he complex between the acid chloride (Or aahydride) and the Lewis acid.

R-C-Cl+ AlCl R-C

O
+0
-
Cl-
-
Al
Cl
lt may be pointed out here that since the aromatic ring is deactivated by the introduction
or an electron withdrawing acyl group, uniike
alkylation, there is no chance of polysubstitution
in acylation
reactions. Besides, the acylium ion does not undergo any rearrangement. It is on
is account that this reaction is often employed for the preparation of alkylbenzenes by reduction
of acy)Benzenes (aliphatic aromatic ketones)
by Clemensen reduction.

N 5 MECHANISMS OF SN, (Substitution Nucleophilic Bimolecular)

It is clear that in such reactions the nucleophile (OH) collides with the reactant (CH,Br)
molecule by the back side attack from the halogen atom (Br) and possesses sufficient energy

Page 1 of 23
 ORGANICc REACTIONS
AND SYNTHESIs
OF A DRUG
MOLECULE
to break the C-Br bond and
a transition state inyolving form C-OH 385
bond, Hence thc
two reactant moleculos. reaction (SN) procceds
takes place. Thus a complete inversion througn
of configurauon
H
H H
HO+H-G-Br
HO...G..Br
H HO- C- H+ Br
H H
Backside attack of mcthyl
Transition state of a bromide
SN, reaction
n the transition stato,
the ccntral carbon atom is sp2-hybridizcd
toms attached to it lic in a and the three hydrogen
planc at bond augles of 120°,
partially bonded to cach lobe The OH group and the Br atom arc
of the p-orbital, which is perpcndicular to the
atois. The C-OH bond is partly formed plane of three
and the C-Br bond is partly broken.

H H sp-hybridized
carbon

HO-- Br

Carbon and
p-Orbitalof Transition state for a SN, reaction three H-atom
sp-carbon lie in a plane

9.5.1 Factors which influencé SN2 reactions

1. Reactivity of alky! halides: The basic requirement of mechanism is the backside
attack of the incoming nucleophile on the carbon atom carrying the halogen atom. This
type of attack is quitec casy in the case of primary halides as the small size of hydrogen
atom does not hinder the attack. However, in case of tertiary alkyl halides, there are
three bulky groups attached to carbon atom carrying a halogen atom. These alkyl groups
cause overcrowding and hinder the incoming nucleophile. This type of hindrance is
called steric hindrance. So the rate of SN2 reaction decreases as the bulk of the
substituents increases
CH3X > Primary alkyl, halide > Secondary alkyl halide> Tertiary alkyl halides > Neopentyl halides

the negative
2. Nature of the halogen atom: In the transition state for SN, reactions,
group. The better
charge is normally distributed over the nucleophile and the leaving
greater stabilization of the
the leaving group, more stable is the transition state due to
is the reacnon.
negative charge by the leaving group and hence more rapid

Nu+R-XlNu X Nu-R+:X

Page 2 of 23
 cONCEPTUAL ENGINEERING CHEMISTRY
386

The stability of an anion is inversely

proportional to its basicity. Therefore, best lcavina
ing
groups arc of weak-bases.
is:
The ordcr of increasing basic strength of halide ions

BC1 <F°
Thercforc, the ordcr of casc of elimination of leaving groups would be:

Br C<F°
The bond dissociation cnergies of C-X bond are: 452 (CH3 F), 351 (CH3 - CI), 293
-

(CH- Br) and 234 (CH, ) kJ mol-1. Thercfore, C-I bond is the casicst to break while
-

C-F bond is the most difficult.

Hence the ordcr or reactivity of alkyl halides having same alkyl group but different
halogens is as R- 1 > R- Br> R-CI> R-F
Nucleophilicity or strength of the nucleophile: Since the transition state in a SN,
reaction is formed by the attack of the nucleophilic reagent on alkyl halide, stronger the
nucleophilic reagent, more rapid would be SN2 reaction. The nucleophilicity of a reagent
may be defined as its ability to donate a pair of electrons to the carbon atom. Thus,
greater is the nuclcophilicity of a nucleophile, the more rapid should be its SN2 reaction. As the
nucleophiles have complete octet and a lone pair of electrons, therefore, all the nucleophilies
should be basic in nature. However, their nucleophilicity does not always
parallel their base
strength. For instance, the hydroxide ion is a strong base and is
also a good nucleophile but
iodide ion is a very good nucleophile though it is very
weak base. In a series ofnucleophiles
belonging to the same family, the nucleophilicity increases
with the increase in the size of the
atom bearing the unsharcd pair (lone pair) of clectrons.
Therefore, the nucleophilicity of halide
ions in the decreasing order is:
I>B> CI>FO
, 9.5.2 Effect of solvent on SN2 reaction
As the transition state in SN, reaction is
non-polar, therefore, non-polar solvent vvill
stabilize it and will lower the activation energy of
the SN, reaction. Hence non-polar solvent
will favour SN2 reaction.
Stereochemistry of SN, Reaction: Due to the
attack of incoming nucleophile on the
alkyl halide from the backside, the configuration
of the molecule in inverted. This is proved
when (-)-2-bromooctane is hydrolyscd under SN2
conditions (high concentration hydroxide
ion), it gives exclusively, (+)-octan-2-ol as shown below: of
H,C
CH
C-Br High conc. of
OH H-O-C
1-----* SN2
H
cH13
CH13
(-2-Bromooctane +)-Octan-2-o

