DIALKYLAMINO ALKYL HALIDES HY OSCAR DAVID BLUTHARDT THESIS FOR THE DEGREE OF BACHELOR OE SCIENCE CHEMISTRY COLLEGE OF LIBERAL ARTS AND SCIENCES UNIVERSITY OF ILLINOIS 1922 rj tu u. UNIVERSITY OF ILLINOIS . _ *. J- v - _SXi * 1 9 2 § THIS IS TO CERTIFY THAT THE THESIS PREPARED UNDER MY SUPERVISION BY ENTITLED. T -i f) — IS APPROVED BY ME AS FULFILLING THIS PART OF THE REQUIREMENTS FOR THE DEGREE OF j Ik i i .. LLii ( .AIL. Instructor in Charge Approved : ;irn • Ul 7 d-*_ j \ HEAD OF DEPARTMENT OF ( ) 4 Digitized by the Internet Archive in 2016 https://archive.org/details/dialkylaminoalkyOOblut ACIirO-L^DGI.hlJT. The author wishes to thank Doctor Carl SJdarvel, under whose supervision this work was carried on, for the helpful suggest- ions the latter has offered during the progress of the invest- igation and the writing of the thesis. Introduction. IA3L3 OF CONTENTS. Historical and Theoretical Part * 1. Experimental part . Phenoxypropyl diethyl amine — 4. Sromprop3^1 diethyl amine hydro bromide 9. Phenoxybutyl amine la . Phenoxybutyl diethyl amine ■ 13. Broinb-utyl diethyl amine, hydrobromide 14. Summary. — — 16. Bibliography 17. Il , of ipj -t! . f . 4 «' . . . * y •j ■ „ MWU Ui'. */< *<** * t„‘- *•< # k t V-* * i: ‘' 3 . J * > iKTHorrjoTroiT Very little is known about di alkyTamlno alkyl halides. The purpose of this investigation was to prepare diethylarnino propyl bromide arid die thy lamina butyl bromide and other di alkyl amino alkyl halides. This type of compound would be of interest in the synthesis of compounds related to novacaine which has a local anaesthetic action. These compounds could be studied in all reactions that are os common to alkyl halides such, as Friedel^Craft* tnd Grignard^s reactions. They ould have the additional value of introducing dialkylamino alkyl groups where alkyl groups are put in by the use of simple alkyl halides. HISTORICAL & THSORETIOAL Dialkylamino alkyl halides have not been prepared with the exception of brometlr r l diethvl amine which was prewared' bv X %J w> X i. 1/ Meyer and Kopff a by treating diethylamino-cthanol with hydro bromic acid in a sealed tube. The first step toward preparing, the brcmpropyl diethyl amine was to prepare phenoxypr o py 1 diethyl amine. Fhenoxypropyl bromide was used as the starting material* One mole of phenoxy— propyl bromide was treated with one mole of diethyl amine, and phenoxypropyl diethyl amine and the Irwlrobromide of diethvl amine were formed. It was thought that one mole o^ bromide and one mole of diethyl :ine would ^ive hydro bromide of phenoxypropyl diethyl amine. i phenoxypr O X, I r , rs -p the H ^-0-cH a -CH 3 -CH a -B>r c a H 5 v M u /\ o-c^CH^-CH^N " C *- H * B r* C* Hs- The reaction did not work as was expected but acted as follows + K:Z>*" 0-CH£-C/f a -C/V x -8ir ^ + C a H | ' e *"' + \y 0V_ The reaction of one mole of phenoxypropyl bromide with two noles of diethyl amine works very good giving 80-90 percent Ids, calcul ated on phenol ^yprop 3 r l bro: iide . To prepare o 1 10 phenoxy qi, X %J ityl diethyl amine, it wa start with phenoxypr o pyl cyanide arid reduce it to le pnenoxy butyl amine j by means o£ sodium and alcohol. Yields of the phenoxybutyl amine were obtained between 4G and 50 percent. The modification of the sodium and alcohol reduction as carried out by Levene and C.llen” was tried and 80 percent yield was tainedh Levene and Alienas modi " . ' ion required five eights as much sodium and one fourth as much absolute alcohol as the Gammon sodi m and alcohol reduction requires* The modification shortened the time of reduction from two hours to twenty mdnut.es. The phene xybu eg 1 amine was now converted to the phenoxybutyl diethyl amine by means of ethyl bromide in presence of sodium hydroxide. One mole of phenoxybutyl amine with one mole of ethyl bromide a id one mole of 30 percent sodium hydroxide were allowed to react. The reacting mixture, was then treated with one more mole of ethyl bromide , and one and one-fourth moles of sodi e \ Iroxide. 