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UNIT I Benzene and its derivatives PDF Download

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    Dr.Mrityunjay Banerjee, IPT, Salipur                                      B PHARM 3rd SEMESTER

                                          BP301T
                            PHARMACEUTICAL ORGANIC CHEMISTRY –II
                                          UNIT I

    UNIT I     Benzene and its derivatives                                                  10 Hours

       A.      Analytical, synthetic and other evidences in the derivation of structure of benzene, Orbital
               picture, resonance in benzene, aromatic characters, Huckel’s rule
       B.      Reactions of benzene - nitration, sulphonation, halogenationreactivity, Friedelcrafts
               alkylation- reactivity, limitations, Friedelcrafts acylation.
       C.      Substituents, effect of substituents on reactivity and orientation of mono substituted benzene
               compounds towards electrophilic substitution reaction
       D.      Structure and uses of DDT, Saccharin, BHC and Chloramine

    Benzene and its Derivatives

    Chemists have found it useful to divide all organic compounds into two broad classes: aliphatic
    compounds and aromatic compounds. The original meanings of the words "aliphatic" (fatty) and
    "aromatic" (fragrant/ pleasant smell).
    Aromatic compounds are benzene and compounds that resemble benzene in chemical behavior.
    Aromatic properties are those properties of benzene that distinguish it from aliphatic
    hydrocarbons.

  Benzene:
     A liquid that smells like gasoline
     Boils at 80°C & Freezes at 5.5°C
      It was formerly used to decaffeinate coffee and component of many consumer products,
       such as paint strippers, rubber cements, and home dry-cleaning spot removers.
      A precursor in the production of plastics (such as Styrofoam and nylon), drugs,
       detergents, synthetic rubber, pesticides, and dyes.
      It is used as a solvent in cleaning and maintaining printing equipment and for adhesives
       such as those used to attach soles to shoes.
      Benzene is a natural constituent of petroleum products, but because it is a known
       carcinogen, its use as an additive in gasoline is now limited.
      In 1970s it was associated with leukemia deaths.


    Structure of benzene
    History, Analytical, Synthetic and other evidences in the derivation of structure of benzene:

       (a) History of benzene:

          Isolated in 1825 by Michael Faraday who determined C:H ratio to be 1:1.
           Synthesized in 1834 by Eilhard Mitscherlich who determined molecular formula to be
            C6H6. He named it benzin later known as benzene.
(b) Benzene has the molecular formula C6H6. The question was: how are these atoms arranged?
The molecular formula of benzene has been found from analytical data, to be C6H6. Relatively higher
proportion of carbon and addition of chlorine to benzene molecule indicate it to be an unsaturated
compound. Depending on the various facts available to scientists from time to time, many structures for
benzene had been proposed. Some are described below.
Open Chain Structure
Based upon observable facts given above and the tetravalency of carbon, the following open chain structures
were proposed for benzene.




Drawbacks of open chain structure: The open chain structure for benzene was rejected due to the
following reasons:
 Addition reactions usually given by alkenes and alkynes are not given by benzene.
 Benzene forms only one kind of mono-substituted product.
 An open chain structure however, can form more than one kind of monosubstituted product as shown
below:



 The open chain compounds do, not give reactions such as FriedelCraft reaction, nitration, sulphonation.
 On reduction with hydrogen in the presence of Ni at 200°C, actually a cyclic compound cyclohexane is
obtained.


In 1858, August Kekule (of the University of Bonn) had proposed that carbon atoms can join to one another
to form chains. Then, in 1865, he offered an answer to the question of benzene: these carbon chains can.
Sometimes be closed, to form rings.

Kekule's structure of benzene was one that we would represent today as




       All the carbon-to-carbon bonds in benzene are equivalent

       The molecule is unusually stable

       Chemists often represent benzene as a hexagon with an inscribed circle




       The inner circle indicates that the valence electrons are shared equally by all six carbon atoms (that is,
        the electrons are delocalized, or spread out, over all the carbon atoms).

       Each corner of the hexagon is occupied by one carbon atom, and each carbon atom has one hydrogen
        atom attached to it.

       Any other atom or groups of atoms substituted for a hydrogen atom must be shown bonded to a
        particular corner of the hexagon.

       The six bond lengths are identical and they are one-and-a half bonds and their length, 1.39 A or 139
        picometer (pm), is intermediate between the lengths of single and double bonds (is shorter than
        typical single-bond lengths, yet longer than typical double-bond lengths).




