OXAZOLONS AND THEIR REACTIONS. RING FORMATION THROUGH THE P-POSITION OF THE BENZENE RING. THE ESTERS OF P- AMINO BENZOIC ACI1). WILMA MCCABE MARLOWE THESIS FOR THE DEGREE OF BACHELOR OF SCIENCE CHEMISTRY COLLEGE OF LIBERAL ARTS AND SCIENCES UNIVERSITY OF ILLINOIS 1921 Digitized by the Internet Archive in 2015 https://archive.org/details/oxazolonstheirreOOmarl UNIVERSITY OF ILLINOIS .%y„.2.7, i$l THIS IS TO CERTIFY THAT THE THESIS PREPARED UNDER MY SUPERVISION BY WILMA MC CABE MARLOWE ENTlTLED..QMS.QfcM§...Mi?...ll^IR...mcII.Qia*....,.jRINO...i , .QRMAT,IOIT...IHRO.U.GH.. .THE . . ,P.“P.0.S. H I Oil. . . .QE. . . THE . . BENZENE . . li ING .» THE. . .E S TEES. . . QE . . B.rrAMl N 0 BENZOIC ACID, IS APPROVED BY ME AS FULFILLING THIS PART OF THE REQUIREMENTS FOR THE degree OF .....Bachelor., of. . . S c i en q g . . i.h. . . .C'/mmi.S/fcrY. Approved : UT \: HEAD OF DEPARTMENT OF. CL i - sd i E-i f—i O o T S ' \ ' PAHT_3. I. Introduction: Method of Preparation Purpose of Work 1 II. Historical: 2 Methods Used in Preparation' of Oxazolons and Pentaoxaxolons III. Theoretical: Chemistry Composition of C ompounds 3 IV. Experimental Work: Processes carried out in Laboratory. 6 V. Conclusion: 10 VI. Bibliography. 12 PART II. I. Introduction. 13 II. Historical 13 III. Theoretical 14 IV. Experimental 16 V. Conclusions 17 VI. Bibliography 18 ' C 0 IT T E IT T S PIET III. 1. Introduction: 19 Commercial Esters of p-Amino Benzoic Acid. Uses of Esters . Purpose of Work. II, Historical: 20 General Anaesthetic's, local Anaetliest ics . Esters of Para Amino Benzoic Acid. III. Theoretical. 23 Chemical Constitution and Anaesthetic' Effects. Effects of Side Chains, IT. Experimental. 25 Preparation of llec'essary Eeagehts, Preparation of Esters, V. Conclusions. 29 VI. Bibliography. 20 VII, Acknowledgment, 32 1 OXAZOIONS THE IP, E E AC T I GITS. IITTR ODUCTIj.it Oxazclons were studied "by carrying cut different reactions in order to determine the most favorable conditions for their for- m a tion and their hydrolysis to the amino alcohols. Oxazolons may be prepared by condensing (3 ohloroethyl chlorcarbonate with a primary amine and refluxing the derivative of c'arbam in ic acid with an aqueous solution of sodium hydroxide. 2 RITH 2 +- C1C00CH 2 CH 2 C1 — ^R1TH-C0-CCH 2 CH2-C1 -f RNH2*HC1 NaOH RNH-C0-0CH 2 CH 2 -C1 ~>RHH»C0-0 , -y- NaCI + H 2 0 \ \ ch 2 — ch 2 If an excess of .sodium hydroxide is sued with a longer period of refluxing the hydrolysis takes place giving the amino alcohol . R1TH-C0-0 2UaOE RNH-0H 2 -CH 2 -0H Na 2 C0 3 CH 2 ch 2 P«nUxazolon» have bean prepared in a similar manner us- ing the prophyl derivative instead of the ethyl derivative. These, too, were hydrolyzed if refluxed with an excess of the sodium hy- droxide for a long time. It was thought from the preparation of the oxazolons and the pontaxazolons that the nature of the ring might be varied by using different chlorine compounds then proceeding in a similar manner . 2 The amino alcohol was used as the working "basis for the preparation of endphenyl ke tomorjiholine , it was refluxed with oxalyl chloride and with chloracetyl chloride to form the keto morpholine rings. 0 ?« RNH-CH 2 CH 0 OH -f-Clcf -C~ °1 RN — CH 2 CE 2 -f 2HC1 . \ JO c — C ' * If 0 0 RNH-CH 2 CH 2 0H C1-CE 2 C-C1 ->> RF^*-CH 2 CH 2x -f 2HC1 C-CH. HISTORICAL . Hernirowshy prepared A chlorethyl chi 0 r ocarb onat e from phosgene and ethylene chlorhydfiin. He condensed this @ chlorethyl chi or carbonate with aniline and with ammonia and ieceived the cor- responding esters of the c'arbaminic acid. The n-phenyl carbaminic chloroethyl ester gave n-phenyl oxazolon when refluxed with con- centrated potassium hydroxide, Paul Otto in following up the work of Nemirowsky prepared hydroyetyl aniline in two ways: first by refluxing the phenyl car- baminic chloroethyl ester with concentrated potassium hydroxide, also, by refluxing ethylene chlorohydrin with aniline. Hydroxyethyi aniline when treated with liquid x^Hosgene in a sealed tube gave n-phenyl oxazolon. He formed the corresponding carbominic oster^, oxazolons, and amino alcohols from methoxy aniline and the and naphthalenes in a similar way. 3 J. B. Segur used the methods of ITemir owsky and