7C-S0- percent yields of phenox} .. . yl diethyl tar® obtained, calculated on the basis of phenoxybutyl a when the pfieno xypr o py 1 diethyl amine was split with fuming ' 2 irobroir.ic acid, it -hi*; not split to give phenol and the hydro bromide of hrompropyl diethyl amine as was expected but gave phenol, trims thyle ie br ' A , and the hydro bromi de of diethyl amine. ■ C ' HS AoH a . CjH5 0r n I J *r The next step was to try one mole of phenoxypropyl bromide with two moles of diethyl amine. 30 grams of phenoxypropyl bromide and 20.5 grams of diethyl amine were dissolved in 70 cc. of dry ether. After standing for two days a white precipitate • ydrobromide of diethyl amine formed. T1 r &ro.hr was filtered off and it weighed 15.5 grams. The ether was distilled from the filtrate on the steam bath. The residue 'which was a heavy liquid was vacuum distilled. The greater portion of the liquid came over between 155-14' 3 wees at 30 mm. pressure . •rt. qualitative, analysis showed that nitrogen was present in the 5 distillate. The distillate was treated with dilute hydrochloric acid and extracted with ether to remove any phenoxypropyl bromide which might he present*. The acid solution was treated with an excess of 25;' sodium hydroxide which freed the amine and it formed in a layer at the top of the solution. The amine layer was separated and vacuum distilled, nearly all the amine distilled over between 130-140 degrees at 70 mm. pressure, field was 9 grams. This method of preparation requires several days to run. so the next step was to try the reaction with the aid of heat. 107 grams of pheno xypropyl bromide was put in a SCO cc. round bottom flash with a reflux condenser. A thermometer was introduc- ed thru the condenser so that it extended into the phenoxypropyl bromide. The apparatus was placed upon a steam bath and when the phenoxypropyl bromide reached 40 degrees, 36.'" grams of diethyl amine was added slowly . At first no reaction was five minutes, the t until it reache 4170 degrees indicating that the reaction was talcing place, .after 15 minutes , the temperature declined until It reached 70 degrees. The flash was hep': at 7.0— SO degrees on the steam bath for 12 hours . A brownish-red sirnpp li quid In d formed to which 100 cc. of 30;$ sodium hydroxide was added and three layers formed. The upper layer was colored slightly yellow. The middle layer was a brownish-red color and the bottom layer was nearly coloress. 150 cc. of ether was added and shakene.d with the mixture. The upper layer was soluble in the ether while the middle, and bottom layers were insoluble. The 5 t • s ■•'tod. The ether ms distilled from the *j j. s tier layer and the residual liquid, mss vacuum distilled. It ©8 sr be tween degrees at 2.1 ores sura. Yield ms ’7 n Is liquid had a slight odor of phenoxypropyl ^raciidfe so i^ was dissolved in dilute hjd] larxc an id, • sracted with ether, and neutralised wltl 25 di \ 'kuxide. II lag or was scu arr.ted aid distilled under vacuum, it came over between 133—142 degrees at 13 mm. pressure. Yield was 37 gra s. 2.1 .7 -o theory' "based on phenoxypropyl bromide. The hydro chloride of the amine was prepared hy passing dry hydrogen chloride thru the amine in solution of dry ether. The hydrochloride melted between 93—102 degrees (unc • ) The middle layer was separated and allowed to stand for several days in which time it solidified, in attempt was made to crystallise it from absolute alcohol but the compound would not crystallize. /7a ter was tried next because the compound was quite insoluble in cold water. In boiling water it readily passed into solution and upon cooling cooling, it did not •stallise at once but aiter srta da several " us,. Ion • hits needle cry stalls formed. n.F. 77.5-79 degrees (unc.) This compound is r quaternary ammonium salt which was formed as a by-product, "fb:: quaternary ammonium salt is diphenoxypropyl d iet hy 1 a: m on i urn b r o m ide. C^Hs-O-cHfCH^-cfK PZciHf Analysis of this compound for bromine gave good checks with the theoretical percentage. The analysis was run hy the Tolhard method for determination of halo ;ens. * 7 Sample was 0^7000 grams. 