An orbital model for the benzene structure
Building the orbital model

Benzene is built from hydrogen atoms (1s1) and carbon atoms (1s22s22px12py1).
Each carbon atom has to join to three other atoms (one hydrogen and two carbons) and doesn't have enough
unpaired electrons to form the required number of bonds, so it needs to promote one of the 2s2 pair into the
empty 2pz orbital.

       Promotion of an electron



There is only a small energy gap between the 2s and 2p orbitals, and an electron is promoted from the 2s to
the empty 2p to give 4 unpaired electrons. The extra energy released when these electrons are used for
bonding more than compensates for the initial input. The carbon atom is now said to be in an excited state.
Hybridisation
Because each carbon is only joining to three other atoms, when the carbon atoms hybridise their outer
orbitals before forming bonds, they only need to hybridise three of the orbitals rather than all four. They use
the 2s electron and two of the 2p electrons, but leave the other 2p electron unchanged.




       The new orbitals formed are called sp2 hybrids, because they are made by an s orbital and two p
orbitals reorganizing themselves.
       The three sp2 hybrid orbitals arrange themselves as far apart as possible which is at 120° to each
other in a plane. The remaining p orbital is at right angles to them.
       Each carbon atom now looks like the diagram on the right. This is all exactly the same as happens in
ethene.
       The difference in benzene is that each carbon atom is joined to two other similar carbon atoms
instead of just one. Each carbon atom uses the sp2 hybrids to form sigma bonds with two other carbons and
one hydrogen atom.
      The next diagram shows the sigma bonds formed, but for the moment leaves the p orbitals alone.




Since sigma bond results from the overlap of above said planar orbital, all H and C atoms are in the same
plane and their generate a hexagonal ring of C atoms.




Each C atom in benzene also has an unhybrid 2pz orbital containing one electron. These 2pz orbital are
perpendicular to the plane of sigma bonds.




Actually these 2pz orbital produce a π (pi) molecular orbital containing six electrons. One half of this π (pi)
molecular orbital lies above the plane of hexagonal ring and remaining half below the ring like a sandwich.




The overlap of these 2pz orbital results in the formation of a fully delocalized π (pi) bond, which extends all
over the six C atoms of benzene nucleus. The molecular orbital approach clearly indicates that these six
electrons could be found anywhere in highly delocalized manner. As a result of delocalization, a stronger π
(pi) bond and a more stable benzene molecule is obtained which undergo substitution reactions more
frequently than addition reactions.
       Benzene is a flat molecule, with every carbon and hydrogen lying in the same plane these
        bonds are designated as a sigma (σ) bonds.
    
       Each sp2 hybridized C in the ring has an unhybridized p orbital perpendicular to the ring
       which overlaps around the ring.
       The six pi (π) electrons are delocalized over the six carbons.
        


(c) Benzene yields only one monosubstitution product, C6H5Y. Only one bromobenzene,
C6H5Br, is obtained when one hydrogen atom is replaced by bromine; similarly, only one
chlorobenzene, C6H5C1, or one nitrobenzene, C6H5NO2, etc., has ever been made. This fact
places a severe limitation on the structure of benzene: each hydrogen must be exactly equivalent
to every other hydrogen, since the replacement of any one of them yields the same product.




(d) Benzene yields three isomeric disubstitution products, C6H4Y2 or C6H4YZ. e.g. like only
three isomeric dibromobenzenes, C6H4Br2 , three chloronitrobenzenes, C6H4ClNO2, etc. This fact
further limits our choice of a structure to Kekule's structure of benzene compare to any other
structures with the molecular formula C6H6.




The relative positions of two substituents on a benzene ring can be indicated either by numbers
or by the prefixes ortho, meta, and para. Adjacent substituents are called ortho, substituents
separated by one carbon are called meta, and substituents located opposite one another are
designated para. Often, only their abbreviations (o, m, p) are used in naming compounds.

However, that two 1,2-dibromo isomers differing in the positions of bromine relative to the
double bonds, should be possible:




On the other hand, it is believed by some that Kekule had unthinkingly anticipated our present
concept of delocalized electrons, and drew two pictures (as shown above). The currently
accepted structure did not arise from the discovery of new facts about benzene, but is the result
of an extension or modification of the structural theory; this extension is the concept of
resonance.



                                                     OR



Resonance: structures that differ only in the arrangement of electrons. Benzene is a hybrid of I
and II. Since; I and II are exactly equivalent, and hence of exactly the same stability, they make
equal contributions to the hybrid.

