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The synthesis of ethylenediaminetetramethanesulfonic acid

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The synthesis of ethylenediaminetetramethanesulfonic acid

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Content THE SYNTHESIS OF ETHYIENEDIAMINETETRAMETHANESULFONIC ACID A Thesis Presented to the Faculty of the Department of Chemistry The University of Southern California In Partial Fulfillment of the Requirements for the Degree Master of Arts by Jean Wynkoop October 1943 UMI Number: EP41548 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. UMI EP41548 Published by ProQuest LLC (20,14). Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 C, q - j y - W?87 This thesis, written hy ...........< j j m j o m q o £ ................ under the direction of her.. Faculty Committee, and a p p ro ve d by a ll its members, has been presented to and accepted by the Council on Graduate Study and Research in partial fu lfill m ent o f the requirem ents f o r the degre:e of MASTER^QF ARTB............ Dean ' Secretary 0ctober,1943 Date. Faculty Committee Chairman TABLE OF CONTENTS PAGE I. INTRODUCTION.................................. 1 II. DISCUSSION......... 3 A. Methods of preparation of chloromethane sulfonic acid...................... 3 B. Reactivity of disubstituted methanes....... 6 C. Relationship of structure to complex formation............................ 10 D. Present results .... 14 E. Possibilities for future work ............. 19 III. EXPERIMENTAL......................... 21 A. Preparation of 1»3,5 trithiane 21 B. Preparation of chloromethanesulfonyl chloride ..•••••..... ................. 23 C. Hydrolysis of chloromethanesulfonyl chloride.................. ........ . 25 D. Condensation of ethylenediamine with sodium chloromethane sulfonate......... 27 E. Preparation of 1-piperidylmethanethiol 31 F. Oxidation of 1-piperidylmethanethiol .... 33 1. Nitric acid ................... 33 2. Neutral potassium permanganate......... 34 3. Acid potassium permanganate ....••...... 36 4.: Hydrogen peroxide. ........... 37 5. Nitrous acid ..... 39 LIST OF TABLES PAGE I* Tabulation of data on trithiane runs .......... 22 II.. Tabulation of data on chloromethanesulfonyl chloride 24 III. Tabulation of data on hydrolysis of chloromethanesulfonyl chloride ......... 26 IV. Tabulation of data on 1-piperidylmethanethiol . • 32 INTRODUCTION 1 Alpha-amino carboxylic acids containing more than one carboxylic acid group per amino nitrogen, such as ethylene- diamine tetraacetic acid (I), have been found to have very 1 excellent water softening properties. Such compounds keep calcium in solution by the form- 2 ation of an inner complex salt (II) of great stability. The object of this study was to prepare a compound similar to (I) which would contain sulfonic acid groups instead of carboxylic acid groups. Several methods of synthesis of ethylenediamine tetramethanesulfonic acid (III), may be envisaged. The carboxylic acid (I) can be synthesized from chloracetic acid and ethylenediamine. This suggests the possibility of making (III) from chloromethanesulfonic acid A. Carpmael, British Patent 474,082, March 24, 1936. Hooc HooCCti% 1 2 P. Pfeiffer and W. Offermann, Ber 75B. 1-12 (1942) 2 and ethylene diamine. Another possible method of prepar ing (III) might be by the oxidation of the corresponding thiol (IV). Ho.scw. rtscHs, , H S C H i i- {&■) (33ZO DISCUSSION 3 A. Methods of Preparation of Ethylenediamine Tetramethane Sulfonic Acid Several methods of preparation of sulfonic acids were found in the literature. Among these were the following: ( 1) oxidation of the corresponding thiol by chromic anhydride 3 or potassium permanganate, (2) preparation of lead sulfon ates by the action of nitric acid on lead mercaptides, (3) treatment of alkyl halides with excess of ammonium sulfite, and conversion of products formed to corresponding 5 barium salts for purposes of separation. However, these methods were not applicable to low molecular weight sulfonic acids. The only method of preparation of chloromethanesulfonic 6 acid found in the literature was that of Demars, who pre pared the compound by heating chloromethane bromide and sodium sulfite. CICHsBr + NaSOaNa * NaBr + ClCHsSOaNa Due to separation difficulties involved in this procedure, 3 G. Collin, T. Hilditch, P. Marsh, A. McLeod, J. Soc. Chem. Ind. 52, 272 (1933). 4 C. Noller and J. Gordon, J. Am. Chem. Soc. 55, 1090 (1933). 5 P. Latimer and R. Bost, J. Org. Chem. 5, 24 (1940). 6 ” ” R. Demars, Bull. Sci. Pharm., 24, 425 (1922). 4 the more straightforward method of preparation of sodium chloromethanesulfonate seemed to be the following: (2) HgC CHg + 7Clg + SHgO - 2ClCHgS0gCl + 10HC1 + HCHO + S (3) CICHgSOgCl + 2NaOH * ClCHgSOaHa + NaCl + HgO After this synthesis was under way, an article by Johnson and Douglass was discovered in which these authors found that the activity of an organic halogen atom is greatly diminished if it is in the alpha position to a sulfone, a sulfonamide, or a sulfonic acid group. They hydrolyzed chloromethanesulfonyl chloride in boiling 5% sodium hydroxide for ten minutes. Upon analysis of the solution only as much chloride was found as was produced in the hydrolysis of the sulfonyl chloride group. On another test, the chloride, after being heated for three hundred and thirty-six hours with aniline at 100°C, had given up only 23% of its halogen. On hydrolyzing chloromethanesulfonamide with 5% boiling sodium hydroxide, complete decomposition took place: CICHgSOgWHg + SNaOH = NaCl + HCHO + Na2S03 + HgO + KHg (1) 3HCH0 + HC1 + 3HgS - HgQ S V Hg Hg 7 7 T. Johnson and I. Douglass, J. Am. Chem. Soc., 63 1571 (1941). The authors reasoned that this decomposition had proceeded by the following mechanism: m m C1CH2S02BH2 + OH * CICHsOH + (S02NH2) and that these products further decomposed to give the end products identified. They also reasoned that the ease of fission between carbon and sulfur seemed to be associated with the presence of ionizable hydrogen on the nitrogen atom. Carbon-sulfur fission was also thought to have taken place in the case of sodium chloromethanesulfonate, which after being boiled one hour in 5% alcoholic sodium hydroxide, had changed only 20% of the chlorine to chloride ion. These results indicated that condensation of chloromethanesulfonic acid with ethylenediamine could not be expected to take place It was thought that perhaps this reaction could be forced to take place by the use of silver oxide as a catalyst However, the reaction could be complicated by the use of 8 silver oxide, for Britton and Williams found that silver oxide dissolved in ethylenediamine to form the stable com plex base, silver ethylenediamine hydroxide. In all probability a silver-dioxane complex could also 9 be formed, for Skarulis and Ricci found evidence for a solid 8 Britton and Williams, J. Chem. Soc. 1935. 