Page 3 of 23
ORGANIc REACTIONS AND SYNTHESIs OF A DRUG
MOLECULE 327
Thus if the alkyl halide is optically activc and lacvorotatory,
the substitution product is also
optically active and dextrorotatory. This inversion
of configuration is known as Walden inversion.
9.6 SN REACTION
A nucleophilic substitution reaction in which
the rate of kinetics depcnds upon the
concentration of only one reactant is called an SN,
reaction.
Rate k [RX]
Mechanism of SN, (substitution nucleophilic unimolecular) reaction
The mechanism suggested for the reaction between tert-butyl bromide and hydroxide
ion is as under:
CH3 CH3
|+8 -8 Slow
I. + Br
HC-C-Br HC-¢
CH3 CH3
tert-Butyl bromide Carbonium ion

2. (CH)C* +0H Fast(CH),C- OH

As the rate-determining step is only the slowest one, it means that the rate
depends upon the concentration of tert-butyl bromide only, Rate = k (CH3),CBr.
9.6.1 Factors which influence SN, reactions
(i) Effect of solvent: As the transition state of SN, reaction is polar, therefore polar
solvents will stabilize it and lower its activation energy. Hence polar solvents favour
SN, reaction.
in the rate-determining
(ii) Nature of nucleophiles: As the nucleophiles do not take part
rate o reaction.
step of SN, reaction, the strength of the nucleophile has no effect the
We have discussed above that the carbocations
(ii) Effect on structure of alkyl halides:
more stable the carbocation formed,
are be intermediates in SN, reactions. Therefore, the
the order of the stability of various
the more rapid should be the SN reaction. As
carbocations follows be order:
Benzyl> Allyl> Tertiary> Secondary > Primary> Methyl carbocation
in SN, reactions follows the same
Therefore, the order of reactivity of alkyl halides
sequences: Benzyl>Allyl>Tertiary> Secondary> Primary » Methyl halides
However, it may be noted here that this order of
reactivity of alkyl halides is opposite to
that of the SN, reactions.
Evidently, better the leaving group, lesser 1s
(iv) Effect of nature of the leaving group:
carbocation and hence
the Eact for the zansition state leading to the formation of the
Thus the order of
more should be the reactivity of the alkyl halide in SN, reactions.
>Br >Ci>F
reactivity of the different leaving groups follows the sequence:

Page 4 of 23
388 CONCEPTUAL ENGINEERING CHEMISTRY

Stereochemistry of SN,
As the carbonium ion has a flat structure, therefore nucleophile can attack the on
carbocation carbon from either of the two directions. But the side of the leaving group is to
sóme extent hindered because of the presence of halides ion, so attack from this side is less.
Thus, the major attack from this side which is just opposite to the halide ion. Hence, partial
racemization takes place in which inverted product is major and retention product is minor.
9.7 ADDITION REACTIONS
Unsaturated compounds containing double and triple bond between the two C atoms
1.C. alkenes and alkynes give addition reactions. Their addition reactions with halogens and
halogcn acids arc given below:
444 flanlo

Page 5 of 23
 390 cONCEPTUAL ENGINEERING
CHEM
STRY
9.711 Plectrophilic Addition Reactions
Alkenes are characterized by the presencc of a double bond
S which consists of
C-C, o-bond and a weak C-C, n-bond. Thc
n-clcctrons form an clectron cloud whicstrong
above and below thc planc of -bonded lies
o carbon atoms. ThCse, t-clcctrons
more exposcd and hencc arc, there
arc less tightly held betwecn the two carbon atoms.
Sincc the
thercforc, the clectrons attract the electrophiles clctrd
are negatively charged particles,
nucleophiles. In other words, alkenes ro
undergo electrophilic reactions. and repcl
Thus, the typical reactions
the electrophilic substitution
of alkenes are electrophilic addilion
reactions. reactions and n0t
Mechanism of Electrophilic Addition
Reactions
Let us illustrate the mechanism
addition of Br, to ethylene. of electrophilic addition reactions
The reaction occurs by a two-step by taking the example
ionic mechanism of
Step 1. Bromine molecule as discussed below
itself is non polar but
molecule, the t-electrons when it comes close
of the double bond,begin to repel to an ethylene
bromine atoms together the electron pair holding
in the bromine molecule. the two
The positive end of this As a result, bromine
bromine dipole behaves molecule gets polarized.
T-electrons ofthe ethylene as an electrophile
molecule to form and is attracted by
and the bromide ion. This a t-complex which subsequently the
step is slow and hence is gives the carbocation
the rate-determining
step of the reaction.
Br-Br Bthylene +
Polarized
Br-Br
bromine molecule

