7? C. Ki liefer’. 
 
 'Resolution Of Am.no /\c,4s Th^h The ^.„o - Camphor' 
 
 Sulfonamides. — 
 
 
 / 
 
RESOLUTION OF AMINO ACIDS THROUGH 
 THE HR O MO-CAMPHOR SULFONAMIDES 
 
 RAYMOND COLONIU8 KILLEPER 
 
 re^ bt x iTj^ 
 
 FOR THE 
 
 DEGREE OF BACHELOR OF SCIENCE 
 
 IN 
 
 CHEMISTRY 
 
 COLLEGE OF LIBERAL ARTS AND SCIENCES 
 
 UNIVERSITY OF ILLINOIS 
 
 1921 
 
Digitized by the Internet Archive 
 in 2016 
 
 https://archive.org/details/resolutionofaminOOkill 
 
28 SEP 21 
 
 UNIVERSITY OF ILLINOIS 
 
 ) < 5L\ 
 
 
 , sT.uft.?. . . . . 7 . * 19 a.z. ? 
 
 THIS IS TO CERTIFY THAT THE THESIS PREPARED UNDER MY SUPERVISION BY 
 
 R&ywwod .. . Q .Q.lQn.3rXia..Mll$.f.QX 
 
 ENTITLED PI ON G? . AM IN 9 ... A P. . . THROUGH . .THE). . BROMO - 
 
 
 
 IS APPROVED BY ME AS FULFILLING THIS PART OF THE REQUIREMENTS FOR THE 
 
 degree of Ba.ch.elar....of...Siiieiic.s...ln...C.h.emis.t.r.y. 
 
 C \i 
 
 Instructor in Charge 
 
 Approved : 
 
 uC A AT* 
 
 
 
 HEAD OF DEPARTMENT OF. 
 
 / r^f-w 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACKKOV.'LEDGMEKS: 
 
 The author wishes to thank Doctor G. 3. ilarvel, under whose 
 supervision this work was carried on, for the helpful suggestions 
 the latter has offered during the progress of the investigation 
 and the writing of the thesis. 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TABLE OP COIJ TENTS 
 
 IMTRODUCTIOK 
 
 HISTORICAL AMD THEORETICAL PART 
 
 EXPERIMEL TAL PART 
 
 oc -amino -cap rylic acid 
 
 Glycocoll 
 
 * -me t hyl - e t hy 1 -amin o - a c e t i c acid 
 Bromo-camphor sulfonic acid chloride 
 Br omo - c ampho r 
 
 Bromo- camphor sulfonamide of oC-amind- 
 oaprylic acid 
 
 SUMMARY 
 
 V 
 
 BIBLIOGRAPHY 
 
 Page 
 
 1 
 
 3 
 
 6 
 
 6 
 
 7 
 
 8 
 9 
 
 9 
 
 10 
 
 11 
 
 
 

- 1 - 
 
 HE SOLUTION 0? AMIKO ACIDS THROUGH THE BROMO- CAMPHOR 
 
 SUIj FOB AMIDE 3 . 
 
 IBTRODUCTIOB 
 
 Amino acids contain a carboxyl group and one or more amino 
 groups in direct union with carbon. They are of physiological 
 importance, since many are decomposition products of proteins, 
 and some are natural products. Many of them contain an asymmetric 
 carbon atom and exist, therefore, in three isomeric modifications, 
 the dextro , the laevo, and the racemic. 
 
 The amino acids prepared synthetically in the laboratory are 
 racemic , while those in the body occur in the active dextro or 
 laevo form. In order to study their physiological action in the 
 body, the racemic form must be resolved into its active forms. 
 
 This is usually done by Fisher's method of resolution. It 
 consists of covering up the amino group with an acyl group, such 
 as R-C-0 , forming a salt of this amide, then separating the dextro 
 and laevo fo 22 ns of the amide, hydrolizing off the R-C=0 group to 
 get back the free amino group. It may be represented graphically 
 as follows : 
 
 R-. 
 