796. 9 Skarulis and Ricci, J. Am. Chem. Soc. 33, 8429 (1941). 6 dioxanate of silver nitrate, containing about 94% of silver nitrate to which the formula (AgN03)sC4Hg02 was assigned. This material formed a solid phase at 25°C. ■ » As for the alternate method of synthesizing ethylene- 10 diaminetetramethanesulfonic acid (III), Binz and Pence synthesized 1-piperidylmethanethiol (V) in the following way: /CHsCHgN ✓'CHsCHsx ^CH2CH2^ HCHO + CH2 MH = CH2 NCHsOH HaS^ CH2 NCH2'SH CH/ ''CHsCHg' (V) It was planned to repeat this synthesis, then to oxidize the thiol (V) to the corresponding sulfonic acid (VI). If this oxidation proved successful, ethylenediamine would be substituted for piperidine to give the thiol (IV) which would then be oxidized to the desired product (III)• / * CH2CH2n ch2 nch2so3h ^CHs jCHsT (VI) B. Reactivity of Disubstituted Methanes 11 The work of Johnson and Douglass concerning the deactivation of the sulfonic acid group by a chlorine atom 10 A. Binz and L. Pence, J. Am. Chem. Soc., 61, 3134 (1939). 11 Johnson and Douglass, op. cit. 7 in the alpha position is but a single instance of the general rule that two negative groups on the same carbon atom have a deactivating influence on each other, 12 Petrenko-KTitschenko and Opotzky found in the alkaline hydrolysis of the ehloromethanes at 90°C., the ethylene dichloride and carbon tetrachloride were the most stable. KOH CgHg ONa Ba(0H)2 CHaCl over 90% around 86% around 47% CHsCla around 10% " 10% " 6% CHCla over 90% " 86% " 82% cci4 around 10% " 36% " 18% Time: 30 Minutes Concentration: 0.1 N Wherever an unbalanced condition occurs, activity results, but a balance of negative atoms brings deaetivation. Chloro- methanesulfonic acid seems to be a balanced system, the sulfonic acid group being about as strongly negative as the halogen. In the case of chlorobromomethane, CICHgBr, a relatively active compound results because the bromine being more positive than the chlorine, can be displaced readily 12 P. Petrenko-Kritschenko and V. Opotzky, Eer. 59B, 2131 (1926). 8 as compared with a chlorine in dichloromethane, CH2CI2. CICHsBr + Na2S03 * ClCH2S03Na + NaBr Dichlorodifluoromethane, ClgGFg is so inert that it is used as a refrigerant, Difluoromethane, CH3F2, would be expected to be even more inert. Activity in the halogens is F<Cl<Br<I, so that sodium bromomethanesulfonate should be more reactive than sodium chloromethanesulfonate, and sodium iodome thane sulfonate, if it could be prepared, the most reactive. The effect of the unbalanced condition is further illustrated by chloropicrin, CI3CNO2, in which the nitro group and chlorines can be successively replaced by alkoxy groups---*»C13C-0R—>C(OEtK. 15 Backer in studying the reactions of halogenated carboxylic acids with sulfites to form sulfonic acids, found that the order of reactivity of the halogen acetic acids was Cl,l; Br,98; 1,172, The following comparison of reactivities of* and $ -propionic acids was made IS 14 Cl Br I l 84 157 7dL 3.3 1.5 1.3 3.3 126 204 13 R. Demars, op. cit. 14 T, Midgley and A. Henne, Ind. and Eng. Chem., 22, 542 15 H.Backer and W.van Mels, Rec.trav.chim. 49, 177 (1930) . 9 A retarding influence was found to be present on the intro duction of a methyl group, such as in CHaGHXCOOH, retarda tion being attributed to the steric hindrance of the methyl group. A retardation was likewise exerted by the addition of a second halogen atom as shown by rate comparisons of chloro- and dichloracetie (39si), bromo- and dibromoacetic (67il) and bromo- and chlorobromacetic (140:1). The most satisfactory yields in this work were obtained by using a bromo acid and potassium iodide as a catalyst. This work substantiates the hypothesis that bromo- methanesulfonie acid would be a better acid to use in condensation with ethylenediamine than chloromethanesulfonic acid, due to the enhanced reactivity of the bromine. How- 16 . ever, Ziegler and Connor, working with °\ -bromosulfones 17 further substantiate the work of Johnson and Douglass in showing that the sulfonic acid group brings a deactivat ing influence to a halogen in the ^-position. These authors found that the sulfone group increased the reactivity of the halogen in oxidation reactions, but that in any other reactions, *-bromosulfones were unusually inert. The recovery of unchanged p-tolylsulfonylmethyl bromide was 16 W. Ziegler and H. Connor, J. Am. Chem. Soc., 62, 2696 (1940). 