1922.1 > t '' ■ I :H : v V ■ ■ - ■ -- „v > . ' /I ' u I, ■ , *%< . • - ‘ - ij fV* v-.-i ., ; ■ I' \ ' \ / I. LOCAL ANESTHETICS CONTAINING A CARBOXYL GROUP II. ADDITION REACTIONS OF ALLYL AMINE AND MERCURIC SALTS BY NORMAN ALBERT HANSEN THESIS FOR THE DEGREE OF BACHELOR OF SCIENCE IN CHEMISTRY COLLEGE OF LIBERAL ARTS AND SCIENCES UNIVERSITY OF ILLINOIS 1922 UNIVERSITY OF ILLINOIS I 0 H 193 K> ■Augus-t— 12- i9-S — THIS IS TO CERTIFY THAT THE THESIS PREPARED UNDER MY SUPERVISION BY -NORMAN- -ALBERT- -HANSEN ENTITLED J>---LQCAI l ^NES.THE.TXGS--C.QNTAIN1NG.-^-GAEB0XYL-GR.QP£^ JE 3A_ __ -AHD IT I_QN_ _SEA CX IUN S. _ QE _ ALL_YL_ AMXNE. _ AND_ -HER GIIRI C _ _S AL IS. * IS APPROVED BY ME AS FULFILLING THIS PART OF THE REQUIREMENTS FOR THE DEGREE OF _3ACHELOR-QP-SO.IENaS rr i Digitized by the Internet Archive in 2015 https://archive.org/details/localanestheticsOOhans ACKNOWLEDGMENT The writer expresses his sincere thanks and appreciation to Dr, Roger Adams for his suggestion of these problems and for the in- terest and assistance rendered during the experimental work. CONTENTS PART I Page I. INTRODUCTION 1 II. HISTORICAL AND THEORETICAL 1 III. EXPERIMENTAL 5 1. Preparation of g-Chloro-Aceto-Acetic Ester 5 2. Preparation of g-Bromo-Aceto-Acetic Ester 6 3. Condensation of Diethyl Amine with g-Chloro- 6 Aceto-Acetic Ester 4. Preparation of Diethyl Ester of Amido Diacetic... 8 Acid 5. Preparation of Ethyl Ester of n- Allyl Glycine.... 8 6. Preparation of Ethyl Ester of Methyl Glycine 9 PART II I. INTRODUCTION AND THEORETICAL 11 II. EXPERIMENTAL. 12 1. Addition of Allyl Amine and Mercuric Chloride... 12 2. Addition of Allyl Amine Hydrochloride to 14 Mercuric Chloride 3. Addition of Allyl Amine to Mercuric Acetate 15 4. Preparation of Diethyl Allyl Amine 15 5. Addition of Diethyl Allyl Amine and Mercuric.... 16 Acetate .til BIBLIOGRAPHY 17 1 PART ONE I. INTRODUCTION. The synthesis of many local anesthetics has been achieved in recent years and many theories have been advanced to explain their physiological activity. This research was begun with the hope that the structure of the particular substituted diakyl amino ester of p-amino benzoic acid, whose preparation was attempted would yield further information upon one or the other of these theories. Also that it would assist in the prediction of anesthetic or mydriatic action in compounds possessing somewhat similar structure. II. HISTORICAL AND THEORETICAL. Atropine and cocain are closely related in chemical structure and in physiological action. The mydriatic action and anesthetic action of this type of compound has been extensively studied. The synthesis of new compounds with slight variation in grouping has been carried out for the purpose of determining more definitely just which groups are responsible for the various physiological proper- ties. Atropine as obtained from the leaves of the belladonna plant is an ester yielding on hydrolysis tropine and racemic tropic acid. Its constitution has been definitely determined through the re- searches of Ladenberg, Willst^ltter 1 and others. For the sake of 2 better comparison of the various compounds discussed the following method of writing the formulae will be adopted. ATROPINS CH s OH Cocain has been the most generally used local anesthetic and it has been definitely proven by the above mentioned workers that it is a derivative of ecognine which in turn is a carboxyllic deriva- tive of tropine and therefore any study of cocain or cocain like substances requires also some study of tropine compounds. Many tropeines have been prepared and their physiological action studied and it was found that the tropeines derived from benzene and cinnamic acid were without mydriatic action, while those derived from mandelic and atrolactinic acid did possess this property. Those that were mydriatics all had a benzene nucleus and an OH group in the side chain containing the -0-C=0 group. This was thought at first to be essential for mydriatic action but later many excep- tions were found. The structure of cocain as finally established is as follows:. 