prepared a series of oxazolons and pentoxazolons . By using aromatic amines as aniline and substituted aniline as the substituent groups and by condensing these with ^3 clloroethyl chlorcarbonate he pre- pared the c’arbarninic esters which were refluxed with an aqueous solution of sodium hydroxide to give the oxazalons. If he wished to prepare the amino alcohols he used an excess of the alkali in a concentrated solution which favored complete hydrolysis. The substituted anilines caused a slower reaction than the simple ring but the nature and position of the group did not affect the reaction. He also prepared n-phenyloxazolon by condensing hy droxyethyl aniline and phosgene. The n-phenyl oxazolon would not react with aniline when they were refluxed together. He prepared the pentoxazolons in an analogous manner, preparing first the carbarn in ic' esters by condensing a primary aromatic amine with if chloroprophyl chlorcarbonate then reflux- ing with the aqueous solution of sodium hydroxide. He formed the hydroxy prophyl amines by using an excess of alkali in a concen- trated solution. This method proved more satisfactory and gave better yields than by using ethylene c’hlorhydrin and the aromatic amine to give the hydroxy amines. THEORETICAL It has been proved that oxazolons may be prepared by - * , •; . 4 using; & substance with active chlorine and a primary aromatic amine to give the carbarn in ic' ester which is hydrolyzed with an aqueous solution of sodium hydroxide. 2 RNHgf C1C00CH 2 CH 2 C1 — RN B-CO-OCHgCHg-Cl-A RNHg* HCL NaOH -f- RNH-C0-0CH 2 CH 2 -Cl — > RN -C0-0^ -f- NaCl+HgO ch 2 - ch 2 These reactions take place very readily using aniline or some amine with substitutions in the ring as c’hl or, methyl, ethyl, methoxy, or ethoxy groups in the ortho or para positions. These substituting groups have no effect on the reaction except to make it slower,, therefore a longer period of refluxing . One mole of carbominic acid when refluxed with one mole of sodium hydroxide in an aqueous solution loses ono mole of hydrochloric acid and forms one mole of the oxazolon. The best conditions for this reaction are one mole of alkali in a 25$ solution for one mole of ester. If the sodium hydroxide is more concentrated it tends to shift the reaction toward a more complete hydrolysis. Eftt if the time of refluxing and the concentration are carefully controlled very little of the ester is hydrolyzed. By using a more concentrated solution, 33$, and five moles of the alkali for one mole of the ester a complete hydrolysis takes place giving a good yield of the amino alcohol. 5 The amino alcohol may also he prepared by cdndensing a mole of a primary aromatic amine with one mole of ethylene c’hl orhydr in . This method however gives much smaller yields, therefore, it is better to use the hydrolysis method. In most casoc the reactions will take place when re- fluxed for two hours, hut if a substituted phenyl group is used the time of refluxing must necessarily ho prolonged to about four hours. Oxazolon may also be prepared by using one mole of phosgene and one mole of the amino alcohol together in a ben- zene solution. This ,howe ver , involved more reactions than the former way of preparation. The pentaoxazolons have been prepared in the same way as the oxazolons. The c'arbaminic ester is first formed 2MTH2+ ClC0-0-CH 2 CH 2 CH 2 Cl >> RI!H-C0-0CH 2 CH 2 CH 2 C1-+- B1TH 2 . HCL then the propyl chlorester is refluxed in an aqueous solution of sodium hydroxide. ENH-C0-0CH 2 CH 2 CH 2 C1 -f-NaOH — *Rlf -CO-O^ \ CH* -f !TaCl+H 2 0 The propyl hydroxy amine is formed if a concentrated alkali solution is used in excess as in the case of the ethyl hydroxy amine. The strength and the amount of alkali ha-"e the same effec.t on the pent oxazolons and amino alchols as on the oxazolons . The substituted groups in the phenyl ring may also bo fe 6 ■used to prepare the pnet oxazolons as well as the oxazolons. Again it takes a longer period of refluxing for the reaction to go to completion. Reduction with absolute alcohol and sodium was tried as a different method for preparing the amino alcohol hut the yield was so small that it seemed impractical as a method of preparation. The manner of