Ajay Dabhade..pdf

NITRATION
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© RamaiahUniversity of Applied SciencesFacultyofPharmacy
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Faculty of Pharmacy © RamaiahUniversity of Applied Sciences
PRESENTED BY
Dabhade Ajaykumar Vikram
Roll.No. – 05
M.Pharm (Sem -2)
(Pharmaceutical Chemistry)
GUIDANCE BY
Prof. M.A. Raskar
(M.Pharm)
Pharmaceutical Chemistry
DR. VITHALRAO VIKHE PATIL FOUNDATION’S
COLLEGE OF PHARMACY, VILAD GHAT AHMEDNAGAR(2022-2023)
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Contents
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• Introduction to Nitration
• Nitrating agents
• Aromatic Nitration & its
mechanism
• Kinetics of Nitration
• Summary
• References
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Introduction
• Nitration is a synthetic method defined as the process of adding a nitro
group to an aliphatic or aromatic compound.
• It is based on substitution principle where nitro group can substitute
one or more hydrogens in an aliphatic or aromatic ring system.
• Aromatic compounds easily undergoes nitration then the aliphatic
compounds.
• The nitro group act as a strong electrophile & attacks on the more
electron rich molecule .
• A mixed acid reagent is used to perform nitration process.
• Nitration process is carried out under specific reaction conditions with
certain reaction kinetics.
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Nitrating agent
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• Nitrating agent is a main reacting species that facilitate nitration process.
• The proportion of two acids is equal in a mixture.
• The mixture of acids is also called as mixed acid reagent.
• Nitric acid act as a sourceof nitro group.
• The role of sulphuric acid is to generatenitro group from nitric acid.
• The nitro group is generatedin situ i.e. in reaction mixture & it is also called as nitryl
or nitronium ion.
• The ion act as electrophile wherein the nitrogen atom bears positive charge.
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Formation of nitro group
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• Number of molecules generatedfrom one mole of nitric acid in sulphuric acid is
given by Van’t Hoff factor (i) :-
• Nitrogen tetroxide, nitrogen pentoxide,ethyl nitrate can also be used as source for
nitro group with sulphuric acid. The Van’t Hoff factor(i) can be shown as: -
• Acetic acid, acetic anhydride, phosphoric acid and chloroform are also used.
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• Percentageof sulphuric acid
affectsionisation of nitric acid –
more concentratedsulphuric
acid causes more ionisation.
• Less than 86% sulphuric acid
causes slight ionisation & more
than 94% causes complete
ionisation of nitric acid.
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Aromatic Nitration
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• Introductionof nitro group on an aromatic ring to produce nitro aromatic
derivatives.
• Nitration can be done for both carbocyclic& heterocyclicaromatic compounds.
• Substituentspresenton aromatic ring affect the nitration process.
• In case of unsubstitutedring, the attackof nitro group occurs on any position
whereas in substitutedring, it is governed by the substituentpresent.
• The substituents include– nitro group, aldehyde, carboxyl, ester, ketone,hydroxy,
alkyl, amino or alkyl amine, halogens etc.
• In monosubstitutedring, nitro group can attackon either ortho, meta or para
positions depending upon the type of substituent& its affect.
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• The substituentcan either activate or deactivate the aromatic ring by increasing or
decreasing the electron density of the ring respectively.This effectis called
Inductive effect.
• Inductive effectcan be positive or negative.
• Based on the above facts, substituentsare of two types: -
• Electron donating: - they show positive inductive effect & activate the aromatic ring
by increasing the electron density & are ortho - para directing in nature. Examples –
hydroxy group, amines, alkyl groups, ether,amides.
• Three types of electrons can be donated – sigma, pie & lone pair electrons.
• Electron withdrawing: - showsnegative inductive effect& deactivatethe ring by
decreasing the electron density & are meta directing in nature. Examples –
aldehyde, carboxyl group, ketone,nitro group, halogens, acid halides, anhydrides.
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Ortho : Para Ratio
• In case of ortho – para directing substrates,both the isomers are formed in different
amounts but the isomer to be consideredas major product depends on various
factors:-
• Steric factor – presence of bulky or large size electron donating groups forms para
isomer as major product. So the ratio is very small.
example : t-butyl benzene on nitration forms para isomer as major product.
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• Conformational factor– para isomer is highly stable conformationdue to symmetry
of structure.
• Inductive effect– greaterthe effect,more ortho isomer will form due to close
proximity of ortho positions towardselectron donating group.
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• Reaction medium – Aniline upon nitration yields ortho, para & meta isomers while
acetanilide gives para isomer as major product. Phenol gives 2,4,6 – trinitrophenol.
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Kinetics of Nitration
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• Kinetics of nitration reaction depends on reaction medium.
• In case of sulphuric acid, the aromatic ring having electron withdrawing groups are
more readily nitrated & the rate depends on concentrationof both substrate& nitric
acid.
RATE = k [HNO3][ ArH]
• Reaction rate increases with increasing strengthof sulphuric acid upto 90% strength
& above this, rate decreasesdue to hydrogen bonding between substrate&
sulphuric acid.
X = H, NO2, F, OH, NH2

Nitration in aqueous nitric acid
• Kinetics of highly reactive & low reactive substratesremain same in 40% aqueous
nitric acid i.e. zero order & first order respectively.
• Presence of water molecules solvatesthe nitryl ion formed in following steps:-
• The rate of nitration of reactive substratesis same as the rate of exchange of oxygen
between water & nitric acid.
• The rate of nitration of low reactive substratesis reduced in aqueous nitric acid.
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Nitration In nitrous acid
• Nitrous acid can show inhibitory effect & catalyticeffect in nitration process
depending on substratebeing nitrated.
• It is used with sulphuric acid or nitric acid & forms nitrosyl ion ( ), a weak
electrophile than nitryl ion.
• Highly reactive substrateslike anisole or dimethylaniline reacts with nitrosyl ion to
form nitroso compoundthat is oxidised to nitro compound.
• Whereas substrateswith no activating groups or low reactive substratesdo not
react with nitrosyl ion & reaction is not continuedfurther.
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Summary
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• Nitration is defined as introduction of nitro group to an aromatic or aliphatic
compound.
• Nitrating agent is used to form nitro group called nitronium or nitryl ion.
• Mixture of concentratednitric acid & concentratedsulphuric acid is commonlyused
as nitrating agent.
• Aromatic compoundseasily undergoesnitration than aliphatic compounds.
• Presence of substituentson aromatic ring affectsthe nitration process.
• The reaction medium affectsthe kinetics of nitration.

Reference
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• Groggins, P.,1958. Unit processes in organic synthesis. 5th ed. New York: McGraw-
hill, pp.60-73.
• Medicinal chemistry by Burger, 6th edition, Volume 1-8 .
• “ Advanced Organic Chemistry, Reaction,Mechanism and Structure” J March John
Wiley and sones , New York .

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