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 UNIVERSITY OF ILLINOIS 
 
 _ , ' Max„.g5i9il., 
 
 -2; 
 
 X 
 
 THIS IS TO CERTIFY THAT THE THESIS PREPARED UNDER MY SUPERVISION BY 
 
 Louis... Arnold. ..Slfigriat 
 
 ENTITLED .Tho...Re.s.o.lu.ti.Qn .o.f...Amino.. .Ac.i.dj3...T.lar.Q.ui5)a....the 
 
 .C. gwp.p.d.Q.r . . . .Su .1 .f. p.n.ara.i da. s. .* 
 
 IS APPROVED BY ME AS FULFILLING THIS PART OF THE REQUIREMENTS FOR THE 
 DEGREE OF L.a.Q.dalo.r...oi...S.c.lfcn.ce 
 
 O 
 
 Instructor in Charge 
 
 Approved ; 
 
 
 
 HEAD OF DEPARTMENT OF 
 
 
Digitized by the Internet Archive 
 in 2016 
 
 https://archive.org/details/resolutionofaminOOsieg 
 
Table of Contents 
 
 Page 
 
 Acknowledgment 1 
 
 I. Introduction 2 
 
 II. Theoretical and Historical Discussion 4 
 
 III. Experimental 6 
 
 Preparation of 
 
 (a) Phenyl amino acetic acid 6 
 
 (b ) Camphor sulfonic acid 7 
 
 (c) Camphor sulfonyl chloride 7 
 
 (d) Camphor sulfonamide of 7 
 
 dl-phenyl anino acetic acid 
 
 (e) Analysis of caiiphor sulfonamide 8 
 
 of dl-phenyl amino acetic acid 
 
 (f) Rotation of camphor sulfonamide 9 
 
 of dl-phenyl anino acetic acid 
 
 (g) Preparation of camphor sulfonamide 9 
 
 of aniline 
 
 (h) Rotation ana analysis of camphor 9 
 
 sulfonamide of aniline 
 
 (i) Hydrolysis of casnphor sulfonamide 10 
 
 of aniline 
 
 (j ) Pre-paration of camphor sulfonaimide 10 
 
 of p-toluidine 
 
 (k) Rotation and analysis of camphor 10 
 
 sulfonamide of p-toluidine 
 
 (l) Camphor sulfonamide of secondary 11 
 
 butyl amine 
 

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 Resolution of dl-phenyl amino 
 
 12 
 
 
 acetic acid 
 
 
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 Sujaaraary 
 
 14 
 
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 Bibliography 
 
 16 
 

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 ACKliOvrLEDGIvOtlJT 
 
 The writer desiree to express his sincere thanks 
 and appreciation to Dr* C*S, Marvel for his helpful 
 suggestions and guidance during the course of this 
 investigation . 
 
2 
 
 THE RESOLUTION OF AMINO ACIDS THROUGH THE CAJ/iPHOR SULFCNAl-HDES . 
 
 I. INTRODUCTION 
 
 Pure, optically active aroino acids are of importance in 
 the study and investigation of the protein minimum. The 
 natural amino acids, however, differ from the synthetic acids 
 in that the former are optically active, v/hereas the latter 
 are inactive. Consequently, a short method of resolving amino 
 acids is desirable . 
 
 The method of resolving amino acids now in general use, 
 is the so-called Fischer method. The amino group is first 
 covered with some radical, such as the formyl or benzoyl 
 radical. An active alEaloid salt of the amido acid is then 
 prepared and submitted to fractional crystallization. The 
 d-and 1- forms of the amino acid are then regenerated by de- 
 composing the salt and hydrolysing off the protective group 
 above mentioned. 
 
 The present work was undertaken v^ith the hope of finding 
 a shorter method of resolving amino acids. It was thought 
 that if the amino group was covered with an acid radical 
 containing an asymmetric carbon-atom, Fischer's method could 
 be shortened by two steps. Cati'jphor sulfonyl chloride when 
 condensed with an amino acid should yield a sulfonamide, easily 
 crystallizable from suitable solvents. Phenyl amino acetic 
 acid was used because it is easily and cheaply prepared. Also, 
 since the rotations of the d-snd 1-acids are known, it was 
 
 easy to check up the accuracy of this method. A condensation 
 as above mentioned should yield, in the case of phenyl aroino 
 

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 acetic acid: 
 
 d-camphor sulfonamide of 1-pdenyl amino acetic 
 d-camphor sulfonamide of d-phenyl amino a.cetic 
 wnich should be easily separated by fractional 
 
 acid 
 
 acid 
 
 crystallization. 
 
