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QUINOLINE DERIVATIVES CONTAINING 
 
 ARSENIC 
 
 BY 
 
 JOHN RAVEN JOHNSON 
 
 B. S. University of Illinois, 1919 
 M. S. University of Illinois, 1920 
 
 THESIS 
 
 SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS 
 FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN CHEMISTRY 
 IN THE GRADUATE SCHOOL OF THE UNIVERSITY 
 OF ILLINOIS, 1922. 
 
 URBANA, ILLINOIS 
 

 
 
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THE GRADUATE SCHOOL 
 
 -May -9, 192-^. 
 
 I HEREBY RECOMMEND THAT THE THESIS PREPARED UNDER MY 
 
 SUPERVISION BY- John Haven Johnson 
 
 ENTITLED "Qui n oline Derivatives Conta in ing Arsenic^ " 
 
 BE ACCEPTED AS FULFILLING THIS PART OF THE REQUIREMENTS FOR 
 THE DEGREE OF Dootor of Philosophy in Ghemistry_ 
 
 Recommendation concurred in* 
 
 
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 Committee 
 
 on 
 
 Final Examination* 
 
 *Required for doctor’s degree hut not for master’s 
 

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TABLE OF CONTENTS 
 Part One. 
 
 Quinoline Derivatives Containing Arsenic 
 
 I. Introduction 1 
 
 II. Theoretical Part 3 
 
 A. General Resume of Methods 3 
 
 B. The Bart Reaction 7 
 
 C. The Dobner Cinchoninic Acid Synthesis 7 
 
 III. Experimental Part 16 
 
 A. Preparation of Aryl Ar sonic Acids IS 
 
 B. Condensation of Aminoaryl Arsonic Acids, with 
 
 Pyruvic Acid and Aldehydes 27 
 
 C. Reactions of the Condensation Products 35 
 
 IV. Summary 42 
 
 V. Bibliography 43 
 
 Part Two. 
 
 Benzyl Arsonic Acid 
 
 I. Introduction 45 
 
 II. Historical Part 46 
 
 III. Theoretical Part 48 
 
 IV. Experimental Part 54 
 
 V. Summary 66 
 
 VI. Bibliography 67 
 
 Vita 63 
 

 
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Digitized by the Internet Archive 
 
 in 2015 
 
 https://archive.org/details/quinolinederivatOOjohn 
 
1 
 
 I. INTRODUCTION 
 
 This investigation was undertaken with the object of 
 studying new organic derivatives of arsenic which might possess 
 valuable therapeutic properties, and to develop a substance which 
 would be superior to Arsphenamine* in the treatment of diseases 
 caused by trypanosomes and spirochetes. 
 
 This field of chemotherapy was opened up by Ehrlich 
 and Bertheim in 1907, and several years later they developed 
 Salvarsan and Neosalvarsan, two substances which have proved to 
 bo very valuable therapeutic materials. Since the development of 
 these substances several hundred new organic arsenic compounds 
 have been prepared, but none has displaced Salvarsan and Neosal- 
 , varsan. Recent clinical work has given evidence that these sub- 
 ' stances are far from ideal, and it is well known that the advanced 
 stages of syphilis cannot be cured by the application of these 
 materials, 
 
 previous observation has shown that in order to 
 possess trypanocidal action the organic arsenical must contain 
 nitrogen in some form; further, that nitrogen atoms covered by 
 certain organic radicals are more active than free amino groups, 
 and that the substances are in general more stable, and conse- 
 quently less toxic. 
 
 From these considerations it was decided to take up 
 
 the preparation of arsenicals containing tertiary nitrogen in a 
 
 ring .system, particularly in the quinoline grouping. This nucleus 
 
 is present in many of the common alkaloids and in other substances 
 » 
 
 The official Anerican Name for "Salvarsan". 
 
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 which arc physiologically active. 
 
 The preparation of quinoline derivatives containing 
 arsenic was the subject of a paper by Frlnkel^ and LO'wy in 1913, 
 and these investigators applied many general reactions without 
 success. They were able, however, by applying the D5bner-Liiller 
 quinaldine synthesis, to obtain small quantities of a substance 
 which they formulated as quinaldine-6-arsonic acid. By reduction 
 with sodium amalgam they obtained a substance which corresponded 
 to quinaldine -S-s-rsenious oxide. These substances were obtained 
 in such small quantities that the authors were unable to make a 
 thorough investigation of them, and it appears uncertain that they 
 were re^ ly quinaldine arsenic derivatives. 
 
 Since the quinaldine synthesis mentioned yielded an 
 arsenic containing product, it seemed worth while to investigate 
 the closely related Ddbner cinchoninic acid synthesis with the idea 
 of preparing cinchoninic acid derivatives containing arsenic. 
 
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 II. THEORETICAL PART 
 
 In considering the 33mthesis of quinoline derivatives 
 containing arsenic there appeared to be two ways of attacking the j 
 
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 problem: the direct method, starting with a quinoline nucleus al- | 
 ready formed and introducing arsenic into the molecule, and the | 
 indirect method, building a quinoline ring into a molecule al- 
 ready containing arsenic. 
 
 for the introduction of arsenic into the quinoline molecule. Of 
 these the follov/ing were considered: 
 
 The Be champ Reaction : This has proved valuable for the arsenation 
 of aryl amines, and of indole® derivatives: 
 
 Frenkel’’ and Ldwy applied this method to quinoline, and tetra- 
 hydroquinoline, but were •'unable to obtain the desired arsenic 
 acids even on heating to 300° under pressure. 
 
 Direct Arsenation with Arsenic Chloride : This had led to a number 
 of p-alkylaminophenyl arsenious chlorides from the corresponding 
 mono and dialkylanilines and arsenic chloride^ 
 
 By the treatment of quinoline, 8-hydroxy quinoline, and tetrahydro- 
 quinoline with arsenic chloride, Frankel and Ldwy obtained addition 
 compounds which on treatment ’^rith water liberated arsenic tri- 
 
 A . General Re sum/ of Methods 
 There are a number of ways which were deemed applicable 
 
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 oxide; the arsenic chloride could not be introduced into the ring 
 by treatment of the addition compounds '.iritn aluminum chloride. 
 
 Interaction of Arsenic chloride, an aryl halide and metallic 
 sodium : This reaction was used by Michaelia** for the synthesis of 
 a large number of arsenic compounds, but the reaction does not run 
 smoothly and is only used at the present time in a few instances. 
 
 The Bart Reaction ^; An aryl amino group is replaced by the arsenic ! 
 acid grouping through the diazo compound, by treating with sodium i 
 arsenite: i 
 
 The Meyer Reaction ^: The treatment of alkyl halides with sodium 
 arsenite proved to be a valuable means of obtaining aliphatic 
 arsonic acids. Since halogens in the 3- and 4-positions in the 
 quinoline ring are aliphatic in character, it might be possible to 
 apply the Meyer reaction. Certainly compounds of the type (b) 
 
 would be expected to react with sodium arsenite to give quinolyl 
 methyl arsonic acids. 
 
 Indirect Syntheses . 
 
 In the literature is reported a large number of syn- 
 theses of quinoline and its derivatives in which the pyridin 
 

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 taining arsenic. 
 
 Skraup* 8 synthesis '^; The treatment of an aromatic amine with gly- 
 cerol, sulfuric acid and an oxidizing agent has given a large 
 number of quinoline derivatives, and the reaction has proved to 
 be quite general. If p-arsanilic acid were used in this reaction 
 it would be expected that quinoline-6-arsonic acid would result, 
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 off and only quinoline resulted^ 
 
 Knorr* s synthesis ^ from aniline and acetoacetic ester: 
 
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 + 3HjO 
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 by FrSnkel and Ldwy and they obtained a product which they stated 
 to be quinaldine-6-ar sonic acid. It i 
 
 s 
 
 A repition of thi 
 
 ,s rather surprising, how- 
 
 s reaction gave large quantities of 
 quinoline, but the formation of a crystalline pierate, decom- 
 posing from 266-275®, led to the belief that some qulnollne- 
 
 6 -areonlc acid was present In the reaction mixture altho It 
 could not be isolated as ouchi. 
 
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 ever, that their product was insoluble in alkalies and in acids, 
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 soluble in both of these reagents. 
 
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 in alkalies which they stated to be the corresponding arsenious 
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 Ddbner* 3 cinohoninic acid synthesis ^^ This reaction is of general 
 
 application and is taken up in detail later. 
 
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 (b) have been prepared ’ivith the ar sonic acid grouping in the p- 
 
 position. It seems likely that cinchoninic acid derivatives could 
 

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 readily be prepared from these substances by application of the 
 above reactions. 
 
 After a consideration of the aoove reactions and the 
 possibilities offered, it appeared that the ir.ost promising methods 
 of obtaining quinoline derivatives containing arsenic V 7 ere the 
 Bart reaction and the Dflbner cinchonic acid synthesis. 
 
 B, The Bart Reaction 
 
 For trying this reaction 6 -amino quinoline was diazo- 
 tized and treated with sodium arsenite according to the usual 
 procedure. Although an evolution of nitrogen occurred on mixing 
 the diazo- and arsenite solutions, no quinoline arsonic acid could 
 be isolated from the material. Since the Bart reaction has proved 
 to be quite general for all substituted types of aromatic amines 
 it seemed unusual that the quinoline arsonic acid was not obtained 
 by this method. It is noted, however, i5hat Schmidt'^ used o- and 
 p-aminodiphenyl and obtained tarry browai substances from which the 
 arsonic acids could not be isolated. 
 
 C, The Dflbner Cinchoninic Acid Synthesis . 
 
 The condensation of aromatic amines with pyruvic acid 
 and aldehydes in alcoholic solution has led to the production of 
 a large number of 2-substituted quinoline-4-carboxylic acids. 
 
 This reaction has been found to be quite general for aryl amines 
 and almost unlimited in its applications. The following examples 
 indicate the many types of aromatic amines which have been con- 
 verted into the corresponding cinchoninic acids: the toluidines, 
 aminophenols and their ethers, anthranilic acid, m- and p-halo- 
 
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 =•: 
 
 ■; ■: --. t**:-:i:v. 
 
 
 
 r .. 
 
 
 
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 V-:. finX'.. ■-';> 
 
 
 
 jj ’ xol SK> 
 
 im 
 
 ,''• /-/‘A " .( 
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 V-:. ‘©©(Bef « ' 
 
 V * 
 
 
 
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 »> 'D 
 
 ■ '„. f 
 
 "IT .rivv":;ci ivi-xf*:? -bcrje 
 
 , .^loeX ecJ, won:.-.r.IiVoo-' vvX^^XJS 
 
 'r.j ■‘- > . :^£- 0 f .*-*iiw- r'. !!o ';oi..Ttf€kCsU*;f>v?* 
 
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 M 
 
 r -*i.j.r 
 
 xrvrt'T «vi;iT' Bcf o?_ ela^V' 
 
 sy 
 
 ■-‘id* 
 
 .. - '. H, ,J 
 
 - \-.t- 
 
 . ■• ’ Kj "* 
 
 P 
 
 . '-‘XN^t^-S'XiQC}* Hli *Ti .X 5 e:U^axix(i/‘‘^i<>/SW'£fti& 
 
 - .-r.r ,.-.r,; f.y •,:••» tio i.f ,7 T.^ tdi U' xOX!* 
 
 /I 
 
 A''* ^. ,.•' :o. ’X'd f. 
 
 v.'SV 
 
 r' I r y no- n Xo ' ^fiiMbqis ^ ‘ O.^0t ^ 
 -c uv^ -f! tf - t-y • V -t.; Rfc ' 1 p. / 
 
 i*. ’fr 
 
 ■ ''■ 
 
 i-^i- 
 
 
 
 r" 
 
 Jh XXiAi I '. .. ; idii-i i ''i^i-'M. 
 
 f 
 
 JirtsiiV 'A 
 
 cm 
 
genated anilines^®, m- and p-aminoacet ophenone^® , p-aminoacet- 
 anilide'®, benzidine'®, and the naphthyl amines. The reaction 
 
 seems to be even more general for aldehydes than amines, since 
 both aromatic and aliphatic aldehydes, incl'jding formaldehyde and 
 furfural, will give cinchoninic acids. 
 
 In a number of cases the yields in this condensation 
 are unsatisfactory, and this is due to the formation of hydrogen- 
 ated by-products and a group of alkali insoluble substances. The 
 nature of the latter was investigated by Dobner", and by Garza- 
 rolli-Thurnlackh’''’^, who assigned to them the formula of the anil 
 of a diketopyrrolidine derivative: 
 
 ,G0-G=1T 
 
 N. 
 
 GH-GHs 
 
 GgHg 
 
 D6bner' 3 "anil" compa’nd, m.p. 335®. 
 
 It was noted that the solvent plays an important part in determin- 
 ing the course of the condensation. Alcohol favors cinchoninic 
 acid formation, whereas ether and benzene lead almost exclusively 
 to the anils of diketopyrrolidines. It was also found that the 
 substitution of esters of pyruvic acid led to the diketopyrroli- 
 dine anil. 
 