17 Johnson and Douglass, op cit. 10 80-95% in the following tests: (a) treatment with two equivalents of dimethylamine for five days at room temperature and five hours at 40-50°. (b) refluxing for forty hours in 75% alcohol with two equivalents of potassium cyanide. P-tolylsulfonylmethyl bromide was recovered unchanged in 72% yield after refluxing with pyridine for forty hours. N-butylsulfonyl bromide was recovered in 80-95% yields from refluxing for seven hours with two equivalents of sodium acetate in alcohol solution. From a survey of the instances cited, the most plausible method of approach would seem to be to try bromo ethane- sulfonic acid, BrCHgGHpSO3H, which would be more reactive than the corresponding**-acid or^-chloroethane sulfonic acid. C, Relationship of Structure to Complex Formation 18 Pfeiffer and Offerraann in studying the comparative stabilities of aminodiacetic acid, NH(CHgC00H)g, CHgCOOH / nitriltriacetic acid, N-CHgCOOH , and ethylenediamine ^CHgCOOH tetraacetic acid . (I) found that with copper hydroxide 18 P. Pfeiffer and W. Offemann, op. cit. 11 all three compounds gave a copper complex, that of (?) being the most stable. On treatment with calcium carbonate only nitriltriacetic and ethylenediamine tetraacetie gave complex formation, that of the tetraacetie acid being the 19 more stable. Demars and Delephine synthesized H2NCH (SO3K) -SO3H, which then reacted with copper hydroxide to give IHsNCH (SO3K)-SOaJ 2CU. The compound was prepared by the method of von Pechmann and Mank (potassium cyanide and potassium bisulfite were added to an aqueous solution of caustic potash containing sulfur dioxide). The acid potassium salt was converted to the neutral salt by the addition of the calculated amount of 0.5 N potassium hydroxide and adding to the solution 0.5 mole of copper sulfate in 5 parts of water. Large blue crystals of more intense color than copper sulfate were obtained by slow evaporation of the dilute solution. If an ethylenediamine group were present in the compound in place of the amino group, (VII) might be expected to result and then might be expected to give (VIII) in complex formation with R. Demars and M. Delepine, Bull. Sci* Pharm.29,14(1922). von Pechmann and Mank, Ber. 28, 2S76 (1895)* 20 Qol inn K0 3 c 19 12 Ethylenediaminetetramethanesulfonic acid (III) would be expected to give the following complex with calcium ion, (IX). °zS ~ ° \ s °o ' G * 1 aJ-CH V i I \ A 9K chj, Sty- So3K There is so little difference in the structures of (VIII) and (IX) that one should be as effective as the other in keeping calcium in solution. The use of BrCHgCHsSOaH with ethylenediamine would be expected to yield the acid (X), which might be expected to form the complex (XI) with calcium ion. HO.SCHaCH '*£~°' Gu & Kr a CH SO M e H ^ r U" * ^ kti-ch S Cf^cHSo W ^ H oSOlCA % & & S' 3 3 Q * - . 21 Demars and Delephine found that although^ -amino acids such as H2NCH2CH2COOH did not undergo complex formation with copper while the corresponding <v-amino acid, HgNgHCOOH did form a complex, both substituted4- and substituted-?-amino- sulfonic acids did give complex formation. When the basicity of the amino group was decreased by the introduction of a phenyl group as in PhHHCH2 CH2 SO3H, copper hydroxide was easily dissolved and a bluish-green solution resulted, which appeared to be unstable and soon turned brown, possibly, 21 Demars and Delephine, op. cit. 13 through oxidation. Proceeding on the hypothesis that the imino hydrogen was responsible for the instability) Bh(Me)HCHaCHsSO3H and Ph(Et)NCHsCHgS03H were synthesized, but their copper salts seemed to be of the same order of stability. On the addition of freshly prepared copper hydroxide the methyl compound momentarily gave a deep blue solution which changed rapidly to a deep violet and the ethyl compound formed a bluish-green solution which yielded greenish-black crystals on evaporation to dryness. The proximity of the sulfonic acid group to the amino group does not seen to be an obstacle in this synthesis, 22 for although Demars and Delephine were not able to make aminomethanesulfonic acid, HgNCHgSOaH, by the action of ammonia on sodium chloromethanesulfonate, forming instead large amounts of sulfhric acid on heating at 150° for nine 23 days, Bumpf did prepare aminomethanesulfonic acid by the action of ammonium hydroxide on the formaldehyde bisulfite addition compound, precipitating the material with dilute 24 sulfhric acid and reerystallizing from water. Backer was able to prepare the barium salt of chloromethionic acid 22 Denars and Delephine, op, cit. 23 P. Rumpf, Bull. Soc. Chim. (5), 5, 871 (1938). 24 ” H. Backer, Rec. trav. chim. 49, 729 (1930). 14 as a by-product in the preparation of ehlorosulfoacetie acid, the yield of the crude product being only 10% CICHgCOOH + 2S03 .= C1CH(S03H)2 + C02 D. Present Results 1,3,5 trithiane, chloromethanesulfonyl chloride and sodium chloromethanesulfonate have been made in fair yields. Attempts to make the p-toluidine derivative of sodium chloromethanesulfonate failed. A product melting at a temperature very close to that of p-toluidine hydrochloride was the only product obtained. This can be explained by the fact that the p-toluidine derivative of sodium chloromethane sulfonate is more soluble than the p-toluidine hydrochloride, so that the hydrochloride would crystallize first. The 1-piperidylmethanethiol (V) has been made in good yields, and has been converted to its corresponding hydro chloride, for purification and identification. Oxidations have been attempted with nitric acid, neutrai potassium permanganate, acid potassium permanganate, nitrous acids, and hydrogen peroxide, none of which has proved successful. Nitric acid of concentrations of 40%, 35% and 10% proved to be too strong as oxidizing agents, causing the compound to decompose and give a sulfur precipitate, while 5% nitric acid was not strong enough to cause oxidation of the thiol on continued stirring at room temperature. Perhaps oxida tion might have been accomplished by heating this mixture 15 gently under reflux for a short time. Neutral potassium permanganate oxidations gave mostly sulfates and carbonates as products. Acid potassium permanganate oxidations, while giving a larger percentage of alcohol-soluble material than had the neutral permanganate, still gave a prepondernance of inorganic material, with any organic material there merely present as impurity. Sulfur was deposited on the sides of the reaction flask in the hydrogen peroxide oxidations. However, the residues formed from evaporation of the filtrates, were the only oxidation residues which burned on ignition. One residue gave a positive qualitative test for both nitrogen and sulfur, but on being converted to its p-toluidine derivative did not give a positive sulfur test. Also the melting point was very close to that of p-toluidine hydro chloride. This seems to indicate that a slight amount of the desired product, 1-piperidylmethanesulfonic acid (VI) may have been formed, but that the p-toluidine derivative is so soluble that p-toluidine hydrochloride crystallizes first. Sulfur was also deposited on the sides of the reaction flask using one-sixth of the calculated amount of nitrous acid for oxidation of the thiol. The p-toluidine derivative melted very close to the p-toluidine hydrochloride and gave a negative test for sulfur. 