This step can simply

be represented as

H,C=CH + Slow
Br-Br
Ethylene HC -CH-Br +Br
Bromoethyl carbocation

Step 2. The carbocation

undergoes nucleophilic formed in step 1
aftack by the bromide being a reactive chemical species immediareiy
product. This step is jast ion present in
and hence does the solution forming the addition
not affect the
rate of the reaction.
Br+ HC-CH Nucleophilic
attack
Br

Br
CH-CH2
Bromoethyl çarbocation Br
1,2-Dibromocthane
Evidence in support of the above mechanism.
If the carbocations are really the intermediates
hald also react with other nucieophiles when in the above mechanism, then
added to the reaction
mixture and hence*

Page 6 of 23
ORGANIC REACTIONS
AND sYNTHESIs OF A 391
DRUG MOLECULE
mixture of products should be formed.
This has indeed been found to be so. For exampic,
ethylene is bubbled into an aqueous
solution of bromine containing sodium chloride, besides
2- dibromoethane, 1-bromo- 2-chloroethane
,
and 2-bromoethanol are also formed.
Br 2 1

Br-CH-H-Br
1,
Br 2-dibromoethane
HC=CH H,C-CH-Br CI
Etlhylene Br Bromoethyl
CI-CH-H-Br
1-bromo-2-chloroethane
carbocation
HO 2
Br-CH,-CH-Br
Br-CH2-CH-Ho
-H
Addition to unsymmetrical alkenes.
When the alkene is unsymmetrical, two products are theoretically possiblc. For example,
the addition of HBr to propene
in the dark and in the absence of peroxides can, in principle,
give two products. But esperimentally, it has been found that under these conditions, the major
product is 2-bromopropane and the minor product is 1-bromopropane.

CH,CH= CH2 +HBr- -

Dark
CH3-CH-CH + CH,CH,CH2 Br
Propene Absence of peroxides
1-Bromopropane
minor product)
Br
2-Bromopropane
major product)

Markovnikov's rule.
Markovnikov, a Russian chemist, studied a large number of such addition reactions
and postulated an empirical rule in 1869 which is known after his name as Markovnikov's rule.
The rule states that,
The addition of unsymmeitical reagents such as HX, H20, HOX, etc. to
unsymmetrical alkenes occurs in such a way that the negative part of the adiendum (i.e.,
adding molecule) goes to that carbon atom of the double bond which car ies lesser number
of hydrogen atoms.
CH CH
Mark addn.
For examnple, CH-C= CHh +H* CI CH-C =CH
2-Methylpropene
CI
2-Chloro-2-methylpropane

Explanation of Markovnikov's rule. The addition of halogen halides to alkenes is

an electrophilic addition reaction. Thus, during the addition of HBr to propene, the first step
involves the addition of a proton. This addition, in principle, can occur in two ways. Ifthe proton
adds on the terminal carbon atom of the double bond, a 2° carbocation () is formed and if the
addition occurs on the middle carbon atom, a 1° carbocation (11) is produced.

Page 7 of 23
 cONCEPTUAL ENGINEERING CHEMISTD
TRY
392
H, Addition at C
H, Addition at C H,C-CH=CH,
2
- H,C-CH-CH
HC-CH-CH3 Slow 1 Carbocation (1)
Slow Propene
2° Carbocation (1) (Less stable)
(more stable)
Fast Br
Fast Br
HC-CH-CHBr
HC-CH-CH3 1-Bromopropane
Br (minor product)
2-Bromopropane
(major product)

Since, a 2° carbocation (1) is more stable than 1° carbocation (11), therefore, carbocation
(1) is predominantly formed. This carbocation then rapidly undergoes nucleophilic attack by the
s
Br ion forming 2-bromopropane as the major product. Thus, Markovnikov addition occurs
through the more stable carbocation intermediate.
Peroxide effect.
It may be noted that Markovnikov's rule is not always followed. In presece of peroxides
such as benzoyl peroxide (CH,CO-0-0-00CHs), the addition of HBr (but not of HCI or
HI) to unsymmetrical alkenes takes place contrary to Markovnikov's rule. This is known as
Peroxide effect or Kharasch effect. Thus,

CH, CH CH+ HBr Anti-Mark. addn.