 The most coiTiprehensi ve study of the limitations of this 
 reaction was made by Borsche who studied the effect of substitu- 
 ents in all three of the reactants. The results of this and 
 
 previous investigations may be stated briefly as follov/s: 
 
 i. The introduction of methyl or hydroxy groups into 
 the m-position in the aryl amines increased the yield of cinchon- 
 inic acid, due to its activating effect on the hydrogen in the 
 o-position to the amino group. This §LCtivating effect seemed to 
 

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 M 
 
 
 
 ti 
 
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9 
 
 "be at a maximum in ^-naphthyl amine, from which no cLiketopyrroli- 
 dine derivative could he obtained even when ether was used as the 
 solvent. The reaction with the nit roanilines went exclusively to 
 the diketopyrrolidines, and from these atriines no cinchoninio acids 
 could be obtained under the most favorable circumstances. 
 
 ii. The reaction is a general one for aldehydes, and 
 with the use of ^-naphthyl amine especially, cinchoninio acids can 
 be obtained from all aldehydes. This reaction had previously been 
 proposed by D5bnsr*° as a specific reaction for all aldehydes. 
 
 iii. The introduction of phenyl, o-nitrophenyl and 
 benzoyl groups into the pyruvic acid molecule caused the reaction 
 to run chiefly to diketopyrrolidine derivatives in the case of the 
 simple aryl amines. With -naphthylamine, however, the usual cin- 
 choninic acids were formed. The introduction of the benzyl group 
 into the pyruvic acid rest led to the usual mixture of both sub- 
 stances, but the diketopyrrolidine derivative predominates in the 
 case of the simple aryl amines. 
 
 When arsanilic acid, benzaldehyde, and pyruvic acid are 
 heated together in absolute alcoholic solution, a condensation 
 product is obtained in good yields. The composition of this su'o- 
 stance corresponds to that of a cinchoninio acid, I, or a simple 
 diketopyrrolidine derivative, II: 
 
 HgOgAS 
 
 I. 
 
 cp^ 
 
 
 GO-CO 
 
 CH-OH, 
 
 ^ ^ II* GgHs 
 
 CieHisOshAe Ci6Hi405NAe 
 
 The usual separation of these substances by the solution of the 
 

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 :ri' ^8Vi^J5vXtei> 
 
 
 
 
 
 
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 llr; \ 
 
 y 
 
 ''■4 
 
 T! 
 
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 vTX 
 
 
 
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 '•>»^t i".ui 
 
 
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 XlO 
 
 L tl Ji 
 
 M 
 
cinchoninic acid in alkalies cannot be applied since an alkali 
 soluble group is already present in the molecule. In order to 
 determine the structure of the substance a study was made of its 
 reactions. 
 
 The condensation product is unstable toward hot mineral 
 acids, and therefore the usual reaction of replacing the arsenic 
 acid group by iodine, and identification of the resulting iodo-com- 
 pound cannot be applied. It was found ttat the compound gave off 
 approximately one mole of carbon dioxide on heating to its decom- 
 position point. This was considered to be evidence for the cin- 
 choninic acid structure since it is well kno’^ that these substance 
 readily loss one mole of carbon dioxide on heating above their 
 melting points. 
 
 It was thought likely that a fusion of the substance 
 with sodium hydroxide would give additional evidence, since the 
 2-phenylquinoline-4-carboxylic acid-6 -ar sonic acid, I, would be^ 
 expected to give either 3-phenyl quinoline or 2-phenyl 6 -hydroxy 
 quinoline under this treatment. It was found, however, that the 
 chief nitrogenous product from the alkaline fusion was aniline. 
 
 This could hardly be explained on the cinchoninic acid formula, 
 and the formation of carbon dioxide is difficult to explain on 
 the diketopyrrolidine formula. It was therefor e decided to pre- 
 pare a diketopyrrolidine derivative and determine whether it gave 
 
 carbon dioxide on heating. 
 
 For this purpose the simple diketopyrrolidine. III, 
 prepared from p-nit raniline was used, and it was found that on 
 

 
 '"i - . 
 
 
 
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 • I 
 
 I ^ 
 
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 ■ 1 ■ .. j ■:'■ * ■' ■ 
 
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 0- f- ^'’ r ...,v L’i 
 
 
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 9 
 
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 ''.’-:'u ■’• “ 
 
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 .’!•*'* •' 1 . •“** 
 
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 :; ._ . • X ; itn-$rv^ ecI i 4 ^ t V o'i 
 . ‘t .I'ty'pi. .:e:z i^y .i c-^yI'^^P J 
 
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 ::r: ^.^3^ 
 
 
11 
 
 NO 
 
 GSaGOGOOH 
 
 •m. 
 
 alcoholic 
 
 GgH^GHO 
 
 NO, 
 
 N' 
 
 / 
 
 GO-GO 
 
 
 III. 
 
 
 heating this substance in boiling ethyl benzoate for fifteen 
 minutes 63^ of one mole of carbon dioxide was evolved. To 
 determine the effect of the arsenic acid grouping a sample was 
 mixed with nitrophenyl arsenic acid and heated in boiling ethyl 
 benzoate under the same conditions. In this case the amount of 
 carbon dioxide amounted to 95‘fo of one mole. 
 
 These results, together with the behavior on alkaline 
 fusion, indicate that the first conclusion was incorrect, and 
 that the compound is not a quinoline arsonic acid. This conclu- 
 sion is supported by the fact that the same condensation product 
 is obtained when the reaction is carried out in ethereal suspen- 
 sion, and also when the ethyl ester of pyruvic acid is substi- 
 tuted for the free acid. In both of these cases the diketopyrroli- 
 dine derivatives would be expected, and the product proved to be 
 identical with the original condensation product. 
 
 Since the evidence for the di ketopyrrolidine is based 
 only on the analogy to p-nit raniline, it seemed advisable to con- 
 duct further experiments. It would be expected that the 4-keto 
 group would easily form an anil with an aromatic amine, leading 
 to compounds of the type IV, containing the arsonic acid grouping: 
 
 R 
 
 IV. 
 
 N. 
 
 /GO-G=N 
 
 
 GH-GHs 
 
 CsHb 
 
t 
 
 ;1 
 
 
 i 
 
 -V 
 
 1 , 
 
 ' •i 
 
 n 
 
 ii 
 
 I j 
 
 \ 
 
 1 
 
 
 
 .V - 5 ii AtflJCi' A 
 
 ■rfS 
 
 
 
 t ‘c: 
 
 
 } . 
 
 ’. ’-J! 
 
 
 •f. - 
 
 ■\)< ' ,» 
 
 
 
 , 1 
 
 ^•■S<'‘'-< - ■ ^ 
 
 . •<. ; . jK: ' - • ^t- d - <?■ ! ,'S'' i t- 
 
 ; -r f>'zr 
 
 V ^ . ' ;=•» . i ' 
 
 t ■ «:, *-dt? iSt •i.vr:'- 
 
 • ^ '■ i . .^' ■ '3 '■ 
 
 - ' ** , 
 
 i- j:»- ■■" J ‘ i vi^ii^' 1' ft h - 
 
 
 
 ■i 
 
 p ■■<'■ X" 
 
 ' . t\Tt t ’.i .'.;S 
 
 i'd» 
 
 A 
 
 s 
 
 ,:S:v 
 
 ■ f 
 
 * 21 
 
 hi 
 
 \ : ■ ■"' . ;-'n-c. .ih?- 
 
 ■• ; I tr i .f'i .' iti :■; i 
 
 V;1 
 
 "“31 ‘... iL 
 
 
 1 
 
 '. If 
 
 ,' I 
 
 S - 
 
 
 • 'I 
 
 
 
 >#i *j 
 
 fir :5;s= V"^:S:fi’ia'’ 
 
 
 o.'xarasq^s^-jJ, ! 
 
is 
 
 One would expect this reaction to take place very readily, since 
 compounds of the type IV are usually formed as by-products when 
 the DSbnor cinchoninic acid synthesis is carried out. 
 
 In order to prepare this anil the condensation product 
 was dissolved in boiling alcohol and treated with one mole of 
 aniline. From the reaction mixture a product was obtained which 
 was insoluble in boiling ISfJo sodium hydroxide and melted from 
 147®-! 48®. The insolubility in sodium hydroxide indicated that 
 the substance no longer contained the arsonic acid grouping and 
 could not be the desired anil, 
 
 A review was made of the literature on the addition of 
 pyruvic acid to benzylidene aniline, and it was noted that Schiff^^ 
 had carried out the reaction in benzene solution. In this way he 
 obtained a compound melting at 147®, which he gave the formula: 
 
 ,G0-C0 
 
 < I 
 
 ch-ch, 
 
 CsHs 
 
 and it seemed possible that the alkali insoluble substance men- 
 tioned aoove was identical with Schiff ' s confound. 
 
 1 7 
 
 Garzarolli-Thurnlackh on repeating the work of 
 Schiff, obtained the compound m.p. 147®-148^, along with larger 
 quantities of Ddbner' s anil compound, m.p. 225®. It seemed likely, 
 therefore, that by using an excess of aniline the D5bner anil com- 
 pound could be obtained from the arsanilic acid condensation 
 product. The latter was treated with two and one half moles of 
 aniline and gave arsanilic acid, but none of the anil could be 
 isolated. 
 
 The behavior of the condensation product on treatment 
 
 C6HsH*GH-06Hs +GH 3 COGO 3 H 
 

 , V i. \ ^ tvo^X-i .•frft V:i‘rJ ^ ^ 'X :- - 
 
 «rtO 
 
 ™ .fv.». L* W/ io’^X/u?o<|B>c^ 
 
 . .. ^ ire: «r.f*l*-tl-SH:iiJ 
 
 ( 
 
 ,:r i)df p 1 cl¥ <i’-u'>^i?T^-'';‘4..'Vei;^0 iil <"' 
 
 - T U'4 V. 
 
 . f : o rc;2;bos- ■ ^a' .'iUmI aoJ-^o*eT e^Sif .mltlpJ' 
 
 “ • * . . - fc . - 
 
 •. . -£ii 5 ’01 jiniliccf v ^>Z(^;/xSaai «?''» 
 
 jf ■ * "' \4 
 
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 iiin 
 
 ■ . . . X 
 
 .:■’ v: 
 
 -■ f 
 
 
 A. - 
 
 , Jt. ij i . ->•• 
 
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 'cf'> 
 
 .1 -- -I #'.<( 
 
 
 
 ./ . 
 
 N 
 
 
 
 ; 
 
 r; u*.- 
 
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 1 .^' 
 
 ^ ^ -.t ;,v' .. ' ; .' i;:':cfe r, tV -■ XX' Cj * 
 
 v: 
 
 r-is 
 
 
 
 
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 »T 
 
 *■ 
 
 
 
 *1 ■ -5J '--s - 
 
 bfit/o^OD 
 
 '-' *'*461 ' " - "^i. 
 
 ^.. 'i-'i XA/' ‘;.o .Jin 
 
 H'r 
 
 
 '5^ 
 
 ' -« 
 
 fo,: Ji;a‘ro*.,->o .-..-i'.' 'jU2V'-m ft-i; -atil Kitted 
 
 S»J 
 
 u/'Jioi;; Yi- ’ * V yr:B’c^ iU 5| 
 
 ^ ' ■'■■'■■' "I. . V ' jVjlEr,1 
 
 • J 'iluoo Nii, •*’ \o--f(fi.oa 'tini ^-fiic^. , '-rf^ 
 
 
 • ■'J» Y\.. 
 
 ■ ■ ■ ■ ■ 
 
 i: ViXr -t' 
 
 T 
 
 kv 
 
 
 
 
 
 
 
 
 
 k' ■ 
 
1 3 
 
 with sodium hydroxide is worthy of mention. The material dis- 
 solves readily in one mole of aqueous sodium hydroxide to a cl 
 yellow solution, which on standing at room temperature deposits a 
 white precipitate. The solution has a strong odor of benzaldehyde, 
 and is acid in reaction to litmus paper. The precipitate contains 
 
 arsenic and is soluble in alkalies; it is very difficult to purify 
 
 0 o 
 
 and the impure material melted with decomposition from 140 -150 . 
 With two or more moles of alkali the condensation product dissolves 
 to a clear yellow solution which does not become turbid or deposit 
 any precipitate. 
 
 explained on the basis of the diketopyrrolidine formula, II, a 
 consideration was mads of other isomers and the following was 
 suggested, formula V: 
 
 Although no compounds of this structure are described in the 
 literature, it was noticed that a compound of this type was sug- 
 gested as a hypothetical intermediate in the formation of D6bner' s 
 
 Since the reactions enumerated could not be adequately 
 
 V. 
 