 f 
 
4 
 
 II. THEORETICAL AND HISTORICAL DISCUSSION. 
 
 The phenyl amino acetic acid was prepa.red according to 
 the method of Zelinsky and Stadinoff^, as modified by Marvel 
 
 and Noyes . No increase in the yield was obtained by substitut- 
 ing benzene for methyl alcohol as the solvent for the benzalde- 
 hyde in the preparation of the amino cyanide. However, by 
 employing a mechanical stirrer, the time was cut from three 
 days to about three hours. The yield varied between 30 and 
 
 D1 phenyl airjino acetic acid has been resolved by two 
 
 3 
 
 different methods. Fischer effected the resolution by cover- 
 ing the amine group with the formyl raaical and then preparing 
 the quinine salt for crystallization. Betti and Mayer"^ 
 effected the resolution by preparing the camphor sulfonic 
 acid salt of the amino acid. 
 
 We attempted to resolve the dl acid through the camphor 
 sulfonamide. Equimolecular portions of dl-phenyl amino acetic 
 acid, cajophor sulfonyl chloride and sodium hydroxide were 
 
 O 
 
 stirred, at 0, until everything dissolved and then the amide 
 
 was precipitated v/ith hydrochloric acid. The camphor sulfonic 
 
 acid and camphor sulfonyl chloride were prepared according 
 
 to the method of Reychler'". His yields were duplicated in 
 all cases. 
 
 Attempts to prepare the camphor sulfonamide of the amino 
 acid by a condensation in inert solvents, such as dry ether 
 and dry benzene were without success. Even after refluxing a 
 mixture of amino acid and camphor sulfonyl chloride twenty 
 four hours, no trace of the amide could be found. This is 
 
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 ring salts. 
 
 0 
 
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 In this type of compound the nitrogen is pentavalent, and 
 the hydrogens on the nitrogen are unreactive. 
 
 In order to study the physical constants, rotations, 
 and ease of hydrolysis of various camphor sulfonamides, we 
 prepared the amide of aniline, p-toluidine , and secondary 
 "butyl amine. They were prepared by condensing the amino acid 
 (2 parts) with camphor sulfonyl chloride (Ipart) in dry benzene. 
 The amide was obtained from the benzene solution. 
 
 It was found that the camphor sulfonamide of aniline and 
 p-toluidine could be readily hydrolysed with 48^^ hydrobromic 
 acid. An attempt to hydrolyse the amide of d-phenyl amino 
 acetic acid was Vi/ithout success, perhaps because of the small 
 quantities of material at hand and the lack of time. 
 
 The resolution of camphor sulfonamide of dl-phenyl amino 
 acetic acid was effected in ' 70 % alcohol. The d-amide separ- 
 
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 LI I . EXP3 HIMENT AL . 
 
 Phenyl Amino Ac etic A cid. The method used was that of 
 Zelinsky and Stadinoff^ as modified hy Marvel and Koyes^. 
 
 One hundred ten gms. of sodium cyanide were dissolved in 
 200 cc. of water and 114 gms. of ammonium chloride were added. 
 
 To this was added, with stirring, a solution of 212 gms. of 
 henzaldehyde in 200 cc. of methyl alcohol, and the mixture 
 was stirred for about five hours. The mixture becomes quite 
 warm at first, cooling down, however, in the course of the 
 reaction. After five hours the stirring was stopped and one 
 liter of water was added which threw out the oily amino cyanide. 
 This was collected in 1 liter of benzene and washed with water. 
 The aminocyanide was extracted from the benzene by shaking tv/ice 
 with oOO cc. of hydrochloric acid (3 parts acid to 1 part water). 
 The acid solution was refluxed about fpur hours, in order to 
 hydrolyse the amino cyanide, cooled, filtered from some tarry 
 material, and the free an'jino acid precipita.ted with ammonium 
 hydroxide. The amino acid was filtered off with suction, and 
 washed with water and alcohol to remove color. The yield 
 varied from 120 to 130 gms, (40-43^ of the calculated amount). 
 
 The following method did not increase the yield of amino 
 acid. One hundred ten gms, of sodium cyanide and 114 gms. of 
 powdered ammoniuni chloride were placed in a. flask and 212 gms. 
 of benzaldehyde dissolved in 500 cc, of benzene was added. 
 
