THE PREPARATION OF GAMMA-DIPROPYLAMI- 
 NOETHYLESTER OF PARA-ANI 
 NOBENZOIC ACID 
 
 BY 
 
 WALTER EMERSON BAUS 
 
 THESIS 
 
 For the Degree of Bachelor of Science 
 
 IN 
 
 CHEMISTRY 
 
 COLLEGE OF LIBERAL ARTS AND SCIENCES 
 UNIVERSITY OF ILLINOIS 
 
 1921 
 

 
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ACKNOWLEDGEMENT 
 The writer wishes, at this 
 
 time, T,o express his appreciation 
 
 for the invaluable assistance of 
 
 Professor Roger Adams, who suggested 
 
 ohe problem and under whose able 
 
 direction this research was done. 
 
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TABLE OP CONTENTS 
 
 PART 1 
 
 I INTRODUCTION 
 
 II HISTORICAL AND THEORETICAL 
 
 III EXPERIMENTAL 
 
 a Propyl bromide 
 b Para-Toluenesulfonamide 
 c Para-Toluenesulfondipropylamlde 
 d Dlpropylamlne 
 e Ethylene oxide 
 f Dipropylaminoethyl alcohol 
 S Para-Nitrobenzoylchloride 
 h G-amma-Dipropylaminoethylester of 
 para-nitrobenzoic acid 
 i G-amma-Dipropylaminoethylester of 
 para-aminobenzoic acid 
 
 IV SUmiARY 
 V BIBLIOGRAPHY 
 PART II 
 
 I REACTION OF ACID CHLORIDES 
 

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THE PREPARATION OF 
 
 G-A]iE'i[A-DIPROPYLA^/.INOETHYLESTSR OF PARA-AMINOBENZOIC ACID 
 
 I INTRODUCTION 
 
 Various anesthetic compounds have been prepared and the 
 work is still being carried on with the object, in view, of 
 finding Some compound that will have the anesthetic properties 
 of cocaine. Novooalne (procaine) 
 
 has met the requirements to a large extent but it has consider- 
 able toxic effect and search is being made for a compound that 
 is readily soluble and having no toxic effects. Novocalne is 
 used very extensively in modern surgery and has met the re- 
 quirements very well to date. However, cocaine has greater 
 penetrating power and consequently is widely used for certain 
 kinds of anesthesia. If a compound could be prepared which 
 would have the penetration power of cocaine with less toxicity, 
 than novocalne, there would be a wide field for its use, also 
 very valuable to the medical profession. The group which has 
 the desired effect is -c.-o and the best manner to 
 
 it ^ 
 
 attack this problem seems to be to prepare a series of compounds 
 in which this group is present, especially replacing the ethyl 
 groups with others. 
 

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II HISTORICAL AND THEORETICAL 
 
 The first, methods to alleviating pain, as used by the oldest 
 Assyrians, were to compress the veins in the neck. The 
 Ssyptlans knew of a few sleep producing compounds. Amoung the 
 first to be used were opium and Indian Hemp. Cocaine was studied 
 very extensively by Dr. H.M.Beggs (2), who has done a large 
 amount of research in anesthetics. A search for a new local 
 anesthetic which would substitute cocaine or offer improvements 
 over it has been carried on ever since the advent of synthetic 
 organic chemistry. The structure of cocaine was studied and the 
 group which had the peculiar anesthetic properties determined. 
 Now, the problem remains, to arrange compounds around this 
 group of such structure and physiological action so as to have 
 no toxic effect and yet be readily soluble. 
 
 Novocaine has been studied by many workers, with a viev/ of 
 improving its physiological action. Various strait chains 
 have been substituted for the aniline group, in all cases giving 
 a compound inert physiologically. The length of the side chain 
 has been varied, also the ester group has been placed various 
 distances from the ring. In fact most all conceivable compounds 
 have been manufactured, some active, some inert. 
 