16.85 oc. of 0.0981 ' silver nitrrte. Found bromine was 18.89y Calculated for OooH-oCol. Br is 13.95,0 bromine. The bottom layer was the water layer which contains sodium chloride and sodium hydroxide. 3y the method of using one mole of phenoxypropyl bromide with one ..ole of li thyl amine, there is too much quaternary ammonium salt formed. Tl next step was to try one mole of phenoxypropyl bromide with two moles of diethyl amine. 55 grams of diethyl amine was placed in a 500 cc. round bobtora flakk with a reflux condenser. The apparatus was placed on the steam hath and the diethyl amine was heated until it began to boil. Then 107 prams of phenoxypropyl bromide was added slowly from a dropping funnel. A precipitate formed and also a heavy brown sirup. After heating on the steam bath for 8 hours, a very sticky semi-solid formed. To this was added 100 cc. of 30p sodium hydroxide and three layers separated. The middle Layer which is the quaternary ammonium: salt was lurch, smaller than it was in the previous run. Benzene was added to extract the amine lender, the water and middle layers being insoluble in the benzene. The benzene layer was separated and distilled to remove the benzene. The amine was vacuum distilled and it came over between 140-1 ’5 degrees at IS mm. pressure. Yield. was 75 _rams. 7 8,4 percent of the theoretical amount. The phenoxypropyl diethyl amine was not purified because it is not necessary to have it pure for the next reaction. A few grams of the pure phenoxypropyl diethyl amine was converted into the hydrochloride by means of passing dry hydrogen chloride thru the , - ' 8 . a. nine in dry ether solution* The hydrochloride separates as a vghite precipitate. It was then filtered off and dried in a vacuum desiccator over sulphuric acid. The hydrochloride was analyzed for chlorine by the Volhard method. Jeight of sample was 0.5071 grams 19.93 cc. of 0.1694 F silver nitrate used. Found chlorine was 14.41$, Calculated for i &13&22.0-N 81 3 -w. Chlorine is 14.56$. It can safely be. said that the amine is pheno xypr opyl diethyl amine. Specific Gravity is 0.9442 at 20 degrees. Index of refraction at 20 degrees is 1.4937. MJP. of the hydrochloride is d The simplest and best method, yielding 80—90$ yields is as follows. 73 grams of diethyl amine is placed in a liter flask with a reflux condenser. It is heated on the steam bath so that the diethyl amine refluxes. Then 10Q grams of pheno xypropyl bromide is added thru the condenser during 30 minutes. A white precipitates forms which causes the flask, to bump a little. The reaction mixture is heated for 12 hours upon the steam bath. At the end of this time, the contents of the flask appears to be almost solid. The contents of the flask are shaken well with 200 cc.of dry ether. The amine dissolves in the ether. The solid is the hydro bromide of diethyl amine. It is now filtered and washed with about 10 Q. cc. more of dry ether. The ether is distilled from the ether extract and the amine is vacuum distilled. B.T, 146—149 degrees at 20 mm. pressure. Yields on. three runs were, 81.5 grams 34.35$ theoretical, 83 grams 85$ theoretical, 90 gram theoretical. This method gives a fairly pure phenoxypropyl diethyl amine with possibility "of a little phenoxypropyl bromide being present as the impurity. In order to get a very pure * t * o c* k ' <, phenoxypropyl die th/1 amine , dissolve it in dilute hydrochloric acid and the extract with ether to remove the phenoxypropyl bromide. Add an excess of sodium hydroxide , separate the anine layer and distill under vacuum. Phis purification lowers the yield of phenoxypropyl diethyl amine about lhn mainly due to mechanical losses. kRATIOH CP BEOI FAOPYL DIETHYL ALIBIS HYDE BBi IDE. 24 /rains of phenoxypropyl diethyl amine was placed in a 100 cc. flask with a reflux condenser a id 00 prams of 40 j hydrobromic .cid was added. This mixture was refluxed for 12 hours over ; sn flame. The contents of the flask war- diluted wit] IDO sc.