16 In the condensation of ethylenediamine with sodium chloromethane sulfonate, it was hoped that enough free diamine would be present at equilibrium to allow the reaction to take place. The amount of free amine could not be calculated definitely because data were not available for all the reactants and products for calculation using the dissociation constant. Also the solubility of silver oxide in dioxane was not known and hence the concentration of silver ion was unknown. Thus too many variables were present to allow any sort of quantitative estimation of free diamine present at equilibrium, although qualitative tests indicated that it would be very small. All reactants had to be dry at the beginning of the reaction, because the presence of water would lead to the - + formation of HO + HHaCHgCHgHHg instead of leaving the free amine available for condensation. If the reaction had pro ceeded in the manner postulated, condensation of the diamine and the sulfonic acid catalyzed by the silver oxide, silver chloride and unused silver-oxide would have been found in the precipitate, ethylenediaminetetramethanesulfonic acid (III), dioxane and water in the filtrate. The filtrate, then, on evaporation should have given (III). There were slight indications that a small amount of this product was formed 5 the brownish-green crystalline residue gave a positive qualitative test for both nitrogen and sulfur, burned on ignition, and possessed minor water-softening properties. However, this could have been due to the + — HgNCHsCHsNHa salt of C1CHsS03 • The positive sulfur test could also have been due to unreacted sodium chloromethane sulfonate, which being extremely water-soluble would have been in the filtrate. There is also the possibility of the silver salt of chloromethanesulfonic acid forming, for on a qualitative test, sodium chloromethanesulfonate formed a tan colored solution with aqueous silver nitrate, which gave a black precipitate on heating. Sodium chloromethanesulfonate was only slightly soluble in dioxane, and was present as a suspension, so that some of it should have been found in the precipitate. This precipitate was treated with ammonium hydroxide so that the sulfonate would have been found in the filtrate. If (III) had foraed a dioxane-insoluble complex with silver, which was water-soluble, traces of this also would have been found in the filtrate. This filtrate was acidified with hydrochloric acid and white, feathery crystals formed on standing. Neither these crystals nor the white crystals which formed on evaporation of the filtrate gave a positive sulfur test, showing that no silver complex of (III) or unreacted sodium chloromethanesulfonate was present. Both of the materials formed in the filtrate gave positive chloride tests, were soluble in water and insoluble in 18 ether, and gave an amine odor on the addition of sodium hydroxide. Both materials sublimed on heating and had negative heats of solution, indicating that they were ammonium chloride. Neither the feathery crystals nor the residue gave a precipitate of silver chloride on addition of hydrochloric acid, denoting a negative silver test. This was surprising because it was thought that these materials would contain traces of either the chloride of the dioxane- silver oxide complex, the chloride of the silver- ethylenediamine complex, or a mixture of both. However, the silver may have been so firmly bound that hydrochloric acid did not break the complex. The black residue which was insoluble in ammonium hydroxide also gave a negative sulfur test, indicating that no formation of a water-insoluble com plex of silver and ethylenediamine had taken place. A blank run which contained all of the reactants but sodium chloromethanesulfonate, also formed a black insoluble residue, which vhen treated with ammonium hydroxide, and hydrochloric acid added to the filtrate, also formed white feathery crystals, which gave a positive chloride test, and an amine odor when treated with sodium hydroxide. The black ammonium hydroxide insoluble residue^ from each of the above reactions, were treated with warm nitric acid, a vigorous reaction ensued; and most of the residue dissolved. The yellow filtrates were treated with hydro- 19 chloric acid, the silver chloride removed by filtration, and the filtrates evaporated to dryness. Both filtrates contained a trace of silver chloride and a very small amount of a yellow material which was difficultly soluble in water. E. Possibilities for Future Work In the method of synthesizing (III), by oxidizing the corresponding thiol, the possibility of running the oxida tion in a basic medium seems plausible. In the following reaction, = - + SOs + l2+2HsO * S04 +21 + 4H as water is decreased, acid is increased, shifting the reaction to the left. The same would be expected to be true in the case of the production of the sulfonic acid, so that the presence of base should shift the equilibrium to the 25 right. Billheimer and Reid found that under continued treatment with sodium hydroxide mercaptans decompose, with three simultaneous reactions perhaps taking place. RSH + 2NaOH * ROH + Na2S + H20 2RSH + 2NaOH = R2S + Ha2S + 2H20 RSH + 2NaOH * CH2=CH2 +.Fa2S + 2H20 Secondary mercaptans reacted more rapidly than the corresponding primary ones. With very dilute solutions of 25 E. Billheimer and E. Reid, J. Am. Chan. Soc. 52, 4338 (1930). 