preparing the keto morphalines may he some what similar, to the method of preparing the oxazolons and the pentoxazolons . As a basis for this work the hydroxy ethyl amine was used as the unit. The reaction with cxalyl chloride was tried 0 0 rhh*ch 2 ch 2 oh + Clff-6-Cl RF — CH 2 CH 2 V /Q o ~ r -f 2HC1. Equal molecular weights v;ere refluxed for four hours. The reac- tion was carried out in a solution of benzene. At first the reac- tion eas a little violent with considerable heating effect but this did not continue long, The reaction mixture was then re- fluxed with an open flame for four hours. The compound on cool- ing was a thick, sticky, white mass. A reaction with c'hlorac'e tyl chloride was also tried. It was carried out in the dame way as the oxalyl reaction. The edmpound formed was a viscous liquid of a yellowish brown color. Using the methods and proportions as given by Hr. Segur 7 'in his thesis for 'taster of Science the different steps of the preparation wore carried out. First thing done was the purifica- tion of the product as prepared "by Mr. Segur. This gave some idea of the physical properties of the compound and also a method of purification. It was recrystallized from hot ethyl alcohol. Then successive steps of the procedure were tried. The first step of preparing the chi or ethylc'hlorcarbonate was not carried out. was dissolved in "benzene then the two "benzene solutions were slow- ly mixed. The hydrochloride of aniline precipitated from the "ben- zene solution; therefore it was necessary to use sufficient quan- tity of "benzene to keep the mixture thin enough to he stirred eas- ily. The aniline hydrochloride was filtered off and the filtrate containing the product was washed, with dilute hydrochloric acid then with water to remove all the aniline and aniline hydrochloride. The "benzene was distilled off and the product crystallized when it Cooled. The product was recrystallized from hot alcohol. This procedure was repeated several times getijng a yield of about 8 Q^, I . PE EP AD . STEF. O F SU BSTI- TUTED CAEBOHIITIC acid For this reaction two moles o the aniline were used for each, mole of the chlorethyl chloscarhonate . Each substance 6 2.3 gr s . Cl Clio CHoCOO Cl 48 grs II. PRE PARA TI ON OF THE QXAZ0L02T AZTD THE All I HO ALCOHOL e Hols per mole of carbaminic ester for alkali were re- flexed together for two hours. The alkali was made into a twenty five per cent aqueous solution. This seamed to he the “best condi- tions for the preparation of the oxazolon. The yields were round 70 per cent. Carbaminic ester 20 gra„ Sodium Hydroxide 4 grs. N-phenyl Oxazolon 10.9 grs. 70 yield Prep aration of A min o A lco hol, by B eductions. Twenty grains of the oxazolon was dissolved in fifty cubic centimeters of ethyl alcohol. Twelve grams of sodium were cut into small cubes placed in a round bottom flask and covered with toluene. The toluene was heated until the sodium melted. The mixture was stirred with a mercury sealed mechanical stirrer run by a motor. The alcoholic' solution of the oxazolon was drop- ped onto the sodium mixture slowly by means of a separatory funnel. The solution was kept hot, no heat was applied to the flask after the initial melting. This mixture was stirred for two and one- half hours. Water was then added slowly to decompose the unused sodium. The contents of the flask were steam distilled and three have fractions collected. The one thought tc/contained the reduced pro- duct was washed with ether and distilled. Three fractions were •> ■ » . i. collected but the yield of yellow oil was extremely low. There- fore this method seemed impractical as a means of preparing the alcohol . Th e P repar atio n of the Amin o Alcoh ol by H yd rolysis . 9 The carhominic' eater was hydrolyzed hy using a large excess of alkali in a water solution. Pive moles of alkali were used for one moo of the carhominic" ester. Using these proportions yields of 85g--SQ^ of alcohol were prepared. It was attempted to prepare the phenylisocyanate deri- vative of the alcohol. Hole per mole was used and the solid which was formed was diphenylurea in an impure state. 