 V.Peckmann and Berkhard (1) have prepared a compound by 
 adding four grams of methyl ester of acrylic acid to a cooled 
 ethereal diazo solution obtained from lOcc of nitroso-methyl 
 urethan. Reaction is complete after one hour and since it does 
 not show any tendency to crystallize, it is allowed to be 
 oxidized by eight grams of bromine. The precipitate obtained 
 

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is boiled with concentrated hydrochloric acid, washed with 
 dilute hydrochloric acid and water and recrystallized from water. 
 
 Ernest A.Wildman (3) prepared the gamma-diethylamino propyl 
 eater of para-toluic acid. It is colorless oil and readily 
 soluble in alcohol and benzene, very slightly in water and of 
 alkaline reaction toward litmus. Upon heating with hydrochloric 
 acid or sodium hydroxide it is decomposed into para-toluic acid 
 and gamma-diethlyamino propyl alcohol, forming a salt with 
 hydrochloric acid readily soluble in water and crystalizing 
 from a mixture of acetone and ether in the form of snow-white 
 crystals, the aqueous solution of which is of anesthetic action. 
 
 Knorr (8) prepared methyl pyrazol by the condensation of 
 sodium formyl acetone, hydraz insulphate, and sodium hydroxide, 
 in molecular proportions. One mole of sodium formyl acetone 
 is dissolved in a little water, and to this solution the 
 mixture of one mole powdered hydrazin sulphate and sodium 
 hydroxide is added, and enough water to keep all in solution. 
 
 This is warmed and the methyl pyrazol seperates as a heavy oil. 
 
 The majority can be fractionated and the rest extracted with ether. 
 
 Dr. O.Kamm (5) in one of his papers of a series on, "The 
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 Action in Local Anesthetics", gives a description of several 
 of the compounds he has prepared, also a discussion of their 
 homo logs . 
 
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1 
 
 This compound has three carbon atoms between the oxygen and 
 nitrogen atoms. The natural occuring anesthetic, cocaine, also 
 possesses such a structure, , 
 
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 whereas cocaine oossesses a chain of three carbon atoms between 
 
 Procaine contains the structure, 
 
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 considered more toxic than procaine but for certain types of 
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 its greater powers of penetration. 
 
 This new homologue of procaine possesses the three carbon 
 atoms the same as cocaine and for that reason one would expect 
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 cocaine. Tests show that this is true, also that this new com- 
 pound is more toxic than procaine. 
 
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 which is very similiar in structure to novocaine. 
 
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 This new compound has greater anesthetic properties than novocaine. 
 It has been found by Dr.O.Kamra that the maximum anesthetic affect 
 

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seems to occur when the carboxyl group is removed from the ring. 
 
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 group by n~propyl groups and see if the compound would have 
 greater anesthetic properties. The toxic effects would be 
 greater but if its effectiveness for the production of surface 
 anesthesia is considerably greater than that of its lower 
 homolog, it would more than counterbalance the effect of 
 slight increased toxicity. 
 
 II EXPERIMENTAL 
 
 The directions followed in the preparation of this compound 
 are given by Dr.O.Kamm (6) for the preparation of n-butyl bromide. 
 In the rpeparation of hydrobromic acid for direct use in 
 connection with the manufacture of alkyl bromides, a smaller 
 PDoportion of water is liised than would otherwise be the case. 
 
 A mixture of 400 g. of bromine and 425 g. of ice is treated in 
 a cooling mixture with sulfur dioxide until the bromine is 
 reduced. 296 g. of n-propyl alcohol are than added and 
 following this there are added in several portions with shaking 
 200 g. of cone, sulfuric acid. The mixture is heated under a 
 reflux condenser for a period of four hours, during vdiich time 
 the formation of propyl bromide is carried to completion. The 
 product is accordingly removed from the reaction mixture by 
 direct distillation. The crude material after washing with 
 water weighs 422 g., and a purification with one-half its volume 
 

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of cold cone, sulfuric acid decreases this quantity by 8 g. The 
 product is washed with sodium carbonate solution, dried with a 
 small quantity of calcium chloride, and distilled. The yield 
 of product boiling at 71-73 degrees is 40S g. , which corresponds 
 to 86^ of the theoretical amount. In a series of experiments 
 the yield varied from 43 to 88 percent. 
 