 Ten cc. of water was added to the mixture, and the flask was 
 shaken vigorously. The reaction mixture was allowed to stand 
 three days, being shaken occasionally. After three days, some 
 
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 insoluble material was filtered off, the benzene shalcen v/ith 
 hydrochloric acid ( 1:2. by volume ) and the acid layer reflux- 
 ed abput two hours. After cooling the mixture, the free amino 
 acid was precipitated Vi^ith ammonium hydroxide. The yield was 
 120 gms. or 41^ of theory. Longer hydrolysis did not improve 
 the yiela in either of the two methods above outlined. 
 
 The amino acid as purified by washing with alcohol still 
 retains some color. An attempt to purify the acid further by 
 boneblacking an alkaline solution, resulted in a decided loss 
 of product. The best method of purification is recrystalliza- 
 tion from hot water using a little boneblack. 
 
 C amphor S ulfo nic A cid. -- The camphor sulfonic acid was 
 prepared according to the method of Reychler^, duplicating 
 his yields in all instances. In one instance, redistilled 
 acetic anhydride was used, and from 227 gms. of cai^iphor a 
 yield of 127 gms. or 55 ^^ of the sulfonic acid v/as obtained, 
 althoutiii the average yields Vi/ere between of theory. These 
 
 yields are based on the amount of camphor actually used. By 
 pouring the filtrate, from the crystallized camphor sulfonic 
 acid, into about three liters of cold water, v/e were able to 
 recover from 70-80 gms. of camphor from each run. 
 
 Camphor Sulfon vl Chloride The camphor sulfonyl chloride 
 was prepared according to the method of Reychler^. The average 
 yields were between 50-65^ of the calculated amount, although 
 in one case 71^ v/as obtained. 
 
 Camphor Sulfo namide of Dl- phenyl A mino Acetic A cid. - -Place 
 
 12.5 gms. of dl-phenyl amino acetic acid in a flask and add 
 

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8 
 
 3.4 gms. of sodium hydroxide in 100 cc. of water. Stir and 
 cool to 0^. Now add 25 , camphor sulfonyl chloride, and 
 
 during two hours, add gradually 3.4 gms. of sodium hydroxide 
 in 100 cc. water, keeping the mixture well agitated. After 
 all the sodium hydroxide is added, continue the stirring for 
 two hours, then filter and precipitate the camphor sulfonamide 
 v.ith hydrochloric acid. Filter the amide and recrystallize from 
 dilute alcohol (50^). The yields varied between 13-15 gms. 
 or 40-50^ of the theoretical amount. The pure amide is a 
 white crystalline product melting at 165-70°. 
 
 An attempt was made to condense the amino acid writh 
 canjphor sulfonyl chloride in dry benzene and dry ether but 
 the results were negative. The sodium salt of dl-phenyl amino 
 acetic acid was prepared and refluxed with camphor sulfonyl 
 chloride in dry ether, but no amide was obtained. 
 
 The rotation on the camphor sulfonamide of dl-phenyl 
 amino acetic acid as freshly prepared varies with the number 
 of crystallizations probably on account of the difference in 
 solubility of the two isomers present. Analysis of the 
 camphor sulfonamide of phenyl amino acetic acid for nitrogen 
 
 (Kjeldahl) gave the following results 
 
 I II 
 
 weitiht of sample 0.15 g. 0.15 g. 
 
 cc. HCl used (N.F. 0.1998) 10.2 10.2 
 
 ca:. NaOH used (N.F, 0.1115) 14.0 13.7 
 
 % nitrogen found 3.6^ 
 
 % nitrogen calculated 3.8/^ 3.8^ 
 
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9 
 
 0.4000 gms. of substarice dissolved ir 12.2645 gms. of 95^ 
 
 Camphor Sulfonamide of Aniline Five gms. of aniline 
 and 7 gms. of campdor sulfonyl chloride were placed in a 
 small flask and covered with 50 cc. of dry benzene. This 
 mixture was allov/ed to stand over night or for several days 
 (if more convenient), with occasional shaking. The solution 
 was filtered from the aniline hydrochloride formed, and the 
 benzene distilled off. The oily residue was taken up in 
 hot dilute alcohol (50^) and allowed to crystallize. Upon 
 recrystallization from 50^ alcohol, the amide melts at 
 117 .5-118. 5*^ (corrected) . The rotation in 95^ alcohol 
 was determined. 0.8616 gras, of substance dissolved in 
 
 o 
 
 12.1206 gms. of 95^ alcohol gave a rotation off-1.65 in a 
 1 dcm. tube for the sodium line, or . 
 