* af water and extracted with ether to remove the phenol. The water solution was evaporated to dryness. The solid was dissolved in 300 cc„ of hot benzene and upon cooling part of it settled out as a white solid. This white solid was analyzed as follows, Q. 3.972 prams of the white solid was Ixed with 0.500 prams of benzoic acid and 10 prams of sodium, peroxide. This mixture was fused in a Farr sulfur bomb. The fused mass was dissolved in water and analyzed for bromine by the Yolhard ethoC. 17.53 cc.of 0*0.981 silver nitrate used. Precent of bromine found was 33.8y. Percentage of bromine ln.br diethyl amine hydrobromide is 58.10$ This analysis showed that the splitting of phenoxypropyl diethyl 'amine with hydrobromic acid had not gone to completion. The mixed hydrobromides of brompropyl diethyl amine and phenoxy- propyl diethyl amine were refluxed for 16 hours more with 50 .rams of fumin- hydrobromic acid. The contents of the flask were 10 extracted with ether and evaporated to dryness which left a dark brown tarry e ;?. ss, This mass was dried in a vacuum desicc or over sulphuric acid. After drying, the solid was dissolved in boiling absolute alcohol. It was then cooled and dry ether was added which forced out the hydrobromide. The ether was decanted which carried the purer hydrabromids with it.. The hydrobromide was filtered and dried. It had a slight brown color The melting point was not very sharp as it melted over a range from 78—88 degrees. An analysis was made by fusing with benzoic acid and sodium peroxide. The bromine was then determined' by tjge Volhard method. "/eight of sample was 0.3209 grams. 24.46 cc .of Q.Q981 K sir nitrate used. Found bromine was 59 *.07^. Calculated for Gy, Hp 7 ti , bromine is 58.13,2. ■ Another run was made by taking 40 grams of phenoxypropyl diethyl amine and 50 grams of fuming hydrobromic acid and refluxing for 19 hours. 100 cc.of water was added to 'the contents of tbs flask a ad part of it was insoluble in the water, leaving an oily liquid. The mixture was extracted with ether which removed the oily liquid and the phenol. The water solution was evaporated to dryness. The hydrobromide would not crystallize from absolute .alcohol and ether-. The oily liquid was chiefly trimethyl ena bromide which indicates that the phenoxypropyl diethyl amine was split to f give phenol, trimethylene brc iide, and the hydrobromide of diethyl amine. It is apparent that fuming hydrobromic acid is too strong and the temperature top high for the formation of brompropyl 11 . diethyl a line* Ih as t< a run with weaker acid a id a lower temperature. The hydro hro aide of phenoxypropyl diethyl amine was prepared by treating 15 grams og phenoxypropyl diethyl amine with 13 grams of 43,1 hydro’oromic acid and evaporating to dryness on the steam hath.. The hydroorouiide was now put in a refluxin par at— us with 45 grams of 48$ hydrobro mic acid and heated on the steam hath for 19 hours. About 100 cc. of water was aided and an oily liquid separated* The amount of this oily liquid present was than much smaller .. when, fuming hydro bromic acid was used. The mixture was extracted with ether and evaporated to dryness. The hydro bromide was dissolved in a mininum amount of boiling ethyl acetate and upon cooling in a mixture of sale and ice_, the hydrobromide crystallized. It was then filtered off and washed three times with dry ether. The hydro bromide was dried in a vacuum desiccator over sulphuric acid. It melted at 86-89 degrees §unc*) Yield of 14.5 grams. 