20 alkali the percentage of alkyl sulfide was high when com pared with total decomposition. However, the conditions were quite drastic, heating for two hours at 260° with 3N sodium hydroxide caused one-half of the n-hutyl mercaptan present to decompose. The presence of base would not be expected to have this effect on the hydrogen peroxide oxida tion of 1-piperidyJmethanethiol which would be carried out at very low temperatures, so that basic oxidation looks like a gjod possibility. Although the present work failed to give any immediate useful material, it has given several ideas as to how to proceed for lUture work. The best possibility seems to be to try the preparation of the disulfonie acid (VIII). The other possibility that looks promising is the preparation of the beta acid (X). EXPERIMENTAL 21 A. Preparation of 1.3.5. Trithiane sS N 3HCH0 + HC1 + 3HsS = Hs< ? CHS + 3H80 S S NC/ Ha 26 The method of Chattaway and Kellett was followed. One volume of 40% formaldehyde was dissolved in two volumes of concentrated hydrochloric acid. This mixture was placed in a flat-bottom flask and hydrogen sulfide was passed in through a delivery tube extending to the bottom of the flask, until the mixture was saturated. This required from eight to twenty-four hours. A short time after the hydrogen sulfide addition was started a -white, crystalline precipitate began to form. The precipitate was collected by filtration at intervals during the hydrogen sulfide addition. The crude product was recrystallized either from acetic acid or nitrobenzene. Neither was found to be very satisfactory, for trithiane is insoluble in both. Benzene and methyl eellosolve were even less satisfactory. 26 F. Chattaway and E. Kellett, J. Am. Chem. Soc., 53. 2187 (1931). TABULATION OF DATA ON TRITHIANE RUNS 22 Wt. HCHO Yield (g) Yield (%) M.P. 40 3.1 5.1 80 5.1 4.1 * 100 71.4 46.5 214-216.5° 40 17.9 29.2 40 29.2 47.6 80 55.8 45.5 80 46.6 38.0 210-2150 Were not saturated with hydrogen sulfide. 23 B. Preparation of Chloromethanesulfonvl Chloride /S\ Es<? CH2 + 7Clg + SH20 a 2 ClCHgSOsCl + 10 HOI + HCHO + S S & 'C' H2 27 The method of Kostova was followed in this preparation. The trithiane was suspended in about 60 ml. of water placed in a 200 ml. round-bottom flask. Chlorine was passed in through a capillary-tipped delivery tube extending to the bottom of the flask, which was surrounded by an ice-salt bath. The chlorine was added at such a rate that the temperature remained 0-10°C; the addition was complete in from two to three hours. The chloromethanesulfony 1 chloride formed as a heavy, yellow, water-insoluble oil in the bottom of the flask. The water was decanted and the chloride was washed once with water. In several of the later preparations a dilute solution of sodium thiosulfate was used to wash the chloride to remove excess chlorine. The chloride was then taken up in ether and the solution dried over magnesium sulfate. The ether was removed at reduced pressure and the product distilled in vacuo. The distilled product was a pale yellow, heavy oil with lachrymatory properties. 27 A. Kostova, Acta Univ. Voronegiensis, 8s Ho. 4, 92 (1936). 24 TABULATION OF DATA ON CHLOROMETHANESULFOHYL CHLORIDE wt. Trithiane Yield 6. (crude) % Yield G (dist.) % B.P. Remarks 2.3 2.2 44.0 29.2 39.5 62.7 5.8 5.9 47.2 22.0 15.6 31.7 18.5 35.2 88.2 15.2 16.9 51.5 5.0 15.2 67r70° Press:22mm 35.7 63.8 82.8 26.0 33.7 70.6-760 Press:19.5- 20 mm. 11.2 11.25 46.4 75-770 Press:17 mm 13.8 12.0 40.2 80-89° Press:25-6mm 13.8 13.2 44.3 75-90° Press:27 mm 13.8 11.8 39.6 73-88° Press:25-8mm Too much ether adhered to the crude product to allow accurate weight* The only satisfactory method of calculating the yield is from the distilled product* 25 C. Hvdrolvsis of Chloromethanesulfonvl Chloride CICHgSOgCl + 2HaOH * ClCHgS03Na + NaCl + HgO If the crude chloride was dissolved in alcohol and solid sodium hydroxide was added to the solution, a violent reaction ensued, and a white precipitate, presumably sodium chloride, formed immediately. After the mixture had been heated under reflux from one-half to one hour, it was filtered and the precipitate was washed several times with hot alcohol. Excess solvent was distilled from the filtrate and the solution remaining was placed in an ice bath. A small amount of material crystallized. The light tan crystals were collected, and recrystallized from alcohol with decolorization. The product consisted of white-glossy flakes, which were very hygroscopic. The material sintered and decomposed at 249-253° and had not melted completely at 280- 285°. Sodium chloromethanesulfonate (1.0 g.) was dissolved in a small amount of boiling water to which was added 0.5 g. of p-toluidine (m.p. 41.5-43-5°) and 2 ml. of concentrated hydrochloric acid. After filtering the solution and cooling, no crystals were obtained. The solvent was partially removed by boiling and the remaining solution cooled. The crystalline material obtained was recrystallized from a small amount of water. The tan cubic crystals decomposed at 197-210° without melting. 26 The method later adopted for hydrolyzing the chloro- methanesulfonyl chloride was that of heating the mixture under reflux with the calculated amount of 5% alcoholic sodium hydroxide for one hour. The precipitated sodium chloride was filtered off, and the filtrate distilled to remove excess solvent. On cooling in an ice-hath, the sodium ehloromethanesulfonate crystallized. The mixture was filtered and the product placed in a desiccator over calcium chloride. Later attempts to prepare the p-toluidine derivative gave a product (m.p. 232-234°) melting close to p-toluidine hydrochloride (m.p. 238-239°). A mixed melting point gave 228-229.8°. DATA ON HYDROLYSIS OF CHLOROMETHANESULFONYL CHLORIDE Wt. chloride Wt, ClCHgSOaNa % yield 11.7 g. 0.2 g. 1.6 11.25 0.8 6.9 14.3 3.9 26.7 12.0 7.1 57.7 13.2 9.1 67.4 11.8 6.8 56.6 2? D. Condensation of ethylenediamine with sodium chloromethanesulfonate . ^chsclH x ni^iSC v _ / _y j f% 1 1 a/ x v3 r i a^CH2 ON2WH1*4MeHtSt.