CH, CH,-CH, Br
Propene 1-Bromopropane
(Propylene) n-Propyl bromide)

Mechanism. The addition of HBr to alkenes in presence of peroxides occurs by ajree

radical mechanism. It consists of the following three steps
(a) Initiation.
O

(i) HC--L_ Benzoyl peroxide

A

Homolytic fission
-2 CgHs--ó

CgHs+cO2

(ii) CcH, + HBr CH + Br

two steps.
(b) Propagation. It consists of

Page 8 of 23
 393
ORGANIC REACTIONS ANDSYNTHESIS OF A DRUG MOLECULE

no
During the first step, a Br adds to the double bond in such a way so as to give
TreC radical. In the second step, the frec radical thus produced abstracts a
H fromi
SttC
to complcte the addition.

i) H,C-CH-CH, +r H,C-CH-CH,Br
2 radical (more stable)
Propcne

H,C-CH-CH,Br + Br
Cii) H,C-CH-CH,Br + HLBr
1-Bromopropane

(c) Termination.

i) 2Br Br2

CH-CH-CH,Br+ Br CH2-CHBr-CH,Br
)
1-Bromopropane
HC CH3
(ii) 2
HyCCH
CH
BrH.CH-H
-HC 4
CH,Br
BrHC
1,4-Dibromo-2, 3-dimethylbutane

understand why peroxide effect is observcd only

Exceptional behaviour of HBr. To two propagation steps.
and not with HF, HCI or HI, let us consider the AH of the
with HBr exothermic and hence
only with HBr, both the steps are
From the AH, it is clear that effect is not observed becusc
peroxide effect is observed. With HCI or HF, the perOxide
the with HCl or HF is endothermic. Further,
sccond step involving the reaction of carbon radical
the
is also not observed wath Hl
because the first step involving the addition of
the peroxidc cffect
endothermic.
iodinc radical to alkenes is
addition
9.7.2 Free-radical unsymmctrical
radicaladdition mechanism is addition of H-Br to an
An cxample of free Thin ir 2n involves the following
antiaMarkonikoff addition It

Page 9 of 23
 ORGANIÇÁEACTIONS AND SYNTHESIS OF 397
A DRUG MOLECULE

ELIMINATION REACTIONS
Reaction with alcoholic potash-Dehydrohalogenation (formation of alkent
When heated with concentrated alcoholic potassium hydroxide, alkyl halides climinat
or
alogen acid to form alkenes. This reaction known as dehydrohalogenation involves the loss
halogen and the hydrogen atom from a carbon adjacent to the onc losing the halogen
(B-climination)

R- -C-H + KOH R-CH =CH, + KX + HO

(Alc.)
H H
it can undergo
Saytzefr's rule: If the structure of an alkyl halide is such that
that contains
dehydrohalogenation in two diffcrent ways, the prcferred product is the alkene
Ieast number of hydrogen atoms on doubly bonded carbon atoms.
The highly substituted alkene
1s the major product.
when heated with alcoholic potash,
This generalization is known as Saytzeff's rule, c.g.
2-bromobutanc forms 2-butenc as a major product.
H Br H H

H-C- -H + KOH H,C=CH-CH-CH+ H,C-CH=CH-CH

(Alc.) 1-Butane 2-Butane
(Minor product 20%) (Major product 80%)
HHH H (Less substituted)

alkyl halides is 3°> 2°> 1°

Order of dehydrohalogcnation of
Mechanism of E2 (Elimination bimolecular) Reactions
9.8.1
a majority of primary alkyl halides occurs by E, mechanism.
The dehydrohalogcnation of
reveal so that the reaction follows second-order kinetics,
i.e.
Kinctic studics of this rcaction
both the alkyl
dchydrogenation rcaction ther Is proportional to the concentration of
rate of
halide and the basc. Thus,
Rate [Alkyl halide] [Base]
a transition
be a onc-step proccss and occurs through
This means that E, rcaction should carbon
hydrooxide ion (hydrogen attached to carbon atom which is next to the
statc. As the
the halogen atom), the carbon hydrogen bond begins to break. The carbon-
atom carrying the
starts forming and the leaving group (i.c. the halogen atom) starts leaving
carbon t bond bond. This is explained
atom taking with it clcctron pair, breaking the carbou halogen
-carbon
dehydrohalogenation of bromocthane
below with the help ot

Page 10 of 23
 cONCEPTUAL ENGINEERING CHEMto
ISTRY

398

I1-0H H H

H-0 H
A H -H
H
=C + H,O +
Br
Hc- H
H
H
Transition staile
Bromo cthanc in
basc and siniultaneous cxpulsion of halide n takes
As climination of a
proton by a
opportunity of rearrangen ent. It is clear from the reaction
tion that
t
the
there is no reaes
placc in one step, the following
alkenc character. T hrs is Cxplained by
transition state lias acquired some

HC-CH2 CH=CH2+ H,O +KCI

HC-CH CH-CH2 + KOH
(Alc.)

