NITRATION

PRESENTED BY
Dabhade Ajaykumar Vikram GUIDANCE BY
Prof. M.A. Raskar
Roll.No. – 05
(M.Pharm)
M.Pharm (Sem -2)
Pharmaceutical Chemistry
(Pharmaceutical Chemistry)

DR. VITHALRAO VIKHE PATIL FOUNDATION’S

COLLEGE OF PHARMACY, VILAD GHAT AHMEDNAGAR (2022-2023)

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Contents
• 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
• 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 source of nitro group.
• The role of sulphuric acid is to generate nitro group from nitric acid.
• The nitro group is generated in 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 generated from 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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 • Percentage of sulphuric acid
affects ionisation of nitric acid –
more concentrated sulphuric
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
• Introduction of nitro group on an aromatic ring to produce nitro aromatic
derivatives.
• Nitration can be done for both carbocyclic & heterocyclic aromatic compounds.
• Substituents present on aromatic ring affect the nitration process.
• In case of unsubstituted ring, the attack of nitro group occurs on any position
whereas in substituted ring, it is governed by the substituent present.
• The substituents include – nitro group, aldehyde, carboxyl, ester, ketone, hydroxy,
alkyl, amino or alkyl amine, halogens etc.
• In monosubstituted ring, nitro group can attack on either ortho, meta or para
positions depending upon the type of substituent & its affect.

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 • The substituent can either activate or deactivate the aromatic ring by increasing or
decreasing the electron density of the ring respectively. This effect is called
Inductive effect.
• Inductive effect can be positive or negative.
• Based on the above facts, substituents are 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: - shows negative inductive effect & deactivate the 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 considered as 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 conformation due to symmetry
of structure.
• Inductive effect – greater the effect, more ortho isomer will form due to close
proximity of ortho positions towards electron 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
• 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 concentration of both substrate & nitric
acid.
RATE = k [HNO3][ ArH]
• Reaction rate increases with increasing strength of sulphuric acid upto 90% strength
& above this, rate decreases due to hydrogen bonding between substrate &
sulphuric acid.

X = H, NO2, F, OH, NH2

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 Nitration in aqueous nitric acid
• Kinetics of highly reactive & low reactive substrates remain same in 40% aqueous
nitric acid i.e. zero order & first order respectively.
• Presence of water molecules solvates the nitryl ion formed in following steps: -

• The rate of nitration of reactive substrates is same as the rate of exchange of oxygen
between water & nitric acid.
• The rate of nitration of low reactive substrates is reduced in aqueous nitric acid.

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 Nitration In nitrous acid
• Nitrous acid can show inhibitory effect & catalytic effect in nitration process
depending on substrate being nitrated.
• It is used with sulphuric acid or nitric acid & forms nitrosyl ion ( ), a weak
electrophile than nitryl ion.

• Highly reactive substrates like anisole or dimethylaniline reacts with nitrosyl ion to
form nitroso compound that is oxidised to nitro compound.

• Whereas substrates with no activating groups or low reactive substrates do not

react with nitrosyl ion & reaction is not continued further.
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 Summary
• 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 concentrated nitric acid & concentrated sulphuric acid is commonly used
as nitrating agent.
• Aromatic compounds easily undergoes nitration than aliphatic compounds.
• Presence of substituents on aromatic ring affects the nitration process.
• The reaction medium affects the kinetics of nitration.

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 Reference
• 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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THANK YOU

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