1 1 1 PREP ARATION OP T HE KET O HO EPHOLIITES End phenyl ko to m orpholine The amino "alcohol was dissolved in "benzene also the oxalyl chloride then the two "benzene solutions added together ana refluxed for four hours. At first the reaction was a little active "but this heating effect did not last long. It then refluxed quiet- ly. The derivative separated out as a thick, sticky mass. At first it would not crystallize from any of the common organic" solvents; hut after it had stood for several weks it seemed grandular in ap- pearance and crystallized easily from alcohol. Yielding a white crystalline solid with a melting point of 158° with a yield of 80 of the crude product. Hydroxy ethyl aniline 5 .33 grs. Oxalyl chloride 5 6 r s . Endphenyl keto morpholine S grs crude 80 $ yield. 10 En dr hen yl di he to morp holine The hydr oxyathyl aniline and chi or ace tyl chloride we re 4ach dissolved in “benzene, then the two solutions slowly added to- gether and refluxed for four hours. The diketomorpholine sepa- rating out as a thick “brown syrupy substance. The “benzene was distilled off then the dikoto morpholine distilled under dimin- ished pressure. 33. P, 215° - 220° with 15 mm pressure yielding 69 fo. Hydroxyl thyl aniline 12 grs. Chloracetyl chloride 10 grs Endphenyl diketo morpholine 12. grs. 69 ^ CONCLUSIONS. The oxazolons and pentoxazolons may “be prepared “by using the chlorethyl chlorcarbonate with aniline then refluxing the ester of c'arbaminic acid with a 25 fo solution of Na OE for two hours . If the amino alcohol is desired an excess of 1: 5 moles of NaOH is uded in order to completly hydrolyze the carbaminic ester . The ring may be altered by using different reagents as chloracetyl , chloride or oxalyl chloride to form the keto morpha- lines. These substances require a longer period of refluxing and use the hydroxy ethyl aniline as the reacting substance. 11 Theoretical amounts were each dissolved of the amino alcohol of chloracttyl chloride and oxalyl chloride in benzene then added to throoretical amounts and refluzed for four hours with a low flame. . ■ B I B L I 0 G R A PHY PART I J ourn . of Pract. Chemie (2). 31; 173-175 Journ* of Pract. Chemie (2) 44; 15- 23 3, The Formation of Oxazolons and Pentoxazolons and Their Hydrolysis to Amino Alcohols* Thesi3 for the Degree of Master of Science at the University of Illinois--1920« 13 RING FORMATION THROUGH THE PARA POSITION OF THE BENZENE RING INTRO D UCTI 0 N Ring formation through the meta position of the ben- zene ring has been prepared by Julius V. Braun , L. Karpf and W. v Garn by using a meta compound. Using a para compound in- stead of a meta compound the formation of the ring would take place in this position instead of the meta position. It was the purpose of this work to prepare a ring compound through the para position using a very similar method of preparation to that used by Braun, Karpf and Garn. HISTORICAL In the preparation of the ring formation meta xylene was used, this was brominated by slowly adding four moles of bromine; the bromide was fractionated a t fifteen milimeters of pressure, then pressed with 150-200 atmospheres for twenty-four hours to remove the oil. The powdered bromide was added to a 10$ excess alcoholic solution of potassium cya- nide and heated for 2- 3 hours on the steam bath yielding from 45 tO 55 $ of the cyanide. One mole of this cyanide in a near- ly boiling solution of absolute alcohol was poured on sixteen atoms of sodium giving a 35 to 40 $ yield of basic compound. This was fractionated giving two fractions A a mono amino i. - . , . - • ■ i * 14 B. P. 97°- 98° and B Ui (J diamino m-diethyl benzene B.P. 160°-170°. The product A is a secondary amine and when attached to a hezene ring probably takes this form -- i. 3 , c 6 h 4 CH~ o / CH« — CHp v \ /NH or 1,3 C 6 H 4 -CH x n ch 2 -ch 2 / nh 2 2 ch 2 - ch/ less probably -- CHr 1, 3 C 6 H 4 -CH \ " NH X CH / CH 3 THEORETICA L The ring formation in the para position might be formed in a somewhat similar fashion. The side chain would have to be sufficiently long to maintain the ring formation and keep the proper spaces between the carbon atoms. Starting with a sodium salt a para nitro phenol and condensing this with trimethylene bromide to form the brcm ether. 