NITRATION, NITRATING AGENTS AND NITRATION EQUIPMENTS

Topic decribe about the nitration, nitrating agents, nitration equipments and kinetics in process chemistry. the chapters related m pharm pharmaceutical chemistry

1. CL BAID METHA COLLEGE OF PHARMACY, CHENNAI-97 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY PHARMACEUTICAL PROCESS CHEMISTRY DR. K. DHUNMATHI MPHARM, Ph.D. BY INDRAKUMAR S 2 ND SEMESTER M PHARM PHARMACEUTICAL CHEMISTRY   In The Topic Of Nitration, Nitrating Agents, Aromatic Nitration, Kinetics and Mechanism Of Aromatic Nitration Process Equipment for Technical Nitration, Mixed Acid for Nitration

2. Nitration The introduction of one or more nitro group (–NO2) into a reacting molecule. A process in which the nitro group (–No2) becomes chemically attached to a carbon, oxygen, or nitrogen atom in an organic compound is known as nitration. For example. Generally three reactions summarize the nitration chemistry 1. Nitro aromatic or nitro paraffinic compounds. CH4+ HNO3 CH3-NO2 + H2O

3. 2. Nitrate ester Nitration in which an ON bond is formed to produce a nitrate. CH3-OH+HNO3 CH3-NO2 +H2O 3. Nitramine: Nitration in which an NN bond is formed. NH3+HNO3 NH2-NO2+H2O IMPORTANCE OF NITRATION PRODUCTS: As a solvent As a dyestuffs As a pharmaceuticals As a explosives They also serve as useful intermediate for the preparation of other compounds, particularly amines which are prepared by the reduction of the corresponding nitro compounds.

4. NITRATING AGENTS A variety of reagents are used for nitration. These include 1. Fuming, concentrated, and aqueous nitric acid 2. Mixtures of nitric acid with sulfuric acid, acetic anhydride, acetic acid, phosphoric acid, and chloroform. 3. Nitrogen pentoxide N2O5 and nitrogen tetroxide N2O4 are also used in certain instances. Nitric acid and sulfuric acid mixture known as mixed acid is the most important nitrating medium from a practical standpoint. There is evidence that nitric acid exists in strong sulfuric acid as the nitryl ion NO2 +

5. In solutions weaker than 86% sulphur acid, the ionization of nitric acid is very slight but rapidly rises as sulfuric acid becomes more concentrated. In about 94% per cent sulphur acid, the nitric acid is practically completely ionized to nitryl ion. AROMATIC NITRATION The nitration of aromatic compounds can be represented by the equation ArH + HNO3 ---> ArNO3 + H2O Orientation The nitration agent is an electrophilic reactant and hence reaction will be favored at the carbon atom of the aromatic ring where the electron density is greatest. When the aromatic compound to be nitrated contains a substituent, the nitro group can enter at the ortho, meta or para positions. Certain substituents cause the electron density to be greater at the ortho and para positions than at the meta positions. Other substituents cause the electron density to be greater at the meta positions than at the ortho and para positions. These are therefore meta directing.

6. The isomer distribution in the nitration of various monosubstituted benzenes

7. Theory of Aromatic Substitution. A substituent influences the electron density in two important ways A. By the inductive effect 1. -I when it attracts electrons eg. -NMe3 + , -NO2, - COOEt , -halogen, COOH. The - I effect reduces the reactivity of all positions in the ring relative to benzene, the effect being greater in the ortho and para positions, leaving the meta positions to be more reactive The effect of a side chain between the substituent and the ring is to reduce the effect of the substituent % of meta derivatives in the mononitration of nitrobenzene and its side-chain homologues

8. 2. +I when it donates electrons Groups which produce a +I effect are - 0- and alkyl, phenyl B. By the mesomeric effect 1. –M -- Substituents can decrease the electron density in the ring by the -M effect. Substituents exhibiting the - M effect deactivate all the positions, the meta being less deactivated than the ortho and para. +M --- Substituents that have an unshared pair of electrons can increase the electron density in the ring by the mesomeric effect +M. +M is more pronounced at the ortho and para positions than at the meta positions Groups that show a +I and +M effect will be ortho-para directing Groups that have a -I and -M effect will make substitution more difficult and will be meta directing When the two effects are in opposition, i.e., +I and - M or -I and +M, the net result will be more difficult to predict. Acetoxy, methoxy, and acetamino groups all show the -I, +M effects. The +M effect is much more powerful than the -I effect, and so is predominantly the ortho-para directing in nitration.