 T7 
 
 anil compound according to the following mechanism 
 
 B 
 
 GHgCH-OH 
 
 HaC-Ca 
 
' ’ Wi 
 
 
 
 ‘."f 
 
 ^ ’ ^Wr . 
 
 -v^rrrrzu-. • ' ~ -rjaCTiS': .‘ ' ~ .64ars.*^~ia;!^ ^ atr 
 
 T'-; 
 
 
 ■.- ^1 
 
 [M 
 
 
 * * ' ■», 
 
 .1 e.rlT . f-tf* 
 
 .. V. C' ' d. l/'.'v':i tf f^t' li ?Jf'^ 
 
 
 ir , ^-u- 
 
 I 
 
 :.r l •' r -t «v -^’OXicv 
 
 • ' ► / • ‘ 
 
 .• . ‘’^*ji;. •■••:«•> ,'X ;rHX..:aA-i> ai o-iiwitw . 
 
 L - 
 
 
 
 
 L'. I 
 
 . et'lc« n^xW 
 
 1 
 
 V- I ^ ^ 
 
 , .a fi ’-• Oi i“ CXiU Irv- i ^i-'i V : ■• i 
 
 ,j.' Ct» . ••C-- i »‘v ■'•■JO 
 
 > »?' 1 Ji J. 'i' v: 
 
 ■^.‘V 
 
 <i 
 
 M 
 
 o> 
 
 
 : X :.^ *»• •• -.?-vy . JN ♦• . .•: ..• ii’*'ii? 
 
 
 •i t 
 
 '.«}•. .B ". 
 
 
 V:K. ‘.’l 
 
 
 *■ 
 
 • 1' 
 
 
 ■*" '• 'iliV'i. 
 
 s 
 
 'r hr..ff '.;;■ cT?? K .>'.‘^*, Tv 
 
 ' ■ I . ' ‘b ’ ^ 
 
 iT^ 
 
 r ts' 7 'lo xj? vi;{'’7Q’d j ^o*i' ■ if iX f|^ 
 
 ' ' ' . ' . .. ' ^” ' ■ . , . .. f '/ 
 
 *v‘ « cueyfcs?^'^’ 
 
 I - 
 
 
 ^■i' B 
 
 ji : ' 
 
 ^ 3' 
 
 ,it;, -' . -\ . "- ... \ 
 
 .v.-r:';-'. ' ... •■..*••■»-. ,N 
 
 
 '“•■tO » J I -T j ■ > V J *:t 
 
 ., ,1 r.?^' ■■■■' 
 
 If * ' *jf I * ", 
 
 r> ^ 
 
 i f '<7 ■' /'* r V "V , 
 
 iL ..;., ' A . .. .. .,. 
 
 ' HS* Vv'-.; 
 
 
 .■i:.'-C^!^ 
 
 •>i>l^5|I.> 
 
 - - ■^■^•\ » - ••»• - ^ > • 
 
 .::^fcr T.i:;^;S5=*S)X- 
 
 ' 
 
 i<gr::^TO\-* r B a to y 3 is w y^ ^ 
 
 
 k\ A. ' 
 
14 
 
 If the condensation product from arsanilic acid has the structure 
 V, it will 00 the first compound of this type to he isolated and 
 it may give additional information concerning the course of the 
 reaction between aryl amines, pyruvic acid and aromatic aldehydes. 
 
 In conclusion, it may be said that altho the structure 
 of the compound formed by the condensation of arsanilic acid with 
 pyruvic acid and benzaldehyde has not been definitely established, 
 between formulae II and V, the formation of one mole of carbon 
 dioxide on heating, the splitting off of aniline on alkaline 
 fusion and the regeneration of arsanilic acid on treatment with 
 aniline, are facts which are more easily explained on the basis 
 of the latter. 
 
 Limitations of the Reaction 
 
 With the idea of studying the limitations of the re- 
 action between aminoaryl ar sonic acids, aldehydes and pyruvic acid, 
 
 a series of reactions was carried out oetween substituted arsan- 
 ilic acids and aldehydes with pyruvic acid. 
 
 It was found that arsanilic acid and pyruvic acid 
 yielded the desired condensation products with all of the aromatic 
 aldehydes tried. These included o- and p-methoxy, p-halogenated, 
 p-dimethylamino, and o-nitrooenzaldehyde^ No condensation products 
 
 were obtained from paraldehyde and n-'ctutyraldehyde. 
 
 When o-substituted aminoaryl arsenic acids were used 
 a condensation took place to give benzylidene derivatives of the 
 amine, but these did not react further with the pyruvic acid even 
 
 1 
 
hi 
 
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 on long heating. The substances used for these experiments were 
 o-arsanilic acid, 3-methyl -4-aminophenyl arsonic acid, and 3- 
 
 bromo-4-aminophenyl arsonic acid. These results are in accord 
 with those of Borsche, who was unable to obtain condensation 
 products from o-ohlorc, and o-nitroaniline^® , 
 
 \*/hen m-substituted atninoaryl arsonic acids were used 
 the condensation occurred in the usual manner, and good yields of 
 the desired products were obtained. The particular acids used 
 for these experiments were 2-inethyl-4-aminophenyl arsonic acid, and 
 3-methoxy-4-a>]-iinophenyl arsenic acid. 
 
 These experiments lead to the following generalizations: 
 
 i. The reaction is general for aromatic aldehydes, but 
 not for the simple aliphatic aldehydes, 
 
 ii. The reaction takes place with substituents in the 
 ffi- and p-positions in the amdnoaryl arsonic acid, but does not 
 occur when o-substituent s are present. In the latter instance, 
 benzylidene derivatives are formed which ao not react further. 
 
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16 
 
 III. EXPEREIF’NTAL PART 
 
 The experimental work is divided into three parts: 
 first, the preparation of substituted aromatic arsonic acids; 
 second, the condensation of arainoaryl arsonic acids with aldehydes 
 and pyruvic acid; third, the constitution and reactions of the 
 condensation products, 
 
 A, The Preparation of Arsonic Acids by the Bart Reaction 
 
 This reaction has been extensively used for the syn- 
 thesis of aromatic arsonic and arsinic acids, and various modifi- 
 cations have been used in specific cases. For the nitro substi- 
 
 X B 
 
 tuted amines, the procedure of Rchraiit is found to be quite 
 satisfactory and was used in preference to that of Jacobs, Heidel- 
 berger and Rolf^^. The yields have been found to vary considerably 
 when only slight changes were made in the procedure. For this 
 reason the method employed is given in detail. 
 
 General Proced^ure i 1 mole of the amine was dissolved (or sus- 
 pended) in 600 cc, of 5-N hydrochloric acid (3 moles), chilled by 
 the addition of ice, and diazotized bv introducing a solution of 
 1 mole of sodium nitrite through a dropping funnel extending be- 
 low the surface of the liquid. With good stirring the nitro- 
 amines dissolve almost cortpletely in the course of 10 - 15 minutes. 
 The diazo-solution was filtered from any insoluble material and 
 transferred to a large container of 13-15 liters capacity. It 
 was thoroughly chilled by the addition of ice, and a few cc. of 
 isoamyl acetate added to cut do'im the frothing when the arsenits 
 was added later. 
 
17 
 
 With good stirring 300 cc. of 5-N sodium hydroxide 
 (1 mole) was added, followed at once by a mixture of 750 cc. of 
 2-N sodium arsenite solution, NajHAsO^ , 60 oc. of 5-N hydrochloric 
 
 acid, 650 cc, water, 650 g. ice .and 300 cc. of 30fc copper sulfate 
 solution, added immediately before using. The addition of the 
 copper sulfate caused the formation of a green precipitate in the 
 arsenite solution. When the arsenite solution was added a vigor- 
 ous evolution of nitrogen occurred and unless the reaction mixture 
 was thoroughly agitated the froth almost filled the container. 
 
 After allowing the mixture to stand for an hour it was warmed to 
 40-50^ and filtered. The clear filtrate, which was neutral or 
 slightly alkaline in reaction, was acidified to litmus with acetic 
 acid, concentrated on a steam bath and filtered hot to remove a 
 yellow flocculent by-product. The filtrate was treated with hydro- 
 chloric acid until acid to Congo paper and the arsonic acid 
 separated out. The precipitate was filtered with suction and 
 washed thoroughly with water. For most purposes the crude product 
 is sufficiently pure without further treatment. 
 
 Prepared by dissolving 198 g.of arsonic trioxide in 800 cc. of 
 5~N sodium hydroxide, and diluting to 1000 cc. 
 
 Attempt to prepare Quinoline-6-Arsonic Acid ; 6-Nitroquinoline was 
 
 7 
 
 prepared by the method of Knueppel , from p-nitranilin, glycerol, 
 arsenic pentoxide and sulfuric acid. For reduction to the amine 
 it was found advisable to use the purified nitro-compound and not 
 attempt to reduce, the crude product. 
 
 The reduction of 6-nit ro quinoline to 6-aminoquinoline 
 was effected by means of powdered iron and a small amount of 
 acid. The crude dark product was purified by vacuum distillation, 
 and the product was oDtained in pale yellow crystals which darkened 
 
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1 e 
 
 on exposure to the air. From 35 g. of nitroquinoline, the yield 
 of amine, h.p. 169^-176° at 5-6 mm,, was 18-30 g. which is 60-70^ 
 of the theoretical, 
 
 15 g. of S-arcinoquinoline was dia 2 Jotized and treated 
 with sodium arsenite according to the above procedure; an evolu- 
 tion of nitrogen occurred and a thick bro’-m material was formed. 
 From the filtrate after concentration and careful neutralization 
 no quinoline arsenic acid could be isolated. On evaporating to 
 dryness and extracting the salt with alcohol, no arsenic acid 
 could be obtained from the alcoholic extract. The reaction was 
 repeated 'JFith the same result, and was then given up, 
 
 2~Nitrophenyl Ar sonic Acid ;^^ 38 g. of pure o-nitraniline ^vas 
 finely pulverized and diazotized at 10°, and the diazo-solut ion 
 treated with sodium arsenite according to the general directions. 
 The product separated out in pale yellow-white needles. The yields 
 were good, varying from 38 -43 g. , which is 75-85^; of the theor- 
 etical. The product was sufficiently pure for reduction without 
 further purification. 
 
 4-Uitrophenyl Ar sonic Acid^ ^ ; 38 g, of technical p-nitraniline 
 was diazotized at 10° and treated in the usual manner. The p- 
 nitrophenyl arsonic acid was obtained in the form of pals yellow 
 crystals weig^iing 38 g, or 53^ of the theoretical amount. This is 
 slightly better than that claimed by Jacobs, Heidelberger and Rolf. 
 
 3~Methoxyphenyl Arsonic Aci d; 13.3 g. of pure o-anisidine was 
 diazotized at 0° and treated according to the general procedure. 
 
 The crude o-anisyl arsonic acid separated in slightly yellow 
 

 ^ T •F.ir 
 
 
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19 
 
 flocks and after drying weighed 15-J- g, which is 65^ of the theor- 
 etical amount. The o-methoxyphenyl arsonic acid crystallized from 
 alcohol in beautiful white needles, ra.p, 1S3°-194°. 
 
 Sub#. 0.2000, 0.1995 required 21.50, 21.48 cc. of 0.0808 N I. 
 Calc, for C7H9O4AS: As, SB.Slfa, Found: 32.57, 32.59*yt-. 
 
 This acid is insoluble in cold water, soluble hot; slightly soluble 
 in cold alcohol, quite soluble hot; insoluble in ether and organic 
 solvents. It is readily soluble in aqueous alkalies, carbonates 
 and ammonia, 
 
 24 
 
 4-Methoxyphenyl Arsonic Acid : Michaelis prepared this acid by 
 the hydrolysis of p-anisyl arsenic chloride, and Bertheim ob- 
 tained it by the methyl at ion of phenol p-arsonic acid. It may be 
 readily prepared from p-anisidine by Bart's reaction, and was ob- 
 tained in 35^'o yield from technical p-anisidine. It was crystallizec 
 from water and was found to melt from 173^-177®, Bertheim reports ; 
 I79O-I8OO. 
 
 2 2 
 
 6-Methyl-2-Nitrophenyl Arsonic Acid : The nitro-toluidines used 
 for the preparation of the corresponding nitrotolyl arsonic acids 
 were prepared through the nitration of o-acetotoluide and 
 separation of the isomeric nitro-acetotoluides by the Witt-Utermann 
 metiiod. The method of Reverdin®*^ and Crepieux was tried for this 
 separation but was found to be less satisfactory. 
 
 30-J g. of 3-nitro-o-toluidine, CH3:l:NHg:2, was diazo- 
 tized and treated' with sodium arsenite in the usual way. The fil- 
 trate after acidification with acetic acid was concentrated, and 
 
 * All analyses for arsenic are by the method of 
 Robert son^^ , unless otherwise stated. 
 
■» r 
 
 1 
 
 i . . ..A 
 
 1 
 
 . i ' < »<i ► r t 
 
 !l 
 
 r 
 
 j 
 
 ! 
 