^4,*tA^O®«^ h45&\ 2 2 'c''as < &H +4-/^cj£ h- + 5Ui2o Dry ethylenediamine was prepared by the method of 28 Bailar. Zinc oxalate, prepared by the action of oxalic acid on zinc nitrate, was mixed with slightly more than an equivalent weight of 70% ethylenediamine and the compound so formed, |TznCaH4 (NHg)g| CBO4, was dissolved in a minimum amount of boiling water, about 1 cc. for each g. of zinc oxalate used. The solution was filtered, and the crystals that formed in the filtrate on cooling were collected and washed with a small amount of alcohol. The crystalline material was dried to constant weight in an oven at 90-110°, and was distilled in vacuo (3.2-4.5 mm.). The ethylene diamine which came over as a colorless, fuming liquid, was distilled (b.p. 116-117°) and dried over potassium hydroxide, 29 Dry dioxane was prepared by the method of Fieser. To 1500 ml. of commercial dioxane was added 20.2 ml. of 28 Bailar, J. Am. Chem. Soc., 56, 955 (1934). 29 Fieser, "Experiments in Organic Chemistry" (D. C. Heath and Company,) p. 368. 28 concentrated hydrochloric acid and 150 ml* of water. The mixture was heated under reflux, and natural gas passed through the system for twenty-four hours. After the orange colored mixture had cooled, potassium hydroxide was added until no more would dissolve. The dioxane was decanted from the colloidal orange precipitate, that had formed on addition of the potassium hydroxide, and dried over potassium hydroxide overnight. The dioxane was then heated under reflux with sodium until the metal stayed bright, distilled, and stored over sodium wire. Silver oxide was prepared just prior to its use by the addition of sodium hydroxide to silver nitrate. The pre cipitate was washed with water until a test portion of filtrate failed to give a positive chloride test for silver ion, then washed with dioxane to remove the water, and added to the reaction mixture while moist. Before the main reaction was run two blank runs were made. One, using the calculated quantities of ethylene diamine, silver oxide, and dioxane, formed a black precipi tate and gave a very slight phenolphthalein test after being heated under reflux for one hours. The other, employing the same conditions, but substituting silver chloride for silver oxide, gave a brown precipitate and a much stronger phenolphthalein test. Ethylenediamine, 0.3 g. (.005 moles) was dissolved in 29 50-100 ml. of dioxane; to this was added 3.05 g. of sodium chloromethanesulfonate (.02 moles - m.p. 254° dec.) and freshly prepared silver oxide (0.04 moles). The mixture was heated under reflux for thirteen and one-half hours. The black precipitate was filtered off and the light green filtrate saturated with dry hydrogen chloride. The white precipitate (0.1 g.) which formed in this filtrate, pre sumably sodium chloride because it was insoluble in alcohol and soluble in water and charred only slightly on ignition, was removed by filtration and the filtrate was evaporated to dryness. The residue which remained was dissolved in alcohol and the alcohol solution evaporated to dryness, leaving a brownish-green material which burned on ignition. This crystalline substance gave a positive test for nitrogen and sulfur, and exhibited slight water-softening properties, as shown by comparing a sample of calcium hard water to which it had been added wiih a few drops of soap solution, with a sample of distilled water with the same number of drops of soap solution. Ammonium hydroxide was added to the dioxane- insoluble portion of the mixture (the black precipitate), the residue that did not dissolve removed by filtration, and con centrated hydrochloric acid added to the filtrate until the solution was acid. On standing, a vfoite feathery crystalline precipitate (6.3 g.) formed, which sublimed on ignition and gave a negative heat of solution in water, indicating that it 30 was ammonium chloride. This was further substantiated by a negative sulfur test, a positive chloride test, a negative silver test, and an odor of amine on the addition of sodium hydroxide. The precipitate (51.7 g.) which formed on evaporation of the filtrate gave the same tests. The ammonium hydroxide insoluble residue (3.0 g) was treated with warm nitric acid; a vigorous reaction ensued, dissolving most of the residue. Concentrated hydrochloric acid was added to the filtrate, the silver chloride (approx. 3.0 g.) removed by filtration, and the filtrate evaporated to dryness. A small amount of yellow residue formed which was only slightly soluble in water. The black residue from the silver oxide run, containing all of the reactants except sodium chloromethanesulfonate, also gave a white feathery precipitate on addition of ammonium hydroxide and hydrochloric acid. This precipitate sublimed on heating, gave a negative heat of solution in water, a positive chloride test, and an odor of amine on the addition of strong sodium hydroxide, indicating that the precipitate was probably ammonium chloride. 31 E. Preparation of l-pjperiflvlmetlianetiiiol ^CHgCHgs ^CHsCHgN ^CHsCHSn HCHO + CHg m = CHg ' * CHgOH HgS CH2 NCHsSH + H20 ^CHgCH/ ^ CHsCHs s CH2CH/ 30 The method of Binz and Pence was followed explicitly in this preparation. A ten gram portion of piperidine was added, over a period of from twenty to thirty minutes, from a dropping funnel into 20 ml. of 40% formaldehyde in a 125 ml. Erlenmeyer flask, which was surrounded hy an ice-bath. To this mixture was added 10 g. of potassium carbonate, and the oily layer was separated, weighed, and saturated with hydrogen sulfide. A large amount of heat was evolved on addition of the hydrogen sulfide. Since the mixture did not absorb the calculated amount of hydrogen sulfide it was assumed that the reaction was complete when no more heat was evolved. A twenty-five ml. portion of 10% sodium hydroxide was then added to neutralize excess hydrogen sulfide, and the mixture was extracted with 75 ml. of ether. The extract was dried over magnesium sulfate, and the ether was removed at the water pump. Since it was difficult to.remove the last traces of ether for purposes of identification and purification, the 1-piperidinemethanethiol (V) was converted to the hydrochloride by solution In toluene and by passage of dry hydrogen chloride into the solution contained in 30 Binz and Pence, op. cit. 32 an Erlenmeyer flask which was surrounded "by an ice-bath. A capillary-tipped delivery tube extended to the bottom of the flask to insure agitation of the mixture. The hydrochloride formed as a gummy, white solid which was filtered and washed with small amounts of ether. TABULATION OF DATA ON 1-PIFERIDYLMETHANETHIOL Wt. piperidine Wt. thiol yield Wt. hydrochloride % yield M.P. 10 g. 11.0 g. 71.4 - - - 10 12.1 78.5 m m - i 5 3.5 45.5 2.8 g. 28.4 153-1760 10 16.0 m m 10.0 50.7 190-202.50 10 ■ i 13.8 70.0 155-1650 10 - 15.6 79.2 - 10 m m 16.2 82.2 177-1880 20 m m - 7.2 18.2* 177-1840 *?Yield was low because material had to be converted to the thiol and hydrogen chloride added a second time before a pure product could be obtained. 