1, N0 2 (4)' ONa C 6 H 4 4 . BrCH 2 CE 2 CH 2 Br 1,4, N0 2 C 6 H 4 0CH 2 CH 2 CH 2 Br j. NaBr Treat the bromine compound as in the meta ring compound with an t ■€ ' r \ I 15 alcoholic solution of potassium cyanide forming the cyanide* 1, 4, C 6 H 4 N0 2 0CH 2 CH 2 CE 2 Br + KCN 1, 4, c 6 H 4 N0 2 0CH 2 CH 2 CH 2 CN f KBr, Then hy reduction with stannous chloride and hydro- chloric acid reduce the nitro group to an amino group* Further reduction in an alkaline solution affecting the cyanide group would close the side chain with the amino group and make a ring through the para position as 1, 4, C 6 H 4 N0 2 0CH 2 CH 2 CH 2 CN -IS.1 ■ > 1,4, C 6 H 4 NH 2 0CH 2 CH 2 CH 2 CN SnCl 2 SnCl 4 -f 2H 2 0. 1,4, C 6 E 4 NH 2 0CH 2 CH 2 CH 2 CN CgE 4 -0 -CH 2 - CH 2 ^ \ NH-CH /Ch 2 It would probably be better to reduce the nitro group before putting on the cyanide group, as it would be difficult to carry out both reductions without destroying one group. r ■ ! • * i ■ 16 EXPERIMENTAL The sodium salt of para nitro phenol was prepared by using molecular weights of little p-nitro phenol and sodium hydroxide in enough water to dissolve the sodium hydroxide. The sodium salt was crys tallized, filtered and dried; then one mole of this sodium salt was refluxed for two days with one and one-half moles of tr imethylene hromide in about six hundred cen- timeters of water. Most of the color left the aqueous layer and went into the trimethylene bromide layer making it a very dark brown. This product was steam distilled to remove the excess trimethylene bromide then the heavy dark brown oily product was vacuum distilled using a pressure of 2 mm. At first the product could not be distilled because a low enough pressure could not be obtained, but after getting a pressure of 2 mm it distilled. It was tried to crystallize the product from the oil by means of a freezing solution of hydrochloric acid and ice but no solid would separate out. The only way to obtain a solid was by vacuum dis- tillation. Reduction was tried on the brown oil, but it would not go into solution. However, after vacuum distillation the crystals were put into the reducing mixture of hydrochloric acid and stan- nous chloride, but no reduction took place. The same product came out through all the processes-- para nitro phenol. Another run was made using three moles of triraethylene .1 . a r . . . : . • « ■ - * •• %J ■ ■ n. r , • • ' • • ' .. • .1 t . ■. 1 > : , . 17 bromide Instead of one and one»llalf moles to one mole of the sodium salt of para nitro phenol but this did not work any bet- ter. An attempt was made to nitrate the phenol brom propyl ether using fuming nitric acid at room temperature but this was not successful. No other methods of nitration were tried. CONCLUSION The ring compound could not be formed by this method unless the para nitro brom ether could be prepared. All the way through the process a heavy brownish green oil adhered to the para nitro phenol, this may be what interf erred frith the reaction and even after re-crystallization with ether and petroleum ether the oil adhered to the crystals. - v ~ ■ v l , \ i. . • , - : .. . , BIBLIOGRAPHY Part II 1 . Bar. 1881 14 2636 2. Am. Chem. Jour. 1 271 3. Ann. Ch. Phys . 3 27,461 4. Ber . 14. 899 5. Bar . 16 2715 6 . Ber. 15 1002 7. Ber . 53 B 98-109 (1920) 8. Chem. Abstracts 11 2492 19 ESTERS OF PARA - AM INO B EN ZOIC ACID INTROD UC TI ON . From the work on anaesthetics it has been found that the esters of para-amino "benzoic acid have a decided anaesthetic power varying in intensity with the different members. Some of the esters as methyl ester, "Orthaf or in u , ethyl ester, "Anaesthesin , prophyl esters "Propaesin" and isobutyl ester, "Cycloforln*', have been prepared as commer- cial products of q.uite general use, the most common being the ethyl ester. It was the purpose of this work to continue in the preparation of other alliphatic esters of para amino benzoic acid. From a comparison of the physical and chemical properties of these esters it was hoped some con- clusions might be drawn as the cause of the anaesthetic properties of the different esters. It was thought that the anaesthetic powers of the esters might be a function of the surface tension and the partition coefficient and these were to be carefully determined. 