 ! f 
 
so 
 
 filtered from the yellov/ floccrulent by-produot. This clear fil- 
 trate on cooling deposited a crop of pale yellow needles. A 
 sample of the latter was collected, washed with alcohol and 
 examined. It was found to be the mono-sodium salt of the nitro- 
 tolyl arsonic acid: 
 
 Subs. 0.2197 g. required 17.13 cc. of 0,0893 N I. 
 
 Calc, for C.,H,y 05 NAsNa : As = 26.50f^ Found: 
 
 for C^HeOgNAsNa : As = 34. 58fc As • 28. 19?^^ 
 
 This salt is moderately soluble in cold water, quite soluble hot; 
 it is very slightly soluble in alcohol and ether. The crystals 
 which separated were redissolved by heating and dilute hydrochloric 
 acid added to acid reaction to Congo paper. The S-rcethyl-3-nit ro- 
 phenyl arsonic acid separated in white flocks and weighed 40 g. 
 or 75fo of the theoretical amount. 
 
 8-L^ethyl-4-Nitrophenyl Arsonic Acid ^^: From 30 ^ g. of 5-nitro-c- 
 toluidine there was obtained 25-26 g. of this arsonic acid, in 
 pale yellow flocks. This is only 50^o of the theoretical yield, 
 the difficulty in this case apparently being incomplete diazoti- 
 zation of the amine. 
 
 2-Methoxy-4-Nitrophenyl Arsonic Acid : The p-nitro-o-anisidine, 
 
 NOs, 4;0CH3, 2jKHa, 1» used for this synthesis ms prepared through 
 the nitration of o-acetaniside and separation of the resulting 
 mixture of m- and p-nitro derivatives®®. 123 g. of pure o-anisi- 
 
 dine, b.p. 99®-103° at S-9 ram., was heated to boiling ’-vith 105 g. 
 of acetic anhydride and 33 cc. of glacial acetic acid. The solu- 
 tion was placed in a 1^ 1. flask provided with a good mechanical 
 
ll 
 
 w-r 
 
 i 
 
 I 
 
 
 
 
31 
 
 stirrer and rapidly cooled by immersion in a freezing mixture. A 
 solution of 65 cc. of fuming nitric acid, 1.52, in 90 cc. of cold 
 acetic anhydride was added during the course of four hours, keep- 
 ing the temperature below 0°. After the addition of the nitric 
 acid was completed the mixture was allowed to warm up slowly to 
 room temperature and stand for 36 hours. The red-brown solution 
 was then poured into a mixture of 1300 g. of ice and water and a 
 yellow precipitate of the mixed ra- and p-nitro-acetanisides 
 resulted. This was filtered with suction, washed thoroughly with 
 water, and dried in the air. The yield was 208 g., which is almost 
 the theoretical amount. 
 
 The crude reaction product was hydrolysed by warming 
 on the water bath with a mixture of 350 cc. of concentrated sul- 
 furic acid and 650 cc. of water. With occasional shaking the 
 material dissolved and after 1-1-^ l^ours the solution was poured 
 into a beaker to cool. The solution was then chilled, and the re- 
 sulting paste of the sulfate of p-nitro-o-anisidine was filtered 
 with suction and pressed as dry as possible. Without washing, the 
 precipitate was transferred to a beaker and thoroughly mixed with 
 cold water. This caused the hydrolysis of the gray sulfate to 
 the free base. The bright yellow base, ^ ^”2 was filtered 
 
 with suction and dried; m.p. 136°-139^ (recorded in the literature, 
 m.p,140O). 
 
 The yield was 102 g. or 60^ based on the anisidine 
 used, and for ordinary purposes the crude product is sufficiently 
 pure. Impure ra-nitro-o -anisidine, ^oc H^was obtained on 
 
 neutralization of the sulfuric acid filtrate with ammonia; the 
 
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22 
 
 amount was 55 g. or 33fo based on the anisidine. It was found that 
 the above procedure, whereby the acet-o-aniside was not isolated 
 gave an increase of 5-10^ of the product. 
 
 33-^ g, of finely pulverised p-nit ro-o-anisidine was 
 suspended in hydrochloric acid, diazotized end treated with sodium 
 arsenite in the customary way. The p-nit ro-o-methoxy phenyl 
 arsonic acid separated in small pale yellov/ needles and the yields 
 were 30-32 g., which is 54-58fo of the theoretical amount. This 
 arsonic acid is very slightly soluble in cold water, more soluble 
 hot; it is soluble to the extent of 6 g. per ICO cc. in boiling 
 905^ alcohol, and crystallized on cooling in aggregates of long 
 pale yellov/ needles; it is insoluble in ether and organic solvents; 
 readily soluble in aqueous alkalies and ammonia. It does not 
 melt up to 250®. 
 
 Subs. 0.1987, 0.2060 reqmred 17.56, 18.27 cc. of 0,0808 N I. 
 
 Calc, for C^HgOgNAs: As = 27.08f.; Found: As - 36.78-^/^, 26. 86?., 
 
 The Preparation of Aminoaryl Arsonic Acids 
 
 There are two general methods of preparing the amino- 
 aryl arsonic aoidp: first, the reduction of nitroaryl arsonic acids, 
 and second, the direct arsenation of aryl amines. The first 
 method is very general in its application and has led to the syn- 
 thesis of a large number of amino arsenic acids, especially o- and 
 m- derivatives. The second method is of limited application and 
 is used chiefly for the preparation of p-aminoaryl arsonic acids. 
 
33 
 
 The Reduction of Nitroaryl Arson! c Acids ^ 
 
 The reagents 'Jirhich have been used for the selective 
 reduction of these acids are ajiunoniura sulfide, sodium hydrosulfite, 
 sodium amalgam, iron powder and alkaline ferrous hydroxide. The 
 last was used by Benda^® , and by Jacobs, Heidelberger and Rolf. 
 
 A modification of the method of the latter authors has proved 
 quite satisfactory. The substitution of ferrous chloride for the 
 sulfate is of considerable advantage, since this obviates the 
 troublesome precipitation and filtration of barium sulfate. 
 
 General Procedure : A solution of ferrous chloride was prepared by 
 treating an excess of powdered iron with hydrochloric acid and 
 heating on a hot plate until no more gas was evolved. This solu- 
 tion was kept over metallic iron until just before using, and 
 after filtration its ferrous chloride content was determined by 
 permanganate titration. 
 
 A solution containing 7 equivalents of ferrous chlor- 
 ide was placed in a large wide mouth bottle fitted with a rubber 
 stopper, and after thorough chilling by the addition of ice, a 
 cold 20^ solution of sodium hydroxide, 14 equivalents, was added. 
 
 In the meantime a solution of the di -sodium salt of the nitro acid 
 was prepared by dissolving 1 equivalent of the nitroaryl ar sonic 
 
 acid in 1000 cc, of 2-N sodium hydroxide. The solution of the 
 nitro compoiind was added at once to the pale green jelly of 
 ferrous hydroxide., and the bottle stoppered and vigorously shalcen 
 for 10-15 minutes. The color of the mixture changed from green to 
 
 brown and after standing a short while with occasional shaking the 
 mass was filtered with suction on a large funnel. The paste of 
 
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34 
 
 ferric hydroxide was sucked as dry as possible and then discarded. 
 
 The alkaline filtrate was concentrated on the steam 
 bath to a volume of 700-750 cc., filtered from sodium chloride 
 ajid the filtrate further concentrated in vacuo, 20 mrn. When the 
 volume is quite small the solution was treated with decolorizing 
 charcoal, filtered and cooled. Dilute hydrochloric acid was then 
 carefully added to the cold solution until it just reacted acid 
 to Congo paper, and the amino arsonic acid precipitated. The 
 products usually had a yellow-pink color and were purified by 
 crystallization from water. 
 
 2-Aminophenyl Arsonic Ac i d, o-Arsanilic Acid ^^; Using 40 g. of 
 o-nitrophenyl arsonic acid and following the directions outlined, 
 24 g. of o-arsanilic acid separated in slightly pink crystals, 
 m.p. 150^-153^. This is 70Jc of the theoretical amount, and is 
 slightly less than the yield obtained by Jacobs, Heidelberger and 
 Rolf, but their results could not be duplicated in this labora- 
 tory, 
 
 2-Methyl -8-Aminophenyl Arsonic Acid ^^; The reduction of 26 g. of 
 2-m ethyl -S-nitrophenyl arsonic acid gave 12 g. of crude amino 
 arsonic acid. This material was crystallized from water and 
 melted from 173^-175®. The yields were 50-55^ of the theoretical, 
 
 2-Methyl-4-Aminophenyl Arsonic Acid ^^: From 26 g. of the nitro 
 acid by the usual method of reduction were obtained 12-15 g. of 
 the crude amino arsonic acid, m.p, 216^-220®, This is 50-60^ of 
 
 the theoretical amount 
 

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25 
 
 2«jiothoxy"»4~Aminophenyl Araonlc Acid : Derivatives related to this 
 substance have been prepared by the arsenation of carbethoxy ra- 
 
 42 
 
 arainophenol, and by the use of 5-nitro-S-arninophenol in the Bart 
 reaction. The methyl ether can be most conveniently prepared by 
 the reduction of 3-methoxy-4-ni trophenyl ar sonic acid, obtained 
 through the Bart reaction. 
 
 38 g. of the nitro ar sonic acid was dissolved in 300 
 cc. of N-sodiura hydroxide, and reduced in the usual way with 
 ferrous hydroxide. The impure material was obtained as a brown 
 crystalline precipitate amounting to 13-13 g. or SO-oO'^ of the 
 theoretical yield. The 3-methoxy-4-aminophenyl arsonic acid v/as 
 crystallized from water, and was obtained in beautiful whits 
 needles. 
 
 Subs. 0.1503, 0.3000 g. required 15.07, 20,32 cc. of 0,0608 N 
 Calc, for C 7 H 10 O 4 NAS: As=30,33f^. Found: 30.38^b, 30,S5f.. 
 
 This acid is slightly soluble in cold water, more soluble hot; 
 almost insoluble in alcohol, ether and organic solvents. It dis- 
 solves readily in alkalies, carbonates, and ammonia, and in mineral 
 acids. When heated rapidly it melts at 208°-209®; heated slowly 
 it melts from 303^-204°. 
 
 Preparation by Direct Arsenation 
 
 5-Methyl-4-Aminophenyl Arsonic Acid : This acid is readily prepared 
 by the Bechamp reaction from o-toluidine^° and arsenic acid. The 
 method used was a modification by W. Lee Lewis for the preparation 
 of arsanilic acid. The crude o-toluidine arsonic acid, which was 
 
 slightly pink in color, was purified by precipitating the mono- 
 sodium salt from its aqueous solution by pouring into absolute 
 
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86 
 
 alcohol. It separated in large white crystals, containing 3 0, 
 
 and not 3-^ HsO as stated toy Pyraan: 
 
 Suds, 0.9700, 1,2576 g. heated at 130^ lost 0.1718, 0.2315.g 
 
 Calc, for CvHeOaNNa, 3H3O: 17,59f. Found: 17,7^c. 
 
 C7Ha03NNa, 3-^H 0: 19.94fc 17.63f^. 
 
 The free acid was obtained on adding the calculated quantity of 
 
 hydrochloric acid to a solution of the sodium salt. It separated 
 
 in white leaflets or plates, ra.p, 195^-198®, 
 
 5~Bromo-»4-Aii!d.nophenyl Ar sonic Acid : Although the halogenated 
 anilines may toe used in the Bechamp reaction, it is usually more 
 convenient to prepare the halogenated aminoaryl arsonic acids toy 
 indirect means, Bertheim®'' obtained mono-toromoarsanilic acid toy 
 the direct toromination of arsanilic acid with half the theoretical 
 amount of bromine, 
 
 110 g, of arsanilic acid, mole) was dissolved in 
 2000 cc. of hot glacial acetic acid and the solution quickly 
 chilled to room temperature, A solution of 40 g, of bromine 
 (i mole) in glacial acetic add was then added with good stirring 
 during the course of 4-5 hours. The product was isolated accord- 
 ing to the 23rocedure of Bertheira, and the monobromo arsanilic acid 
 separated in white leaflets weighing 52 g. or 70^ of the theor- 
 etical amount. The yield stated by Berthe im was 47^ and the im- 
 provement was probably due to the very slow addition of the 
 
 bromine, good stirring and the use of a slightly larger amount of 
 solvent. • 
 

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S7 
 
 B, The Condensation of Arylsunino Arsonic Acids with Pyruvic Acid 
 
 and Aldehydg3 . 
 