0 // c-och 3 Einhorn thought after its synthesis that the ester grouping was responsible for the anesthetic action and mydriatic properties. This he found by further experiment to be more or less true but that it was an extremely variable factor. It appeared then that there must be some relation between physiological action and the structure of the side chain. Attention was then directed toward the alkamino esters of benzoic acid and later toward the alkamino esters of p-amino benzoic acid. These researches have yielded compounds of varying anesthetic power and toxicity. Generally of less or equal toxicity but pos- sessing higher anesthetic power than cocain for certain kinds of anesthesia. This fact may be said to be particularly true for most of the compounds of the procain series, having the following general formula :- NH 2 - - C-O-CHa-CHa-fl-CJHe ? 2 h 6 Dialkyl amino alkyl compounds are prepared by the interaction of halogen alkyl dialkyl amines and the alkali salts of the type 0 R-fl-H-RiX where R and R x are H or any radical and X is an electro negative group such as -COOC 2 H 5 , C0CH 3 , C0C 6 H 5 , CN for example aceto acetic ester, malonic ester, cyan acetic ester, succinyl suc- cinic ester. Or alternately they may be prepared from the halogen alkyl derivatives of bodies of the above type such as chloro ethyl 2 acetate, chloro aceto acetic ester and alkyl amines. The compound desired in this Investigation had the following 9 structure:- / \ 0 CH 2 -C-CR^C 2 H 5 NH 2 C-0-9-CH 2 -N^C 2 H 5 4 from which it is seen that it is similar to the procain type and also similar to cocain but with the complex tropine ring broken* It was expected that this compound would show both anesthetic and mydriatic properties* Its preparation was attempted through the condensation of g-chloro aceto acetic ester with diethyl amine, changing the ketone to the alcohol by means of Grignar&s reaction, condensation of this alcohol with p-nitro benzoic acid and then re- duction of the nitro group to an amino group* Structurally the steps are represented as follows CH 3 6=o — CHo-COOR GHgCl 9=0 ch 2 -coor (CoH 5 ) 2 NH CH s -N ( C 2 H 5 ) 2 CH 2 -N(C 2 H 6 ) 2 C=0 =-*■ R-C-OH CH 2 -C00R Grignard CH 2 -C00R NO. — \ P bc-o-9-c / CH„ h 2 -coor ch 2 -n(c 2 h 5 ) 2 NH. oh 2 -ooor c-o-9-ch 2 -n(c 2 h 5 ) j CH, Lucius and Brdning have succeeded in making a somewhat similar compound but by the reverse method, i.e., starting with the halogen alkyl dialkyl amine. The structure of the compound is:- ^0 H COOR .C 2 H 5 c-o-o-q-ch 2 -ch 2 -n^ CH3 p{ c 2 H 5 It was prepared by allowing chloro ethyl diethyl amine to react with the sodium salt of aceto acetic ester. The ketone arising from this reaction was reduced with sodium amalgam to the alcohol and then condensed with benzoyl chloride. The compound was reported to have marked anesthetic properties 3 . 5 III. EXPERIMENTAL. Preparation of g-Chloro-Aceto-Acetic Ester • The method used in the preparation of g-chloro-aceto-acetic ester is that of Hamel 4 . One atom of Mg. for two moles of ethyl - chloro-acetate. The ethyl -chloro -acetate was added slowly in order to keep the reaction from becoming violent. The addition requires approximately two hours. A small amount of mercuric chloride is introduced as a catalyst. According to Hamel the reaction may take place in, ether, benzene, or chloroform. It was found that ether as the solvent yielded the best results. When benzene was used as the solvent, the reaction was vigorous but it was impossible to hydrolize v/ith water due to the formation of an emulsion, very difficult to separate. Even the addition of NH* Cl to the water did not prevent the formation of Mg(0H) 2 . The reaction in ether solution ran smoothly and the product hydrolyzed by pouring it into ice water acidulated with acetic acid. The oily layer w as separated and vacuum distilled. The ester dis- o tilled at 110 at 25 mm. From a half mole run 10 gms. of ethyl- ° , chloro-acetate was recovered, the yield of the ester was 30 / • The index of refraction was found to be 1.4458. Hamel reported 1.4545. The use of redistilled materials, and also using the ethyl- chloro-acetate recovered in previous rims, increased the yield of ° / ° / crude product to 47 /o. Redistilled the yield was 40 /o of theory. i 6 Hydrolyzing by means of ice and H2SO4 proved to be the best, as the solution was more easily handled. o Andranoff reports yields of 55 / Q by a somewhat similar method 6 . o Hamel reports yields of 56 /o of theory. Preparation of g-Bromo-Aceto-Acetic Ester . One mole of bromine was added