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 is used with the resultant loss of some of the material due to 
 absorption of the drying agent. After a careful seperation of 
 the propyl bromide from the water it was found that from 3 to 
 8 g. of calcium chloride were sufficient for the drying of the 
 product. 
 
 Para-toluenesulf onamide 
 
 In the preparation of this compound para-toluenesulf ochloride 
 was treated with stronger ammonia water. The reaction was very 
 rapid and considBrable heat given off. The flask should be 
 cooled at intervals when the reaction becomes too rapid. 60 g. 
 of para-toluenesulf ochloride and 17 S* ammonia were placed 
 in a beaker and slightly heated, to start the reaction. After 
 the reaction had stopped the mixture was heated to boiling and 
 filtered. The filtrate is evaporated to dryness on the steam 
 bath. The solid is white in color and melts a.t 137 degrees. 
 
 On a series of experiments the yield ranged from 90 to 9^ percent 
 of para-toluenesulf onamide. 
 
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Para-toluenesulf ondipropylamlde 
 
 Following the method and general synthesis for the methyl- 
 amide compound as given in Friedlaender (7), this compound was 
 manufactured from para-toluenesulf onamide and n-propyl bromide. 
 171 g. of para-toluenesulf onamide are heated with 100 g. of a 
 40fo solution of sodium hydroxide and one liter of ethyl alcohol. 
 244.5 g. of n-propyl bromide are added and the whole mass re- 
 fluxed on a steam bath at 100 degrees. After one day the mixture 
 becomes neutral and 40 g. of a 40^ solution of sodium hydroxide 
 are added. This is refluxed as before until neutral and 40 g. 
 more of sodium hydroxide (40^) are added. The whole mass is 
 refluxed at 100 degrees until neutral, which takes from one to 
 two weeks, after the last portion of sodium hydroxide nas been 
 added. The solution is light brown in color. After the mixture 
 is neutral to litmus, the alcohol is recovered by distillation 
 and the remaining mass is washed with 500c c of water. The water 
 dissolves the sodium bromide and the oil seperating from the 
 water solution is para-toluenesulf ondipropylamlde. This oil 
 is light brown in color and has some impurities present as 
 propyl alcohol, water, etc. In order to get it in a pure con- 
 dition it is necessary to distill and this must be done in 
 vacuo as the compound v;ill decompose at high temperatures. 
 
 The oil was distilled at 15 nim pressure and i-emperature ranging 
 from 218 to 224 degrees C. In a series of experiments Lhe 
 yields ranged from sixty to eighty percent ot the theory. 
 

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Dipropy lamine 
 
 68 g. of para-toluenesulf ondipropylamide are placed into a 
 
 4 
 
 two liter flask and 31*6 g. of chlorosulphonic add added. The 
 temperature rises very rapidly and the reacting mixture should 
 he placed under a reflux condenser at once. Sulfurous rumes 
 come off in considerable quantity and the reacting should oe 
 carried out in a hood. After the rirst reaction has ceased, 
 a small flame is placed under the flask. Very little neat is 
 necessary as the heat of reaction is quite high. When the fumes 
 have stopped coming off and the former liquid is a viscous 
 black mass, the neat is removed and the flask allowed to cool. 
 Wlien cold there should oe a black solid left in the flask. 
 
 Enough sodium hydroxide- is added to the solid to make it alkaline 
 to litmus and than steam distilled. Tne condenser should be 
 fitted with an adapter which is fastened into an erlenmeyer 
 flask with a cork. This erlenmeyer is emersed in an ice oath 
 because dipropylamine has a low coiling point. Tne distillate 
 is made acid to litmus with hydrochloric acid and evaporated. 
 
 The dipropylamine is present as the hydrochloride and is a solid. 
 This solid is dissolved in an alkaline solution and the amine 
 seperates as an oil on the solution. It has such a low boiling 
 point that it can be distilled off in the pure condition. Di- 
 propy lamine is a light yellow liquid v/hich boils at 66 to 71 
 
 degrees and has a strong odor of ammonia. 
 