Stability:

The most striking evidence to unusual stability of benzene ring is found in the chemical reactions
of benzene & the heat released in a hydrogenation reaction of one mole of an unsaturated
compound.

 Benzene undergoes substitution rather than addition.

       Kekule's structure of benzene is one that we would call "cyclohexatriene." We would
        expect this cyclohexatriene, like the very similar compounds, cyclohexadiene and
        cyclohexene, to undergo readily the addition reactions characteristic of the alkene
        structure.

       Example: cyclohexene an alkene undergoes rapid addition reaction, under same
        conditions were benzene reacts either not at all or very slowly and this exhibited a high
        degree of unusual chemical stability of benzene compared with known alkenes and
        cycloalkenes (aliphatic compounds).




            Example: In addition reaction an alkene reacts with an electrophile, thereby forming a
             carbocation intermediate. In the second step of an electrophilic addition reaction, the
             carbocation reacts with a nucleophile to form an addition product.
If the carbocation intermediate formed from the reaction of benzene with an electrophile were to
react similarly with a nucleophile (depicted as event b in Figure below), the addition product
would not be aromatic. If, however, the carbocation loses a proton from the site of electrophilic
attack (depicted as event a in Figure below), the aromaticity of the benzene ring is restored.
Because the aromatic product is much more stable than the nonaromatic addition product, the
overall reaction is an electrophilic substitution reaction rather than an electrophilic addition
reaction. In the substitution reaction, an electrophile substitutes for one of the hydrogens attached
to the benzene ring.




In place of addition reactions, benzene readily undergoes a new set of reactions, all involving
substitution. The most important are Halogenation, Nitration, Sulfonation, Friedel–Crafts
acylation & Friedel–Crafts alkylation.
In an electrophilic aromatic substitution reaction, an electrophile is put on a ring carbon, and the
H+ comes off the same ring carbon.
    Heat of hydrogenation (resonance energy) and combustion.

       The heat released in a hydrogenation reaction of one mole of an unsaturated (double
       bonded) compound is called the heat of hydrogenation.
      A quantitative data which show how much more stable is benzene.
       Cyclohexene has a heat of hydrogenation of 28.6 kcal and cyclohexadiene has one about
        twice that (55.4 kcal.)
       We expected cyclohexatriene (i.e. in imagine that benzene contains three double bonds in
        it) to have a heat of hydrogenation about three times as large as cyclohexene, that is,
        about 85.8 kcal. Actually the value for benzene (49.8 kcal) is 36 kcal less than this
        expected amount.

       The fact that benzene evolves 36 kcal less energy than predicted can only mean that
        benzene contains 36 kcal less energy than predicted; in other words, benzene is more
        stable by 36 kcal than we would have expected cyclohexatriene to be.
                              Aromatic character: The Huckel 4n + 2 rule

    In 1931, German chemist and physicist Erich Hückel proposed a theory to help determine if a
    planar ring molecule would have aromatic properties. His rule states that if a cyclic, planar
    molecule has 4n+2 π (Pi) electrons, it is considered aromatic. This rule would come to be known
    as Hückel's Rule.

    Criteria for Aromaticity & Anti-Aromaticity:

               Aromatic                         Anti-aromatic                    Non-aromatic
    The molecule is cyclic (a ring      The molecule is cyclic (a ring
    of atoms)                           of atoms)
    The molecule is planar or flat      The molecule is planar or flat
    (all atoms in the molecule lie in   (all atoms in the molecule lie
    the same plane)                     in the same plane)               Fails any one of the criteria on
    The molecule is                     The         molecule          is             the left
    fully conjugated (p orbitals at     fully conjugated (p orbitals at                OR
    every atom in the ring)             every atom in the ring)                  everything else
    The molecule has 4n+2 π             The molecule has 4n π
    electrons (n=0 or any positive      Electrons
    integer)
    Unusually stable                    Unusually stable


                                                Cyclobutadiene
                   Benzene
                                                                                Cyclooctatetraene
                                                                 ◦
    Resonance energy (heat of           Only stable below -100 C
    hydrogenation energy) 36
    kcal/mol