In case of an alkyl halide having two different types of hydrogens, two

alkenes can be
obtained. It is, thus, clear that more substituted the 2lkene the more stable the transition state
and hence more of this alkene would be formed. This cxplains the formation of 2-butene as the
major product in the dehydrohalogenation of 2-bromobutan
9.8.2 Mechanism of E, (Elimination unimoiecular) Reactions
The rate of reaction in these reactions depends only on one reactant molecule.
The E reactions arc shown by tertiary alkyl halides and in solution of low base
concentration.
The complete mechanism may be depicted as
shown below.
Step I. Dissociation of halide to a carbonium ion
by splitting a halogen anion.
E, (Unimolecular climination)

Slow)
H
(Carbonium)
Step II. Splitting a proton in prescncc
of a base forming
an alkene.

B
C=C<+ H:B Fast)
Action of heat: Alkyl halides when moleeuleot
hydrogcn halide fo alkenes. hcated above a
cnd to lose
573 K tenaa

C H, Br71
CH=CH+HBr
Page 11 of 23
OROANIC REAGMIONS AND9YNTUESID 399
oF A DRUO MOLEGULE

.90XIDATION REACTION
Most of tlho organic
compomds undero oxidation reactions as exanplificd De
1. Oxidation of alkanos
() ox on
Combustion: Whon bunt exces ofairor Oxygen, alkanes undergo complcte
in
to produce carbon dioxide, waler ad large quantitics of heat. For Cxmp
KJ
CL 20, CO, 211,0; Al-890
2C,1,+70, 400, +611,0; AH-3 110 KJ
rcaction
Duc to thc large quantities of heat produccd during combustion of alkancs, this
irom
S Tremcndous practical importanco. Vast quantitics of hydrocarbons obtaincd
petroleunn are used as fucls for the production of hcat and power by combustion.
() Incomplete combustion of alkanes duc to insufficient supply of air or oxygen resuits
C 1ormation of soot or carbon black. This is uscd in the manufacture of
Indian ink,
printer's ink, black varnish and as a filler for rubbers.
pressurc
Culalytic oxidution: When hcatcd in a regulated supply of air or oxygen at high
and in the prescncc of suitable metallic catalysts, lower alkancs arc oxidized to
alcohols
when
and aldchydes wlhile higher homologucs yicld long-chain fatty acids. For example,
a mixturc of mcthanc and oxygcn, in suitablc proportions compresscd to 100 atm and
passcd through copper tubes at 475 K, methanc is oxidized to mcthanol.
475/100 atm
2CH+O2 Cu tube 2CH, OH
CH4+O2-MolybdenumHCHO
Oxide
+H,0
Formaldchyde

2.Oxidation with Hot Alkaline KMn0, (Oxidative Cleavage ofAlkenes)

an
If alkene is heated with concentrated solution of alkaline KMnOg at 373-383 K,
cleavagc of the C-bond takes placc rcsulting in the formation of ketones and/or carboxylic
acids and CO, depending upon naturc of the alkcne as shown below:
(a) Terminal CH, is oxidized to CO,.
(b) Ifthere is any hydrogen attached to the double-bonded carbon atom, it is oxidized to COOH.
(c) If therc is no hydrogen attached to the doubly bonded carbon, it is oxidized to ketone.
For cxamplc,

CH-CH=CH 6) (ii)KMnO4CH-C-OH+CO,+HO2
Hot
(i) I1*
Propylene Acctic acid
(Ethanoic acid)
O

i) CH,-CH,-CH = CH, nO/KOCH,-CH,--OH

(ii) I1+
+H,0+CO
Propionic acid
(Propanoic acid)

Page 12 of 23
N

Page 13 of 23
 ORGANIC REACTIONS 401
AND SYNTHESIS OF A DRUG MOLECULE

(11) Fehling's solution: Fchling's solution is preparcd by mixing cqual volumes o hling's
solution "A', which is copper sulphate solution containing d
few drops of conc. H,>4
Fchling s solution B', wlhich is alkaline solution Rochelle salt. Rochelle salt is sodium
of
potassium tartaratc.
Aldehydes form complex with Cu2 (from Fehling's solution) and are oxidized to
carboxylic acid and is reduccd to red colourcd
Cup.
CuSO+2NaOH 4 Cu(OH), + Na^S04
Cu(OH) CuO + H,O
RCHO+2CuO Cu,0J +RCOOH
(Red ppt)
Notea Aromatic aldehydes, however, do not reduce Fehling's solution.

.10 REDUCTION REACTIONs

Most of the organic compounds undergo reduction to give different products under
varying reactions condition as illustrated by the following examples.
1. Reduction (Hydrogenation) of Alkenes
Alkenes react with hydrogen in the presence of certain finely divided metal, such as
nickel at 523-573 K (Sabatier-Senderen's reaction) or palladium or platinunm at room
temperature (298 K) to form alkanes.
Ni or Pd at 298 K
+H2 or Ni at 523 - 573 K
Alkene H
Alkane
Examples: (1) H,C= CH,+H2 H,C-CH,
or Pt
Ethylene Ethane
(Ethene)
Ni orPd
(ii) H,C-CH CH,+H or Pt
H,C-CH2-CH3
Propylene Propane
(Propene)

Hydrogenation of alkenes is an exothermic reaction. The heat evolved when 1

mole of
saturated compound is hydrogenated, which is known as heat of hydrogenation.
2. Hydrogenation of Alkynes
Depending on the conditions and the catalyst employcd, one or two molar equivalents
of hydrogen will,to a carbon-carbon triple bond.
When a platinum catalyst is uscd, the alkync generally reacts with two molar equivalents
of hydrogen to givcn an alkanc:
CH,C = C-CH, +H2 CH,CH =CHCH l,PCHCH,CH,CH,CH,
Palladium or Rancy nickcl can also be used as catalyst.

