A Practical Book of Medicinal Chemistry- I (Sem.

- V)

SECTION-B

4. SYNTHESIS & PURIFICATION OF FOLLOWING COMPOUNDS USING

PRECIPITATION OR RECRYSTALLIZATION.

A. SYNTHESIS OF BENZIMIDAZOLE.

Aim: To Synthesize Benzimidazole from o-phenylenediamine by Cyclization Reaction.

Apparatus: Round Bottomed Flasks (250ml), Beakers, Reflux Condenser, Buchner

Flasks, Buchner Funnel, Thermometer, etc.

Instruments: Weighing Balance, Melting Point Apparatus, Hot Air Oven.

Chemicals: o-phenylenediamine, Formic Acid, Sodium Hydroxide,

Reference:

1.Furniss B. S., Hannaford A. J., Smith P.W.G., Tatchell A. R., Vogel‟s Textbook of
Practical Organic Chemistry; 5th edition, Page no.1162.

2. Arun Sethi, Systematic Lab Experiments in Organic Chemistry, Second Edition, New
age international publishers, Page no 691.

General Reaction:

~31~
 A Practical Book of Medicinal Chemistry- I (Sem.-V)
NH2 NHCHO
-H2O
H C OH

O
NH2 Formic acid NH2
o-Phenylenediamine N-(2-aminophenyl)formamide

NaOH -H2O

N
H
1H-benzo[d]imidazole

Principle/Theory:

It is cyclization reaction. o-phenylenediamine on treatment with formic acid gives

benzimidazole. In this the o- phenylenediamine having N atom contains lone pair of
electrons i.e. negative charge. The formic acid contains the carboxylic group, it will
attack the nitrogen atom of o- phenylenediamine eliminating water molecule. Further
the carboxylic group will attack another nitrogen atom and the elimination of water
molecule will lead to formation of benzimidazole as final product by electron
rearrangement. Thus the synthesis of benzimidazole includes cyclization reaction.

Procedure:

~32~
 A Practical Book of Medicinal Chemistry- I (Sem. - V)
Place 27 g of o-pheylenediamine in a 250 ml round bottomed flask and add 17.5 g of 90
per cent formic acid. Heat the mixture on a water bath at 100oC for 2 hours. Cool, add
10 per cent sodium hydroxide solution slowly, with constant rotation of the flask, until
the mixture is just alkaline to litmus. Filter off the crude benzimidazole at the pump
wash with ice cold water, drain well and wash again with 25 ml of cold water. Dissolve
the crude product in 400 ml of boiling water, add 2 g of decolourising carbon and digest
for 15 minutes. Filter rapidly at the pump through a preheated Buchner funnel and flask.
Cool the filtrate to about 10oC, filter off the benzimidazole, wash with 25 ml cold water
and dry at 100oC.Report, yield and Melting point of the product. (Note: Start with 1 gm
of o-pheylenediamine)

Characterization of the Compound:

1. Progress of the reaction is monitored by performing thin layer chromatography.

2. The compound synthesized is purified by Recrystallization / distillation.
3. The compound synthesized is characterized by detection of elements, functional
groups, confirmatory tests and determination of melting point/ boiling point.
4. The compound synthesized is further characterized by qualitative analysis/
structural elucidation by FT-IR spectroscopy wherein presence of different
functional groups is confirmed.

Observation Table:

Chemical Tests:
Test Observation Inference

Physical constant

Calculation of % yield:
Theoretical Yield (X) = --------

Moles of the reactant = Moles of the product

Thus „A‟ gm of reactant = „X‟ gm of the product

X = (Moles of the product ÷ Moles of the reactant) x A

Practical Yield (Y) = ---------

~33~
 A Practical Book of Medicinal Chemistry- I (Sem.-V)
%Yield = ( Y÷X ) x 100 = --------

Result:
Name of the Compound

Theoretical Yield (gm)

Practical Yield (gm)

Percentage Yield (%)

Physical Actual
Constant
Practical
M.P.

Rf value

I.R. Observations:

Sr. No Functional Group IR Value (cm-1)

Theoretical Observed

Calculation of Rf value:

Rf = 0.69

Rf = 0.15

~34~
 A Practical Book of Medicinal Chemistry- I (Sem. - V)
Label:
Name of Compound

Structural formula

IUPAC name

State and Color

Molecular Weight

Molecular Formula

Melting point

% yield

Use

Prepared by

~35~
 A Practical Book of Medicinal Chemistry- I (Sem.-V)
B. SYNTHESIS OF 1, 2, 3, 4-TETRAHYDRO CARBAZOLE

Aim: To Synthesize 1, 2, 3, 4-tetrahydro Carbazole Cyclohexanone and

phenylhydrazine by Hoffman‟s Rearrangement.