33 F. Oxidation of l-pjperidvlmethanethiol 1. Bv nitric acid /CHsCHsn ✓CHgCHg\ Is N N CHgCHg/ CHg NCHgSH + 3HN03 * CHg NCHgS03H + 3NOg / (VI) CHgCHg'' (V) Attempts to prepare 1-piperidylmethanesulfonie acid (VI) by the nitric acid oxidation of the thiol (V) were not successful. Nitric acid in concentrations of 40%, 35% and 10% was used. The nitric acid was added to the crude thiol and the mixture was heated under reflux until the evolution of brown fumes ceased. In each case a yellow residue of sulfur appeared on the surface of the solution. The pre cipitate was filtered off and the excess solvent was removed from the filtrate by distillation. Four volumes of concentrated hydrochloric acid for one volume of residue were added, but no crystalline material could be obtained. In another attempt using 5% nitric acid, the thiol (.01 mole) was obtained from its hydrochloride (m.p. 177-188°) by the addition of sodium carbonate, taken up in petroleum ether, to which was added a few drops of Aerosol OT to facilitate emulsion of the ether layer and the aqueous nitric acid. The calculated amount of nitric acid (.03 mole) was added and the mixture allowed to stand at room temperature for approximately forty-eight hours. No visible reaction was noted, so the material was neutralized with 10% sodium 34 hydroxide, and oily globules of thiol separated. The mixture was extracted with petroleum ether until no reduction of potassium permanganate was given by the water layer. The calculated amount of 5% nitric acid (.03 mole) was again added with Aerosol OT and the mixture stirred overnight. On standing, the ether layer evaporated and when the mixture was neutralized with 10% sodium hydroxide, oily globules again separated. The mixture was treated with petroleum ether; the petroleum ether layer reduced potassium permangan ate, showing that unreacted thiol was still present. 2. Bv neutral potassium permanganate /CH8CH2\ /CH2CH2n CH2 NCHsSH + 2KMnO^ + H20 * CH2 NCH2S03H + 2K0H ♦ 2Mn02 n CH2CH2' \ CH2CH2 1-piperidylmethanethiol was recovered from 10.0 g. of its hydrochloride by the method described above. One-half of the calculated amount of potassium permanganate (9.4 g.) was added, and the mixture was allowed to stand several hours. The reaction flask was heated slightly until the water layer remained colorless. The second portion of potassium per manganate (9.4 g.) was added, and the reaction mixture allowed to stand overnight. Then the mixture was heated under gentle reflux for one hour; the manganese dioxide was removed by filtration and washed with water. The yellow filtrate was evaporated to dryness. Concentrated hydrochloric acid was added to a sample of the residue, whereupon carbon dioxide 35 was evolved. The residue was digested with alcohol, and the insoluble portion (19.5 g.) charred only slightly on ignition, and gave a positive test for sulfur and sulfate, and a negative test for nitrogen. The alcohol soluble portion (0.5 g.) gave a negative test for sulfur and a positive test for nitrogen. These teste indicated that the product was a mixture of potassium and sodium carbonates, with very little, if any, of the desired product. The above procedure was modified slightly for the second oxidation. After the thiol had been obtained from 17.0 g. of hydrochloride (0.1 mole) by the addition of sodium carbonate, it was extracted with ether, the extract dried over sodium sulfate, and the ether removed by a water-pump. A solution of saturated potassium permanganate containing 35 g. (0.22 mole) was then added to the thiol, contained in a flask which was cooled externally to hold the reaction at room temperature. The manganese dioxide (29.1 g.) which formed was removed by filtration, washed with hot water, the filtrate evaporated almost to dryness, and alcohol added to bring down the pre cipitate. This precipitate (2.4 g.) gave a positive test for sulfur and sulfate, and a negative test for nitrogen. Con centrated hydrochloric acid was added to the alcohol soluble portion, and a Tifcite precipitate (1.5 g.) formed, which on ignition left a large amount of residue. 36 3. By acid potassium permanganate / CHgCHs' ^CHgCHs. 6CHS NCHsSH + 9H2S0A + 6KMnO. * 6CHS NCH8S03H \CHsCHs N CHg CHg + 3KsS04 + OtoS04 + 9HgO The thiol was obtained from 9.1 g. of hydrochloride (.054 mole) as previously described, extracted with ether, and the extract dried over sodium sulfate. When most of the ether had been evaporated by means of the water-pump, a 15.7 g. portion of sulfuric acid (.16 mole) in SM solution was added. A solution containing 11.4 g. of potassium permanganate (.072 mole) was then added slowly from a dropping funnel, causing a brown precipitate to form which disappeared on shaking. At the end of the addition, hydrogen peroxide was added to destroy the remaining color. Barium hydroxide (87.2 g.) was added to the mixture until no more barium sulfate formed. The sulfate (65.7 g.) was removed by filtration, solid carbon dioxide added to convert excess barium to barium carbonate, which was removed by filtration, and the filtrate evaporated to dryness. The residue that formed was heated under reflux with alcohol, the alcohol decanted from the residue (4.3 g.), and evaporated to dry ness. A small amount of oil remained, which on addition of concentrated hydrochloric acid, gave a white precipitate (0.4 g.), which yielded negative tests for both nitrogen and sulfur. 