 41 
 
 Arsanilic Acld> Pyruvic Acid and Benzaldehyde : A mixture of 21.7 
 g, of arsanilic acid (1 mole), 10,6 g. of benzaldehyde (1 mole) 
 and 300 cc. of absolute alcohol ^as heatea to boiling under reflux 
 on a steam bath. After a short while moat of the arsanilic acid 
 passed into solution and 8.8 g. of pyruvic acid (1 mole) were 
 added. The solution was then heated to boiling for 3-^-4 hours 
 and then filtered hot to remove a slight amount of insoluble mater- 
 ial. On cooling the filtrate a yellow precipita-te resulted which 
 was filtered, washed sparingly with alcohol, finally with ether 
 and then dried in vacuo. The crude condensation product thus ob- 
 tained was pale yellow in color and melted with complete decomposi- 
 tion at 130^-183°. After one crystallization from ordinary alcohol 
 and washing with alcohol followed by ether, the substance is pure 
 and is then a cream colored powder which starts to darken at 
 about 180^, and melts with decomposition at 183^-187° (cor.) The 
 yields of crude product varied from 18-34 g, which is 50-35^ of 
 the theoretical amount. After repeated crystallization from 
 alcohol the substance was obtained in pure white leaflets. 
 
 The arsenic was determined by Ewins* method, the 
 nitrogen by the Kjeldahl method, and the carbon by the Parr total 
 carbon method: 
 
 Subs, 0.5001, 
 
 0.5005 
 
 g. , COg, 563.5 cc. 
 
 565.3 cc. 
 
 (28.5^, 
 
 746 mm) 
 
 
 
 ( 30 . 5 ^, 
 
 746 mm) 
 
 0.1999, 
 
 0.2033 
 
 g, required 14.43, 
 
 14,49 c 
 
 c. 0.0736 N I 
 
 0.5001, 
 
 0,5034 
 
 g, 18.33, 18.36 cc. 
 
 0.0699 
 
 N HCl. 
 

 
 I 
 
 
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 i 
 
 i' 
 
 i 
 
 I 
 
 
 1 
 
 
 ’S:2aae 
 
 • » » ^ • j - * ^1 A- 
 
 .^ - J ,*f . ‘.J - 
 
 ' . r ’ . or • ‘l 
 
Calc, for Cje^j^OgNAs: C, 51.20fo; As, 20.00fo; N, 3,73;;. 
 
 Found; C, 51.54, 51.30foj As, 19.97, 19.77foj N, 3.58, 3.57f.. 
 This substance is slightly soluble in water; mors soluble in cold 
 methyl and ethyl alcohol and glacial acetic acid, very soluble in 
 these solvents hot; insoluble in ether and organic solvents. It 
 is re>adily soluble in alkali hydroxides and carbonates, and in 
 ammonia; insoluble in dilute mineral acids in the cold, decomposed 
 on warming. 
 
 When the crude material was recrystallized from 
 alcohol a certain amount of insoluble material remained, which 
 consisted in part of benzylidene arsanilic acid. The latter was 
 isolated by boiling the residue with a large volume of absolute 
 alcohol and allovving the filtrate to cool and concentrate. The 
 benzylidene arsanilic^* acid separated in white heavy granular 
 crystals, readily soluble in alkalies, and decomposing on heating 
 to 235°. 
 
 Subs. 0.2078, 0.2100 g. required 15.27, 15.43 cc. 0.0893 N I. 
 
 Calc, for C 13 H 12 C 3 HAS: As, 24.5Sf5. Found; As, 34.S0fc, 24.82^. 
 In addition to the benzylidene arsanilic acid a less soluble sub- 
 stance remained in the insoluble portion. 
 
 A number of experiments were made to determine the 
 best conditions for carrying out the reaction and it was finally 
 decided that the use of mechanical stirring and a temperature of 
 65^-70° are the most favorable conditions. It was found that only 
 half of the alcohol was essential to carry out the reaction and 
 obtain complete solution of the products, but the mass becomes so 
 solid on cooling that it is advisable to use the larger quantity. 
 
\ 
 
 } 
 
 • w* 
 
 
 
 ..3 
 
 I '■•C- 
 
 •• r , a * -a ( rrwi«»-iiB 
 
S9 
 
 It was found that ethyl alcohol could he replaced by methyl, and 
 the condensation effected in the usual mannei^^ . It is unneces- 
 sary to use absolute alcohol for the solvent, and fair results 
 were obtained by the use of 95^ and 90fo alcohol. In these cases, 
 however, the yields were not so good and the product was more 
 highly colored. 
 
 The saiue product resulted from the use of ethyl 
 
 34 
 
 pyruvate instead of pyruvic acid, under the same conditions. 
 
 11.6 g. of ethyl pyruvate ms substituted for 8.8 g, of pyruvic 
 acid in the above directions. The product was isolated in the 
 usual manner but the yield was poorer than when pyruvic acid was 
 used. The product after recrystallization from absolute alcohol 
 melted from 1S5°-187®, w. dec., and a mixed melting point with the 
 first condensation product was not lowered. 
 
 Subs. 0,3074 g. required 1^.42 cc. of 0,0893 N I. 
 
 Calc, for CieHi 405 Ms: As * 30.00^. Found: 20,06^. 
 
 The condensation ms also carried out in ether, but 
 in this case the reaction was incomplete, due to the insolubility 
 of the arsanilic acid. A mixture of 10.6 g. of benzaldehyde and 
 8.5 g. of pyruvic acid was added to 21.7 g. of arsanilic acid 
 covered with 350 cc. of ether. The mixture was stirred vigorously 
 for 40 ho'urs and at the end of this time a flocculent precipitate 
 had formed in the ether. This was sepsxated by decantation from 
 the heavy granular crystals of unused arsanilic acid and then 
 filtered from the ether. The material weighed 20 g. and was much 
 darker yellow in color than the ordinary crude condensation 
 product. After two crystallizations frcm alcohol the material 
 was obtained in white leaflets, ra.p. 185^-187°, w, dec, and was 
 
A 
 
 
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 I 
 
 I 
 
 ;r 
 
 r 
 
 I 
 
 ) 
 
 I 
 
 vK- ^ 
 
 I 
 
 » 
 
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 Xf Xv . '. -..i -Tv-. 
 
 • ^ -^. •' 0‘iiu 
 
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 k 
 
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 il 
 
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 ■ I 
 
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 II 
 
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 H 
 
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30 
 
 proved to ’00 identical with the first condensation product by 
 mixed melting points and analysis: 
 
 Subs. 0,1516 g. required 9.10 oc, of 0.0893 N I. 
 
 Calc, for C1GH14O5NAS: As, 20.00^. Found: 30. 10*^. 
 
 The reaction between arsanilic acid, pyruvic acid and substituted 
 aldehydes was carried out according to the directions given for 
 benzaldehyde, using each one of the constituents in equimolar 
 proportions. 
 
 Sal ioyl aldehyde : This aldehyde gave an orange red solution from 
 which a product separated on concentration. This was more highly 
 colored than that from benzaldehyde, and it rapidly darkened on 
 exposure to the air. No suitable method of purification was found. 
 
 3~Methoxy benzaldehyde : Using the methyl ether^® of salicyl alde- 
 hyde instead of the free phenol, a good yield of the condensation 
 product was obtained. The material after crystallization from 
 alcohol, was obtained as a pale yellow powder, m.p. 173^-176°, w. dec. 
 Subs. 0.2025, 0.2032 required 12.61, 12.25 cc. 0.0808 N I. 
 
 Calc, for 0 As, 18.5Sf., Found: 18.87fc, 18.36^'. 
 
 4-Methoxy benzaldehyde : Aniaaldehyde gave a product which after 
 crystallization from alcohol was almost white; m.p, 164^-165^, w, dec. 
 Subs. 0.2005, 0,2000 g, required 10.38, 10,51 cc. 0,0954 N I. 
 Calc, for Ci^HisOgNAs: As, 18.56^^, Found: 18. 53-^., 18.63f^. 
 
 4-Dimethylamino benzaldehyde : When the pyruvic acid was added to 
 
 3 6 
 
 a mixture of arsanilic acid and dimethylaraino benzaldehyde , a 
 deep red color was formed which became darker during the heating. 
 
** 
 
 
 
 t 
 
 i 
 
 I 
 
 j 
 
 I 
 
 ! 
 
 i 
 
 c 
 
31 
 
 The product separated as a dark red powder, which was purified 
 with difficulty from alcohol. 
 
 5. 4 ~Methyl 9 nedloxy henzaldehyde i Piper onal was found to give a 
 good yield of the condensation product, which after crystalliza- 
 tion from alcohol was obtained as a light yellow powder, m.p, 
 176^-178° w. dec. 
 
 Subs. 0,1474 g. required 7,80 cc. 0.0893 N I. 
 
 Calc, for Ci^^i^O^NAs: As, 17.S0fr. Found: l?.73^c>. 
 
 4-Chlorobenzaldehyde : This aldehyde gave satisfactory yields of 
 a product which after two crystallizations from alcohol was ob- 
 tained as a white powder, m.p, 133°-165^, w. dec. 
 
 Subs, 0,3505 g, required 14,90 cc. of 0,0808 N I. 
 
 Calc, for Cl eHiaOsNClAs: As, 18,39^. Found: 18.0Cf/c. 
 
 Cinnamic Aldehyde : This aldehyde seemed to react with the arsan- 
 ilic acid and pyruvic acid, but only a colored impure condensation 
 product was obtained, and no method was found for its purification. 
 
 Paraldehyde : In place of 103 g. of benzaldehyde, 4,4 g. of paralde- 
 hyde was used and in this case no condensation product separated 
 from the cooled solution. On allowing ^ of the alcohol to evapor- 
 ate, 18 g. of a yellow solid remained, A portion of this was 
 crystallized from ''vater and proved to be impure arsanilic acid: 
 Subs. 0.2001, 0.1996 g. required 24.50, 24.13 cc. 0.0736 N I. 
 Calc, for CiiHigOsNAs: As, 23,96/('. Found: 
 
 C 17 H 10 O 7 N 3 A 33 : As, 29.30^4 33.79 
 
 Arsanilic Acid: 34.56fo 33. 35f. 
 

33 
 
 n~Butyr aldehyde was also tried, but no condensation product was 
 obtained. 
 
 8~Aminophenyl Arsenic Acid. Pyruvic Acid and Benzaldehyde ; In con- 
 trast to the p-compound, o-arsanilic acid is quite soluble in 
 alcohol. To carry out the reaction the o-arsanilic acid ivas dis- 
 solved in the liot alcohol, and the benzaldehyde and pyruvic acid 
 added to the hot solution, A crystalline precipitate was formed, 
 but on heating for 1-1-j hours at 70^ this redissolved. On filter- 
 ing and cooling the reaction mixture to 20° no precipitate formed, 
 but on concentrating and cooling to -10° a yellow precipitate 
 resulted. This was analysed and found to be the benzylidene deri- 
 vative of o-arsanilic acid, m.p. 227°-339°. 
 
 From a simils.r experiment the crystalline precipitate 
 obtained at first was filtered and washed with alcohol and ether. 
 
 It is a heavy granular material, m.p. 826°-228°, with previous 
 darkening. Analysis indicated that it was benzylidene o-arsanilic 
 acid, CeHBCH-N.CeH^.AsOaH^: 
 
 Subs, 0.1997 Tequired 14.70 cc, 0.0893 II I. 
 
 Calc, for CisHisOsNAs: As, 24.58fc. Found: 24.66f.. 
 
 The filtrate from the crystalline precipitate on cooling deposited 
 an additional amount of material, almost white in color. This was 
 filtered, washed with alcohol and ether, and found to melt from 
 325^-228®. This indicated that it was benzylidene o-arsanilic 
 acid, and was confirmed by analysis: 
 
 Subs. 0.1985 g, required 14,63 cc. 0.0893 N I. 
 
 Calc, for CisHjgOsN As: 24.58^4, Found: 24,74fo, 
 
33 
 
 For comparison a sample of benzylidene o-arsanilic acid was pre- 
 pared by heating o-arsanilic acid with one mole of benzaldehyde 
 in alcoholic solution. The product crystallized out in granules, 
 m.p, 288^-330®, and was identical with the above compounds, 
 
 3- Methyl~4-Aminophenyl Ar sonic Acid, Pyruvic Acid and Benzaldehyde : 
 Methyl arsanilic acid was treated with benzaldehyde and pyruvic 
 acid in the usual way and no condensation product separated. On 
 evaporating ^ of the alcohol and cooling, a product separated 
 which was filtered and washed with alcohol and ether. This was 
 recrystallized from alcohol and obtained as a cream colored 
 powder, m.p. 202°-305®, w, dec. The analysis indicated that it 
 was the benzylidene derivative: 
 
 Subs. 0,2001, 0,2000 g, required 13,80, 13,90 cc. 0.0893 N I. 
 Calc, for Ci 4 Hi 403 WAs: As, 23.5lf^. Found: 33. lOf^, 23.38fo. 
 