Reaction:

Mechanism:

Procedure:
A mixture of 98 g. (1 mole) (Note 1) of cyclohexanone and 360 g. (6 moles) of acetic
acid contained in a 1-l. three-necked round-bottomed flask equipped with a reflux
condenser, a slip-sealed stirrer, and a dropping funnel is heated under reflux and stirred
while 108 g. (1 mole) of phenylhydrazine is added during 1 hour. The mixture is heated
under reflux for an additional hour and poured into a 1.5-l. beaker and stirred by hand

~36~
 A Practical Book of Medicinal Chemistry- I (Sem. - V)
(Note 2) while it solidifies. It is then cooled to about 5° and filtered with suction, the
filtrate being cooled in ice and refiltered through the filter cake. The final filtrate is
discarded. The filter cake is washed with 100 ml. of water and finally with 100 ml. of
75% ethanol. Each wash is allowed to soak into the filter cake before it is sucked dry.
The crude solid is air dried overnight (Note 3) and crystallized (Note 4) from 700 ml. of
methanol after treatment with decolorizing carbon (Note 5); yield 120–135 g. of
1,2,3,4-tetrahydrocarbazole, m.p. 115–116° (Note 6). The mother liquor is concentrated
to one-fourth of its original volume and yields an additional 10 g. of product (total yield
76–85%) (Note 7).
Notes:
1. Equivalent amounts of cyclohexanone (after suitable compensation for purity) and
phenylhydrazine are used. The cyclohexanone was about 90% pure (analyzed by the
procedure of Bryant and Smith2). Instead of analyzing the ketone, it is safe to
assume 90% purity.
2. The stirring should be sufficiently vigorous to prevent the formation of lumps.
3. The crude product requires 50–70 hours of air-drying to attain constant weight
(145–155 g., 85– 91%). It is preferable to crystallize the partially dried product.
4. The approximate solubility of 1,2,3,4-tetrahydrocarbazole in 100 ml. of methanol at
10°, 35°, and 55° is 5, 12, and 18 g. respectively.
5. A heated funnel is desirable for filtration of the hot solution, for the product
separates on slight cooling.
6. The capillary melting point of tetrahydrocarbazole ranges from 113° to 114° with
slow heating and from 116° to 118° with fast heating.
7. 1,2-Benzo-3,4-dihydrocarbazole may be prepared by the same general procedure. A
solution of 172 ml. (2 moles) of concentrated hydrochloric acid (sp. gr. 1.18) in 500
ml. of water is heated at the reflux temperature and stirred in a 2-l. three-necked
round-bottomed flask equipped with a reflux condenser, a slip-sealed stirrer, and a
dropping funnel while 108 g. (1 mole) of phenylhydrazine is added during 5
minutes. α-Tetralone (p. 898) (146 g., 1 mole or a correspondingly larger amount of
material of 90% purity; see (Note 1)) is added in a period of 1 hour, and the mixture
is stirred and heated under reflux for an additional hour. The product is cooled to
room temperature with stirring, and the beadlike product is filtered, washed as
above, and crystallized from 2.3 l. of methanol after treatment with decolorizing
carbon. The first crop amounts to 105–110 g. and the second crop to 75–80 g.,
making the total yield 82–87%; m.p. 163–164°.

~37~
 A Practical Book of Medicinal Chemistry- I (Sem.-V)
C. SYNTHESIS OF 2, 3-DIPHENYL QUINOXALINE

Aim: To Synthesize 2, 3-diphenyl Quinoxaline from o-phenylenediamine and Benzil

by Condensation Reaction.

Reaction:

Mechanism:

Procedure:
To warm solution of 2.1g (0.01 mol) of Benzil in 8ml of rectified spirit , mix a solution
of 1.1g(0.01mol) of o-phenylenediamine in 8 ml rectified spirit. Warm in a water bath
for 30 min and add water until a slight cloudiness persists and allow to cool, filter and
recrystallized from aqueous ethanol to give 1.43g (51%) of 2, 3-diphenyl Quinoxaline.
M.P. 125-1260C

~38~
 A Practical Book of Medicinal Chemistry- I (Sem. - V)
D. SYNTHESIS OF BIS-Β-NAPTHOL.

Aim: To Synthesize Bis-β-napthol from β-napthol.