          According to Hückel's Molecular Orbital Theory, a compound is particularly stable if all
          of its bonding molecular orbitals are filled with paired electrons.
          With aromatic compounds, 2 electrons fill the lowest energy molecular orbital, and 4
           electrons fill each subsequent energy level (the number of subsequent energy levels is
          denoted by n) leaving all bonding orbitals filled and no anti-bonding orbitals occupied.
         This gives a total of 4n+2 π electrons.
          In benzene, each double bond (π bond) always contributes 2 π electrons. Benzene has 3
          double bonds, so it has 6 π electrons.
          Its first 2 π electrons fill the lowest energy orbital, and 4 π electrons remaining fill in the
          orbitals of the succeeding energy level.
          Notice how all of its bonding orbitals are filled, but none of the anti-bonding orbitals
           have any electrons.
       To apply the 4n+2 rule, first count the number of π electrons in the molecule. Then, set
        this number equal to 4n+2 and solve for n. If is 0 or any positive integer (1, 2, 3,...), the
        rule has been met. For example, benzene has six π electrons:
                                                 4n+2=6
                                                  4n=4
                                                   n=1
        For benzene, we find that n=1, which is a positive integer, so the rule is met. Benzene is
        aromatic compound.
        Aromatic Ions
       Hückel's Rule also applies to ions especially aromatic ions. As long as a compound has

        4n+2 π electrons, it does not matter if the molecule is neutral or has a charge.

      For example, cyclopentadienyl anion is an aromatic ion.
       Carbons 2-5 are sp2 hybridized because they have 3 attached atoms and have no lone
       electron pairs.
       If an atom has 1 or more lone pairs and is attached to an sp2 hybridized atom, then that
       atom is sp2 hybridized also.
       Therefore, carbon 1 also sp2 hybridized, it has a p orbital. Cyclopentadienyl anion has 6 π
        electrons and fulfills the 4n+2 rule.
Heterocyclic Aromatic Compounds

       Heterocyclic compounds contain 1 or more different atoms other than carbon in the ring.
       A common example is furan, which contains an oxygen atom.
      All carbons in furan are sp2 hybridized.
       The oxygen has at least 1 lone electron pair and is attached to an sp2 hybridized atom, so
       it is sp2 hybridized as well.
       Notice how oxygen has 2 lone pairs of electrons. How many of those electrons are π
       electrons?
       A sp2 hybridized atom only has 1 p orbital, which can only hold 2 electrons, so we know
        that 1 electron pair is in the p orbital, while the other pair is in an sp2 orbital. So, only 1 of
       oxygen's 2 lone electron pairs are π electrons.
       So, Furan has 6 π electrons and fulfills the 4n+2 rule




Working example I: Using the criteria for aromaticity, determine if the following molecules
are aromatic:
Working example II: Using the criteria for aromaticity, determine if the following molecules
are aromatic:




Reactions of Benzene:
Benzene readily undergoes a new set of reactions, all involving substitution i.e. Electrophilic
Aromatic Substitution Reactions. It involves the reaction of an electrophile with an aromatic
compound, were electrophile substitutes for a hydrogen of an aromatic compound.

General Mechanism for Electrophilic Aromatic Substitution Reactions:

       Similar to alkenes, benzene (aromatics) has a cloud of π electrons available to attack
       electrophiles (the aromatic ring is nucleophilic)
       The resulting carbocation is stabilized by resonance and is called: Sigma complex
       These reactions are greatly facilitated by addition of Lewis acid catalyst.
      Key bonds formed C-Y and key bonds broken C-H
       Electron donating substituents increase the rate of substitution reaction by activating the
       benzene ring to electrophilic attack.
       Electron withdrawing substituents decrease the rate of substation reaction by deactivating
        the benzene ring to electrophilic attack.




The general mechanism can be applied to the following reactions and the only difference will be
the nature of the electrophile, and how it is formed.
1. Halogenation: A bromine (Br), a chlorine (Cl), or an iodine (I) substitutes for a hydrogen
(Lewis acid: AlCl3/FeCl3/AlBr3/FeBr3, etc.)
2. Nitration: A nitro (NO2) group substitutes for a hydrogen (acid: H2SO4).
3. Sulfonation: A sulfonic acid (SO3H) group substitutes for a hydrogen (acid: H2SO4).
4. Friedel–Crafts acylation: An acyl (RC=O) group substitutes for a hydrogen (Lewis acid:
AlCl3/FeCl3)
5. Friedel–Crafts alkylation: an alkyl (R) group substitutes for a hydrogen (Lewis acid:
AlCl3/FeCl3)
Halogenation of Benzene: The bromination or chlorination of benzene requires a Lewis acid
such as ferric bromide or ferric chloride. Recall that a Lewis acid is a compound that accepts a
share in a pair of electrons.