 The reaction was repeated wixh longer heating, but the same 
 product was obtained, 
 
 4- Chlorobenzaldehyde : Using p-chlorobenzaldehyde in place of bena- 
 aldehyde, a yellow precipitate was obtained from the reaction 
 mixture on cooling. This was crystallized frora alcohol and ob- 
 tained as a pale yellow po^wier, m.p, 355^-260®, w, dec. The 
 analysis indicated that this was the benzylidene derivative and 
 that the pyruvic acid had not taken part in the condensation: 
 
 Subs. 0,2018, 0,2001 required 13.74, 13,31 cc. 0,0803 TT I, 
 
 Calc, for Ci^HigOgNClAs: As, 31,20fo. 
 
 2-Nit robenz aldehyde : From this reaction a product was obtained 
 
-r»ia-i:«rSlCS^ 
 
 
 
34 
 
 which was purified with difficulty from alcohol. Analysis in- 
 dicated that it was a mixture of arsanilic acid, and a small amount 
 of other material: 
 
 pubs. 0,3003 g. required 17.98 cc, 0.0893 N I, 
 
 Calc, for arsanilic acid. As 34.56 a'« Foiond: 30,1^. 
 
 3-3romo-4-Aminophenyl Ar sonic Acid. Pyruvic Acid and Benzaldehyde : 
 When bromo-arsanilic acid was used in place of arsanilic acid it 
 was very difficult to isolate any product from the reaction mixture. 
 On concentrating to a small volume, a precipitate was obtained which 
 was purified with difficulty from alcohol. This substance proved 
 to be chiefly unchanged bromo-arsanilic acid, probably contaminated 
 with some of the benzylidene derivative: 
 
 Subs, 0,3334 g. required 16.07 cc. 0.0393 N I 
 Calc, for Bromoarsanilic acid. As, 35.335^. 
 
 Benzylidene derivative. As, 19.53';^ 
 
 Found: As, 33.16f5. 
 
 2- Methyl-4-Aminophenyl Arsenic Acid. Pyruvic Acid and Benzaldehyde : 
 
 A suspension of the ar sonic acid in absolute alcohol was treated 
 with benzaldehyde and pyruvic acid, and vigorously stirred under 
 reflux at 70°. The acid gradually passed into solution and after 
 
 3- 3^ hours heating the reaction mixture was filtered and cooled. 
 
 The condensation product separated in good yield and after washing 
 with alcohol and ether remained as a cream colored powder decompos- 
 ing on heating from 130°-186°. 
 
 Subs, 0.1981, 0,2003 g, required 11.33, 11,55 cc. 0.0893 N I, 
 Calc, for Ci7Hi60b^As: As, 19.37^. Found: 19.14'^, 19.27/c, 
 
■V 
 
35 
 
 3~M3thoxy~4~Aminophenyl Arsonic Acid. Pyruvic Acid and Eenzaldehyde : 
 Using the same method as in the preceding example, the condensa- 
 tion product was obtained as a yellow powder decomposing on heating 
 to 175°-130°, with previous darkening. 
 
 Subs. 0.1472 g. required 7.79 cc. 0.0893 N I. 
 
 Calc, for Ci^HieOsNAs: As, 18.56fo. Found; 17 . 73 ^ 9 , 
 
 Condensation of an Aminoaryl Arsinic Acid : An arsinic acid derived 
 from p-arsanilic acid was available and this was treated with 
 pyruvic acid and benzaldehyde in the usual manner. From p-amino- 
 phenyl arsinic (acid) acetanilide’, p-NHsCeH^AsOgH. CHgCOITHCeHs, a 
 yellow solid was obtained decomposing at 173°-175°. 
 
 C. Reactions of the Condensation Products . 
 
 For studying the structure of the condensation products- 
 the substance was used that was obtained by heating p-arsanilio 
 acid, benzaldehyde and pyruvic acid in absolute alcoholic solution. 
 The material was recrystallized from alcohol and was obtained as a 
 cream colored powder melting with decomposition from 185°-187^, 
 with previous darkening. 
 
 Decomposition on Heating ; A qualitative experiment showed that the 
 material evolved carbon dioxide on heating to its decomposition 
 temperature, and in order to obtain definite information the ex- 
 periment was carried out quantitatively. A weighed sample was 
 suspended in ethyl benzoate, heated to boiling for 20 minutes, and 
 the carbon dioxide in the gas evolved was determined by difference 
 after absorption in potassium hydroxide. 
 
 Prepared by the action of ohIoroacotanMtde upon 
 sodium phenyl arsenlte, Peferonoe 58. 
 

 f 
 
 li 
 
 It 
 
 I 
 
 i 
 
 I 
 
 ■0^ ..ii ■ I 
 
 ’ . ' 1 
 
 y 
 
 :r:, ^ 
 
 
 I, ,<. J • 
 
 t.' 
 
 . . . • t. • V . 
 
 v,l ' ■ ' •' ri 
 
 t.i 
 
 ■f . •• 
 
 . -Jt\ 
 
Subs, 1,000 g, gave 53,5 cc. COg, 24° and 743 mm. 
 
 Converted to standard conditions 5S.3 cc. 
 
 Calculated for one mole COg 60,0 cc. 
 
 These date indicated that the amount of carbon dioxide formed 
 corresponded roughly to one mole. 
 
 This reaction was first considered to be evidence of 
 the cinchoninic acid formula for the product, but in order to be 
 sure of the conclusion it was decided to try an experiment with a 
 known diketopyrrolidine , For this purpose the compound prepared by 
 Borsohe^® from p-nit rani line, pyruvic acid and benzaldehyde in al- 
 coholic solution was used. On repeating Borsche’s work the com- 
 pound was obtained as a yellow powder, ra.p. 182°-183°, after re- 
 peated crystallization from glacia.1 acetic acid. 
 
 The decomposition was carried out exactly as in the 
 preceding case; 
 
 Subs, 1.042 g. gave 54.2 cc. COg, 25® and 755 mm. 
 
 Converted to standard conditions 49.3 cc. 
 
 Calculated for one mole COg 78,8 cc. 
 
 Found; of one mole. 
 
 Since it was thought that the presence of an arsonic acid grouping 
 might affect the decomposition, a similar experiment •'^^s carried 
 out in which 2 g. of o-nitrophenyl arsonic acid was ad.ded to the 
 material 'oaf ore heating. 
 
 Subs. 1,118 g. gave 89,4 cc. COs, 38® and 755 ram. 
 
 Converted to standard conditions 80,7 cc. 
 
 Calculated for one mole COs 84.7 cc. 
 
 Found; 95fo of one mole. 
 
• ^ 
 
37 
 
 These results were altogether unexpected since it is not easy to 
 explain the formation of a mole of carbon dioxide on the decomposi- 
 tion of a diketopyrrolidine derivative, 
 
 COgH / \ ,CO-CO 
 
 
 H gO 3 As 
 
 N; 
 
 eHj 
 
 CH-CHg 
 
 CeHs 
 
 II 
 
 This indicated that the formation of carbon dioxide on decomposing 
 the condensation product could not be taken as evidence for dis- 
 tinguishing between these formulae, providing the compound ob- 
 tained from p-nitraniline is a true diketopyrrolidine derivative, 
 as it is formulated by Borsche to be. 
 
 On boiling the condensation product with mineral acids, 
 a heavy viscous oil is formed which sinks to the bottom of the 
 container and on cooling sets to a brittle mass. An attempt was 
 made to esterify the substance by treating with dry hydrochloric 
 acid in alcoholic solution, but the acid caused decomposition of 
 the condensation product. 
 
 Fusion with sodium hydroxide : The fusion of phenyl arsonic acid 
 with alkalies was carried out by La Coste who states that it 
 gives with potassiuin hydroxide ^ phenol and benzene, but with 
 sodium hydroxide chiefly benzene. It thus appeared that by fusion 
 of the condensation product with sodium hydroxide an arsenic free 
 substance would be obtained that could easily be identified. To 
 test out the reaction two preliminary experiments were run: 
 
 a.. 25 g. of phenyl arsonic acid was mixed thoroughly 
 with five times its weight of sodium hydroxide and distilled from 
 

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3 3 
 
 ammonium salt may toe prepared. The toehavior on treating with 
 sodium hydroxide is rather unusual: 
 
 The material dissolved readily in one mole of aqueous 
 sodium hydroxide to a clear yellow solution which was filtered and 
 allowed to stand at room temperature. After a short while the 
 solution toecame turtoid, and deposited a white precipitate. A 
 strong odor of toenzaldehyde was noticed. After 24 hours the pre- 
 cipitate was filtered and examined. It contained arsenic and was 
 solutole in alkalies; it was purified with difficulty from alcohol 
 and obtained as a white poiivder melting with decomposition from 
 140^-150°. 
 
 On treating the condensation product with two or more 
 moles of sodium hydroxide a clear yellow solution resulted which 
 remained perfectly clear for an indefinite period, A few tests 
 were made to determine in a rough way the Pjj values of solutions 
 of the condensation product in various quantities of alkali. The 
 Clark-Lutos series of indicators was used: 
 
 Sodium Hydroxide 
 
 value 
 
 Notes 
 
 a, 1 mole 
 
 approx 3,0 
 
 deposits white precipitate 
 
 D. 1-^ moles 
 
 3,5 - 4.4 
 
 deposits white precipitate 
 not as much as in a. 
 
 c, 2 moles 
 
 7,2 - 8.0 
 
 clear yellow solution 
 
 d, 2i moles 
 
 approx 8.8 
 
 clear yellow solution 
 
 e. 3 moles 
 
 8.8 - 9.6 
 
 solution darker than c. 
 
 From a solution of the condensation product in two 
 moles of alkali, copper sulfate precipitates a green salt; silver, 
 lead, mercurous, mercuric, cadmium nitrates light yellow salts and 
 cotoalt and ferric nitrates red-torown salts. 
 
mi 
 
 Vf> 
 
 Hft 
 
 ; . ^ .. jVltiS} t' -fl 1 - p^ L^ch,t^{LMUtt^9 
 
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3B 
 
 a copper flask. From the distillate there was obtained 5 g, of 
 benzene, water and a small amount of a crystalline substance, 
 presumably diphenyl. 
 
 b, 35 g, of arsanilic acid was fused with sodium 
 hydroxide under the same conditions and gave 7 g, of aniline, 
 
 c, 30 g, of the condensation product on fusion with 
 150 g, of sodium hydroxide gave a distillate which consisted of a 
 red oily substance and water. This was treated as indicated: 
 
 Acidiftad with dilute hydrochloric 
 acid and extracted with ether: 
 
 §ther_Extr§£t; ii^^3:®£]jl£EiS._££i5_§5i£3£i* 
 
 Oried over calcium 
 clori demand thee 
 distilled: 
 
 a. 2-5 cc.b.p. 120 - 150 ® 
 probably phenyl 
 ethylene. 
 
 Treated with sodium 
 a red-brown oi Intake 
 dried and distilled: 
 a. 4-5 cc. 175-185° 
 identified as anil- 
 ine, by conversion 
 to acetanllid. 
 
 hydrox ide ,gave 
 n up in ether. 
 
 b. few drops 
 a very hish-botl 
 ing base, which 
 decomposes on 
 distillingl. 
 
 The formation of aniline from the condensation product indicated 
 that it was not the phenyl cinchoninic acid derivative , since 
 this would yield phenyl quinoline, but it does not help to distin- 
 
 guish between the formulae II and V: 
 
 HgOs As 
 
 >N^ 
 
 CO-CO 
 
 H 3 O 3 As 
 
 CK-CKs 
 
 CsHs 
 
 >1^=C-C0. 
 
 I > 
 
 H 3 C-CH 
 
 CgHs 
 
 II. V. 
 
 Tres.tment with aqueous alkalies : The condensation product is 
 readily soluble in caustic alkalies, carbonates, and ammonia. By 
 passing dry ammonia into a solution in absolute alcohol, a mono- 
 
1 ; 
 
 - ^ 'iT cT? V - ♦ ‘ '. *' 
 
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 *1 
 
 
40 
 
 An attempt wa-s made to isolate a sodium salt by pour- 
 ing an aqueous solution of the mono-sodium salt into absolute 
 alcohol. A white precipitate resulted which was filtered and 
 washed with dry ether. An analysis indicated that this was the 
 di-sodium salt of arsanilic acid: 
 
 Subs. 0.1830, 0.3105 required 15.36, 17.70 cc. 0.0893 N I. 
 
 Calc, for CsHeOgNAsNag : As, 28,73^-. Found: 38.07^, SB.lTf;. 
 
 This salt forms very hygroscopic white crystals which dissolve 
 readily in water to a clear solution. It does not appear to have 
 been described in the literature. 
 