20 H ISTO RI CAL For many ages the people of the Orient have used sleep producing substances as opium, Indian Hemp, and other herbs; with the advance of science anaesthetics and other saporifica have been synthesized and used. As early as 1799 Sir Humphrey Davy discovered the anaesthetic power of nitrous oxide, Dr. W. C. Long found that ether had anaesthe- tic power in 1842, while a short time later in 1847 Prof. Simpson introduced chloroform as an anaesthetic. 5 Dr. H, M. Biggs made a very extensive study of local anaesthetics and tested the properties of cocaine which has been the most widely used local anaesthetic. A good deal of work has been done in organic chemistry to find some synthetic compound which might replace the cocaine as a local anaesthetic. The esters of para amino benzoic acid have been rather widely studied in order to obtain their relative anaesthetic power. Patents in Germany, Great Britian, and the United States have been taken out for several of these esters. The most important paper on the relative value of these esters is n 13 by Stunners and Luders. They made a comparative study of the solubilities and anaesthetic properties of the methyl ethyl normal propyl, isoprophyl and isobutyl esters concluding that the normal prophyl ester was most satisfactory as it comes 21 midway in the aeries. The anaesthetic power seems to increase with the size of the esterifying group, hut the esters become more insoluble as the group increases in we ight ; therefor e those esters in the mean portion of the series are most satisfactory. 21 Mr. Westermann in further work concluded that the normal amyl ester had the strongest anaesthetic power with the mildest ef- fects of those which he studied. 4 Beilstein gives the method of preparation and properties 8 of the methyl ester as prepared by Einhorn and Oppenlioimer. 12 Salowski prepared the ethyl ester by passing hydrochloric acid gas through a solution of p-amino benzoic acid in ethyl al« cohol, the hydrochloride thus formed was decomposed by neutral- ising with soda solution giving the free amino ester. Limpricht 10 and Sarr esterfied the p-nitro benzoic acid then reduced the nitro ester with ammonium sulfide to the amino ester. Torlander 14 and Meyer also give a method of preparation. 15 16,17 The normal prophyl and iso prophyl esters are described in patents of Germany and Great Britain, These esters are prepar- ed in the same way as the ethyl ester. 18 The isobutyl ester is covered by a patent in which several methods of preparation are given: by direct esterf icat ion of the para amino benzoic acid with isobutyl alcohol and passing in dry hydrochloric acid gas; by direct esterf icat ion of the para nitro benzoic acid with isobutyl alcohol and reduction with stannous 22 . chloride; "by esterification of benzoic azo beta napihol with isobutyl alcohol and reduction with bromide of the alcohol as the esterifying unit. 21 Mr. Richard Wilbur Westermann in his thesis on "Various Esters of Para Amino Benzoic Acid" gives methods of preparing the methyl ethyl normal prophyl isopropyl, is- obutyl normal amyl , and isoamyl esters. He found the method of direct esterification of the alcohol and the p-nitro benzoic acid, with a little hydrochloric or a little sulphuric acid as catalyt then reduction the best for the alcohols of low molecu- lar weight. While those of higher molecular weight the p-nitro benzoyl chloride is used instead of the acid and alcohol is used as solvent in the reduction using powdered iron and hy- drochloric acid to reduce the nitro esters. 