MYDRIATICS and BETA AMINO ACIDS By GLENN FABER ZELLHOEFER B. S. University of Illinois, 1921 THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE IN CHEMISTRY IN THE GRADUATE SCHOOL OF THE UNIVERSITY OF ILLINOIS, 1922 URBANA, ILLINOIS / 9 2 2 238 ft. UNIVERSITY OF ILLINOIS a. 01 THE GRADUATE SCHOOL 5V Ju ly 36, - 192 - 3 * I HEREBY RECOMMEND THAT THE THESIS PREPARED UNDER MY supervision by Glenn Faber Zellhoefer . entitled Mydriatics and Beta-Am ino Ac ids BE ACCEPTED AS FULFILLING THIS PART OF THE REQUIREMENTS FOR the degree of Master of Science* Recommendation concurred in* o Committee on Final Examination* •Required for doctor’s degree but not for master’s Table of Contents. MYDRIATICS. Page Introduction 1. Experimental 1 . BET A- AMI NO ACIDS. Introduction 5. Experimental 5. Bibliography 10. Digitized by the Internet Archive in 2016 https://archive.org/details/mydriaticsbetaamOOzell Page 1. MYDRIATICS. Certain compounds of the general formula R. C.R OH CH a NR 2# where R represents an alkyl or aromatic group, have mydriatic ( 1 ) properties. The following compounds of this general formula were synthesized to be tested for their mydriatic properties: CH 3 C Ph OH. CH a N (Et) 2 , C 2 H 5 . C Ph OH. CH 2 N (Et) 2 , C 3 H 7 . C Ph OH. CH 2 N (Et) 2 , C 4 Hq. C Ph OH. CH 2 N (Et) 2 and CH 3 C Ph OH. CH 2 N HCH 3 . EXPERIMENTAL WORK. CH 3 . C Ph OH. CH 2 N ( Et ) 2 . An equimolecular amount of chi orace tone, dissolved in ab- solute ether, was added drop by drop to cold phenyl magnesium bromide. After warming for a short while, the mixture was poured on crushed ice, the ether layer washed with water containing a few cc. of sulphurio acid, and the product distilled. Under fifteen millimeters of pressure, the Chlorhydrin boiled at 123 to 135 degrees C. A yield of 36$ of the theory was obtained. Diethyl amine was dissolved in twice its volume of alcohol and a little less than one-half the molecular amount of the chlor-hydrin added. The mixture was warmed on a water bath for two hours then most of the alcohol was distilled off and the sol- ution made acid with dilute hydrochloric acid. After wahsing with benzene to remove the chlorhydrin, the aqueous solution was made alkaline with sodium hydroxide. The amino alcohol was ex- tracted from the aqueous solution with ether and distilled under diminished pressure. Page 3. An analysis for nitrogen gave 6.4 5$. Specific gravity at 38 degrees C. is .978, index of refraction is 1.519 and the boiling point is 133 to 135 degrees C. under sixteen millimeters of pressure. The yield wa3 48$ of the theory. C 3 H 5 . C Ph OH. CH 3 N (Et) 3 . Chloracetophenons, dissolved in absolute ether, was added slowly to a little more than an equivolecular amount of ethyl magnesium bromide. During the addition of the chloracetophenone the temperature was kept at about 5 degrees C. but after the chloracetophenone was added the solution was warmed on a water bath for a half hour. The solution was then poured on crushed ice and the ether layer washed with water containing a few cc. of sulphuric acid. The ether was distilled off and the chlor- hydrin distilled under diminished pressure. The boiling point of the C 3 H 5 . C. Ph OH. CH 3 Cl was 135 to 130 degrees C. under 17 millimeters of pressure. A yield of 33$ of the theory was obtained. The chlorhydrin was treated with diethyl amine in the manner described above for CH 3 C. Ph OH. CH 3 Cl. The CH 3 C. Ph OH. CH 3 N(Et) ls boiled at 133 to 138 degrees C. under 15 millimeters pressure. Index of refraction was 1.503 and specific gravity, .980 at 38°C, Upon analysis 6.18 $ of N was found. The yield was 30$ of the theory. C 3 H 7 C. Ph OH. CH 3 N (Et ) 2 , The chlorhydrin C 3 H 7 C. Ph OH. CH 3 Cl was prepared by treat- ing chloraoeto-phenone with propyl magnesium bromide in the Page 3 manner described for the preparation of the C 2 H S C. Ph OH CH 2 Cl The boiling point of the C 3 H 7 C. Ph OH. CH 2 Cl is 154 to 157 degrees C. under 30 millimeters of pressure. The