37 In the second run, potassium permanganate 9.5 g. (.06 mole) was added to the thiol obtained f*om the thiolhydro- chloride 8.4 g., (.05 mole) which was dissolved in 33 ml. of 3M sulfuric acid (.09 mole). Barium hydroxide (28.4 g.) was added to the solution, the barium sulfate (32.3 g.) was removed by filtration, the filtrate saturated with solid carbon dioxide, and the carbonate (0.6 g.) removed by filtration. The filtrate was evaporated almost to dryness, and alcohol and ether added until a white precipitate (1.1 g.) formed, which gave a positive sulfur test and negative tests for nitrogen and sulfate.- The filtrate was treated with concentrated hydrochloric acid, forming a white precipitate (1.4 g.) which gave positive tests for sulfur and nitrogen. Ignition tests showed these products to be largely inorganic. 4. Bv hvdroeren peroxide ^ CHg CHg s /CH2GH2n CHg NCHgSH + 3Hg0g = CHg NCHgS0sH + 3 HgO CHg CHg7 ^ CHg CHg'' Three attempts to oxidize l-piperidylmethanethiol with hydrogen peroxide were made; each of these proved unsuccess ful. In each run thiol hydrochloride 1.7 g., (.01 mole) and 3.8 ml. (.03 mole) of 30% hydrogen peroxide were used. For the first run, the hydrochloride was dissolved in water and was placed in a flask, surrounded by an ice-bath. The hydrogen peroxide was added to this in two portions, the mixture allowed to stand one-half hour, and the excess water 38 removed by the water-pump. A white crust, with the appear ance of sulfur, formed, the liquid turned yellow, and a slight odor of chlorine was noted. The residue remaining on evaporation of the filtrate gave a positive test for nitrogen and sulfur. An attempt to make the p-toluidine derivative of this residue gave a product melting 235-238.5°. The melting of the p-toluidine hydrochloride was 235-239°. For the second run, a water solution of the hydro chloride was added, drop by drop, to the hydrogen peroxide contained in a flask surrounded by ice, and the flask shaken at intervals. The mixture turned milky white, and, after standing, a white precipitate had coated the sides of the flask. An ignition test showed this precipitate to be sulfur. The solution was placed in a beaker and the excess water was removed by drying in a desiccator over calcium chloride. The residue which remained on evaporation gave a positive test for nitrogen and sulfur. An attempt to make the p-toluidine derivative gave a product melting at 225-228° (unrecrystal lized), which gave a negative test for sulfur. For the third run, because of the fact that chlorine had been detected, the thiol was used in place of the thiol hydro chloride; it was extracted twice with ether, a few drops of Aerosol OT added to facilitate emulsion of the ether extract and the aqueous hydrogen peroxide, and the thiol solution added, drop by drop, to the peroxide which was in a flask 39 surrounded by ice. During the addition the mixture was shaken constantly, but an oily precipitate separated. The residue obtained on evaporation of the filtrate, when dis solved in hot water* and p-toluidine and hydrochloric acid added, gave a product from which a negative sulfur test was obtained. 5. By nitrous acid f CH2CH2v ^CH2CH2N CHS NCHgSH + 6HNOs = CH2 NCH2S03H + 3H20 + 6N0 " CH2CH2 ' ^ CH2CH2" To the thiol in ether solution was added 10% acetic acid (1/6 of the calculated amount). Natural gas was passed through the solution and sodium nitrite (1/6 of the calculated amount) was added from a dropping funnel over a period of ten minutes. The reddish-orange mixture was allowed to stand overnight. A sticky residue of sulfur formed on the sides of the flask, a greater amount than had formed on any other type of previous oxidation. On evaporation of the water layer to dryness a white, crystalline precipitate formed. The same type of precipitate, a very small amount, formed on evapora tion of the alcohol layer. This material gave a p-toluidine derivative of m.p. 233-238°, and a negative sulfur test. BIBLIOGRAPHY 1. A. Carpmael, British latent 474,082, March 24, 1936. 2. P. Pfeiffer and W. Offermann, Ber. 75B, 1 (1942). 3. G. Collin, T. Hilditch, P. Marsh, A. McLeod, J. Soc. Chem. Ind., 52, 272 (1933). 4. C. Noller and J. Gordon, J. Am. Chem. Soc., 55, 1090 (1933). 5. P. Latimer and R. Bost, J, Org. Chem., 5, 24 (1940). 6. R. Deraars, Bull. Sci. Pharm., 24, 425 (1922). 7. T. Johnson and I. Douglass, J. Am. Chem. Soc., 63, 1571 (1941). 8. Britton and Williams, J. Chem. Soc., 1935. 706. 9. Skarulis and Ricci, J. Am. Chem. Soc., 63, 3429 (1941). 10. Binz. and Pence, J. Am. Chem. Soc., 61, 3134-9 (1939). 11. Johnson and Douglass, op. cit. 12. P. Petreriko-Kritschenko and V. Opotsky, Ber. 59B. 2131 (1926). 13. R. Demars, op. cit. 14. T. Midgley and A. Henne, Ind. and Eng. Chem. 22, 542 (1930). 15. H. Backer and W. van Mels, Rec. trav. chim. 49, 177 (1930). — f ' • - 16. W. Ziegler and R. Connor, j. Am. ChemJ Soc., 62, 2596 (1940). 17. Johnson and Douglass, op, cit. 18. P. Pfeiffer and W. Offermann, op. cit. 19. R. Demars and M. Delepine, Bull, des Sci. Pharm. 29, 14 (1922). 20. von Peckmann and Mank, Ber. 28, 2376 (1895). 21. Demars and Delepine, op. cit. 22. Demars and Delepine, op, cit. 23. P. Rumpf, Bull. Soc. Chim. (5), 5, 871 (1938). 24. H. Backer, Rec. trav. chim. 49, 729 (1930). 25. E. Billheimer and E. Reid, J. Am.'Chem. Soc., 52. 4338 (1930). 26. F. Chattaway and E. Kellett, J. Am. Chem. Soc., 53. 2187 (1931). 27. A. Kostova, Acta Univ. Vor., 8, No. 4, 92 (1935). 28. Bailar, J. Am. Chem. Soc., 56, 955 (1934). 29. L. Fieser, "Experiments in Organic Chemistry" (D. C. Heath and Company) pg. 368. 30. Binz and Pence, op. cit.

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Creator Wynkoop, Jean (author)

Core Title The synthesis of ethylenediaminetetramethanesulfonic acid

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