72$ of theoretical calculat- ed on basis of phenoxypropyl diethyl amine. Great care must be taken that the hydrobromide is dry before trying to crystallize from dry ethyl acetate because a small amount of water will hinder the crystallization. Ad analysis of the hydrobromide of brompropyl diethyl a ine was made by determining the amount of bromine which is combined in the form of the hydrobromide by the Yolhard method. ./eight of sample was 0.5000 grams. 18.53 cc*of 0*0.981 IT silver nitrate used. Bromine found was 29*16$. Calculated for £ 7 , Eiviji j^rs. . Bromine is 29*09$ 12 / FSEFARATrON OF PEZ^OXmVTn^^mZEl . TOO grams' of phenoxypropyl cyanide was dissolved in 2 liter s of absolute alcohol and placed in a 5 liter round bottom flask, fitted with an upright condenser of large bore. 200 grams of sodium was added slowly, until the alcohol began to boil and then fast enough to keep it boiling continually, it was then heated in an oil bath until all the sodium dissolved. The alcohol was removed by steam distillation. The phenoxybutyl amine was extracted with ether, then with dilute hydrochloric acid and freed with alkali. It was now vacuum distilled. B.F. 158—16 degrees at 33 mm ..pressure* Upon two runs mate there, was 41 grams yield which is ical. The above the low yield's required. €0$ the ore tical a 3 15 grams which is 43,* theoret— procedure was not very satisfactory because of and large amounts of sodium and absolute alcohol Another method was tried which gave ? good yield, about G2 >j theoretical with much smaller amounts of sodium and ah alcohol required. This method is known: as Levsae and ..lien’s modification _ . 300 cc. of dry toluene was put in a 5 liter round bottom flask and 123 grams of sodium was added. The fla^k was hi it d .... an oil bath. ..hen the sodium melted , the contents . C he flask were stirred very rapidly by means of 'a mercury 1 . stirring was continued ~ 3 the sodi was broken into fii , 3 oil bath was re a d i id the Hum was allowed to solidify. Aft .r t.3 : cc ts of he- f 1 sk had led, 100. grams of pher oyl z d in IOC cc. of absolute alcohol, was means of a dropping funnel*.!? which was dissolv- added to the sodium by v/ as required for this 13 , addition* An Ice "bath must ' e ' ept at hand so as to rets 3 1 e reaction when it joes too rapidly. 500 cc.of absolute alcohol was. added in 50 minutes' and the st irring was continued for one- half an hour,. Then 300 oo.of water was added slowly,. five minutes being required for this addition and it was then refluxed on the oil hath for one-half hour. The mixture was distilled on the steam bath until all the : hoi and toluene was driven off, •as added to bring the volume up to one liter. The amine layer was separated and distilled under vacuum. B .P, 149— 151 degrees at 19 mm. pressure. Yield was 85 grams. 82,1 of the theoretical amount oaZci lated on the phenoxypropyl cyanide. By t&is method, the yield was doubled, about five-eights as much sodium and one— fourth as much absolute alcohol were used. This method of reduction only required 2.0 minutes while the other method took about twp hours. FiSP.JuiTIOl-r CF K-mo:CYBUTYL DIFT1IYL AhllKB. 85 grams of phenoxybutyl amine was placed in a 500 cc. flask, and 55.5 grams of ethyl bromide and 20.6 ^rams of sodium hydroxide in water solution were added. The mixture was shakened for a short time. Heat -was liberated denoting that the reaction was taking place. The flask was stoppered and allowed to stand for a dap r . 55 _S grams of ethyl bromide and 25 jrams of sodium hydroxide are added with shaking. The mixture was allowed to stand for another day. The contents of the flask are boiled in a reflux for one-half hour. Three layers formed of which the top layer was the amine, the middle was probably qtu t raary ammonium compound, arm 1 bottom lap ‘was tl s< d'ium h 3 Lie solution. The amine is extracted with ether and then the ether 14 was distilled off. The amine was distilled und r vacuum. B.F. 152-158 at SI mm. pres sure, and with another run Lie B.F, was 196- 201 decrees at 37 mm. pressure. Yield was 84 prams, 73m of the theoretical amount. Upon another run with smaller quantities of materials 33.3 grams were obtained, 80,4 theoretical amount* A small quantity of the hydrochloride of the phenoxybutyl diethyl amine was prepared by passing dry hydropen chloride thru a solution of the amine in dry ether. The hydrochloride was filtered off and dried in a vacuum desiccator. U. P.118-120 (unc) The hydrochloride was analyzed for chlorine by means of the Vo 1 hard method for determination of halogens. Weight of sample was 0..40Q3 grams. 