Bromination: Electrophile Br+




Chlorination: Electrophile Cl+
Iodination: For iodination, iodine is simply oxidized with nitric acid (HNO3) to liberate the
I+, which is then used as the electrophile.

                                H+ + HNO3 + ½ I2 →I+ + NO2 + H2O

                                                OR




Nitration of Benzene: Nitration of benzene with nitric acid requires sulfuric acid as a catalyst.

                                Electrophile:
Sulfonation of Benzene: Fuming sulfuric acid (a solution of in sulfuric acid) or concentrated
sulfuric acid is used to sulfonate aromatic rings. Electrophile: HSO3+




Sulfonation of benzene is a reversible reaction. If benzenesulfonic acid is heated in dilute
acid, the reaction proceeds in the reverse direction.
Friedel–Crafts Acylation: Friedel–Crafts acylation places an acyl group on a benzene ring.




Either an acyl halide or an acid anhydride can be used for Friedel–Crafts acylation.




An acylium ion is the electrophile required for a Friedel–Crafts acylation reaction. This ion is
formed by the reaction of an acyl chloride or an acid anhydride with AlCl3 a Lewis acid.




Example:

The synthesis of benzaldehyde from benzene and formyl chloride (the acyl halide required
for the reaction), which is unstable and obtained by means of the Gatterman–Koch
formylation reaction. This reaction uses a high-pressure mixture of carbon monoxide and HCl
to generate formyl chloride, along with an aluminum chloride–cuprous chloride catalyst to
carry out the acylation reaction.
Example: Preparation of Acetophenone from alkyl halide and acid anhydride.




LIMITATIONS of Friedel-Crafts acylation:

   1. Acylation can only be used to give ketones. This is because HCOCl decomposes to CO
      and HCl under the reaction conditions.
   2. Deactivated benzenes are not reactive to Friedel-Crafts conditions, the benzene needs to
      be as or more reactive than a mono-halobenzene.
   3. The Lewis acid catalyst AlCl3 often complexes to aryl amines making them very
      unreactive.
   4. Amines and alcohols can give competing N or O acylations rather than the require ring
      acylation


Friedel–Crafts alkylation: Friedel–Crafts alkylation places an alkyl group on a benzene ring.
       A carbocation is formed from the reaction of an alkyl halide with AlCl3, Alkyl fluorides,
        alkyl chlorides, alkyl bromides, and alkyl iodides can all be used. Vinyl halides and aryl
        halides cannot be used because their carbocations are too unstable to be formed.




       An alkyl-substituted benzene is more reactive than benzene. Therefore, to prevent further
        alkylation of the alkyl-substituted benzene, a large excess of benzene is used in Friedel–
       Crafts alkylation reactions.
      A carbocation will rearrange if rearrangement leads to a more stable carbocation.
       When the carbocation can rearrange in a Friedel–Crafts alkylation reaction, the major
        product will be the product with the rearranged alkyl group on the benzene ring.

Example: less stable primary carbocation to stable secondary carbocation
Example: less stable primary carbocation to stable tertiary carbocation




       We have just seen that Friedel-Crafts alkylation rarely provides a straight chain alkyl
       function on the aromatic (due to rearrangement)
       To avoid this problem, one can use either of the Clemmensen reduction of acyl benzene
       to form the desired alkylated aromatic.
       The Clemmensen reduction is a series of 2 reaction, (1) Friedel-Crafts Acylation, (2)
        decarbonylation of the resulting ketone.

Example 1:




Example 2:




Any other carbocation source can be used in the presence of an aromatic ring to give
Friedel Crafts substitution products.
Example: Friedel–Crafts alkylation
Example: When secondary and tertiary alkyl halides are used, the electrophile is the
corresponding carbocations.




