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NITRATION
By
Burhanuddin Madriwala
M.Pharm – SEM II
Department of Pharmaceutical Chemistry
M.S Ramaiah University of Applied Sciences
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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.
• Mixture of concentrated sulphuric acid & concentrated nitric acid is used as nitrating
agent.
• 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 insitu 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 organic solvents
• Organic solvents include acetic acid, acetic anhydride, acid halides etc. which can be
used in place of sulphuric acid.
• Formation of nitryl ion occurs due to protonation of nitric acid or any other nitro
group sources by the mineral acid or organic solvent. More acidic & polar the acid or
solvent is, easy formation of nitryl ion occurs.
• Highly reactive substrates like toluene, xylene, aniline etc. gets nitrated with same
rate & thus formation of nitryl ion becomes rate determining step. Thus, these
substrates follows zero order kinetics.
Rate = k
• Low reactive substrates like nitrobenzene, benzaldehyde, benzoic acid etc. gets
nitrated very slowly & with different characteristic rate. Thus formation of nitryl ion
is same & rate of reaction depends on concentration of substrate. Hence, these
substrates follows first order kinetics.
Rate = k [substrate]
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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.

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Nitration

  • 1. © Ramaiah University of Applied Sciences 1 Faculty of Pharmacy © Ramaiah University of Applied Sciences 1 Faculty of Pharmacy © Ramaiah University of Applied Sciences 1 Faculty of Pharmacy © Ramaiah University of Applied Sciences 1 Faculty of Pharmacy NITRATION By Burhanuddin Madriwala M.Pharm – SEM II Department of Pharmaceutical Chemistry M.S Ramaiah University of Applied Sciences
  • 2. © Ramaiah University of Applied Sciences 2 Faculty of Pharmacy © Ramaiah University of Applied Sciences 2 Faculty of Pharmacy © Ramaiah University of Applied Sciences 2 Faculty of Pharmacy © Ramaiah University of Applied Sciences 2 Faculty of Pharmacy Contents • Introduction to Nitration • Nitrating agents • Aromatic Nitration & its mechanism • Kinetics of Nitration • Summary • References
  • 3. © Ramaiah University of Applied Sciences 3 Faculty of Pharmacy © Ramaiah University of Applied Sciences 3 Faculty of Pharmacy © Ramaiah University of Applied Sciences 3 Faculty of Pharmacy © Ramaiah University of Applied Sciences 3 Faculty of Pharmacy 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.
  • 4. © Ramaiah University of Applied Sciences 4 Faculty of Pharmacy © Ramaiah University of Applied Sciences 4 Faculty of Pharmacy © Ramaiah University of Applied Sciences 4 Faculty of Pharmacy © Ramaiah University of Applied Sciences 4 Faculty of Pharmacy Nitrating agent • Nitrating agent is a main reacting species that facilitate nitration process. • Mixture of concentrated sulphuric acid & concentrated nitric acid is used as nitrating agent. • 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 insitu 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.
  • 5. © Ramaiah University of Applied Sciences 5 Faculty of Pharmacy © Ramaiah University of Applied Sciences 5 Faculty of Pharmacy © Ramaiah University of Applied Sciences 5 Faculty of Pharmacy © Ramaiah University of Applied Sciences 5 Faculty of Pharmacy Formation of nitro group
  • 6. © Ramaiah University of Applied Sciences 6 Faculty of Pharmacy © Ramaiah University of Applied Sciences 6 Faculty of Pharmacy © Ramaiah University of Applied Sciences 6 Faculty of Pharmacy © Ramaiah University of Applied Sciences 6 Faculty of Pharmacy • 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.
  • 7. © Ramaiah University of Applied Sciences 7 Faculty of Pharmacy © Ramaiah University of Applied Sciences 7 Faculty of Pharmacy © Ramaiah University of Applied Sciences 7 Faculty of Pharmacy © Ramaiah University of Applied Sciences 7 Faculty of Pharmacy • 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.
  • 8. © Ramaiah University of Applied Sciences 8 Faculty of Pharmacy © Ramaiah University of Applied Sciences 8 Faculty of Pharmacy © Ramaiah University of Applied Sciences 8 Faculty of Pharmacy © Ramaiah University of Applied Sciences 8 Faculty of Pharmacy 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.
  • 9. © Ramaiah University of Applied Sciences 9 Faculty of Pharmacy © Ramaiah University of Applied Sciences 9 Faculty of Pharmacy © Ramaiah University of Applied Sciences 9 Faculty of Pharmacy © Ramaiah University of Applied Sciences 9 Faculty of Pharmacy • 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.
