BP301T Poc Unit I
BP301T Poc Unit I
BP301T Poc Unit I
BP301T
PHARMACEUTICAL ORGANIC CHEMISTRY –II
UNIT I
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
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:
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.
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).
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.
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.
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.
Cyclobutadiene
Benzene
Cyclooctatetraene
◦
Resonance energy (heat of Only stable below -100 C
hydrogenation energy) 36
kcal/mol
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.
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.
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+
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.
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
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.
1. Works only with benzene and activated derivatives (no reaction when deactivators are
present).
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
> >
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.
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
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
Dichlorodiphenyltrichloroethane ( DDT)
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) 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)
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.
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.
Preparation :
In dilute aqueous solution, chloramine is prepared by the reaction of ammonia with sodium
hypochlorite:
NH3 + NaOCl → NH2Cl + NaOH
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