There are 3 important LIMITATIONS to the Friedel-Crafts Alkylation:

1. Works only with benzene and activated derivatives (no reaction when deactivators are
present).

2. Rearrangements of carbocations or carbocation like species is common.

3. Vinyl or aryl halides do not react (their intermediate carbocations are too unstable).

4. The Lewis acid catalyst AlCl3 often complexes to aryl amines making them very unreactive.

5. Poly-alkylation is often the result since the alkylation product is more reactive than the
original compound (Note: This can usually be controlled with an excess of the benzene). For
example:
    Effect of Substituents on Reactivity and Orientation of Mono Substituted
        Benzene Compounds towards Electrophilic Substitution Reaction

       The reactions of substituted benzenes are similar to those of benzene, but can take place
       faster or slower than benzene depending on the substitution pattern.
       The substituent can either increase or decrease the rate of the reaction depending on its
        nature.
                                                                               D
                             A
                                    >                           >



                     Most                   reactivity                  Least

       Activating (A) if the benzene ring it is attached to is more reactive than benzene i.e. one
       that provides more electrons (electron donating groups) to the aromatic system
       Deactivating (D) if the ring it is attached to is less reactive than benzene i.e. one that pulls
       electrons away from the aromatic system.
      Substituent(s) direct the incoming electrophile to a specific location.
       As shown in Table 1, nearly all groups fall into one of two glasses: activating and ortho,
        para directing, or deactivating and meta-directing. The halogens are in a class by
        themselves, being deactivating but ortho, para-directing.

The Effect of Substituents on Reactivity
There are two ways substituents can donate electrons into a benzene ring: inductive electron
donation and electron donation by resonance. There are also two ways substituents can withdraw
electrons from a benzene ring: inductive electron withdrawal and electron withdrawal by
resonance.

Inductive Electron Donation and Withdrawal
     It is a permanent effect
     It operates on sigma bonded electrons
     Electron shift take place towards more electro negative atom
If a substituent that is bonded to a benzene ring is less electron withdrawing than a hydrogen, the
electrons in the sigma bond that attaches the substituent to the benzene ring will move toward the
ring more readily. Such a substituent donates electrons inductively compared with a hydrogen.
If a substituent is more electron withdrawing than a hydrogen, it will withdraw the sigma
electrons away from the benzene ring more strongly than will a hydrogen. Withdrawal of
electrons through a sigma bond is called inductive electron withdrawal. The NH3+ group is a
substituent that withdraws electrons inductively because it is more electronegative than a
hydrogen.

Resonance Electron Donation and Withdrawal

If a substituent has a lone pair on the atom that is directly attached to the benzene ring, the lone
pair can be delocalized into the ring; these substituents are said to donate electrons by resonance.
Substituents such as OH, OR, and Cl donate electrons by resonance.




If a substituent is attached to the benzene ring by an atom that is doubly or triply bonded to a
more electronegative atom, the pi electrons of the ring can be delocalized onto the substituent;
these substituents are said to withdraw electrons by resonance. Substituents such as C=O, C≡N,
O=N-O (NO2) and withdraw electrons by resonance.
Note: The moderately activating substituents also donate electrons into the ring by resonance
and withdraw electrons from the ring inductively. These substituents are less effective at
donating electrons into the ring by resonance because, unlike the strongly activating substituents
that donate electrons by resonance only into the ring, the moderately activating substituents can
donate electrons by resonance in two competing directions: into the ring and away from the ring.




The moderately deactivating substituents all have carbonyl groups directly attached to the
benzene ring. Carbonyl groups withdraw electrons both inductively and by resonance.




The strongly deactivating substituents are powerful electron withdrawers. Except for the
ammonium ions (+NH3, +NH2R, +NHR2 and +NR3), these substituents withdraw electrons both
inductively and by resonance. The ammonium ions have no resonance effect, but the positive
charge on the nitrogen atom causes them to strongly withdraw electrons inductively.
The Effect of Substituents on Orientation

When a substituted benzene undergoes an electrophilic substitution reaction, The substituent
already attached to the benzene ring determines the location of the new substituent.

All activating substituents and the weakly deactivating halogens are ortho–para directors, and all
substituents that are more deactivating than the halogens are meta directors. Thus, the
substituents can be divided into three groups:




The above classification is based on the stability of the carbocation intermediate that is formed in
the rate-determining step.
Example:

If a substituent donates electrons inductively like a methyl group, for example in Toulene, the
substituent is attached directly to the positively charged carbon, which the substituent can
stabilize by inductive electron donation. These relatively stable resonance contributors are
obtained only when the incoming group is directed to an ortho or para position.
Example:

If a substituent donates electrons by resonance, like a methoxy group, for example in Anisole,
the carbocations formed by putting the incoming electrophile on the ortho and para positions
have a fourth resonance contributor. This is an especially stable resonance contributor because it
is the only one whose atoms (except for hydrogen) all have complete octets. Therefore, all
substituents that donate electrons by resonance are ortho–para directors.
Example:

Substituents with a positive charge or a partial positive charge on the atom attached to the
benzene ring, withdraw electrons inductively from the benzene ring, and most withdraw
electrons by resonance as well. For all such substituents, the indicated resonance contributors in
Figure below are the least stable because they have a positive charge on each of two adjacent
atoms, so the most stable carbocation is formed when the incoming electrophile is directed to the
meta position. Thus, all substituents that withdraw electrons (except for the halogens, which are
ortho–para directors because they donate electrons by resonance) are meta directors.
Effect of Multiple Substituents on Electrophilic Aromatic Substitution
When 2 substituents are already on the ring

      the stronger activator usually predominates.
       Steric factors will also play a role in determining the structure of the new product.




                Structure and uses of DDT, Saccharin, BHC and Chloramine

                             Dichlorodiphenyltrichloroethane ( DDT)

Dichlorodiphenyltrichloroethane ( DDT) is a colorless, tasteless, and almost odorless crystalline
organochlorine known for its insecticidal properties and environmental impacts.

Name: Dichlorodiphenyltrichloroethane
 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane
Molecular formula : C14H9Cl5
Molecular weight : 354.48 g·/mol.


Structure :
                                                       Cl




                                                 Cl
                                            Cl                   Cl
                                                 Cl    H

                                                      DDT
Preparation :

DDT, prepared by the reaction of chloral with chlorobenzene in the presence of sulfuric acid.
Chlorobenzene reacts with chloral (CCl3CHO) in presence of concentrated H2SO4 to give
Dichlorodiphenyltrichloroethane (D.D.T.).

                                                                        Cl


          Cl   H       H               Cl
 Cl                +                        H2SO 4                Cl
          Cl   O
                                                            Cl                     Cl
                       H               Cl
                                                                  Cl    H
  Chloral                  Chlorobenzene                               DDT




          DDT is used as an insecticide on crops, particularly for mosquitoes,Flies and Crop Pests.
          DDT was initially used by the military in WW II to control malaria, typhus, body lice,
           and bubonic plague.


                                  SACCHARIN (benzoic sulfimide)


saccharin (benzoic sulfimide) is an artificial sweetener with effectively no food energy.. Both
salts are highly water-soluble: 0.67 g/ml in water at room temperature.Saccharin, or 2H-1λ6,2-
benzothiazol-1,1,3-trione, is a molecule that has found extensive use as an artificial sweetener. It
possesses the following structure:

Name: 2H-1λ6,2-benzothiazol-1,1,3-trione
Molecular formula : C7H5NO3S
Molecular weight : 183.18 g·mol−1
Appearance : White crystalline solid.
Density : 0.828 g/cm3
Structure: Saccharin is Orthobenzenesulfonamide
                                                           O


                                                               NH
                                                           S
                                                               O
                                              Saccarin O


Preparation :

Saccharin can be produced in various ways. The original route by Remsen and Fahlberg starts
with toluene; another route begins with o-chlorotoluene. Sulfonation of toluene by chlorosulfonic
acid gives the ortho and para substituted sulfonyl chlorides. The ortho isomer is separated and
converted to the sulfonamide with ammonia. Oxidation of the methyl substituent gives the
carboxylic acid, which cyclicizes to give saccharin free acid.

    CH3

                                  CH3                              CH3
          ClSO 3H                           NH3
                                      Cl                               NH2
                                  S                                S         O-Toluenesulfonamide
Tolune                                 O                                O
                              O                                O
                                                  KMNO 4
                    O-Toluenesulfonyl Chloride
                                                                   O
                      O

                                                                         OH
                                           -H2O
                                                                        NH2
                        NH
                                           Heat                     S
                    S                                                    O
                                                               O
                          O
                  O
            Saccharin


Uses:
Saccharin is an artificial, or nonnutritive, sweetener that is used in the production of various
foods and pharmaceutical products including: Baked goods. Jams. It is about 300–400 times as
sweet as sucrose but has a bitter or metallic aftertaste, especially at high concentrations.
Saccharin is used to sweeten products such as drinks, candies, cookies, and medicines. In its acid
form, saccharin is not water-soluble. The form used as an artificial sweetener is usually
its sodium salt. The calcium salt is also sometimes used, especially by people restricting
their dietary sodium intake.
                                Benzene hexachloride (BHC)