Page 14 of 23
 402 cONCEPTUAL ENGINEERING CHEMte
HEMISTRY

3. Reduction of Aromatic Compound

(a) By thc catalytic reduction of benzenc and its derivativcs, we can casily obtain
membered cyclo compounds. Six

Ni 200°C
+ 3H2-
OH Benzene OH Cyclohexane

Ni, 200°C Zn dust

+3H2
P
Phenol Cyclohexanol Cyclohexane
(b) On reduction with hy'droiodic acid at 520 K
or hydrogen under
of finely divide nickel at 470 K, arenes form cycloalkanes. pressure in the presence
reduction gives methylahydrocyclohexane. For example, toluene on
CH3 ÇH3

N/Ni/A

Methylcydohexane
(c) On reduction with nascent hydrogen
alkyl cyanides from primary amines. obtained by the activity of sodium and ethanol,
This reaction is known as Metallic
redction. Thus,
CH-C N+4[H]Czio
CH-CH-NH,
Methyl cyanide
(Ethanenitrilc) Ethyl amine
(Amino ethane)
Reduction can also be achieved
with H,/Ni or lithium-aluminium
4. Reduction of Carboxylic hydride (LiAIH).
Acids
(i) Reduction to alcohol: Carboxylic
initial products arc alkoxide from acids can be reduced to alcohol by LiAlH,. The
which alcohol is
liberated by hydrolysis.
4R-COOH+2LiAlH, >
4H,+ LiAlO,+(RCH,
0), AILi-H,04 RCH,
(ii) Reduction to alkanes:
Carboxylic acids can
4
RCH,OHOH

of red phosphorous at 430 K. be rcduced to alkane

with HI in presencc

R-COOH+6HI-RedR-CH,+2H,0+31,2
Red P
CH,COOH +6HI- >CH-CH+2H,0+3l2
430 K

Page 15 of 23
 ORGANIC REACTIONS AND 403
SYNTHESIS OF A DRUG
MOLECULE
5. Reduction of Acid Chloride
(i) Reduction to aldehydes (Rosenmund's reduction): uccd
Acid chlorides can be r
With H in the presence of fincly divided palladium precipitated on BaSO4 and
aldehydes. Sulphur is used to partially Doison
to alcohol the catalyst to prevent further reduo
or alkane.
Pd
R-C + H2
c BaSO/S
RCHO +

Aldchydes
H,o

(11) Reduction to alcohols: Alcohols are formed

from acid chlorides with soaiun aand
alcohols or LiAIH4.

R-C
=o +4[H]
R-CH,OH + HC
CI
6. Reduction of Acid Amide
ACid amides on reduction with LiAlH, give primary amincs with the samc number or
carbon atoms.
R-CONH LiAlH4R-CH,NH,+2H,0
1 Aminee
9.11 CYCLISATION
Cyclisation can be carried out by catalytic reforming. It involves reforming the pctrolcum
hydrocarbon molecules to enhance their octane umber for gasoline blending. In this proccss,
normally paraffin and naphthene (alicyclic hydrocarbon) molecules are reshaped intoaromatics.
For instance, n-heptane (C,H1o) is changed to toluene (C,Hg), n-octane (CgH18) to ortho-
xylene (CH1o), cyclooctane (CgH16) to p- and m-xylenes. The process is carricd out for the
manufacture of benzene, tolue and xylene etc.
The process is carried out at a temperature range of 250-550°C in an adiabatic reactor
at a pressure of 10 kg/cm* in the presence of bimetallic catalysts platinum and rhenium, tin or
germanium on a silica-alumina support.
1. Cyclisation and Aromatisation (n-heptane is converted to toluene)
CH3
CH3 CH3
H,C CH
CH3 CH2 H,C CH2
cyclisation aromatisation

HC CH2 H HC CH2 -3H

CH CH2
Toluene
n-Heptane Methyl cyclolhexane

Page 16 of 23
 cONCEPTUAL ENGINEERING CHEMISTRY
404

2. Dehydrocyclisation of alkanes

+4 H2
HC-CH -CH-CH,- CH-CH,
n-hexane

CH

(ii) HC-a HCH-CH-CH-CH, +4Ha

1- heptane

Among these reactions, the first one takes place comparatively at a faster rate because
it involves only dehydrogenation and other two involve.isomerization and cyclisation is addition
to dehydrogenation.
3. Reforming of n-octane
n-octane under reaction conditions can undergo cyclisation at three positions namely
1,6; 2,7; or 3,8 giving rise to ethyl cyclohexane or 1,2-dimethyl
cyclohexane. These two on
aromatisation would yield ethyl benzene or 1,2-dimethylbenzene (o-xylene).
2
H3c 4 6
CH2- CH2-CH2- -CH-HzCH2-H
1,6