to one mole of aceto-acetic ester, v O dissolved in carbon disulphide cooled to 0 . It was poured into water after the addition was complete and allowed to stand for 12 hours. After separating and drying with CaCl 2 the product was o O 0 vacuum distilled. It was fractionated at 80 , 125 , and 140 at o 25 mm. The 140 fraction should have been the g-bromo-aceto-acetic ester. The yield was very small and its preparation was not again attempted. The bromine atom enters in the alpha position but on standing shifts over to the gamma position 6 . Condensation of Diethyl Amine Y/ith g-Chloro-Aceto-Acetie Ester . One mole of g-chloro-aceto-acetic ester was added slowly to two o moles of diethyl amine dissolved in ether and cooled to 0 . The hydrochloride of diethyl amine formed during the reaction was fil- tered from the solution and the condensation product then precipi- tated. It in turn was filtered and it was spread upon filter paper to dry thoroughly. The crystals assumed a pink color and the pro- duct was then placed in a bottle and stoppered. An intense heat soon developed and the product decomposed. Diethyl amine hydro- 7 o o chloride and another compound whose melting point was 128 -130 were isolated from the charred material. The reaction proceeded as fol- lows : - / 0 0 H ,0 0 (C 2 H s ) 2 NH + C1CH 2 -C-CH 2 -C-0C 2 H 5 = ( C 2 H 5 ) 2 N- CH a - C - CH 2 - c - oc 2 h 5 The decomposition product is: r 2 ch 2 c=o CH 2 C00R C00R ?H 2 c=o CHO H s COOR L H -C — — ► o=c. c=o / H COOR H. The reaction was also tried at room t emperature but the decom- position then took place immediately. Analysis of the decomposition product gave the following percentages Sample I .1301 gms. Weight of water formed .0837 gms Weight of C0 2 formed .2686 gms /o H 2 = 7.14 /„ /. c =56.3 /< Sample II .1806 gms. Weight of water formed .1083 gms Weight of C0 2 formed .3813 /o H 2 =6.66 f /< Theory Hydrogen = 57.17 6.3°/ 0 O 56.2 / Carbon Preparation of the Diethyl Ester of Araido Diacetic Acid* 8 The hexamethylene tetramine and NaCN were dissolved in water and o then cooled to 0 . H 2 S0 4 was then slowly dropped into the mixture. After standing several days the solution was extracted with ether hut no product was recovered. The method in the literature calls for the use of pure HCN but the attempt was made here to form the product using NaOH and HsSOa 7 . Reactions : (CH 2 ) 6 N 4 + 6HCN CN-CHa-NH-CHa-CN G00C 2 H 5 ch 2 g 2 h 5 oh NH * — GOOC 2 Hg COOH CH 2 NH -=r- Ba( OH) 2 i ?H 2 COOH The Preparation of the Ethyl Ester of n-Allyl Glycine. The method of preparation attempted was that iof Alpern and Weiz- s man . The calculated quantity of allyl amine was slov/ly added to a o dry ether solution of ethyl chloro-acetate cooled to 0 . At the end o of one hour 33 / 0 of sodium hydroxide was added and then potassium carbonate in sufficient quantity to make the aqueous layer syrupy. This then was extracted with ether, and the extract dried v/ith an- hydrous potassium carbonate. According to Alpern and Weizman the o o ester should boil at 75 -80 at 15 mm. pressure. Working at 25 mm. pressure, no product was isolated which would correspond to the 9 o o above mentioned product* A fraction at 130 -140 was made, the tem- O o perature then quickly rose to 165 -180 • A large amount of residue always remained in the distilling flask. The distillate which were clear and colorless at first, turned yellow on standing. On redisi o o tillation the 130 -140 fraction yielded no definitely boiling com- pound and decomposition occurred. This product was thought to be an amide but it did not yield any qualitative tests for that group. The Preparation of the Ethyl Ester * of Methyl Glycine. This compound was to be prepared thro the esterification of worked methyl amino-aceto-nitrile . The idea being also if that n-allyl glycine might also be prepared similarly from n-allyl amino-aceto- nitrile • The method used for the preparation of methyl amino-aceto-nitrile 9 was essentially the same as Adams and Marvel use in the preparation of methylene amino-aceto-nitrile. Methyl amine hydrochloride was used instead of ammonium chloride. Relative proportions of two moles of formaldehyde to one mole of methyl amine hydrochloride were placed in a flask fitted with a mechanical stirrer. A thermometer was placed in the liquid, the