9. The halogens also produce the -I and +M effects –ortho para directing Thus a compound in which the +I effect is dominant will, upon nitration, yield a larger ortho: para ratio of products than will a compound in which the +M effect is dominant. The ortho:para ratio is also influenced by the nitration medium.

10. Kinetics and mechanism of aromatic nitration The kinetics of the nitration reaction depends upon the reaction medium. In strong sulfuric acid. Compounds which are nitrated at a conveniently measurable rate in this system are those which have strong -I and -M effects such as nitrobenzene, anthraquinone, and ethyl benzoate. The rate of all these nitrations is proportional to the concentration of added nitric acid and of organic substrate. Rate = k (HNO3) ( ArH ) The reaction rate rises sharply with increasing sulfuric acid concentration and reaches a maximum at about 90 per cent H2SO4 and then falls off at higher acid concentrations. The generally accepted mechanism is

11. 2. Nitration in Organic Solvents . In the organic solvents nitromethane or acetic acid, with nitric acid in large excess, the kinetics of the nitration process depends upon the aromatic compound being nitrated. Compounds such as nitrobenzene or ethyl benzoate which possess strongly deactivating groups are nitrated at a rate which is proportional to the concentration of the substrate, i.e., the reaction is first order. Compounds which are more reactive than benzene, such as toluene, xylene, and p- chloranisole , react at a rate which is independent of the concentration of the substrate, i.e. ,the reaction is zero order. For substrates of intermediate reactivity reaction rate depends on concentration and kinetics is intermediate between first and zero order. 3. Nitration in Aqueous Nitric Acid Highly reactive substrates show zero-order kinetics, and less reactive compounds show first-order kinetics in about 40 mole per cent aqueous nitric acid. The rate-determining step in each reaction is the formation of the nitryl ion. The exchange of oxygen between nitric acid and water occurs in the following steps:

12. Effect of Nitrous Acid on Nitrations . Nitrous acid or nitrogen dioxide in certain instances exerts an inhibiting effect and in other instances exerts a catalytic effect on aromatic nitrations .  The inhibiting effect is observed in the nitration of compounds having no activating groups. These reactions are necessarily carried out either in strong nitric acid or in mixed acid. In these media the nitrous acid forms the nitrosyl ion, NO+ which decreases the concentration of nitryl ions and thus reduces the reaction rate.  The catalytic effect is observed in the nitration of reactive substrates such as anisole or dimethylaniline, which are nitrated in relatively weak nitric acid where the nitryl ion concentration is low. The catalysis is due to the formation of a nitroso compound which is oxidized to the nitro compound.

13. Nitration of paraffinic hydrocarbons Gas-phase Reactions. Paraffins are quite inert to nitryl ion but are susceptible to attack by free radicals. The nitration of these compounds as practiced commercially is carried out in the vapor phase and at temperatures of 350-450°C. These reactions are proceeds via free radical mechanism. Nitric acid of 70 % or less is generally used, although nitrogen dioxide can also be used.

14. Highly branched hydrocarbons undergo less fission during nitration than do their less-branched isomers. Bromine has a beneficial effect on both yields and conversions to nitroparaffins using nitric acid. 2. Liquid-phase Nitration. This reaction is of less importance than the gas phase nitration because of low yields, lower conversions, and the occurrence of unwanted side reactions. The principal liquid-phase nitration reaction of hydrocarbons is replacement of hydrogen atoms by nitro groups.  Under the proper conditions nitration can be carried out safely and products could be obtained in good yield. Nitrogen dioxide is the nitrating agent, and air is added to oxidize any nitric oxide to the dioxide.

15. Heat of Nitration. The nitration reaction must be controlled by systematic cooling designed to withdraw the energy evolved. When all the energy set free by an exothermic reaction is forced to appear as heat, the quantity of it lost to the cooling mechanism equals the decrease in enthalpy: Q = the heat of reaction To determine the heat evolved during the actual process of nitration of a hydrocarbon by mixed acids, it is necessary to consider not only the heat of nitration but also various heats of solution.

