I General Introducti On

CHAPTER - I

GENERAL INTRODUCTI ON

CopyrightKharagpur IIT CHAPTER I GENERAL INTRODUCTION

The oxidation of the methyl group in various mono methyl pyridines, commonly called picolines, leads to the formation of the corresponding pyridinecarboxylic acids. The oc , ^ , and Y-picolines give on oxidation picolinic, nicotinic and isonicotinic acids respectively :-

(i)

oL -or 2-picoline picolinic acid or pyridine 2-carboxylic acid

(ii)

jS -or 3-picoline nicotinic acid,"niaciann or pyridine 3-carboxylic acid

CHo COOH 02 (iii)

isonicotinic acid or CopyrightKharagpurpyridine 4-carboxylic acid. 1 . Importance of Pyridine Carboxvlie Acids

The pyridine earboxylic acids, particularly nicoti nic and isonicotinicIIT aciSs are very important as precursors of a

1 2

number of potential drugs ^ *

Nicotinic acid, commonly known as niacin, had been synthesised long before its function in the human system could be discerned. The acid in the form of its amide was later found to be one of the members of the vitamin B-eomplex group. It is an antineuritie factor and highly effective in curing human pellagra (a disease characterised by skin lesions and inflammation of the tongue)•

Nicotinic acid is the starting material for the synthesis of coramine (N,N-diethylnicotinamide ), a very powerful analeptic and respiratory stimulant•

A number of derivatives of nicotinic acid have been tested for their action on blood-vessels• 3«Pyridyl metha nol is the most promising compound in this group* Another deri vative of nicotinic acid, isopropyl nicotinate, has been introduced as a powerful vasodilator and also as a local anaesthetic*

Nicotinic acid is needed in the human system for the synthesis of two important coenzymes, DPN (diphosphopyridine nucleotide,Copyright coenzyme I) andKharagpur TPN (triphosphopyridine nucleotide, coenzyme I I ) •

A number of compounds derived from isonicotinic acid have beenIIT found to be very effective in the chemotherapy of tuberculosis* The tuberculostatic activity of isoniazide i3 several times more than that of any other synthetic substance or antibiotic* The compound has very low toxicity and is generally used in combination -with streptomycine* It is prepared in excellent yields by reacting an ester of isonicotinic acid with hydrazine:

COOCH3 NH2NH2 C0NHNH2

o 0 2 * Raw materials for the production of pyridine carboxylic acids:-

k number of methods using raw materials other than picolines have been reported for the production of the indivi dual pyridinecarboxylic acids* 4 short description of these methods is given below:

(i) Production of nicotinic acid:

(a) Oxidation of nicotine with nitric acid:

CHg - CHg JH CHg ---5222--- ^ f S ^ C O O H ^ ^ ^ (oxidation) T J CH3 Kharagpur h Copyright(b) Oxidation of quinoline followed by decar boxylation at the 2-position: IIT °... >■ 0H heat _ ri^C O O H U c o o h U

The oxidation Is carried out with sulphuric acid using selenium as catalyst* The method is an important one for the commercial production of nicotinic acid novTa^days*

The cyanopyridine is obtained from pyridine

1 . Brg | hr 2 .

(d) Oxidation of 2-methyl 5-ethylpyridine, followed by decarboxylation in the 2-positions

COOH

(ii) Production of isonicotinic acid:

Isonicotinic acid has been industrially obtained makingCopyright use of the followingKharagpur reactions!- (a) From citric acid - The triamide of citric

acid when heated with sulphuric acid is converted to citra- zinic acid, whichIIT on subsequent treatment with POCI3 and HI, gives isonicotinic acid* « 5

COOH CHg - COOH h ^ o NH3 . J °*NH2 4 9 (OH)- COOH ■> >H -XbH^CH HO OH CHg - COOH 29 2 HgFIOC C0NH2

COOH COOH COOH POCI3 HI HO C g J OH o o

(b) By oxidation of 4-ethyl pyridine, produced

by the reductive acylation of pyridines Q^ 5— CHo - CH3 a Q COOH

Plcolines as raw materials for pyridine carboxylic acids

The picolines are important starting materials for the production of pyridine carboxylic acids* They can be derived either from natural sources or synthetically* The major supply is from coal Kharagpur carbonisation and coal tar industri es.Copyright Approximately 0*014 lb* of total pyridine bases are present per 1000 cuft. of the coke oven gases, of which about 70$ is pyridine itself; the remainder is a mixture of various alkylatedIIT pyridines, such as picolines, lutidines, .collidines and quinolines* 6

Recovery of the pyridine bases from coal distillation products

(a) From coal tar?

