Nitration

it is a unit process widely used in laboratory & industrial scale to synthesize nitro compounds.

1. NITRATION By Burhanuddin Madriwala M.Pharm – SEM II Department of Pharmaceutical Chemistry M.S Ramaiah University of Applied Sciences

2. Contents Introduction to Nitration Nitrating agents Aromatic Nitration & its mechanism Kinetics of Nitration Summary References

3. 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. 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. Formation of nitro group

6. 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. 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. 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. 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. 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.

11. 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.

12. Reaction medium – aniline upon nitration yields ortho, para & meta isomers while acetanilide gives para isomer as major product. Phenol gives 2,4,6 – trinitrophenol.

13. 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

14. 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]

15. 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.

16. 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.

17. 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.

18. Reference Groggins, P., 1958.  Unit processes in organic synthesis . 5th ed. New York: McGraw-hill, pp.60-73.