o stirrer started and the whole cooled to 0 . A concentrated solution of one mole of NaCN was then slowly dropped into the mixture. When one half of the sodium cyanide was run in, glacial acetic acid (380 cc. for molecular proportions) was also slowly run into the solution so that the addition of acid and cyanide were complete at 10 the seme time. NaCl separates during the reaction, the nitrile formed as an oily layer. The solution was made alkaline, the ni- trile separated and distilled under vacuum. The product boiled con- o stantly at 152 at 20 mm. According to the literature methyl amino- o o aceto-nitrile should boil at 50 -70 at 12 ram. This product then could not be the nitrile sought. Esterification of this nitrile, using a dry solution of HC1 in o absolute alcohol yielded a product melting at 169 uncorrected. Analysis of this ester hydrochloride for N by Kjeldahl Method gave the following results :- Sample I .1190 gms • N / 22.6 cc. of /10 HC1 N / 11.8 cc. of /10 NaOH used for back titration N. 10.8 cc. of /10 HC1 neutralized by NH 3 °/o N = 12.7 Sample II .1441 gms. N 22.32 cc. of /lO HOI N. 9.56 cc. of / 10 NaOH used for back titration 12.76 cc. acid neutralized by the NH 3 °/o N = 12.41 No further investigation of this compound was carried out 11 V PART TWO MERCURY COMPOUNDS OF ALLYL AMINE. I. INTRODUCTION AND THEORETICAL. This investigation was -undertaken with the idea in view of de- termining whether allyl amine formed similar mercury compounds to allyl alcohol. Considerable work has been done upon the compounds of allyl alcohol with mercuric salts 10 . While the problem is still unsettled the probable structure of these products has been narrowed down to two classes of compounds, the propylene glycol mercuric salts of the type C H 2 OH- C HOH- C H 2 HgX and the dipropylene oxide di- mercuric salts of the type XHgCH 2 -CH-CH 2 6 6 6h 2 (Jh -CH 2 HgX The formation of the two types is explained by assuming that the product first formed is the simple addition of HgX and -X to the double bond and a hydrolysis of the X radicle in an alkaline solution yielding the CH 2 OH-CHOH-CH 2 HgX compound. The dipropylene oxide dimercuric salt forms in an acid solution, two molecules unit- ing with the elimination of two molecules of HX. Upon the addition of allyl amine to an aqueous solution of H gCl 2 an insoluble white compound is precipitated. Based upon reasoning similar to the above the compound might possess one of the following formulae:- 12 HgCl - GH 2 OH - GHOH - CH 2 NH 2 CH 2 = CH - CH 2 NH 2 HgCl 2 HgCl - CH 2 - CH - CH 2 H - N N - H CH 2 - CH - CHgHgCl The solution of this problem was approached as follows: (1) Attempt to replace the HgCl group with iodine, reduction of the iodine compound, with the sub- sequent formation of 2,5 dimethyl piperazine. (2) Attempting to condense the mercury compound with p-nitro benzoyl chloride or benzoyl chloride • During this research the anesthetic properties of some of these probable compounds v/as kept in mind. If water soluble to a high enough degree, it might be expected that they would also exhibit decided antiseptic properties without increasing the toxicity very much. A compound of which we might expect these combined physiologi- cal properties would possess the following structure Prom which it is seen that it possesses great similarity to the procain type of anesthetic. II. EXPERIMENTAL. Allyl Amine and Mercuric Chloride . The addition of allyl amine to a solution of mercuric chloride Hg — 0 — C — CH 3 13 Is followed Immediately by the precipitation of a white compound virtually insoluble in all ordinary solvents. The possible struc- tures of this compound are as follows: - H (1) HgCl - CH 2 - C - CH 2 H s l I /$■ HC1— N N — HG1 I \ CH 2 - C - CH 2 - HgCl ft (2) ch 2 = ch 2 - NH 2 - HgCl 2 (3) HgCl - CH 2 H - C - CH 2 - nh 2 OH The dihydrochloride, represented by formula (1) seemed the most logical but attempts to free the base through treatment with NaOH, NH 4 OH and Na 2 CO a were all unsuccessful. Upon treatment with the calculated amount of alkali necessary to liberate the free base, the only observable result was a darkening of the compound. Pyridine was tried as a solvent and the compound appeared to go Into solution very easily. Upon filtering and diluting with water a white crystalline compound