15.43 cc.of 0».C(931 IT silver nitrate used. Found chlorine was 13.424, Calculated for 0q • ij Ql. . Chlorine is 13.77;'. P {EPARATIOR OF RRGMBUTYL DIETHYL 'AMINE HYD'RQBROMIDE. 30 grams of phenoxybutyl diethyl amine and 50 grams of fuming hydrobr omi c acid were refluxed for 12 he . XQC cc.of water was added to the contents of the flask and all of the reacting mixture did not dissolve but left an oily liquid. The presence of this oily liquid Indicated that the phenoxybutyl diethyl amine split to give phenol, tetramethylene bromide , and the. hydrobr omi de of diethyl amine. It was evident that the hydrobromide had split too far aid that the hydrobro lie acid was too strong so another run was made with 48,1 hydrobr omi c acid. The hydrobromide of phenoxybutyl diethyl amine was prepared first, by treating 15 grams of phenoxybutyl diethyl amine with 15 -rams of 48,2 hydrobromic acid and it was evaporated to dryness on the steam bath. The solid was placed i:v a flask with reflux 15 and 45 grates of 48$ hydro bromic acid. It was refluxed for on the steam bath for 21 hours* About ICO cc*of r was added to the contents of the flask and an oily liquid separated • ’ ich was very much smaller in quantity as compared to the amount which is formed when fuming hydrobromic acid is used* The mixture was extracted with' ether to remove the ph nol and tetramethylene bromide* The water solution was evaporated until all the water was removed. Avery thick viscous liquid formed which v o .Id not solidify upon cooling* This sirupy liquid is pro bally the hydrobromide of bromhutyl' diethyl amine* The liquid was placed in a vacuum desiccator over sulphuric acid for a week but would not solidify*. Attempts were made to crystallize it from, ethyl ac u :e , absolute alcohol and drv ether without air~ success. 16 3u:.:.i,RY fc 1* ' 1 d3 .1 % m ' • has been prepared in 80-10 percent yields from phenoxypropyl bro dde and di thyl •■mine. 2 ... 3rompropyl diethyl anna hydrabromidc has been prepared in 70-80 percent yields by the splitting of phenoxypropyl diethyl 'amine with hydros ro lie acid. 3 ^ rhft yield of phono xybutyl amine from the reduction of phenaxy- propyl cyanide has been increased from 40-30 percent yields to 80 percent by use of Levene and Allen-? s modification of the sodium and alcohol reduction. 4„ Fheno.xyb.utyl diethyl amine has been prepared in 70—80 percent yields from phenoxybutyl amine. 5 The splitting of phenoxy butyl diethyl amine to the hydrobrom— ide of brornbutyl diethyl amine by means of hydro bromic acid was attempted but the resulting product has not been purified and analysed. Diphenoxy propyl diethyl ammonium bromide was isolated as a by-pro d'uo t from the preparation of phenoxypropyl di hyl amine. ....... ft . ■ - i*> * - • 7 * . « . i k • » * i V i 4 . / \ - • ^ ‘ - * r *J j i't : , v ni / • ' . .W. n . ( r: . “.r ^ ;o ^ r » * . - ' : j ■' , i ' 1 • ■ * • / » *. i \ t • .* v • V . ■ \* j. s t\ : 1 . . % * 4 v / . i 5 / .s. < 5 ‘ s i i > ' -? '- » / ». -i t ii f ..... t •• ■ i ». • i '*•> ■* - * ^ *' ■ :.. ^ v - — •' l > y * • : *.V I ^ / ' K ♦. V . \ * ■>*> • ' * «v J # „• - - Ji » . - I ' v .v f a > \ - J •■ ■ ' ' < ’ fa . . - . . •■• r -‘ '• <■•’•» s <. - -■ T .V , ! ;• <■ «i, ' t > • j.* • • ' i.. v i . , ,V . • 1 • V ■ = . y Ji >■>..• i\* V S ’ i I* ~ii , -V -I - .... * • t < V '« • > ' V’ *- ' if . " t 17 bibliography:. 1. Berichte 2A 3232 2. Berichte 2274 3. Journal of biological Chemistry 27 4. Berichte 39 4121 443