About 40# of the total pyridines present in

the coke oven gas condenses with the tar* On distilling the tar these bases come in the middle oil fraction* After separating the naphthalene by cooling and extracting the acids with caustic soda the oil is distilled* The distillate is extracted with sulphuric acid to separate the tar bases as their water soluble salts* The non-aqueous layer is separated . and if necessary, the aqueous layer may be steam distilled to remove any dissolved oils* The pyridine bases are regene rated by neutralising this extract with caustic soda or ammonia solution* They are dried by azeotropic distillation with benzene, and further purified by fractional distillation*

(b) From the mother liquor left after ammonium sulphate crystallisation in the ammonia recovery system;

In the ammonia recovery unit, the mother liquor left after ammonium sulphate crystallisation contains about 2-6$ pyridines in the form of their sulphates* This liquor is Copyright neutralised by passing Kharagpur ammonia vapours through it to liberate the bases* The effluent from the neutraliser is adjusted to pH 6 and is returned to the ammonia saturator and the vapoursIIT are passed through a reflux condenser at 92-96°C and finally condensed* The condensate separates into two layers,

the lower layer is worked up for ammonia recovery* The upper layer consisting of pyridine bases contains about 15# water ■which is removed by azeotropic distillation -with benzene.

The bases are further refined by fractional distillation« The crude contains about 70$ pyridine, 8$ picolines and 2,6 lutidine, 0*6$ 2,4,6 - collidine and the remainder is a mixture of aniline and quinoline bases.

During the distillation of this mixture pyridine

(b.p. 115.3°) and 2-pieoline (b.p.l28°) can be obtained in

good purity. The next higher boiling fraction which contains 3-picoline (b .p .143.5°), 4-picoline (b .p .143.1°) and 2 ,6 -

lutidine (b .p .143° ) is the commercial" p-picoline*' • These

bases cannot be separated by fractional distillation, because the boiling points are too close to each other# The methods of separation of 3- and 4-picolines and also the elaborate methods of their purification will be discussed in detail later.

Synthetic methods for the production of pyridine bases:

Numerous synthetic methods have been suggested for the production of pyridine bases. A few of them involving

cheaper starting materials will be listed here* In all these methods ammonia is condensedKharagpur either with an aldehyde, alcohol or Copyright acetylene to build up the pyridine molecule*

(a) Condensation of aldehydes with ammonia

IITThe condensation of crotonaldehyde and ammonia was studied by Chichibabin^2^ . The reaction mixture consist

ing of the vapours of ammonia and crotonaldehyde was passed over alumina at 340° • A mixture of 3-ethyl 4-pieoline, 5-ethyl 2-picoline, 2-picoline, 4-picoline, and some other homologues was obtained. This condensation when carried out in the liquid phase at 250°C and under pressure using ammo nium acetate as a catalyst led to a higher yield (18$) , but the product was exclusively 5-ethyl 2-picolijne^ . in most of the experiments carried out with acetaldehyde and ammonia, in liquid phase, 5-ethyl, 2-pieoline was the main product* Conversions as high as 70$ have been reported by using ammonium acetate as catalyst in a continuous reactor, o (4) temperature being 225-265 C *

The yield of pieolines was found to be higher in the vapour phase than in the liquid phase* A mixture of acetaldehyde and ammonia when passed over alumina (!I$) on silica catalyst at 500°C, gave 20.4$ 2-picoline and 17.6$ 4-picolinev ' . The condensation of acetaldehyde and ammonia in presence of a catalyst containing 82$ silica, 15$ alumina and 3$ thoria, gave 34# 2-picoline, 32$ 4-picoline, 10$ 5- /M ethyl 2-picoline and 3$ 3-ethyl 4-picoline at 450°C • 3-picoline was obtained in 50-57$ yield by vapour phase condensationCopyright of erotqnaldehydeKharagpur with ammonia at 350°C, using aluminium phosphate catalyst and benzene vapour or steam as a d i l u e n t ^ ^ • Traces of pyridine was also produced.