yield ob- tained was 16$ of the theory. The amino alcohol, C 3 H 7 C. Ph OH. CH 2 N (Et) 2 , was prepared by the action of C 3 H 7 . C Ph OH. CH 2 Cl on diethyl amine in the same manner as described for the preparation of CH 3 C. Ph OH CH 2 N (Et)a from CH 3 C. Ph OH. CH 2 Cl. The C 3 H 7 C. Ph OH. CH 2 N (Et) a boiled at 145 to 147 degrees C. under 30 millimeters of pressure. The index of refraction is 1.510 and specific gravity .993 at 38 degrees C. The yield was 13$ of the theory. An analysis for nitrogen gave 5.8$. C 4 H 9 C. Ph OH. CH 2 N (Et) s . C 4 Hg C. Ph OH. CH a Cl was prepared by the action of chlor- acetophenone on butyl magnesium bromide by the same method as described for the preparation of chlorohydrins. The C 4 Hg C. Ph OH. CH 2 Cl boiled at 135° to 143 degrees C. under 15 millime- ters pressure. The yield was 51$ of the theory. The C 4 Hg C. Ph OH. CH 2 Cl was treated with diethyl amine and the C^g C. Ph OH. CH 2 N (Et ) 2 obtained boiled at 169 to 173 degrees C. under ten millimeters of pressure. The yield was 17$ of the theory. The index of refraction is 1.501 and specific gravity .960 at 38 degrees C. An analysis gave 5.3$ N. . Paae 4 CH 3 C. OH Ph. CH 2 MH CH 3 The CH 3 C. OH Ph CH a Cl was prepared as described in the first section of this paper. Fifteen grams of the chlor-hydrin was dissolved in twice its volume of alcohol and methyl amine bubbled through the solution for three hours. The process for the isolation of the amino alcohol was carried out as described in the other prepar- ation but no trace of CH 3 C. Ph OH CH 2 HH CH 3 was found in the ether extract. In the benzene extract CH 3 C. Ph OH. CH 2 OH was found, indicating that the chlorine had been hydrolyzed off during the process. Fifteen grams of CH 3 C Ph OH. CH 2 Cl was dissolved in one- third its volume of alcohol and cooled to -13 °C. , while methyl amine was passed into the solution. The vessel was tightly stoppered and the solution allowed to stand at room temperature over night. As in the other oases, no trace of amino alcohol was found and the chlor-hydrin suffered hydrolysis. Ten grams of the CH 3 C. Ph OH. CH a Cl was placed in a glass bomb and the bomb packed in carbon dioxide snow. Seven grams of methyl amine was distilled into the bonb, the bomb sealed and heated on the steam bath for twenty-four hours. Only a trace of the amino alcohol was formed. Page 5 BETA AMINO ACIDS. Introduction. At present there is no satisfactory method for the production of the beta amino acids, R C. NH S H. CH 2 COOH. In this work effort was made to treat aceto acetic ester with ammonia to (3) form CH 3 C :EH CH a COOC 2 H 5 and then reduce the beta amino crotonic acid ester to CH 3 CH NH 2 CH 2 COOC s H s by the action of hydrogen under pressure in the presence of finely divided platinum.' Experimental Part. For the production of the beta amino crotonic acid ester the procedure as given by J. N. Collie (A. 336, 301) was followed. Dry ammonia gas was passed into a solution of one part aceto- acetic ester and two parts dry ether at zero degrees Centigrade. A white crystalline mass was formed, as described by Collie, which was proven to be C 6 H]_3N0 3 . However upon standing the CeH-^jNOs did not split out water to form C 6 H 11 N0 2 , as Collie described, but a disintegration into ammonia and aceto acetic ester took place, slowly at zero degrees but rapidly at room temperature. An exceptionally high grade of aceto-acetic ester (B.P. 85° -94° C. under 30 millimeters pressure) was used and the ammonia was dried by passing through lime towers of sodium hydroxide, two chilled with ice and the third chilled with carbon dioxide snow. Every precaution was made to have the reacting mixture dry and to protect it from moisture during the reaction. But even with these precautions the procedure was unsuccessful. However the splitting out of HOH from CeH-^gNOs fo rm C 6 H 11 N0 2 was effected by keeping a pressure of twenty pounds of ammonia Page 6. over