Ethylene oxide 
 
 50 g. of ethylene chlorhydrate are refluxed with 25 S* 
 sodium hydroxide. The ethylene chlorhydrate is placed in a 
 liter flask which has a seperatory funnel and reflux condenser 
 attached. The sodium hydroxide, 50^ solution, is placed in the 
 seperatory funnel, and the reflux condenser is connected with 
 a tube to another condenser immersed in ice. The chlorhydrate 
 is heated to boiling and the sodium hydroxide solution added 
 slowly. The water and chlorhydrate are condensed in the 
 condenser and flow back into the flask, whereas the ethylene 
 oxide, which boils at ten degrees, passes on thru the tube into 
 the ice condenser where it is liquified. Below the ice condenser 
 the oxide compourd is collected in a tube v/hich is completely 
 surrounded with ice and salt. IThen the tube is filled it is 
 sealed and in that condition the ethylene oxide can be kept 
 indef initely . It is colorless liquid with an odor similar to ether 
 
 Dipropylaminoethyl alcohol 
 
 30 g. of dipropylamine were placed into a carous tube and 
 the whole placed in a tube of ice and salt. The reason being to 
 cool the tube and compound below zero so as to add the 
 ethylene oxide. The sealed tube of ethylene oxide is cooled 
 below zero and the top broken off. The oxide is than introduced 
 into the carous tube. The top of the tube is sealed with an 
 

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 great care must be taken to have the glass heavy around the 
 whole seal. If the glass is drawn out too much it will not 
 stand the pressure. The tube is than placed into a steel Jacket 
 and the whole placed into a steam cone and heated to about 100 
 degrees. The reaction goes to completion in sixteen hours. The 
 top is broken off and the liquid distilled. The final product 
 is a heavy viscous liquid, colorless and having a boiling point 
 of 132 to 188 degrees. In the experiment carried out the yield 
 was 62 % of theory. 
 
 Para-nitrobenzoylchloride 
 
 The best manner to manufacture this compound on a small 
 scale is by use of phosphorous pentachloride and para-nitro- 
 benzoic acid. The final product must be distilled and here is 
 where caution must be taken as the phosphorous pentachloride, 
 which has not reacted, will distill at about the sa^me temperature 
 as the nitro compound and sublime in the tube, causing an ex- 
 plosion. 34 g. of phosphorous pentachloride were added to 35 S* 
 of para-nitrobenzoic acid and heated on the steam bath. Akter 
 the reaction has ceased the liquid is distilled under vacuo. 
 
 The yield was 82^ of theory. 
 

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G-anima-dipropylaniinoethylester of para-nltrobenzoic acid 
 
 20 g. of dlpropylarainoethyl alcohol V7ere placed in a liter 
 flask and 26 g. of para-nitrobenzoylchloride added. The nitro 
 compound is powdered before addition and introduced slowly as 
 the reaction is exothermic and must be cooled at intervals in 
 ice water. After all the nitro compound has been added the 
 resultant product is refluxed for a short time, to insure complete 
 reaction. The clear liquid turns dark brown in color and is 
 very viscous. The yield was 46 g. or 99 % of theory. 
 
 G-amma-dipropylaminoethylester of para-aminobenzoic acid 
 
 There are various reducing compounds but the one chosen 
 in this case was iron. It being most economical also best 
 fitted for this reaction. Five grams of gamma-dipropylamino- 
 ethylester of para-nitrobenzoic acid were placed in a beaker and 
 25 g. of iron added. This was stirred until well mixed and than 
 a little water added, to make a thick paste v/ith the iron, care 
 being taken not to have any liQuid on top of the iron. The 
 mixture was stirred until quite hot and than a small piece of 
 ice introduced. The stirring was continued intil the mixture 
 was cool and than placed on a steam cone for one hour. It was 
 than filtered while hot and washed with water. The compound 
 was extracted from the filtrate by use of ether. The ether 
 evaporated and the mass dissolved in alcohol. This was 
 neutralized by the addition of hydrochloric acid in adsolute 
 

 
 
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alcohol. The solution was made exactly neutral, and this is 
 very important, because if it is acid or alkaline the product 
 is decomposed. The alcohol was evaporated and the product 
 crystallized out. It is a light brown crystalline solid. 
 