  • 10. © Ramaiah University of Applied Sciences 10 Faculty of Pharmacy © Ramaiah University of Applied Sciences 10 Faculty of Pharmacy © Ramaiah University of Applied Sciences 10 Faculty of Pharmacy © Ramaiah University of Applied Sciences 10 Faculty of Pharmacy
  • 11. © Ramaiah University of Applied Sciences 11 Faculty of Pharmacy © Ramaiah University of Applied Sciences 11 Faculty of Pharmacy © Ramaiah University of Applied Sciences 11 Faculty of Pharmacy © Ramaiah University of Applied Sciences 11 Faculty of Pharmacy
  • 12. © Ramaiah University of Applied Sciences 12 Faculty of Pharmacy © Ramaiah University of Applied Sciences 12 Faculty of Pharmacy © Ramaiah University of Applied Sciences 12 Faculty of Pharmacy © Ramaiah University of Applied Sciences 12 Faculty of Pharmacy 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.
  • 13. © Ramaiah University of Applied Sciences 13 Faculty of Pharmacy © Ramaiah University of Applied Sciences 13 Faculty of Pharmacy © Ramaiah University of Applied Sciences 13 Faculty of Pharmacy © Ramaiah University of Applied Sciences 13 Faculty of Pharmacy • 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.
  • 14. © Ramaiah University of Applied Sciences 14 Faculty of Pharmacy © Ramaiah University of Applied Sciences 14 Faculty of Pharmacy © Ramaiah University of Applied Sciences 14 Faculty of Pharmacy © Ramaiah University of Applied Sciences 14 Faculty of Pharmacy • Reaction medium – aniline upon nitration yields ortho, para & meta isomers while acetanilide gives para isomer as major product. Phenol gives 2,4,6 – trinitrophenol.
  • 15. © Ramaiah University of Applied Sciences 15 Faculty of Pharmacy © Ramaiah University of Applied Sciences 15 Faculty of Pharmacy © Ramaiah University of Applied Sciences 15 Faculty of Pharmacy © Ramaiah University of Applied Sciences 15 Faculty of Pharmacy
  • 16. © Ramaiah University of Applied Sciences 16 Faculty of Pharmacy © Ramaiah University of Applied Sciences 16 Faculty of Pharmacy © Ramaiah University of Applied Sciences 16 Faculty of Pharmacy © Ramaiah University of Applied Sciences 16 Faculty of Pharmacy 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
  • 17. © Ramaiah University of Applied Sciences 17 Faculty of Pharmacy © Ramaiah University of Applied Sciences 17 Faculty of Pharmacy © Ramaiah University of Applied Sciences 17 Faculty of Pharmacy © Ramaiah University of Applied Sciences 17 Faculty of Pharmacy Nitration in organic solvents • Organic solvents include acetic acid, acetic anhydride, acid halides etc. which can be used in place of sulphuric acid. • Formation of nitryl ion occurs due to protonation of nitric acid or any other nitro group sources by the mineral acid or organic solvent. More acidic & polar the acid or solvent is, easy formation of nitryl ion occurs. • Highly reactive substrates like toluene, xylene, aniline etc. gets nitrated with same rate & thus formation of nitryl ion becomes rate determining step. Thus, these substrates follows zero order kinetics. Rate = k • Low reactive substrates like nitrobenzene, benzaldehyde, benzoic acid etc. gets nitrated very slowly & with different characteristic rate. Thus formation of nitryl ion is same & rate of reaction depends on concentration of substrate. Hence, these substrates follows first order kinetics. Rate = k [substrate]
  • 18. © Ramaiah University of Applied Sciences 18 Faculty of Pharmacy © Ramaiah University of Applied Sciences 18 Faculty of Pharmacy © Ramaiah University of Applied Sciences 18 Faculty of Pharmacy © Ramaiah University of Applied Sciences 18 Faculty of Pharmacy 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.
  • 19. © Ramaiah University of Applied Sciences 19 Faculty of Pharmacy © Ramaiah University of Applied Sciences 19 Faculty of Pharmacy © Ramaiah University of Applied Sciences 19 Faculty of Pharmacy © Ramaiah University of Applied Sciences 19 Faculty of Pharmacy 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.
  • 20. © Ramaiah University of Applied Sciences 20 Faculty of Pharmacy © Ramaiah University of Applied Sciences 20 Faculty of Pharmacy © Ramaiah University of Applied Sciences 20 Faculty of Pharmacy © Ramaiah University of Applied Sciences 20 Faculty of Pharmacy 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.
  • 21. © Ramaiah University of Applied Sciences 21 Faculty of Pharmacy © Ramaiah University of Applied Sciences 21 Faculty of Pharmacy © Ramaiah University of Applied Sciences 21 Faculty of Pharmacy © Ramaiah University of Applied Sciences 21 Faculty of Pharmacy Reference • Groggins, P., 1958. Unit processes in organic synthesis. 5th ed. New York: McGraw- hill, pp.60-73.