 DH; 
 
 . 
 
 h 
 
 R /KHCOOR 
 H GOOH 
 
 R /DHGO R 
 
 ,A 
 
 El GOO alkaloid 
 
 - d salt 
 ^ 1 salt 
 
 d amino acid 
 1 amino acid 
 
 — * d amide — » 
 
 — * 1 amide — »• 
 
 It was thought that by combining the amino acid with an acid 
 
 that contained an asymmetric carbon atom, it would be possible to 
 
 obtain crystalline amides which could be used for the resolution 
 of tne amino acid, thus avoiding a number of steps in Fisher's 
 
 method. Brorno- camphor sulfonic acid was chosen for the prepara- 
 

 
 
 
 t 
 
 
 
 i 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 f 
 
 
 
 
 
 
 
 
 
 
 
 
- 2 - 
 
 tion of the amides from the amino acids, as it has often been 
 used in working with optically active bases. A graphical outline 
 of t.ie method would be : 
 
 
 H 
 
 . d 
 
 amide — » 
 
 d amino 
 
 acid 
 
 R-C - COOH 
 
 * R-(f 
 
 
 
 
 
 V i,H 2 
 
 w r K 
 
 ^ 1 
 
 amide — * 
 
 1 amino 
 
 acid 
 
 
 14=8 
 
 
 
 
 
 I 
 
- — -:j- 
 
 HIS TORI CAL ALT) THEORETICAL PART 
 Several amino acids were prepared, and. a study of the reaction 
 and best conditions of preparation was made. 
 
 a -amino-caprylic acid which was selected for resolution, 
 was prepared first. This acid has been prepared in 35$ yields 
 
 by treating the ammonium addition compound of heptaldehyde with 
 
 1 
 
 aqueous hydrocyanic acid followed by hydrolysis. It has been 
 
 prepared in larger yields (45$) by treating the heptaldehyde with 
 
 ammonium chloride and sodium cyanide and subsequent hydrolysis of 
 
 2 
 
 the nitrite group. This latter method was the one used in this 
 work, and the same yields were obtained. An attempt was made to 
 increase the yield by use of mechanically stirring in the prepara- 
 tion of the amino cyanide, and by lengthening the tine of hydroly- 
 sis. It was not possible, however, to increase the yield. 
 
 Glycocoll was next prepared. The usual method is that of 
 Kraut’s, in which chloroacetic acid is treated with ammonia, and 
 
 the glycocoll resulting purified by crystallizing as the copper 
 3 
 
 salt. The method used in thos work was that of treating chloro- 
 acetic acid with ammonia in the usual way, and then removing the 
 ammonium chloride by means of lead oxide. The lead oxide reacts 
 with ammonium chloride to form insoluble lead chloride, and 
 ammonia, which is boiled off. It was found necessary to filter 
 off the lead chloride, and treat with lead oxide again, in order 
 to remove all the ammonium salts. A large amount of lead oxide 
 
 was necessary as a soluble lead salt of glycocoll is formed. In 
 order to remove this lead from the solution, it was found necessary 
 to precipitate the lead with hydrogen sulfide under pressure. A 
 
 large bulky precipitate is obtained, which is quite diffi G ult to 
 
 - 
 

 
 
 
 
 
 
 
 . 
 
 
 
 
 . 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 , 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 . 
 
 ■ 
 
 
 
 
 
 
 
 
 
 
-4- 
 
 handle . The glycocoll obtained, by this method is a fairly pure 
 compound, but has a sour taste. A test was made to see if it 
 were due to hydrochloric acid, but not chlorides were formed. 
 
 <X -amino-rnethyl-ethyl-acetic acid has been prepared by treat- 
 ing the cyanhydrin addition product of methyl-ethyl ketone with 
 
 ammonia, followed by hydrolysis and purification from ammonium 
 
 4 
 
 salts by means of lead oxide. It was prepared in this work by 
 treating methyl-ethyl ketone with ammonium chloride and sodium 
 cyanide followed by hydrolysis of the nitrile groupe , and puri- 
 fication by means of lead oxide. A fairly pure product was ob- 
 tained in 45 ~]o yields. 
 
 Bromo-camphor sulfonic acid has been prepared by treating 
 
 5 
 
 bromo-camphor with anhydro sulfuric acid." A newer method, using 
 
 chi oro sulfuric acid, as developed by Xippling and Pope, can be 
 6 
 
 used. This latter method was used with fairly good resutls. 
 However, in every case, our yields were only about two thirds of 
 those given in the leterature. 
 
 It was necessary to prepare bromo-camphor. Armstrong’s and 
 
 7 
 
 Mathew’s method was used. A pure product was obtained, though 
 in only about two thirds the yield given in the literature. 
 