was precipitated. This new compound did not redlssolve in pyridine except upon the addition of HC1# It was evident then that these two compounds were not identical. The Q original did not melt while the second melted at 178 . Recrystal - O o lized at 182 -185 • It was thought that possibly the alkalinity of the pyridine had been sufficient to liberate the free base but this idea was discarded because the other alkalis had no such action. Upon treatment of the second compound with NaOH, yellow mercuric 14 oxide precipitated and the odor of pyridine was easily noticeable. What had happened was that pyridine removed not the HC1 group but the HgCl groups forming either C 5 H s NHgCl 2 or C 6 H 5 N - HC1 - 2 HgCl 2 , o o o melting points 180 and 177 -178 respectively. Analysis of the original compound for mercury did not indicate a great deal because structures represented by formulas (1) and (2) have identical percentage compositions. Hydrochloric acid decomposes the compound again into allyl amine and mercuric chloride, upon refluxing for a short while. In attempting the preparation of the iodine compound, the origi- nal material was ground up rather finely, suspended in water and treated with KI. The yellow Hgl compound was formed and this was treated in the same solution with the calculated amount of I. A dark, almost black, viscous liquid separates upon standing and this was thought to be iodine compound. A zinc-hydrochloric acid reduction of this compound was made without success. However, the amount made was so small that it was impossible to investigate it thoroughly. Working with larger quan- tities would yield more definite information. If this reduction of the iodine compound could be made successfully, 2-5 dimethyl pipera- zine would be formed and this would definitely prove the ring struc- ture of the compound. Addition of Allyl Amine Hydrochloride to Mercuric Chloride. Water solutions of allyl amine hydrochloride and HgCl 2 were 15 heated slightly until the reaction, judged by entire solution, was complete. The solution was then chilled, when a white crystalline product separated. This w as filtered and recrystallized from butyl o alcohol (m. p. 158 ). On the addition of alkali to a water solution of these crystals, yello w mercuric oxide precipitates. Addition of Mercuric Acetate to Allyl Amine . Allyl amine was added to an alkaline solution of mercuric acetate and C0 2 passed into the solution. Upon careful evaporation, a crys- talline product remained which was thought to have the following composition: CH 3 - G - 0 - Hg - CHg - CH - CH 2 - NH S OH o o It melted at 59 -50 • NaOH does not precipitate HgO and the com- pound is easily soluble in water. Condensation with p-nitro benzoyl chloride was attempted with the idea of preparing an anesthetic of the type mentioned in the introduction. This condensation was not successful. The Preparation of Diethyl Allyl Amine . One molecular part of allyl bromide was slowly dropped into two parts of diethyl amine, cooled by means of an ice salt mixture. The solution was made alkaline with NaOH when the amine separated. It O o was then distilled and the fraction between 110 -113 collected. This is pure diethyl allyl amine and the reaction gives almost quan- titative yields. 16 Addition of Mercuric Acetate to Diethyl Allyl Amine , On adding diethyl allyl amine to a solution of mercuric acetate, yellow mercuric oxide is precipitated and it is therefore necessary to add enough acetic acid to keep the oxide from forming* Upon evaporation white plate like crystals separate from the solution. These crystals do not melt and they are insoluble in ordinary or- ganic solvents and water. An attempt to condense this compound with p-nitro benzoyl chloride was also unsuccessful. BIBLIOGRAPHY 1. May, Synthetic Drugs. 2. Chemical and Metallurgical Engineering 25., 25, 1064. 3. Centrall blatt, p.259, July 27, 1921 4. Hamel. Bulletin Societe de Chimique de France 29., 1921; Hamel. Bulletin Societe de Chimique de France 50 , 1921. 5. Andranoff. Berichte 46, 1021. 6. Berichte 25., 2, 25; Ann. 266, 77; Cohen. Organic Chemistry, p.218. 7. Ann. 122 , 276; 278, 299. 8. Journal of the Chemical Society £9, 84-87. 9. Adams and Marvel. Organic Chemical Reagents. 1921. 10. Whitmore. Organic Compounds of Mercury, p.131. 11. Ann. 134, 11 (1865).