IIT(b) Condensation of ammonia with alcohols:

The reaction proceeds probably through the

intermediate conversion of alcohol to the corresponding aldehyde and the products in general are the same as those with the aldehydes* Vapour phase condensation of ethylene glycol with ammonia over alumina at 400°C, produced 2- and (9) 4-picolines and no pyridine * It has also been reported that the condensation of allyl alcohol with ammonia in pre sence of alumina catalyst gave 20% yield of 3-picoline at o 400 C, nitrogen was used as a- diluent in thfe case',J-w/ •

A great deal*of research has been done on the condensation of ammonia with acetylene leading to the formation of pyridine bases and encouraging results have thus been obtained* Catalysts like the oxides or carbides of iron,chromium, tungsten or aluminium and also cadmium chromate, molybdate, tungstate or vanadate, supported on silica, alumina or clay were found to be promising for this reaction, the favourable range of temperature being 250-350°c. ( )( ) It has been reported 11 12 that under optimum conditions, the yield of pyridine bases was as high as 79$.

Separation and purification of picolines from a mixture of pyridineCopyright bases: Kharagpur Commercial picoline, irrespective of the method of production, is always a mixture of the three isomers as well as some otherIIT pyridine bases* Separation of the indivi dual picolines from such mixtures has been a subject for investigation by many workers and many processes have been developed. The preliminary separation is effected by 10

fractional distillation of the crude. By this process, pyridine (b.p.ll5.3°C) and 2-picoline (b.p.l28°C) can be obtained in sufficiently pure state. The next higher frac tion, wp -picoline" of commerce, is a mixture of 3-picoline

(b.p.l43.5°C), 4-picoline(b.p*143.1°C) and 2,6 lutidine

(b.p.l43°C)• The boiling points are so close to each other that fractionation by ordinary methods is not possible. Much thought has been given to the separation of this mix ture and plenty of patented and published literature is available on this issue.

The methods make use essentially of the following

principles viz.

(a) Methods based on the difference in physical properties of the components.

(b) Methods based on the formation of salts or complexes.

(c) Methods based on chemical reactivity. (a) Methods based on the Kharagpur difference in physical properties Copyright(i) Distillation of mixture of hydrochlorides of 3- and 4-picolines and 2,6 lutidine^13) .

(ii) Steam distillation with sulphur dioxide (3- and 4-picolinesIIT of high purity are thus obtained. (iii) Azeotropic distillation with acetic acid (it gives 2,6 lutidine in 32$ yield and of 95% purity, 3-picoline 11

in 26$ yield of 97$ purity and 4-picoline 28$ yield of 98$ purity.

(b) Methods based on the formation of salts or complexes

Several methods have been hit upon in -which advan tage has been taken of the differences in the solubility of various salts of these bases* Thus 4-picoline can be preci pitated as its salicylate from a mixture of 3- and 4-picolines* The base can be regenerated by treatment with alkali* From a mixture of the three bases, 4-picoline, 2,6 lutidine and 3-picoline, the hydrochlorides can be fractionally pre cipitated by treatment with hydrogen chloride* 2,6 lutidine is first to precipitate, followed by 4- picoline^• Similarly, oxalic acid separates 4-picoline of high purity in the form of its oxalate^19^*

The methyl group at 2, or 4-positions in the pyridine ring is more reactive than that in the 3-position. Consequently when a mixture of the three picoline isomers is refluxed with phthalic and Kharagpur acetic anhydrides for several hours,Copyright the bases having methyl groups at 2, and 4-positions react readily to form dark brown condensation products while 3-picoline is left unreacted^•

MethodsIIT have also been suggested for the purifica tion of the M^ -picoline” fraction by vapour phase oxidation with air over a solid catalyst like Y20&^22\ The more # reactive bases are oxidised to their acids leaving behind most 12

of the 3-picoline*

Any one of the above mentioned methods can be used for separating the picolines* The method to be used will depend on the nature and composition of the mixture to be worked upon* The methods utilising the high chemical reactivity of the methyl group in 2- and 4-position can be utilised only in cases where the chief component of the mixture is 3-picoline, otherwise much of the bases will go to waste*

3 • Oxidation of picolines to the corresponding carboxylic acids:

The oxidation of picolines can be carried out either in the liquid phase or in the vapour phase.