Reaction:

Mechanism:

Procedure:

Weigh 10 g of 2-naphthol are dissolved in an excess of ether, and 16 g (excess) of

anhydrous iron(III) chloride are gradually added to the solution in a flask fitted with a
reflux condenser. Much heat is evolved during this operation. The mixture is then
refluxed on a water bath until most of the 2-naphthol is oxidised. (To test this a small
portion of the ethereal solution is treated with an excess of dilute hydrochloric acid, and
the etherevaporated. The 1,1′-bi-2-naphthol separates out even in the warm as an oil
~39~
 A Practical Book of Medicinal Chemistry- I (Sem.-V)
while 2-naphthol crystallises out on cooling.). When this is the case, the ether is
removed on a water bath, water and powdered calcium carbonate are added to the
residue, and the whole well shaken. Excess sodium hydroxide is then added, the
solution is filtered and precipitated with dilute sulfuric acid. The precipitate is washed
with boiling water or boiling ligroin, and recrystallised from benzene. Yield 4• 0%
theoretical (8 g). Colourless needles from alcohol, prisms from a mixture of carbon
disulfide and alcohol; insoluble in water; slightly soluble in chloroform; soluble in
alcohol and ether; m.p. 216-218° C.

~40~
 A Practical Book of Medicinal Chemistry- I (Sem. - V)
E. SYNTHESIS OF ANTHRANILIC ACID.

Aim: To Synthesize Anthranillic Acid from pthalimide by Hoffmann‟s Rearrangement

Reaction.

Reaction:

Mechanism:

Procedure:
Prepare a solution of 30 gm of NaOH in 120 ml of water in 250 ml conical flask and
cool to 0˚c or below in a bath of ice. Add 26.2 gm of bromine in one portion and shake
until all bromine has reacted. Temperature will rise slightly again. Cool the mixture.
Prepare solution of 22gm of NaOH in 80 ml of water. Add 24gm of phthalimide in a
portion to cold NaOBr solution in terms of smooth paste with water rapidly with
stirring. Remove the flask from cooling bath and shake vigorously until a clear yellow
solution is obtained. Add prepared NaOH solution rapidly in one portion. Heat the
solution at 80˚C for about 2 minutes and filter if necessary. Cool in ice and add conc.
HCl slowly with stirring until the solution is just neutral. Precipitate Anthranilic acid
completely by gradual addition of glacial acetic acid (20-25 ml will be required). Filter
off the acid at pump and wash with a little cold water. Recrystallized from hot water
with addition of little decolorizing agent. Collect the acid on Buckner funnel and dry at
100˚c.
~41~
 A Practical Book of Medicinal Chemistry- I (Sem.-V)
F. SYNTHESIS OF SULPHANILAMIDE

Aim: To Synthesize Sulphanilamide from p-acetamidobenzenesulfonamide by

Hydrolysis Reaction.

Reaction:

Mechanism:

~42~
 A Practical Book of Medicinal Chemistry- I (Sem. - V)
Procedure:

4-acetamidobenzenesulfonamide is weighed and placed in a 50 mL round-bottom flask

equipped with a magnetic stir bar. Dilute hydrochloric acid (6 M) is added to the flask
in an amount equal to twice the weight of the 4-acetamidobenzenesulfonamide. The
flask is fitted with a cold water condenser and heated at reflux with constant stirring for
45 minutes, after which it is allowed to cool to room temperature. If any solid appears
upon cooling, the mixture is reheated at reflux for another 15 minutes. After cooling,
the reaction mixture is neutralized by slow addition of a saturated Na2CO3 solution
with stirring until it tests slightly alkaline to pH paper. A precipitate may have begun to
form during neutralization. Cool the beaker in an ice bath to complete the precipitation
of product. It may be necessary to gently scratch the inside bottom of the beaker to
induce crystallization. The product is collected by vacuum filtration, washed with a
small amount of ice cold water and air dried. A small sample of the crude product is
saved, and the remainder is purified by recrystallization by dissolving in a minimum
amount of boiling hot water, allowing the solution to slowly cool to room temperature,
then further cooling in an ice bath to crystallize as much product from solution as
possible. The recrystallized product is collected by vacuum filtration. The product is
weighed and % yield is calculated. The overall yield for the five-step synthesis of
sulfanilamide from nitrobenzene is calculated and reported. IR and NMR spectra are
obtained on the final product.

~43~
 A Practical Book of Medicinal Chemistry- I (Sem.-V)
G. SYNTHESIS OF BENZOIC ACID FROM BENZYL ALCOHOL.

Aim: To Synthesize Benzoic Acid from Benzyl Alcohol by Cannizaro‟s Reaction.

Reaction:

Mechanism:

Procedure:

Benzaldehyde (20g) are treated in a stoppered cylinder or a thick-walled vessel with a

cold solution of 18 g of potassium hydroxide in 12 g of water, and mixed until a
permanent emulsion is formed. The mixture is then allowed to stand over night. The
vessel is closed by a cork, and not a glass stopper, since at times a glass stopper
becomes so firmly fastened that it can be removed only with great difficulty. To the
crystalline paste (potassium benzoate) separating out, water is added until a clear
solution is obtained from which the benzyl alcohol is extracted by repeatedly shaking
with ether. After the evaporation of the ether the residue is subjected to distillation;
benzyl alcohol passes over at 206° C. Yield, about-8 g. The benzoic acid is precipitated
from the alkaline solution on acidifying with hydrochloric acid and purified from hot
water yielding final product with melting point 121° C.