23 THEORETICAL All aromatic compounds have some anaesthetic power* 3 Speigel in his book, "Chemical Constitution and Physiological Action" presents many interesting ideas and conclusions on the subject of anaesthetics. It has been found that certain nucleii have a given physiological action, this action may be weakened or strengthened by introduction of side chains on the nucleii. Different groups hare different effects; some groups bring out the properties of the nucleus while others counteract its effects* The effects of the amino, hydroxyl, and carboxyl groppe are very striking and are often times strong enough to make it necessary to introduce another group into the ring to make the compound reliable for therapeutic purposes. The amino compounds may be weakened by introducing an acid constituent which neutralizes the basic effect of the amine, care must be taken that all the power is not removed by the neutralizing group. The effect of the side chains is often altered by changing the length of the chain. In the study of para amino benzoic esters it has been found that the anaethetic power increases withthe length of the chain, sometimes the action becomes stringent and it is not pleasant to use, but this can be controlled by the substituting gropps* X . . . : . , t * % ' ..... , , v‘ - 24 Nearly all amino hydroxy esters of benzoic acid have local anaesthetic powers, it was found by experiment that the hydroxy group was not neaessary that the esters of para amino benzoic acid have the same anaesthetic power and are more soluble therefore more usable in anaesthetic work* The less soluble esters may be used in external work* Where they may be dusted on to affect the nerve ends, but little use can be made if they have to be injected. The hydrochlorides of the amines are soluble but are too stringent to be used* Therefore, study must be made to find esters that are soluble having a strong anaesthetic action, but not astringent action. i • * < . . . . <- E X P E RIM E N T A L 15 According to the methods given by Mr. Westermann the work was taken up. The esterification was made by using the p- nitro “benzoyl chloride with the alcohol, then the nitro ester was reduced by using powdered iron with a little hydrochloric acid. For the higher esters he could not get sufficient amounts to have a large excess as in the case of the methyl ester, so a slight ex- cess only was used. In the case of the higher esters it is nec- essary to use ethyl alcohol as a solvent in the reduction, in or- der that the re-acting substances may be more intimately mixed in the reducing mixture. PREP ARATI ON OF TEE ISOPROPHY L ESTE R. Forty grams of the p-nitro benzoyl chloride was put in a 500 c.c. flask and twenty cubic centimeters of isopropyl alco- hol was added. The mixture was heated on a water bath. At first the reaction took place rapidly giving off hydrochloric acid fumes. This small amount of alcohol can hardly keep the mixture in solu- tion unless the water bath is kept fairly warm, it was refluxed on the bath for six hours. The excess of isopropyl alcohol was distilled off then the ester distilled under diminished pressure, it boiled at 195° - 200° with 15 mm. of pressure, yielding 3? grs , or 84$ yield. 2 6 . The purified ester was then reduced by using 30 grs. of p-nitro benzoic ester with 160 grs. of powdered iron. The two powdered solids were put in a flask and shaken long enough to he mixed well, then enough water and ethyl alcohol were added cent imeter 8 to make a thin paste. A few cubic/ of hydrocloric acid were added to catalyze the process and it was stirred for one hour with a mechanical mixer driven by a motor. The reduction mixture was allowed to cool then ether was added to extract the amine, equal volumes of solid and ether were shaken together several times to be sure and dissolve as much of amino as was possible. Then the reduction residue was neutralized with Na 2 CO 3 and extracted twice with ether. The ether extractions were filtered, the ether distilled off and the amine a brownish residue remained. This brownish residue was dissolved in methyl alcohol, then water was added until the amine was perc ipitated. The yield was about 95 % of this crude ester which haa the anaesthetic power. It was not purified further. Prepa ra tion of Secondary Butyl Alcohol. Secondary butyl alcohol was prepared by a modification 6 of Clark’s method according to directions given by Dr. Marvel, Twenty-four grams of magnesium with two hundred cubic centimeters of dry ether were put in a flask and one hundred and fifteen grama of ethyl bromide were added slowly by means of a separatory funnel. After all the magnesium was dissolved an sther solution of freshly c7 ^ • distilled acetyl aldehyde was dropped into the magnesium reagent* This reaction was very violent and had to he kept