(i) Liquid phase oxidation of picolines:

The liquid phase operation has been the conven tional commercial method for a very long time* Various oxi dising agents have been tried. Only the important methods are described here and the other possible ones are briefly outlined*CopyrightKharagpur The most common oxidising agents for the liquid phase process are (a) sulphuric acid (with selenium as catalyst) (b) IIT potassium permanganate and (c) nitric acid. (a) Sulphuric acid as the oxidising agent:

Woodward, Badgett and Kaufman^23^ studied the 13

oxidation of 3-picoline, quinoline and nicotine to nicotinic acid in presence of sulphuric acid* These investigators used mercuric sulphate, bismuth nitrate, copper selenate and selenium as catalysts, the last one showing the best per formance. Muller^24*25) used SeOCl2 and Hjpe03 as catalysts and found that the oxidation of 3-picoline could be carried out at lower temperatures on addition of a little nitric acid (250-260°C instead of 305-315°C without nitric acid)• The pyridine carboxyllc acids were recovered from the above reaction mixture by precipitation with copper sulphate. The copper salt was decomposed by boiling with sodium hydroxide. The nicotinic acid was liberated from the sodium nicotinate by neutralising with concentrated hydrochloric acid. Cook and Yunghaus^2^ oxidised 2, and 4, picolines with selenium dioxide in diphenyloxide solution at a much lower temperature (155-185°C). The product could thus be isolated more easily. (27) Jerchel, Bauer and Hippchen reported the oxidation of pure alkylpyridines with Se02 at reflux temperatures, with out any solvent.

(b) Potassium permanganate as the oxidising agent? CopyrightPotassium permanganateKharagpur is the most widely used oxidising agent for the oxidation of picolines. It has been conveniently used in neutral solutions below 100°C. The time of reaction dependsIIT largely on the temperature (about 6 hrs. at 70°C), Manganese dioxide, which is formed during the re action, is filter pressed, the filtrate concentrated and the acid? precipitated at pH 3.6 by concentrated hydrochloric acid. Yields ranging from 50-60$ have .been reported(28“31) .

Pyridine earboxylic acids have been obtained in good yields by oxidising the picolines with nitric acid* The oxidation has been reported in the liquid phase at temperatures around 200°C under a pressure of 30-40 kg/cm2^ 2’ * ^ * Use of very strong acid is disadvantageous* Most of the patented processes make use of phosphoric or sulphuric acid in each batch probably to raise the temperature of the reaction^34’ 35) • Yields as high as 93.5$ of isonicotinic acid from 4-picoline have been claimed^33) .

Nitric acid has also been used for the vapour phase oxidation of alkylpyridines in presence-of catalysts like the oxides of boron and selenium^

(d) Molecular oxygen as the oxidising agent:

The recent practice in most of the oxidation processes is to avoid the costly oxidising agents and replace them with air. Much work has been reported in this direction and Copyright alkylpyridines have beenKharagpur oxidised to the corresponding carboxylic acids in good yields • It has been reported that oxidation is favoured under pressure in the presence of a metal oxideIIT (cobalt, copper and manganese) and bromine or a bromine containing compound• A minimum of 4-atmos pheres pressure and a temperature near about 200°C have been 15

found to be optimum^41^ • Yields ranging from 61-84$ have been reported^4®’41) •

(e) Other oxidising agents:

Use of other oxidising agents such as manganese dioxide^42’ 43^ , chlorine^44^ and sodium dichromate^4®^ has been reported* The electrolytic oxidation of picolines was also tried without any appreciable success^4®^•

