3 19 10 5 4 6 9 8 7 14 12 18 13

20

C
16 15

17

Deoxycorticosterone pregnene-3,20-dione.

is It is

21-hydroxy-4a mineralo-

O

deoxycorticosterone

corticoid, it controls water and mineral balances.

salts

O O
1 2 3 19 10 5 9 8 7 6 14 11 12 18 13

20

CH2 OH OH
16 15 1 2 3 5

21

C

O HO
19 10 9 8 7 14 11 12 18 13

20

CH2 OH OH
16 15

21

C

17

17

O 6 4 cortisone hydrocortisone (17,21-dihydroxy-4-pregnene-3,11,20-trione) (11,17,21-trihydroxy-4-pregnene-3,20-dione)
4

O

O O
1 2 3 19 10 5 4 6 9 8 7 14 11 12 18 13

20

CH2 OH OH
16 15 1 2 3

21

C

O HO
19 10 5 4 6 9 8 7 14 11 12 18 13

20

CH2 OH OH
16 15

21

C

17

17

cortisone (17,21-dihydroxy-4-pregnene-3,11,20-trione)

O

hydrocortisone (11,17,21-trihydroxy-4-pregnene-3,20-dione)

O

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:
11 1 2 3 4 19 10 5 6 9 8 7 14 12 18 13 17 16 15

androstane

Androsterone was the first androgen isolated from the male urine:
O
17

Androsterone – (3-hydroxy-17-androstanone). OH

3

17

HO

The other male hormone is testosterone (17-hydroxy-4-androsten-3-one): testosterone propionate:
OH
17

3

O testosterone

Testosterone is used as a drug in form of the ester with propionic acid;
O-CO-CH 2 -CH3
17

3

+ CH3 -CH2 -C testosterone

O Cl
3

O

O 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:
1 2 3 4 10 5 6 9 12 11 8 7 18 13 14 17 16 15

estrane

Estrone was the first female hormone which was isolated from the urine of pregnant women. Then two other hormones were isolated – estradiol and estriol:
12 11 1 2 3 10 5 4 6 9 8 7 18 13 14

O
12 17 16 15 1 2 3 10 5 4 6 9 11 8 7

18 13 14

OH
17 16 15

HO

HO

estrone (3-hydroxy-1,3,5(10)-estratriene-17-one)

estradiol (1,3,5(10)-estratriene-3,17-diol) OH
17 14

12 11 1 2 3 10 5 4 6 9 8 7

18 13

OH
16 15

HO

estratriol (1,3,5(10)-estratriene-3,16,17-triol)

Estrone can be reduces in estradiol by catalytic hydrogenation:
O OH

[H] HO estrone [O] HO estradiol

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:

O H H OH HO H

O

Rings A/B The and C/D are lactone cis-fused. cycle is unsaturated

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
N N CH3

molecule consists of pyridine and pyrrolidine Nicotine is used as incecticide and usually

rings. It is a base, it can form salts with two molecules of the acid. manufactured from tobacco.
[O] COOH N nicotinic acid

nicotine

Nicotine is oxidized into nicotinic acid:
N CH3 N nicotine

CH=CH2 HO CH3 O N quinine CH3 O CH3 O N CH2 CH N

Quinine molecule salts

contains quinoline of

and quinoclidine rings.Quinine and its are used for the treatment It also possess malaria. analgetic,

antipyretic, cardiac depressant properties. Papaverine is isoquinoline obtained from synthetically. Its derivative. opium or It is prepared in

hydrochloride is used as a example

OCH3 smooth muscle relaxant, for papaverine OCH3

hypertension treatment..

Synthetic analogous of papaverine that is used as smooth muscle relaxant is no-spa:
C2 H5 O C2 H5 O H OC 2 H5 OC 2 H5 N C H

no-spa

Alkaloid morphine can be considered as isoquinoline derivative also:
HO

Morphine molecule contains two hydroxyl groups; one of them is alcohol, the other – phenol hydroxyl.
N-CH 3

O

As phenol morphine reacts with FeCl3. and acid properties (due to

Morphine exhibits both basic properties (due to nitrogen atom)

HO

morphine

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:
CH3 O

O N-CH 3 HO codeine

Diacetyl derivative of morphine is heroine. Alkaloid reserpine is indol derivative:
N

CH3 O

N H

CH3 OOC

O-CO CH3 O

OCH3 OCH3 OCH3

reserpine

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.

O CH3 N O N

H N N

O HN O N N N

CH3 CH3 N O

O N N N

CH3

CH3 theophilline

CH3 theobromine

CH3 caffeine

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