 Bromo-camphor sulfonamide of -amino- cap rylic acid was pre- 
 pared by the usual method of condensing an amino acid with a sul- 
 fonic acid chloride in the presence of sodium hydroxide. An 
 amide was formed, but instead of being a crystalline solid, it 
 was found to be a sticky substance which could not be crystallized. 
 An attempt was made to prepare sulfonamides of phenyl-amino -ace tic 
 acid, and other amino acids, but in every case it was found that 
 these amides were sticky, oily substances. It was therefore con- 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 , 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- 5 - 
 
 cluded that it 
 tives of amino 
 result , it was 
 of resolution. 
 
 was the nature of the bromo-camphor sulfon aeriva- 
 acids to be sticky and uncrystallizable . As a 
 impossible to oontinure from this point with the work 
 
-G- 
 
 EXIERIMEKEAL 
 
 cj - amino - cap r;/l i c Acid . 
 
 fifty-five grams of sodium cyanide was dissolved in ICO cc. 
 of water and to the solution 57 grams of ammonium chloride was 
 added. To this solution was added a solution of 114 grams of 
 heptaldehyde in 100 cc. of methyl alcohol. The solution became 
 warm and after about a half hour, a layer of the amino cyanide was 
 taken up in ether, and the ether distilled off. To accomplish 
 the hydrolysis, 500 cc. of HC1 (550 cc . of acid, sp. gr. 1.19 
 and 150 cc. of water) was added and the solution refluxed for six 
 hours. It was cooled and filtered to remove most of the oily 
 impurity which had separated. The amino acid was precipitated 
 from the filtrate by adding ammonium hydroxide. The product 
 obtained was quite dark in color. for purification, it was 
 dissolved in dilute liaCH solution (10-15, .. ) and boiled with bone- 
 black. The solution was filtered end the amino acid precipitated 
 by means of a saturated solution of ammonium chloride. The 
 product was filtered with suction and washed with water and dried 
 on filter paper. Tie yield was 70-75 grams ( 43-47/0 of the cal- 
 culated amount.) 
 
 Glycocoll . 
 
 ninety-five grama of chloroacetic acid was dissolved in 12GCcc. 
 of ammonia water (sp. gr. .90) and 95 cc. of water added in a large 
 flask. The solution was shaken well and allowed to stand for 
 twenty-four hours. The glycocoll solution was poured into a large 
 evaporating dish and boiled until the excess ammonia was driven off. 
 To accomplish the removal of the ammonium chloride, the glycocoll 
 solution was diluted with water to 900 cc. and 200 grams of lead 
 

 / 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 . 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 / . 
 
 / 
 
 
 
 
-7- 
 
 oxide added. The mixture was rapidly boiled to a small volume on 
 the hot plate,, and then heated on a steam cone until most of the 
 water had been driven off. The mixture of lead chloride and 
 glycocoll was taken up in 900 cc . of water and the lead chloride 
 filtered off. The filtrate was treated again with 200 grams of 
 lead oxide , boiled on a hot plate , and finally heated on a steam 
 cone to drive off the last traces of ammonia. The mixture was 
 taken up in 400 cc. of v/ater and the lead chloride filtered off 
 with suction. The lead in the filtrate was precipitated as lead 
 
 sulfide with hydrogen su! ide under pressure, and then filtered. 
 
 The filtrate was evaporated until a fairly concentrated solution 
 of glycocoll was obtained, and then a large volume of 95$ alcohol 
 was added. The crystallized glycocoll was filtered off with 
 suction, washed with a little 95$ alcohol arid dried on filter paper. 
 T Le yiel a 30-34 grams (40-45$ of the calculated amount ) . 
 
 (X - am in o - me t hy 1 - e t hy 1 - a c e t i c ^ciC . 
 fifty-five grams of sodium cyanide was dissolved in 100 cc. 
 of v/ater and to the solution 54 grams of ammonium chloride v/as 
 added. To this solution v/as then added 72 grams of ethyl -methyl 
 ketone. The solution bee me warm and a layer of the amino cyanide 
 began to separate after an hour. The reaction mixture v/as allow- 
 ed to stand for twenty- four hours. The amino cyanide v/as taken 
 up in ether and the ether distilled off. To accomplish the 
 hydrolysis 30C cc. of hydrochloric acid (sp. gr. 1.19) v/as added, 
 and the solution refluxed for six hours. The solution v/as then 
 evaporated to dryness in a large evaporating dish to remove any 
 
 impurities. To remove the ammonium salts, 200 grams of lead oxide 
 waa added " to ^ ie solution, which was boiled to drive off the 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
—rr~ 
 
 ammonia. The solution was boiled, down to a small volume on the 
 hot plate and heated on the steam cone to dryness. The residue 
 was taken up in 900 cc. of water, and the lead chloride filtered 
 off. The filtrate was once more treated with lead oxide, and the 
 boiling and evaporation carried out to remove all the ammonium 
 salts. The residue was taken up in 400 cc. of water, and the lead- 
 chloride filtered off with suction. The lead remaining in the 
 solution was precipitated with hydrogen sulfide under pressure, 
 and the lead sulfide filtered off. The filtrate was evaporated 
 to dryness on the steam cone. The amino-methyl-ethyl-acetic acid 
 remained as a residue. The yield was 51-54 grams (43-46 )o of the 
 calculatedamount ) . 
 