(ii) Vapour Phase Oxidation of Picolines with Air Review of the published and patented literature:

Efforts have been made for the last two decades to oxidise the picolines in the vapour phase over suitable oxidation catalysts, but none of the earlier workers has reported any satisfactory yield of acids* The earliest pub lished work in this line is that of Lewis and Brown^4? ) •

These investigators studied this reaction using vanadates of silver tin, iron, barium and potassium as catalysts* The vanadates were found to be too active for the oxidation of picolines* Though a total conversion of 8^*4 percent of 3-picoline was obtained in presence of tin vanadate, only 18.2Copyright percent was the conversionKharagpur to nicotinic acid* Under almost similar conditions 2-picoline gave 18.8$ of picolinic acid and 4-picoline gave 13$ isonicotinic acid. Cislak and Wheeler in theirIIT patents describe the formation of pyridine carboxylic acids from alkylpyridines* Ishiguro,

Kimura and Utsumi^^"®3^ oxidised 2-, and 4-picolines over V2O5 catalysts promoted with Mo03,Crg03 and W03* They 16

reported the formation of pyridine from 2-picoline(perhaps due to decarboxylation of the picolinic acid formed as an intermediate) and isonicotinic acid from 4-picoline.

Very interesting observations were reported by (54) W.Mathes et alw . These authors oxidised 2-picoline m th air in the gas phase using a V2O5/M0O3 catalyst. The chief product of oxidation was found to be 2-pyridoin. The for mation of this compound had not been reported by earlier ■workers. A patent by CIBA Ltd.^55^ claims 50% yield of nicotinic acid and 80$ of isonicotinic acid from 3- and 4-picolines respectively, using an acid activated V2O5-K2SO4 silica gel catalyst at 265°C*. Shimanskaya and S.Hillers^56^ carried out the vapour phase oxidation of the Mp -picoline fraction" of pyridine bases (boiling range 142-146°C) contain ing 17 + 2$ 4-picoline (besides 2,6-lutidine and 3-picoline), using suitable catalysts for the selective oxidation of the methyl groups in 2, and 4-positions. They observed that

3-picoline remained materially unaffected. The acids formed by the oxidation of the methyl groups in 2- and 6-positions decarboxylated, while isonicotinic acid (formed by the oxi dationCopyright of the methyl groupsKharagpur in 4-position) remained unchanged and was isolated from the products of ^the reaction. Roy, * The present IIT author has however, failed to obtain any appre ciable yield of the acids with this catalyst under the

conditions claimed by the patent* Banerjee and Basu^5^ oxidised picolines over fluidized bed of vanadium pentoxide in a temperature range of 400-450°C• 4-picoline was oxidized to isonocotinic acid to the extent of 28$ and the conversion of 3-picoline to nicotinic acid was found to be 25.2$*

4 . Scope of the present investigation:

As already stated the pyridine carboxylic acids are products of great importance because of their medicinal

values* Efforts are being made all over the world to find out a faster and cheaper method for the oxidation of pico-

\ lines and other alkylpyridines, which can be made available from the coal distillation industry as well as synthetically, into the corresponding carboxylic acids*

From the literature survey it became clear to the author that a thorough and systematic study on the catalytic vapour phase oxidation of picolines had not been made by the previous workers in this field and there was considera ble scope for the developement of this process • Encouraged by theKharagpur results obtained by Bhattacharyya and Copyright coworkers^58-63) laboratory on the vapour phase oxidation of various organic compounds like ortho,para and meta xylenes, benzene, crotonaldehyde, ethylene etc; it was considered desirableIIT to undertake the subject matter of this -thesis and to make an extensive and intensive study on the vapour phase oxidation of 2,3 and 4-picolines in order to 18

evaluate the most active catalysts and also the most favour able conditions for achieving the maximum yields* The influ ence of catalyst composition, temperature, contact time, air/ picoline ratio and catalyst support has been thoroughly investigated* The experimental data presented in this thesis indicate some improvement over the existing processes in many respects and promise great industrial importance*

From the results, a possible reaction mechanism has also been suggested for the oxidation of 4-picoline*