in an ice hath, in order not to decompose the acetaldehyde. After all the acet- aldehyde was dropped in, the mixture was allowed to stand one-half hour then the Greynard'a reagent was decomposed hy pouring slowly on ice and hydrochloric acid, the ether layers were dried with Kg C0 3 and distilled. Yield about 20 grams. This was much low- er than Dr. Marvel had obtained. P repar ation of the Secondary Butyl Ester. The preparation of the secondary butyl ester was then tried. It was prepared in the same way as the isopropyl ester; but only the theoretical amount of alcohol was used; this mix- ture could not be heated with the direct flame as it charred very easily driving off the alcohol, leaving a black mass which yielded nothingbut p-nitro benzoic acid, on distillation. Another run was tried using an oil bath heated to about 60° for about six hours but this was not hot enough to cause the reaction to take place. The alcohol was given off on distillation also the p-nitro benzoyl chloride and no reaction had taken place. Therefore, more heat must be applied but not too much. Lack of time prevent further work on this secondary butyl ester of p-nitro benzoic acid. Prepara tion of t he P a ra -Nitro Benz oyl , Chlori de . The p-nitro benzoyl chloride was prepared by mixing finely ground p-nitro benzoic acid and phosphorus pentachloride i- r ■ t *• , t. , . . » . - .. 23 . together. Both substances must he absolutely dry and powdered and the PCL_ gradually added with constant stirring to the acid, o Theoretical amounts were used after the violent reaction ceased the mixture was heated on the steam hath for one hour then the ochy- chloride distilled off and the p-nitro benzoyl chloride distilled under diminished pressure-- good yields were obtained. 0 - - • k ^ . ' • • . - , . ■. ■ s CONCLUSION & . The method of esterifying the para nitro henzohl chloride with the alcohol proved very successful for the preparation of the isoprophyl ester. Good yields were obtained , therefore , the method would be a good one for practical work. The method of preparing the p-nitro benzoyl chloride by means of distillation after the reaction had taken place proved to be more successful than to decompose the oxychloride and the penta- chloride by means of water. In the latter method much of the chloride is converted back to the acid. Therefore, the para-ni- tro benzoyl chloride was prepared by using theoretical amounts of dry phosphorus chloride with dry powdered para-nltro benzoyl chloride. After the first violent reaction had ceased the mixture was heated for one hour on the steam bath then the oxychloride was distilled off and para-nitro benzoyl chloride distilled under diminished pressure* The para-nitro ester was reduced by powdered iron and hydrochloric acid using ethyl alcohol as a solvent for the reducing mixture* If the heating is properly controlled secondary butyl ester can be prepared in the same way as the isopropyl ester of para-amino benzoic acid. 30 BIB LI OG RAPHY PART III BOOKS: 1« Corning J, Leonard 2 . Knapp , H . 3. Speigel, Leopold translated by Leudkwig and Boylstar 4. Bielstein PAPERS IN PER IODIC ALS AND JQ1 5. Biggs, Dr. H. M. 6. Clark 7. E inhorn and Seuffert 8. Einhorn and Oppenheimer 9. Erdman 10. Limpricht and Sarr 11. Borris and Green 12. Salowski 13. Sturmers and Luders 14. Yorlanders and F. Meyer Local Anaesthesia Appleton and Co. (1886) Cocaine and its Uses in Surgery. Putnam Sons ,N.Y. (1885) Chemical Constituents and Physiological Action D.Van Nostrand & Co. N.Y. (1915) Bandbuch der Leopold Voss, Hamburg (1801) J . Ame r . Med. Assoc. ; 176 ; Ja. 17, (1885) J.A.C.S. 30; 1149 Ber. 43 2995-300 K (1910)' Ann. 311; 158 (1910) Ber. 32; 1215 (1899) Ann. 203; 278 (1899) Amr, Ch. Jor, 26; 305 Ber. 28; 1921 (1895)' Deut. Med. Wochschr. 34; 2310 (1908)’ Ann. 320 ; 135 (1902) PATENTS 15. D. R. P. 213459 16. D. R. P. 211801 17. Brit. Pat. 4321 (21) CO . D. R. P. 218389 19. U.S. A. P. 958110 (23)' • o CM Brit. Pat. 17928 (23) 21, Various Esters of Para Amino Benzoic Acid Thesis for Bachelor of Science in Chemistry , 1920. The author wishes to express her thanks and appreciation for the guidance and assistance given her hy Doctor Roger Adams during this work. I \