-
1,6
2,7
3,3

-CH2- CH
-CH3
H3C-Hhc
CH3
n-octane under idcal laboratory conditions predominantly
yield ethyl benzene and oru
xylenc. Under actual commcrclal conons isomerization
and rearrangement leads to sevet
other compounds such as benzenc, toucne, meta xylene and para
xvlenc.
It can undergo cyclisation at 1,0 position to give
1.4-dimcthvl cvclohexane or at 4"
position to give 1,2-dimethyl cyclohexane.

Page 17 of 23
 ORGANIC REAGTION6 AUD 405
6YUTESIS Of A DG MOLEGULE

C1
CH
an

1,2-dirncthyl cyclohczane
CH
1,4-dimcthhyl cyclohexanc

The products can undergo dehydrogenation giving rise to p-xylenc and

o-xyiene
respectively
CH3 CH3
CH3

and

0-xylene
CH3
p-xylenc
namely m-xylene and
These products may undergo isomerízation to give other isomers
cthyl benzenc.
4. Preparation of Cyclo-alkanes by cyclisation reaction
cycloalkanes.
The following methods arc commonly used for the preparation of
dibromoalkanes having terminal
(i) Freund's Method from a,0 -dihalides: Dichloro or
corresponding cycloalkanes.
halogen atoms, when treated with sodium or zinc, yield the
For examplc,

CH2Br
CH
Ethanol
HC + 2Na HC +2NaBr

CH,Br 'CH
cyclopropane
1,3-dibromopropane

H,C-CH,Br HC- -CH

Ethanol
+ Zn
+ZnBr2

HC-CH,Br H,C- -CH2

cyclobutane
1,4-dibromobutane

Page 18 of 23
 406 cONCEPTUAL ENGINEERING CHEMISTRY

The method is an extension of Wurtz reaction and may be regarded as an internal Wurtz
reaction. The reaction is useful for the synthesis of three- to six-membered rings.
(ii) From barium or calcium salts of dibasic acids (Wislicenus method): On dry
distillation of barium or calcium salts of dicarboxylic acids, a cycloketone is obtained
which can be reduced to cycloalkane by Clemmenson's reduction (Zn-Hg/HC1).

HC-CH-C00 H,C- CH HC-CH

Heat Reduce
Ca CO+ZnCO CH2
H,C-CH-COO Zn-Hg/HC
HC-CH2 HC-CH2
Calcium adipate
Cyclopentanone Cyclopentane

This method is useful for the preparation of only,

six-and seven-membered ring ketones,
which can be further reduced to cycloalkanes.
(ii) Condensation of a,0-dihalide with malonic
di halide is
ester (Perkin's method): a,0 -
condensed with mal onic ester in the presence
carboxylic ester thus obtained is hydrolysed of NaOC,H5. Alicyclic
and decarboxylated to yield cycloalkane.

CHBr COOC,Hs
NaOC H, H COOCHs
+ HC
CHBr cooC,Hs -
2HBr

1,4-dibromobutane Hc cooCHs
Hydrolysis:
-2CHOH
H,C

CH
A
A
H COOH
CHCOOH
-
CO - CO2
HC HC HC COOH
Cyclopropane Cyclopropane
carboxylic acid

In general, any other suitable a,o

-dihalide can be condensed
Dresence of sodium etnoxiae to get the desired with malonic ester
cycloalkane.
iv)
(iv) From disodio acetoacet ester and dihalogenated
paraffins: Disodio derivativ
of accto ester condcnses w nalogcnated paraffin to form hydrolysis
Torm an ester which on hydrolysis
cyeloptathins. Cvl
and dec ylation gives cycloparaffins tOcannot
Cyclobutane be obtained by this methou.

Page 19 of 23
 ORGANIC REACTIONS AND SYNTHESIS
OF A DRUG MOLECULE 407

CH-CH2|Br Na cOCH,
CH-CH,Br Na
C COOC,H, -2NaBr CH-CH,
CHCH2
cCOCH
cooc,H,
Disodioacoto acetic ester
H,O: CaH,OH
CH-CH Soda limne CH-CH2 COCH
CH 4
CH-CH2 Heat CH-CH coOH
Cyclopentyl COCH,
methyl ketone

Diels-Alder reaction [4+21 Cycloadditi on: The [4+2] cycloaddition reaction

betiwecn a conjugated dicnc (4 -clectron system) to form an adduct is known as Dicls--
Alder reaction. A in typical example is the addition of 1,3-butadiene with acrolein at
100°C to form tetrahydrobe aldehyde.