Benzene hexachloride (BHC), any of several stereoisomers of 1, 2, 3, 4, 5 , 6-
hexachlorocyclohexane formed by the light-induced addition of chlorine to benzene. One of
these isomers is an insecticide called lindane, or Gammexane. Lindane, also known as gamma-
hexachlorocyclohexane (γ-HCH),                      gammaxene,                   Gammallin and
sometimes incorrectly called benzene hexachloride (BHC), is an organochlorine chemical and an
isomer of hexachlorocyclohexane that has been used both as an agricultural insecticide and as
a pharmaceutical treatment for lice and scabies.
Lindane is a neurotoxin that interferes with GABA neurotransmitter function by interacting with
the GABAA receptor-chloride channel complex at the picrotoxin binding site. In humans,
lindane affects the nervous system, liver, and kidneys, and may well be a carcinogen. A specific
exemption to that ban allows it to continue to be used as a second-line pharmaceutical treatment
for lice and scabies.

Molecular Formula : C6H6Cl6
Name : Benzene hexachloride.
Molecular Weight/ Molar Mass: 290.814 g/mol.
Density : 1.89 at 66°F.
Melting Point: 113°C.
Boiling Point: 323°C.

Preparation

   1. Chlorine combines with benzene, in the presence of sunlight and in the absence of
      oxygen as well as substitution catalysts, to form hexachlorocyclohexane.
   2. Lindane can be prepared from chlorine and benzene by photochlorination. The product
      obtained i.e benzene hexachloride comprises of isomers from which only the gamma-
      isomer is wanted. Gamma-isomer is got by treating the reaction mixture with acetic acid
      or methanol in which only the alpha and beta isomers dissolve easily.




Lindane is prepared by treating chlorine with benzene in the presence of sunlight and in the
absence of oxygen as well as substitution catalysts.Lindane is the gamma isomer
of hexachlorocyclohexane ("γ-HCH"). In addition to the issue of lindane pollution, some
concerns are related to the other isomers of HCH, namely alpha-HCH and beta-HCH, which are
notably more toxic than lindane, lack its insecticidal properties, and are byproducts of lindane
production.
BHC. It is prepared by chlorination of benzene in presence of sunlight.The mixture of
stereoisomeric hexachlorides is an active component in BHC is γ isomer, called gammaxene or
lindane.

Uses: BHC is an important agricultural pesticide mainly used for exterminating white ants, leaf
hopper, termite etc.

      Benzene hexachloride is used as an insecticide on crops, in forestry, for seed treatment.
      It is used in the treatment of head and body lice.
      It is used in pharmaceuticals.
      It is used to treat scabies.
      It is used in shampoo.


                                          Chloramine

Monochloramine, often called simply chloramine, is the chemical compound with the formula
NH2Cl. Together with dichloramine (NHCl2) and nitrogen trichloride (NCl3), it is one of the
three chloramines of ammonia.

Molecular formula : NH2Cl
Molecular weight : 51.476 g mol−1
Appearance : Colorless gas.
Melting point −66 °C (−87 °F; 207 K).


    Preparation :
    In dilute aqueous solution, chloramine is prepared by the reaction of ammonia with sodium
    hypochlorite:
       NH3 + NaOCl → NH2Cl + NaOH



    Gaseous chloramine can be obtained from the reaction of gaseous ammonia
    with chlorine gas (diluted with nitrogen gas):
       2 NH3 + Cl2 ⇌ NH2Cl + NH4Cl
    Pure chloramine can be prepared by passing fluoroamine through calcium chloride:
       2 NH2F + CaCl2 → 2 NH2Cl + CaF2


Use: Chloramine is used as a disinfectant for water. It is less aggressive than chlorine and more
stable against light than hypochlorites. Chloramine is commonly used in low concentrations as a
secondary disinfectant in municipal water distribution systems as an alternative to chlorination.
This application is increasing. Chlorine (referred to in water treatment as free chlorine) is being
displaced by chloramine—to be specific monochloramine—which is much more stable and does
not dissipate as rapidly as free chlorine. Chloramine also has a much lower, but still active,
tendency than free chlorine to convert organic materials into chlorocarbons such
as chloroform and carbon tetrachloride. Such compounds have been identified as carcinogens.
Books:
1. Organic Chemistry by Morrison and Boyd
2. Organic Chemistry by I.L. Finar , Volume-I
3. Textbook of Organic Chemistry by B.S. Bahl & Arun Bahl.
4. www. google.com
Subject:
Pharmaceutical organic chemistry 2
Semester:
3rd Sem
Cource:
Bachelor of Pharmacy

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