 Analysis of the amide for nitrogen (K.jeldahl) gave the 
 following results 
 
 alcohol gave a rotation offO.S^* in a 1 dcm. tube for the 
 
 sodium line, or C°<Jjj=fil,4 
 
 0 
 
 weight of sample 
 cc. HCl. used (K.F, 0.1998J 
 cc. KaOH used (K.F. 0.1115) 
 % nitrogen found 
 % nitrogen calculated 
 
 10.0 
 
 13.6 
 
 0.15g 
 

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10 
 
 Hydr olysis o.f the Caiuphor Sulf onairjide of An Hire . 
 
 Three gms. of the ajDide v.?ere refluxed for about two 
 hours v.'ith 48^ hydrobronic acid. After cooling the solu- 
 tion was made alkaline and extracted v/ith ether, and the 
 
 ether evaporated. The oily residue had the odor of aniline, 
 
 0 
 
 The benzene sulfonyl chloride derivative melted at 95-100. 
 Correct melting point 110°, 
 
 C amph o r S ulfonamide p_f P-toluidine :-- Five gms. of p- 
 
 toluidine end 5,7 gras, of camphor sulfonyl chloride were 
 
 mixed in a small flask end covered with 50cc, dry benzene. 
 
 This reaction mixture was v;orked up in a manner similar to 
 
 the one described in the previous experiment. The pure 
 
 amide melts at 137-138 (corrected), 
 
 0,2148 gms. of substaiice dissolved in 12.2333 gms, of 
 
 0 
 
 95^0 alcohol gave a. rotation of +0.32 in a 1 dem, tube for 
 
 the sodium line, or R 7- +23.2 , 
 
 D 
 
 Analysis of the aiwiae for nitrogen (K.1eldahl) gave 
 the following results :-- 
 
 weight of sample 
 
 0 . 30g 
 
 cc. HGl. used (II. F. 0.1998) 
 
 10.4 
 
 cc. NaOH. used (K.F. 0.1115) 
 
 10.6 
 
 % nitrogen found 
 
 4.1^ 
 
 ^ nitrogen calculated 
 
 4.3^ 
 
 The hydrolysis of a 1 gra . sample of amide v;as carried 
 out in the same manner as described in the previous experi- 
 ment. This amide was also readily hydrolysed. 
 
•V ' /’ . ••' -.f . ',; 
 
 i • it i : : i ; .•: •' . 
 
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 -. ...••:’ \.’i i jj|f.7.x.t< r 
 
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11 
 
 Camphor S ulfonamide of Secondary Butyl Amine;-- Three gms. 
 of secondary "butyl amine and b.3 i^s. of camphor sulfonyl 
 chloride v/ere placed in a small flask and covered with 30 cc. 
 dry "benzene. The secondary butyl amine hydrochloride formed, 
 being quite valuable, was filtered off and saved. The oil 
 left after evaporation of the benzene was taken up in hot 50^ 
 alcohol, and allowed to cool. But it was only after standing 
 in a refrigerator for several hours that crystals, mixed 
 v/ith an oily product appeared. The crystals were white needles, 
 A second crop of crystals was obtained by placing the alcoholic 
 solution of the oil in a. refrigerator for another twenty four 
 hours. Since secondary butyl amine contains an asymmetric 
 carbon-atom, it was thought that we could thus obtain the 
 optical isomers of the amide. But due to the low melting 
 point of the amide this v/as not further investigated. No 
 rotation was .axen on the amide and no analysis v/as made. The 
 first crop of crystals melted 40-46 (uncorrected}. 
 
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12 
 
 Resolution of Dl-Pinenyl Airano Acetic Acid 
 Solubi lity of Carfluiior S ulfonainide o f Dl«Phenvl A mino 
 Acetic Acid in Alcoholj-- Five gms. of the amide were 
 dissolved in 100 cc. of hot alcohol (s.g. 0.88) and allow- 
 ed to stand for 24 hours. 1.64 gms. of the amide separated 
 out during this period. This crop of crystals had a specific 
 
 O 
 
 rotation of-t8.8 . After another 24 hours, a second crop 
 of crystals (1.01 gms.) separated out, and these possessed 
 
 a specific rotation of only +5.4°. In order to check the 
 above solubility, if possible, an excess of the amide was 
 allov/ed to stand in contact with lOcc. of 70^ alcohol (cold). 
 After three days the undissolved amide was filtered off and 
 the filtrate carefully evaporated. This yielded 0.1593 gms* 
 of dry amide. Hence lOOcc. of cold 70^c alcohol will dissolve 
 approximately 1.6 gms. of the camphor sulfonamide. 
 