16. PROCESS EQUIPMENT FOR TECHNICAL NITRATIONS Changed from batch-type operations to continuous-type processes carried out in stainless-steel vessels. The high heats of reaction and dilution involved in nitration, are taken up by coils or jackets cooled by refrigerated brine. Batch processes have the following advantages compared to continuous processes Flexibility. Each batch of material passing through the process is separate. It is usually easier to introduce process variations into a batch process than into a continuous one. Plants may be readily converted from the production of one nitrated material to another. Labor Usage. For high rates of production when large batches are used the labor efficiency of a batch process may be just as good as that of a continuous process. Continuous processes Advantages Lower Capital Costs. For a given rate of production, the equipment needed for a continuous process is smaller than for a batch process.

17. Safety. Because of the relatively small size of continuous-process equipment, there is less material in process at any time. In the case of high explosives made by nitration, such as nitroglycerine , this safety factor of a continuous process is very attractive. Labor Usage . In the nitration field, a continuous process is usually a more efficient labor user than a batch process. Batch Nitration. Nitration is usually done in closed cast-iron/steel vessels/mild carbon steel Nitrator consists of an upright cylindrical vessel containing some kind of cooling surface, a means of agitation, feed inlet or inlets, and product outlet lines. Most nitrators are also equipped with a large-diameter quick dumping line for emergency use if the reaction gets out of control or the temperature rises because of failure of agitation or cooling In such an emergency the contents of the nitrator may be dumped rapidly into a large volume of water contained in a "drowning tub."

18. A common accessory for a nitrator is a suction line in the vapor space above the liquid charge to remove the acid fumes and oxides of nitrogen which may be liberated. The two factors of prime importance in the design of nitrators are (1) Degree of agitation -Agitation must be very efficient to obtain smooth reactions and to avoid local overheating (2) Control of temperature –Cooling or other temperature control in nitrators is generally accomplished by coils of tubes through which either cold water or brine for cooling may be circulated or hot water or steam for heating. Ommercial nitrating operations generally include the separation of nitric and sulfuric acids, the manufacture of nitric and sulfuric acids, and the separation of the nitrated product from the spent acids. Product purifications by unit operations such as washing, distillation, and crystallization are also commonly employed.

19. CONTINUOUS NITRATION Nitration reactions in a continuous process are carried out in the same type of vessels as those used for batch nitration, with the exception that an overflow pipe is provided for the continuous withdrawal of products and continuous feed of all reactants. Schmid nitrator In this apparatus the material to be nitrated is fed into the top of the nitrator and is immediately drawn down through the sleeve and thoroughly mixed with the spent acid and reacting materials. In the bottom of the nitrator, fresh mixed acid is fed in and is immediately mixed with the other reactant using the high flow rate induced by the agitator and the baffles. The reacting materials then pass upward with high velocity through the tubes surrounded by refrigerated brine circulating in the jacket. Product and spent acids are withdrawn continuously from the nitrator through the overflow line.

20. BIAZZI NITRATOR In this apparatus the turbine-type agitator provides intensive agitation. A vortex is formed in the centre about the agitator shaft. The reactants, both of which are fed into the nitrator through the top, are immediately drawn into this vortex, thoroughly mixed, and circulated down through the centre of the bank of cooling coils and back up through and around the coils. The high velocity imparted to the nitrator contents makes for efficient mixing and heat transfer.

21. PREPARATION OF NITROBENZENE Hot sulphuric acid at 90 °C is run from the heat-insulated storage tank (B) into one of a battery of nitrators. Under vigorous agitation, sufficient 63% nitric acid is added to the nitrator to produce a mixed acid containing 4% HNO3. Sufficient benzene is then delivered from its storage scale tank to react with all the nitric acid in the nitrator. Upon completion of the reaction, which takes about 10 min, the agitation is stopped and the charge permitted to settle. While the separation of the nitrobenzene and spent acid proceeds, another nitration is started, thus providing a continuity of operation. The crude supernatant nitrobenzene is drawn off through side outlets (C) on the nitrator and sent to the neutralizer. The spent acid, which is free of nitric acid but contains small amounts of nitrobenzene, is drawn off in operating sequence at the outlets (Dl to D4) located at the base of the nitrators. The spent acid is first directed to the acid heater (E) for concentration.