CH2 CHO
CHCHO

CH2
CH2
1,3-butadiene Acrolcin

CH2
Butadicnc O
Malcic
anhydridec
-
Similarly, the addition of maleic anhydride to butadiene gives tetrahydrophthalic dride

Tetrahydrophthalic
anhydride

9.12 RING OPENING REACTION

are examples of ring opening reactions:
The following reactions of cycloalkanes
and undergocs addition reactions like
(i) Cyclopropane (bond angle 60°) is very reactive
alkanes.

Page 20 of 23
 CONGEPTUAL ENGINEERING CHEMIG TY
40

ll,cC1,C1,tr
I,3-dibronopropanc

C1 CH,CHC1,r
Propyl bromide

CI,
() Conc. 11,SO,
Cyclopropno --Cl,CL,CIL,O
(i) 1,0 Propanol-1

1, Ni
CH,Cl2C13
Propanc
(n) Cyclobutane (bond angle 90°) is generally less reactive because of less ring strain and
thercfore, does not undergo addition rcaction under normal conditions.

11,C-CI2 N, Ni
ClC1,CH,CH3
1,-l2 120 °C
n-Butane
Cyclobutanc

(ii) Dicarboxylic acid formedwhen cycloalkanes arc oxidizcd

by alkaline alkalinc potassium
permanganate.

C
HC Cll2
CH,CHCOOH
HC CH
CH2 Alk. KMnO,
CH,CH,C0OH
CiH
Adipic acid

9.13 SYNTHESIS OF A COMMONLY USED

DRUG MOLECULE
Chemical substance used 1or tlic treatment
of discases and for reducing the suftering
from pain are callcd meaicmes Or urugs,. These
chcmicals are mainly
(i) Antipyretics
classificd as
(i) Analgcstics
(ii) Antiscptics and disinfectants (iv) Transquilisers,
and
(v) Antibiotics
We will not go ino the details of the above
noted types of drugs.
The most commonly uscu us spirn whose synthesis is discussed below

Page 21 of 23
 409
ORGANIC REACTIONS AND SYNTHESIS OF A DRUuG MOLECULE

Aspipin is obtaincd by the actylation of Salicylic acid (o-hydroxy benzoic acid) wi

acetic anhydride or acetyl chloride in the presencc of little concentrated sulphuric acid or pyria
respectivcly.

-OU H,sO -OCOCH

O -COO
Salicylie acid
(CI1,CO)0-
O -COO CH,CoOH

Acctic Anlydride Aspirin

Pyridinc

O
Salicylie acid
-OIl
COOI
+CllCOCI-

Acctyl chloride
OLAspirin
-OCOCH
-cOoI
+ HCI

Requirements:
Acetylation with acetic anhydride Acetylation with acetyl chloride
gm
a) Salicylic acid
5 gm a) Salicylic acid = 5
b) Acctic anhydridc =8 ml. b) Pyridine = 4 ml
c) Conc. H,SO, =2-3 drops c) Acctyl chloride = 4 ml
Procedure:
Step I. Acetylation with acetic anhydride
i) Place 5gm of salicylic acid and 7 ml of acctic anhydride in a small absolutely dry
conical flask.
i) Add 2-3 drops of conc. H,SO and rotate the flask for thorough mixing.
i) Warm thc conical flask on a water bath to about 50-60 °C, while shaking, for about 15
minutes.
iv) Allow the mixture to cool and stir occasionally.
v) Add about 80 ml of water, stir well and filter at the pump.
vi) Rccrystallize the crude product from a mixture of cqual volume of water and acetic
acid.
Step II. Acetylation with acetyl chloride
i)Dissolve 5gm of salicylic and in 4ml of dry pyridine containcd in a small conical flask.
i) Then without delay run in 5ml. of acetyl chloride, adding about Iml of chloride at a
time.
il) Shake the content continuously during the addition.
iv) Sincc the rcaction is exothermic, maintain the temperature betwecen 50°C and 60°C
throughout the addition, cooling the flask occassionally in cold water, if necessarv.
5 minutes.
v) Finally heat the mixture on a boiling water both for
a thin stream into about 200 ml of cold water,
vi) Then cool in cold water and pour in
stirring the mixturc vigorously.
vin) The crude aspirin solidifies.

Page 22 of 23
 cONCEPTUAL ENGINEERING CHEMISTRY

vii) Filter the solid at pump and wash thoroughly with water.
ix) Recrystallize from a mixture of cqual volumos of water and acctic acid,

Precautions:
i) The conical flask must be absolutely dry. Rinse it with alcohol and dry it an clectric oven.
ii) Coal the contents of the flask in water after addition of cach small instalment of
acetylating agent.
il) Use an air condenser while heating the reaction mixture on a water bath.
iv) Use minimum quantity of the solvent for recrystallisation.

Solved Typical Problems

Page 23 of 23