 Treatment with aniline : With the ilea of obtaining an anil from the 
 4-keto group in the formula II, a solution of 19 g. (l mole) of the 
 condensation product in 100 cc. of hot absolute alcohol was treated 
 with 4.5 g. (1 mole) of aniline. The solution turned red in color 
 and was heated for -l—J hour. On cooling a precipitate formed which 
 was filtered, washed with ether and examined. It was found that a 
 considerable portion of the material was insoluble in boiling 10^ 
 sodium hydroxide, and therefore did not contain the arsonic acid 
 groupirig-. This material was filtered and investigated. It melted 
 with decomposition from 147^-148® and was thought to be identical 
 with the compound ra.p, 147®-148° obtained by Schiff®^ and by 
 Garzarolli-Thumlackh’-’’'on treating benzylidene aniline in benzene 
 solution with pyruvic acid. 
 
 It was thought that by treating the condensation 
 product with an excess of aniline, the Dfibner anil compound, rn.p, 
 335® could be obtained, and an experiment was carried out as above 
 using 3-5 moles of aniline. On concentrating and cooling a precipi- 
 

 !' 
 
 II 
 
 i: 
 
 M 
 
 i 
 
 : < ... ■ 1.. ’ ;i 
 
 i 
 
 iKi •;:I aci/.ti.- i| 
 
 .. ». ^ 
 
 r» ^ • V • 
 
 !i 
 
41 
 
 tats was obtained which was completely soluble in cold soditan 
 hydroxide. On neutralizing the filtered alkaline solution, a 
 precipitate was obtained which proved to be arsanilic acid. None 
 
 The regeneration of arsanilic acid on treatment with 
 such a mild reagent as aniline seems to give evidence that formula 
 V is more likely than II. Using formula V the reactions of the 
 condensation product can be explained according to the following 
 diagram : 
 
 of the compound melting at 325® could be isolated 
 
 n 
 
 NHs 
 
 CH=CH2 
 
 + 
 
 CeHs 
 
 + CeHs-NC^HsOs-CsKs 
 ra.p.l47°-148° 
 
 A8O3H2 
 
 CHsCH-OH-CeHs 
 
 O 
 
 1^2 + CO 
 
 CH2CH*0H-C6Hb 
 
 C 02 H 
 
 CH 3 COC 02 H 
 
 CgHs- CHO 
 
 + 
 
 H 2 O 3 As< 
 
, V 
 
 ? 'ii? ' 
 
 I 
 
 
 t 
 
 „■ ne. .l<vr vi; /r > ft :v '-' ' 
 
 l^,: ■' i-p.^; .' • C' t^'*r:3:rjf -’rn/.fifl. tf&i’’ 
 
 . . •, ' . V'j^r ,“j.<ii .r'Hf 
 
 \ I .' 
 
42 
 
 IV. STM ARY 
 
 The application of the DSbner cinchoninic acid syn- 
 thesis to arsanilic acid, benzaldehyde, and pyruvic acid gave a 
 condensation product of the composition: Qi 6H14.O5 NAs. 
 
 The reactions of this condensation product were studied 
 and the follo'/Ving formulae proposed: 
 
 The structure of the product ms not definitely established, but 
 the evidence favors formula II, 
 
 By the use of various aldehydes and aminoaryl ar sonic 
 acids, the following generalizations were made concerning the 
 
 limitations of this reaction: 
 
 i. Aminoaryl arsonic acids with substituents in the 
 ortho position to the aadno group form benzylidene derivatives 
 which do not react further \vith pyruvic acid. 
 
 ii. The usual condensation products are obtained 
 from compounds substituted in the met a position to the 
 amino group. 
 
 iii. The reaction is general for aromatic alde- 
 hydes, but not for the simple aliphatic aldehydes. 
 

 
 r/f. :A.t Ir <0i »'4Tf 
 
 iTf;\|#r .ri 
 
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43 
 
 V. BI3LlOGRj!|PHY 
 
 1, Frl^kel and L5wy, Ber. 2546 (1913)« 
 
 3. Boehringer and SShne, D.R.P, 240,793. Frdl. 1252. 
 
 3. Miohaells and others, Ann. 241 (1893); 330 . 318 (1902). 
 
 , Mroczkowski, Diss. 1910, - Berthe im ' s HandlDuch, 58, 108. 
 
 Poulenc and Oechslin, Fr, Pat. 450,214; 462, 276; 473,704. 
 Morgan’s "Organic Compounds of Arsenic", 166-7. 
 
 4. Michaelis, Ann. 321. 141-248 (1902); Pope and Turner, J. Chem. 
 
 Soc. 177, 1447 (1930). 
 
 5. Bart, D.R.P. 250,264. Frdl. 1^, 1254; cf. D.R.P. 366,944 and 
 
 237,307. Frdl. n, 1033. 
 
 6. Meyer, Ber. 1440 (1883); Klinger and Kreutz, Ann. 249 . 
 
 147 (1388); Auger, Co^iipt. rend. 137. 935 (1903); Quick and 
 Adams, loc. cit. 
 
 7. Skraup, M. 1, 316 (1330), 3, 139 (1831); Kneuppel, Ber. 
 
 703 (1893); Barnett, Chem, News 121. 205 (1920). 
 
 8. Knorr, Ann. 333 . 70 (1886); Swins, J. Chem. Soc. 103 . 108 (1913) 
 
 9. Kulisch, M. 15, 373 (1894). 
 
 10. DS’oner and v. Miller, Ber. lA, 2812 (1831); 13, 136 4, 3465 
 
 (1883); ]^, 1398 (1884); 2259, 3484 (1890); Decker and 
 
 Remfry, 38, 3775 (1905); Bartow and McCollum, J, Am. Chem. 
 Soc. 704 (1904); note, 43, 2257 (1921); Mills, Harris 
 and Lamhourne, J. Chem. Soc. 119 . 1294 (1921). 
 
 11. Dobner, Ann. .242. 265 (1387); 249 . 98 (1388); m, i (1894). 
 
 12. Friedl^nder, Ber. ,2574 (1833); 16, 1833 (1883); 25, 1753 
 
 / 
 
 ( 1393 ) . 
 
i 
 
 I 
 
 I 
 
 ! 
 
 
 I 
 
 ) 
 
 I 
 
44 
 
 13. Pfitzinger, J. prakt. chea, (3) 283 (1897); 66, 233 (1902); 
 
 Mulert, Ber. 1904 (1903); Ornstein, Ber. 40, 1083 (1907). 
 
 14. Hubner, Bar. 432 (1908); Borsohe, Ber. 354 (1914). 
 
 15. Schmidt, Ann. 421 . 168 (1931). 
 
 IS. Borsche, Ber. 3884 (1908); Ber. 4073 (1909). 
 
 17. Garzarolli-Thurnlackh, M. 483 (1899); Ber. 2274 (1899). 
 13. D.R.P. 394,159, (1914); C.A. 11, 2581 (1917). 
 
 19. Sharing, Brit. Pat. 15,481 (1913). C.A. 9, 127 (1915). 
 
 20. Dobner, Ber. 2030 (1894). 
 
 21. Schiff and Gigli, Ber. 1310 (1898). 
 
 22. Jacobs, Heidelberger and Rolf, J. Am. Chem. Soc. 40, 1580 (1917). 
 
 23. Claus, J. prakt. chem. (2) 84, 441 (1911); of. Knueppel, Ann. 
 
 310 . 75 (1900). 
 
 34. Michaelis, Ber. 51 (1887) ; Ann. 320 . 298 (1902) . 
 
 25. Bertheim, Ber. 276 (1914) . 
 
 33. Franzen and Engle, J. prakt. chem. (2) 103 , 156 (1921) ; 102 , 187 
 
 27. Reverdin and Crepieux, Ber. 33 . 2498 (1900). 
 
 28. Meldola, Proc. Chem. Soc. ]/7, 133 (1901). 
 
 39. Benda, Ber. 44, 3302 (1911); ^7, 1006, 1313 (1914). 
 
 30. Pyman and Reynolds, J. Chem, Soc. cf. 1181 (1908). 
 
 31. Bertheim, Bar. 539 (1910). 
 
 32. D.R.P. 193,542. Frdl. 8, 1339. 
 
 33. C.W.Rodewald and Adams, unpublished notes. 
 
 34. Simon, Bull. soc. Chim. (3) 476 (1895) 
 
 35. Kostanecki and Kat schalowsky, Ber. 2347 (1904) Anm, 
 
 36. Ingvaldsen and Bauman, J.Biol. Chem. 145 (1930). 
 
 37. La Coste, Ann. 2 ^, 9 (1881). 
 
 38. Quick and Adams, J. Am. Chem. Soc. 805 (1933). 
 
44 
 
 39. W. Lee Lewis, Comsiunioation reported at the Birmingham 
 
 Meeting of the American Chemical Society ,1933. 
 
 40. Robertson and Stieglitz, J, Am. Chem. Soc. 179 (1931). 
 
 41. Adams and Johnson, J. Am. Chem. Soc. 43 3355 (1931). 
 
 43'. Bauer, Ber. 48 1579(1915). 
 
 43. Robertson, J. Am. Chem. Soc . 183 (1931). 
 
 General References. 
 
 Bertheim, ”Handbuch der Organischen Arsenverbindungen" , 1913. 
 Morgan, "Organic Compounds of Arsenic and Antimony ", 1918. 
 
 Meyer and Jacobson, "Lehrbuch der Organischen Chemie% 
 
 Volume 3, part 3 pp.913 - 1014 (1930). 
 
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PART TWO 
 BENZYL AR30NIC ACID 
 
"W 
 
4 
 
 BSNZYL ARSONIC ACID 
 INTRODUCT ION 
 
 This work on benzyl arsonic acid was undertaken with 
 the object of obtaining new organic arsenic compounds which 
 might prove of therapeutic value. Although a large number of 
 derivatives of phenyl arsonic acid have been prepared in the 
 last fifteen years, due to the stimulus of Ehrlich and Bertheim’ 
 work, there has been little development along the line of ali- 
 phatic arsonic acids. For our work benzyl arsonic acid seemed 
 especially desirable, since it contained an aliphatic arsonic 
 acid grouping, -CH3A8O3H2 , and in addition a phenyl group, by 
 means of which it was hoped to introduce certain other physio- 
 logically active groupings into the molecule. 
 
 The only series of aliphatic arsenic compounds which 
 has been thoroughly studied and applied in medicine, is the 
 methyl series. Methyl arsonic acid and dimethyl arsinic acid, 
 were until recently the most readily accessible arsenicals of 
 the aliphatic series. These two substances are used thera- 
 peutically in the form of their salts, most commonly, disodium 
 methyl arsonate (Arrhenal), and solium cacodylate. Gautier^ 
 recommended the use of Arrhenal in therapeutics and stated that 
 it has specific action on malaria; however, it does not possess 
 trypanocidal properties. The latter fact is in keeping with 
 recent work which has 3ho^vn that nitrogen must be present in 
 some form in order to produce specific trypanocidal substances. 
 
 Benzyl arscmic acid can be very easily prepared, and 
 the problem was to study the properties of this substance with 
 
46 
 
 the hope of preparing a derivative Thich would possess trypano- 
 cidal action and be of low toxicity* The relatively low toxicity 
 of the aliphatic arsenic acids in general, makes them very desir- 
 able as starting materials, 
 
 HISTORICAL PART 
 
 The first work on arsenic compounds of the benzyl 
 series was reported by Michaelis^ and Paeto^v in 1885, From the 
 products of the interaction of benzyl chloride, arsenic trichlor- 
 ide, and metallic sodium in dry ether suspension, they obtained 
 dibenzyl arsinic acid, tribenzyl arsine, and tribenzylarsine 
 oxide. From these substances a large number of more complex 
 substances were obtained, the most important of which were: 
 
 (a) Tribenzyl alkyl arsonium halides. These were made by 
 heating tribenzyl arsine with alkyl iodides at 100®. 
 
 (b) Tribenzyl methyl arsonium hydroxide and tetrabenzyl 
 arsonium hydroxide^ , These were made from the corres- 
 ponding iodides with silver oxide; they are very strong 
 bases and rapidly absorb oarbon dioxide from the air, 
 
 (c) Benzyl arsenious chloride. This was made by heating 
 tribenzyl arsine with arsenic chloride; it is very un- 
 stable and decomposes in the air: 
 
 C eKsCHsAsCl 2 + 0 C gHsCHsCl + AsOCl | 
 
 After this work, no important contribution to the | 
 
 4 
 
 benzyl arsenic series was reported until Dehn and McGrath in 
 1906 showed that the extension of Meyer's reaction to benzyl 
 iodide gave good yields of benzyl axsonic acid. They studied 
 
 
 
I i 
 
47 
 
 the properties of this acid, and found that the arsenic was split 
 off frora the organic residue more readily than in other simple 
 
 5 
 
 aliphatic and aromatic ar sonic acids. Dehn obtained benzyl 
 arsine by the reduction of benzyl ar sonic acid with amalgamated 
 zinc dust and hydrochloric acid. By the treatment of benzyl 
 magnesium chloride in ether soluticn with arsenic tri oxide, 
 
 Sachs and Kantorowicz obtained a substance which they formulated 
 as a hydrated dibenzyl arsenious acid,(C 6 HsCH 3 ) ^AsOH* HgO , but 
 the constitution of this acid was not proved and needs verifica- 
 tion. 
 