 The physiological action of this compound was not determined 
 by the author as the time was too short in order to make a 
 large enough quantity. But from the structure one would predict 
 that it had fairly good anesthetic action. 
 

 
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SUI'-CvIARY 
 
 I. A discussion of the work done on anesthetics, 
 especially novocaine, is given and some of the properties 
 of the latter compound. 
 
 II. Abstracts are given of the methods of preparing 
 gamma-diethylaminopropyl ester of para-toluic acid, and 
 methyl pyrazol. 
 
 a. 
 
 III. Directions for the preparations of propyl bromide 
 by the use of hydrobromic acid, also preparation of para- 
 toluene sulfonamide, para-toluenesulf ondipropylamide, 
 dipropylamine, ethylene oxide, di propylamine ethyl alcohol, 
 para-nitrobenzoylchloride, gamma-dipropylaminoethylester 
 
 of para-nitro benzoic acid, and gamma-dipropylaminoethylester 
 of para-aminobenzoic acid is given. 
 
V BIBLIOGRAPHY 
 
 1. 
 
 Ibid 
 
 
 3595 
 
 2. 
 
 Ber. 
 
 11 
 
 41 
 
 3. 
 
 U.S. Patient 
 
 1,193,651 
 
 (1916) 
 
 4. 
 
 Fried laender 
 
 8 
 
 1007 
 
 5. 
 
 Jour. am. Chem. Soc. 
 
 42 
 
 1030 
 
 6. 
 
 Jour. Am. Chem. Soc. 
 
 12 
 
 305 
 
 7. 
 
 Friedlaender 
 
 1 
 
 34 
 
 8. 
 
 Fried laender 
 
 1 
 
 939 
 
 9. 
 
 Friedlaender 
 
 213 
 
 ( 1912) 
 
 10 
 
 . Friedlaender 
 
 212 
 
 ( 1912) 
 
 1 1 
 
 . Winther 
 
 1 
 
 60 
 

 
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REACTION OF ACID CHLORIDES 
 
 There are three ways of preparing this compound as found 
 by the author. 50 g.(9) of sodium salcylate are added to 
 200cc of carbonyl chloride in toluene. This is shaken for 
 some time and allowed to stand over night. The toluene is 
 distilled in vacuo and the metahydroxybenzoylchloride is 
 dissolved in ligroin or carbon bisulfide. The solution 
 filtered and evaporated. The oil remaining is the meta compound. 
 
 The second method (10) of preparation is, to 16 parts of 
 sodium salcylate there are added 25 parts of thionyl chloride, 
 sulfur dioxide coming off. The temperature should not exceed 
 30 degrees. As soon as the boiling ceases the reaction is 
 complete and the remaining thionyl chloride is distilled off 
 in vacuo. The oil is dissolved in ligroin and filtered. The 
 ligroin is distilled under diminished pressure at lowest possible 
 temperature. The oil remaining is the meta compound. 
 
 This last method was used by the author. (11) 1 10 g. of 
 thionyl chloride and 120cc of benzene are mixed and 100 g. of 
 sodium salcylate are slowly added. The temperature of the 
 reacting mixture should be kept as low as possible. The mass 
 will become colloidal in apperance and should be placed in ice 
 for two hours. The thionyl chloride and benzene are distilled 
 under vacuo and tha remaining solid dissolved in benzene and 
 filtered. The filtrate is distilled under diminished pressure 
 with the temperature as low as possible. The remaining oil is 
 the meta compound. From several experiments the yield ranged 
 

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from 80 to 90 percent. 
 
 This meta compound decomposes upon standing and therefore 
 the paraformaldehyde was added at once. To 92 g. of meta- 
 hydroxy benzoylchloride there v;as slowly added 35*5 S« para- 
 formaldehyde. The reaction mixture becomes very hot and has 
 considerable effervescence, chlorine being given off. After 
 the reaction there was a white solid left. This was tested 
 by qualitative methods and paraformaldehyde and the meta 
 compound were found present. There is appa-rently no reaction 
 between these compounds. The acid chlorides and aldehydes 
 react with ease but the phenol acid chlorides will not react 
 with the alaphatic aldehydes. 
 
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