 Fractional Crystallization o f th e Camphor S ulfonamide 
 of D l-Pheny l Airin o^Ace iic A cids i-- Fifteen gms. of camphor 
 sulfonamide of dl-phenyl amino acetic acid v/ere dissolved 
 in 100 cc. hot 70?"^ alcohol. After 24 hours, 11 gms. of amide 
 were filtered off. 0.3980 gms. dissolved in 12.2190 gras. 
 
 O 
 
 9b% alcohol gave a rotation of-tO.56 in a 1 dcrn . tube for 
 
 0 
 
 the sodium line, or [c< +13.8 . The filtrate was concec- 
 
 trated one third its voluTne and after 24 hours 2 gms. of amide 
 
 were filtered off. 0.3850 gms. of substance dissolved in 
 
 0 
 
 12.3480 gras. 95^ alcohol gave a rotation of -0.05 in a 
 1 dcm. tube for the sodium line, or [°<]^- -1.9 . 
 
13 
 
 The second filtrate was again concentrated one third 
 its volume and after 24 hours, 1 gm. of ainide was filtered 
 off. 0.3080 gras, of substance dis :;olved in 12.S210 gms. of 
 9dfo alcohol gave a rotation of -0.24 in a 1 . dcm. tube for 
 
 the sodium line, or[c(J~ -11.3 • 
 

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14 
 
 SUIMARY 
 
 1. A shorter method of preparing dl-phenyl amino 
 acetic acid was worked out. 
 
 2. The method of Reychler for preparing camphor sulfon- 
 ic acid and aamphor sulfonyl chloride were studied and his 
 yields duplicated. 
 
 3. The camphor sulfonamides of various primary amines 
 were prepared and studied. They could be readily hydrolysed 
 with hydrobromic acid, 
 
 4. The camphor sulfonamide of dl-phenyl amino acetic 
 acid could not be prepared by condensing the amino acid with 
 camphor sulfonyl chloride in an inert solvent, 
 
 5. The dextro and laevo rotatory amides of phenyl amino 
 acetic acid were prepared but the free acids could not be 
 isolated, 
 
 6. In the course of this investigation the follov/ing new 
 compounds were prepared 
 
 (a) d-camphor sulfonamide of aniline. 
 
 (b ) d-camphor sulfonaaide of p-toluidine, 
 
 (c) d-ca;;phor sulfonamide of secondary butyl amine. 
 
 (d) d-caraphor sulfonamide of dl-phenyl amino acetic acid. 
 

 
 
 
 
 r 
 
 c: 
 
 'i ^ 
 
 >-.r W.a>4WPTMi^ -i--4 
 
 “ii. 
 
 \. 
 
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15 
 
 Camphor Sulfon- 
 
 M.P. 
 
 Specific 
 
 Analysis 
 
 Calcu- 
 
 amide of 
 
 
 Rot at i on 
 
 for Nitro- lated 
 gen found 
 
 (a) secondary 
 butyl amine 
 
 40-44° 
 
 — 
 
 
 
 (b ) aniline 
 
 117.5 -- 
 18.5" 
 
 t28.8° 
 
 4.4f/^ 
 
 4, 5 fa 
 
 (c )p-toluidine 
 
 137-8° 
 
 +23. 2" 
 
 4,1 fa 
 
 4,3fo 
 
 (d) dl-phenyl amino 
 acetic acid 
 
 165-70° 
 
 +11.4° 
 
 z.efa 
 
 
ffiSSMB, '% , i.'icr ■ ',%■ 
 
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 ■,. 
 
 iii '."* 
 
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 ^ i. -' 
 
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 y* 
 
 
 t 
 
 U - * * "• • • V?c 'ii' -'• ’■• ;■’ ' * ‘«->r ■:■ 
 
 i'i* • 'W' V 1 l 1 Z‘ '• " /■ • ’-f' ;5t • ' ?r ' f- 
 
 
 
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16 
 
 BIBLIOGRi>J>HY 
 
 1. Zelinsky and Stadinoff, 
 
 2. Marvel and Noyes, 
 
 3. Fischer and Meichland, 
 
 4. Betti and Mayer, 
 
 5. Reychler, 
 
 Ber., 39, 1725 (1906). 
 
 J. Amer. Chem, 8oc., 42, 
 2264 (1920). 
 
 Ber., 41, 1287 (1908). 
 Ber., 41, 2072 (1908). 
 Bull. Soc. Ohem,, (3) 19 , 
 120-128 (1898).