~44~
 A Practical Book of Medicinal Chemistry- I (Sem. - V)
H. SYNTHESIS OF PROPRANOLOL

Aim: To Synthesize of Propranolol from 1 napthol.

Reaction:

Mechanism:

~45~
 A Practical Book of Medicinal Chemistry- I (Sem.-V)
Procedure:

Step I: Transfer 1.25gm (0.0085mol of 1 napthol CPM 144.18 per mole ) 0.5gm of
KOH to a round bottom flask and add ethanol, After dissolution add drop wise 2 ml of
epichiorohydryl , The reaction is left under magnetic stirrer at room temp for 48 hrs,
TLC is an carried out in an eluent system (hexane ethyl acetate) to monitor the yield of
reaction , extract aqueous phase with ethyl ether, ethyl ether extract is dried with
anhydrous sodium sulphate, filter and remove solvent to obtained crude brown oil.

Step II: Transfer 0.2gm of crude oil with menthol to round bottom flask heated with a
stopper and add 4ml of isopropyl amine, keep the reaction under temp control for 2 hrs.,
remove solvent by Vaccum evaporator, obtained product add 30ml of 2 mole per liter
HCL and transfer to separating funnel.

~46~
 A Practical Book of Medicinal Chemistry- I (Sem. - V)
I. SYNTHESIS OF 1, 4-DIHYDROPYRIDINE

Aim: To Synthesize 1, 4-dihydropyridine form formaldehyde by Hantzsh Synthesis.

Reaction:

Mechanism:

~47~
 A Practical Book of Medicinal Chemistry- I (Sem.-V)
Procedure:

Take 1ml aldehyde 2ml ethyl acetoacetate 1ml/gm aminoacetate 1ml water remaining
space charge with water steam air or nitrogen then close round bottom flask. Mixture
stir for desire time at 70-750C on composition final mixture was ten cool at room temp
and stay over neighs Mixture was filter to isolated precipitate product recrystallized
product 90% ethanol give product.

~48~
 A Practical Book of Medicinal Chemistry- I (Sem. - V)
BIBLIOGRAPHY

References:
1. Vogel's Textbook of Quantitative Chemical Analysis, J. Mendham, R.C. Denney, J.
D. Barnes, M. J. K Thomas, 6th Edition, Pearson‟s Education Ltd , Page No. 68-67.
2. Practical Pharmaceutical Chemistry, A. H. Beckett, J. B. Stenlake, 4 th Edition,
CBS Publication, Page No. 114-122.
3. Vogel‟s Textbook of Practical Organic Chemistry, B. S. Furniss, A. J. Hannaford ,
P.W.G. Smith, A. R Tatchell, 5th edition (2008), Pearson‟s Education Ltd , Page No.
898,589, 1284.

4. Systematic Lab Experiments in Organic Chemistry, Arun Sethi, Second

Edition(2003), New Age International Publishers, Page No .741, 722, and 764.

5. Practical Medicinal Chemistry , Dr.R.S.Chavan, S.J.pawar, Dr. H.N.More , Dr

S.D.Swant , 1st Edition , Aug 2013, Nirali Prakashan, Page No.1.3, 7.1, 17.1, 48.1.

6. Instrumental Methods of Chemical Analysis, G.R. Chatwal, S.K. Anand, First

edition (2003), Himalaya Publishing House, Page No. 2.602-2.603.

7. A Systemic Identification of Organic Compounds, Shriner, Hermann, Morrill,

Curtin, fuson, 7th Edition(1998), John Wiley & Sons ltd Publications. Page No.
1123.

8. Handbook of Practical Chemistry (Inorganic & Organic), DR K.R.Mahadik,

S.H.Bhosale, 8th Edition (2008), Nirali Prakashan, Page No. 235.

9. Advanced Practical Medicinal Chemistry, Ashutosh Kar, New Age International ltd,
2004 1st Edition, Page No.130

10. Reaction Mechanisms in Organic Synthesis, R.K.Parashar, John Wiley & Sons Ltd
Publications, 2009, 1st Edition, Page No. 23-40.

11. The Merk Index, An Encyclopedia of Chemicals Drugs and Biological, edited by
Maryodele, J.Meli, P.E. Heckelman, 14th edition, Page No. 130

12. Experimental Pharmaceutical Organic Chemistry by K.S.Jjain, P.B.Miniyar,

T.S.Chitre 2nd edition, Career Publication, Page No. 19-25.

~49~

View publication stats