 Bromo- camphor aulfonic Acid chloride . 
 
 One hundred grams of brorno- camphor was dissolved in 200 grams 
 of chloroform. To this solution 75 grams of freshly distilled 
 chloro sulfonic acid was added, and the mixture heated on the steam 
 cone for twelve hours. It was then cooled, poured into water 
 and the chloroform layer separated. The aqueous solution was 
 neutralized with calcium carbonate, and the calcium sulfate formed 
 filtered off with suction. To the filtrate, which was heated 
 nearly to boiling, 45 grams of ammonium carbonate was added. 
 
 Calcium carbonate was precipitated which was filtered off. The 
 filtrate was evaporated until the ammonium salt of the bromo-cam- 
 phor sulfonic acid began to crystallize out. It was allowed to 
 cool, and the ammonium salt filtered off by suction. The product 
 was of a brown color. It was not purified further though it may 
 be by washing with methyl alcohol, and then re crystallizing from 
 boiling water. The yield was 78-81 grams (55_ 5 7$ of calculated). 
 
 — — — - - - 
 
-9- 
 
 Bromo- camphor . 
 
 One hundred and fifty grams of pow dered c mphor was placed in 
 a large flask and heated on a water hath. To it 160 grams of 
 bromine was added veiy slowly with constant stirring. The mixture 
 was poured into a large volume of cold water. The hro mo-camphor 
 which separated v/as filtered off by suction, and washed with water. 
 It was crystallized twice from boiling methyl alcohol. A pure 
 product was obtained which melted at 74 0. The yield was 120-125 
 grams (52-54$ of the calculated amount). 
 
 Bromo - camnho r sulfonamide of <x-amino-oaprylic Acid. 
 
 sixteen grams of a( -amino- caprylio acid was dissolved in 25 cc. 
 of water containing 4 grams of sodium hydroxide. Thirty- two 
 grams of bromo-camphor sulfonic chloride was added, and the mixture 
 mechanically stirred. J?our grams of sodium hydroxide in 10 cc. 
 of water was gradually added withlng the next half hour. After 
 stirring for four hours the solution wras acidified with hydrochloric 
 acid. The product obtained was a sticky mass that could not be 
 crystallized from any of the common solvents. A qualitative test 
 was made showing the presence of nitrogen and sulfur, thus indicat- 
 ing that the amide v/as formed. An attempt was made to prepare 
 the sulfon amides of phenyl-amino-acetic acid and other amino acids, 
 but in every case it was found that these amides were sticky, oily 
 substances. It was therefore concluded, that it was the nature of 
 the bromo-camphor sulfon derivatives of amino acids to be sticky 
 and uncrystallizable . 
 
-1C- 
 
 SUICuS. RY 
 
 1. cX-amino-caprylic acid was prepared in 43-47 $ yields as a 
 fairly pure product. 
 
 2. Glycocoll was obtained in 40-45$ yields by purifying from 
 ammonium salts by means of lead oxide. It has a sour taste which 
 is due to some impurity. 
 
 3. Methyl-ethyl-amino-acetic acid was prepared in 45$ yields 
 
 as a pure product. Lead oxide was used to remove the ammonium salt. 
 
 4. Bromo-camphor sulfonic acid chloride and bromo-camphor were 
 prepared in yields equal to aboovt two thirds of those given in the 
 literature . 
 
 5. The bromo-camphor sulfonamide of <x_amino-caprylic acid 
 was prepared , and was found to be a sticky product which could not 
 be crystallized from any common solvents. Several other amino 
 acids we re tried among them being phonylamino-acetic acid, a id the 
 same kinds of sticky products were obtained. It was , therefore, 
 concluded that it was the nature of the bromo-camphor s lfon 
 derivatives of amino acids to be sticky and uncrystallizable . 
 

 
 
 
 
 ■ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 I 
 
 
 
 
 
 
■=TT^ 
 
 BIBLIOGRAPHY 
 
 1. Ann. 176 ; -344 (1875). 
 
 2. J. 0. 0. 42 ; -2259 (1920). 
 
 3. A. 266 ; -295 (1891). 
 
 4. Ann. d. Chem. 204;-18 (1880). 
 
 5. J. 0. G. 63 ; -577 . 
 
 6. J. 0. G. 67 ; -356 . 
 
 7. Chem. hews 1878, 37; -4.