the C 6 H 13 N0 3 for thirty-six hours. The mixture was kept at zero degrees centigrade. When this method was used a yield of ninety-three per cent, of the theory was obtained even though a mediocre grade of acetoacetic ester was used and no effort made to dry the ammonia. Upon standing three months some of the beta amino crotonic acid ester decomposed into acetic acid and ammonia. To effect the reduction of the ethylic beta amido crotonate to form beta amino butyric acid ester the unsaturated product was dissolved in twice its volume of alcohol and .5 grams of platinum oxide (prepared according to the method of Voorhees and Adams, Journal of the American Chemical Society, June 1922, page 1397) added. The mixture was agitated for forty-eight hours under a pressure of forty pounds of hydrogen. This method proved unsuccessful so the solution was acidified with acetic acid. This likewise failed to effect reduction. The hydrochloride of the beta amino crotonic acid exter was prepared by passing perfectly dry hydrochloride into a solution of 25 grams of the crotonate and 25 grams of dry ether, (Soc. 71, 303). The ether was then decanted off and absolute alcohol added with .5 grams of the platinum oxide. The mixture was agitated under about forty pounds pressure of hydrogen for twenty hours. About .2 moles of H 2 reacted. The product was filtered and in the precipitate was ammonium chloride and a compound which proved to be CeH 13 NO a This compound has been isolated by Collie (Soc. 71, 303) and identified by F. N. Fleiechman (Soc. 91, 257) as t . . Page 7. CH S C - H -N- ■C:0 C C — C:0 CH 3 oc 2 h 5 -C-H .3000 grams. .03138 B 7.i 7 . 3 $ The product was purified by recrystalization from hot water. The melting point was 138-139°Centigrade. Analysis for the nitrogen gave the following results: Sampl e . . 3000 grams Nitrogen .03156 w Per Cent of N 7.13 $ Theory 7.3 # After distilling off the alcohol in the filtrate a resin- ous product remained which was water insoluble and ether soluble. It suffered decomposition at about 150° when effort was made to distill it under 30 millimeters of pressure. Evidently some products of disintegration of the crotonate hydrochloride formed a platinum salt, (Soc. 71, 303-311) for the theoreticel amount of platinum black was not recovered and the resinous material derived from the filtrate contained plat- inum as indicated by tests made on its residues after ignition. In hope that the benzal amino crotonic acid ester could be reduced without suffering rearrangement it was prepared (B. 36, 467) by treating equimolecular amounts of benzal dehyde and beta amino crotonic acid ester and heating on the steam bath for fifteen minutes. The benzal amino crotonic acid ester is a viscuous product which suffers decomposition when attempt is m&de to distill it under fifteen millimeters of pressure. No : ' s< . • . • • t. > ■- > Page 8 effort was made to effect its reduction. Summary and Conclusion. While it is possible to obtain the beta amino crotonic acid ester in excellent yields by the action cf ammonia upon aceto acetic ester it is not possible to effect the reduction by the action of hydrogen under pressure with platinum as a catalyst because of rearrangement of the moleoule. However it is possible that a derivative of the beta amido crotonate, or some homo- logue can be satisfactorily reduced by this method. ■ Page 9. ACKNOWLEDGEMENT. The writer wishes to acknowledge hie indebtedness to Professor Roger Adams, who proposed these problems, and for his assistance and interest during the investigation. Page 10 Bibliography. (1) D. R. P. 169,746 D. R. P. 189,481 D. R. P. 101,175 (3) Comptes Rendus 138, 766-68. Ber. CO CO w 3-1895, p. Ber. 11, 1194. n 15, 1386 N 30, 455, 3055. II 32, 544, 353 It 36, 388 II IB, 619. Annalen, 313, 173. n 226, 301 it 314, 301 Bielstein I, 1206. Soo. 59, 173. Meyer and Jacobson, vol. 1, part 1, p. 774. Soc. 71, 303. Soc. 91. 257 J. Amer. Chem. Soc. v. 44, No. 6, 1397 Ber. 36, 467.