 7 
 
 In 1915 shortly before his death, Bertheim studied 
 the mixed aromatic-aliphatic secondary arsinic acids, and ob- 
 tained benzyl phenyl arsinic acid by treating sodium phenyl 
 arsenite with benzyl chloride. 
 

 
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THirOPSTICAL PART 
 
 Sinoe considerable quantities of benzyl arsonic acid 
 would be required for this work it was desired to find a conven- 
 ient method of preparing the substance. The method of Dehn and 
 McGrath is too unwieldy for the preparation of large quantities 
 of the substance and involves a considerable loss of material 
 due to a side reaction; 
 
 CeHsCHgl + K3ASO3 aicohat CsHbCH^AsOsK^ + KI 
 
 "5” 60J 
 
 Side reaction; 
 
 C6H5CH3I + CgHsOK C6H5CH3OC2H5 + KI 
 
 By omitting the use of alcohol, and using a higher temperature 
 and vigorous mechanical stirring, benzyl arsonic acid was pre- 
 pared in good yields from benzyl chloride or bromide, and aqueous 
 sodium arsenite. 
 
 Benzyl arsonic acid was thus readily available at a 
 
 low cost, and seemed promising as a starting point for a number 
 
 of derivatives. By reduction, benzyl arsine is obtained, and it 
 
 seemed worth while to study this substance by trying to react it 
 
 with aldehydes to produce substances similar to those obtained 
 
 8 
 
 by Adams and Palmer ; 
 
 CgHsAsHg + 3RCH0 CgHsAs 
 
 It was found that the reaction did not proceed as smoothly as 
 with phenyl arsine, and the chief products of the reaction were 
 benzyl arsonic acid and a red condensation product, (probably 
 
 CHOH-R 
 
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 identical with that obtained by Dehn from benzyl arsine), which 
 is presumably arseno-phenylmethane, (CeHsCHgAs^AsCHgCeHs)^. 
 
 Recent work in this laboratory has given two new 
 methods by which derivatives of the arsines may be prepared, and 
 these may prove to be useful in the case of benzyl arsine. The 
 reactions involved are: 
 
 (af CsHsAsHa — CgHsAsNaa - 2 -^' CgHgAsRa + 3NaCl 
 
 10 
 
 (b) 
 
 CeHsAsHa 
 
 R M q B r 
 
 CsH^Ab (M gBr), 
 
 CgHg AsRR ’ 
 CgHg AsRg 
 
 It seems likely that a number of interesting derivatives could be 
 prepared from benzyl arsine by the application of these new re- 
 actions. 
 
 During the course of the work on the preparation and 
 properties of benzyl arsonic acid some interesting observations 
 were made on the products of its decomposition. It was noted that 
 in general the arsenic compounds of the benzyl series were very 
 easily broken down into inorganic derivatives of arsenious acid 
 and organic benzyl derivatives. Michaelis and Paetow observed 
 that on heating, dibenzyl arsinic acid was decomposed into 
 arsenic, benzaldehyde and dibenzyl: 
 
 CeHsCHg 
 
 AsOgH 
 
 heat 
 
 ASg + 3HgO + 3C6H5CHO + (CsHsCHs), 
 
 CeHsCHs 
 
 By strong hydrochloric acid it is decomposed completely into 
 arsenic chloride, benzyl chloride and toluene: 
 
 (CgHsCHs) AsOgH + 4HC1 =» CsHsCHgCl+CsHsCHa+AsCla+HgO 
 These reactions are somewhat similar to the decomposition of 
 
ty -I 
 
 
 
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 9 
 
 beat 
 
 acetrc"^ CeHsCHgOAo + CsHsCHg + Hg 
 
 Michaelie and Paetow observed that the quaternary benzyl arsonium 
 hydroxides on heating with alkalies gave tolu5ne and a tertiary 
 arsine oxide: 
 
 (CgHgCHg)^ AsOH (CsHbCHsJj AaO + CeHsCHg 
 
 Benzyl arsenious chloride was also found to be extremely easily 
 decomposed; with water it gives benzaldehyde and arsenic trioxide. 
 
 Dehn and McGrath showed that strong hydrochloric acid 
 decomposed benzyl arsonic acid into benzyl chloride and arsenic 
 trioxide: 
 
 3 CeHsCHgAsOaHg + 3HC1 -SCsHsCHgCl + AsgOa + 3HgO 
 
 and Bertheim states that warm hydrochloric acid converts the 
 secondary arsinio acid, benzyl phenyl arsinic acid, into benzyl 
 chloride and phenyl arsenious chloride: 
 
 CsHsCHgAs^®^® ' > CsHsCHgCl + CsHsAsClg + 3HgO 
 OgH 
 
 It was observed that the halogenated benzyl arsonic acids behaved 
 in the same way, yielding the halogenated benzyl chlorides on 
 treatment -with strong hydrochloric acid with slight warming. 
 
 On heating sli^tly above its melting point, benzyl 
 arsonic acid is decomposed into arsenic trioxide and a liquid 
 product. The liquid was investigated by Dehn and McGrath and 
 stated to consist of benzyl alcohol, benzaldehyde, atilbene and 
 water. They give as the most Important reaction: 
 
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51 
 
 3 CgHBCHsAaOsHa CgHsCHsOH + CsHgCHO + ASgOa + SHgO 
 
 It will be noted on careful observation that this equation does 
 not balance; the products of the reaction have two hydrogens and 
 two oxygens in excess of the starting materials. 
 
 On carefully decomposing a large quantity of benzyl 
 arsonic acid the chief reaction was observed to be: 
 
 3 CsHsCHsAsOaHs-i^^^ SCsHbGHsOH + ASgOg + HgO 
 No benzaldehyde 'me found in the lirquid product obtained from two 
 
 hundred grams of benzyl arsonic acid, but a high boiling material ' 
 
 was obtained which was shown to be dibenzyl ether. This may be 
 
 accounted for by the following equation: 
 
 3 CeHsCHsAsOaHs^^^ (CsHsCH2)20 + A 82 O 3 + SHgO 
 or possibly by a secondary reaction whereby a part of the benzyl 
 
 alcohol formed is dehydrated under the influence of unchanged 
 
 benzyl arsonic acid in the reaction mixture. The hi^ boiling 
 
 material obtained by Dehn and McGrath was shown to be dibenzyl 
 
 ether, and not a mixture of benzyl alcohol and stilbene as they 
 
 considered it to be. 
 
 By decomposing benzyl arsonic acid under vigorous 
 heating it was noted that benzaldehyde was obtained among the 
 decomposition products, along with an ill-smelling gas. From 
 these considerations it seemed likely that benzaldehyde is not 
 one of the main products of the reaction, but is formed by a 
 side reaction: 
 
 5 CeHsCHsAsOsHs-^^SGsHBCHO + AS 2 O 3 •fAsH3 + SHgO 
 
 The decomposit ion ‘'ol' fcenzyl arsonic acid by mineral 
 acids, such as hydrochloric and sulfuric, is quite complete at 
 
♦ . 
 
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elevated temperatures, and it was found that this procedure could 
 he used to determine benzyl arsenic acid quantitatively. The ease 
 of preparing very pure benzyl ar sonic acid has led to the use of 
 the latter as a standard for determining the titre of iodine solu- 
 tions, and very good results have been obtained. 
 
 In determining the melting points of various samples 
 of benzyl arsenic acid it was observed that in some cases the acid 
 seemed to melt near 190° instead of the recorded melting point of 
 167°, which was observed in other samples. It was thought at 
 first that this could be explained by the manner in which the 
 samples were heated, but a series of experiments showed that this 
 would not completely account for the two melting points of the 
 substance. This suggested that perhaps the results were due to 
 the existence of tautomers of the type observed in the phenyl 
 nitromethane series: 
 
 m.p.167^ m.p.l 90 ° 
 
 CeHsCHaAB^^Qg' Z : ; CsHsCH=A3 (OH) , 
 
 However, no method could be found for the interconversicn of the 
 "tautomers", and it was decided to prepare certain substituted 
 benzyl arsenic acids. 
 
 Attempts were made to obtain m- and p-nitrobenzyl 
 arsenic acids by the reaction of m- and p-nitrobenzyl chlorides 
 with sodium arsenite under the same conditions used for benzyl 
 chloride, but no arsonic acid could be isolated frari the reaction 
 mixture. Similar negative results were obtained with diphenyl 
 chlorome thane, and 1 -phenyl -1 -or omoe thane. The halogen ated benzyl 
 
 halides reacted normally and the following halogen substituted 
 

 
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54 
 
 EXPERIMENTAL PART 
 Benzyl Araonic Acid 
 
 Dehn and McGrath obtained this substance by the 
 action of benzyl iodide on potassium arsenite in alcoholic solu- 
 tion at room temperature, but the great difficulty in handling 
 benzyl iodide and the cost of the reagents indicated that this 
 would not be a suitable method. After several experiments with 
 benzyl chloride and potassium and sodium arsenites in boiling 
 alcohol, it was found that excellent results could be obtained by 
 the use of benzyl chloride and aqueous sodium arsenite at 100^ to 
 130^. Results of this and similar experiments with various other 
 halides are reported by Quick and Adams' ^ and in general it has 
 been found advantageous to omit the use of alcohol. The only ex- 
 ception to this is the case of methyl arsenic acid which separates 
 from the alcoholic reaction mixture almost quantitatively as the 
 di sodium salt. 
 
 Preparation : In a flask provided with a mechanical stirrer and a 
 
 good reflux condenser was placed a solution of 99 g. of arsenic 
 trioxide (i mole) and 134 g, of sodium hydroxide (3 moles) in 
 350 cc. of water. The solution was heated to 100^ to 110 in an 
 oil bath and during the course of 30 minutes 137 g, of benzyl 
 chloride (1 mole) was added by means of a dropping funnel. The 
 mixture was boiled vigorously for 1^ to 3 hours longer and then 
 cooled to room temperature. The oil which floated on the surface 
 was extracted with a small q;uantity of benzene and the alkaline 
 solution diluted with li to 3 moles of water and carefully 
 
5B 
 
 n eutralized to litmus. This must be done by the addition of 
 dilute acid with good stirring bet’,veen additions, or some of the 
 benzyl arsonic acid will be precipitated. If this procedure was 
 carried out properly, a slight flocoulent precipitate was obtained , 
 at this point. The neutral solution was filtered and the precipi- 
 tate discarded. 
 
 Dilute hydrochloric acid was added to the clear fil- 
 trate until it reacted acid to Congo paper, and the benzyl arsonic 
 acid separated out as a thick white curd. This was filtered with 
 suction, washed with water until free from acid, and dried in 
 vacuo at 90^. The yields were from 130 to 135 grains, which is 
 30 to 63*^ of the theoretical amount. The oil v/hich is formed in 
 the reaction consists of benzyl alcohol (75f^) and dibenzyl ether 
 (25fc) and this accounts for 30 to 35fo of the original benzyl 
 chloride. 
 
 Benzyl arsonic acid may be purified by crystallization 
 from water, 95^ alcohol, or glacial acetic acid. Alcohol is to 
 be preferred since the acid is much more soluble in this solvent 
 at the boiling point, than in hot water. From water, the benzyl 
 arsonic acid crystallized in stout white needles; from alcohol in 
 small needles or plates; from glacial acetic acid in small needles. 
 
 A sample was analysed by Fwins* method: 
 
 Subs. 0,2023 g, required 25,10 cc. 0,0736 N Iodine; 
 
 Fo^ond: As » 34.41*i^; Calculated for C^HgOgAs: As • 34. 72fc. 
 
 0 
 
 The melting point given by Dehn and McOrath is 167 and a number 
 of samples were obtained with this melting point, but in certain 
 oases the melting point was in the neighborhood of 190° and a 
 

 
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56 
 
 number of experiments were made to determine the reason for this. 
 
 It was definitely shown that the difference was not 
 due to water of crystallization, since material crystallized 
 from alcohol and analysed for arsenic showed similar behavior. 
 
 It was noticed that the rate of heating had a marked effect on | 
 the melting point, but this could not account for all of the dis- 
 crepancies, A sample of material, for example, that crystallized 
 from glacial acetic acid, was heated slowly in the bath and 
 melted from 191^-193®; a sample of the same material immersed at 
 170° and heated more rapidly melted at 192°, 
 
 The two melting points observed could be explained by 
 
 the existence of the tautomeric forms, 
 
 -CHs-As -CH=As (OH) a 
 
 but in this case no means could be found for passing from one 
 form to the other with certainty, and it was decided to prepare 
 substituted benzyl arsenic acids to see if the same double melt- 
 ing point would be observed. 
 
 Disodium Benzyl Ar senate : This salt was prepared by adding two 
 
 moles of sodium ethylate to a hot alcoholic solution of benzyl 
 arsonic acid. It separates in crystalline leaflets which were 
 filtered with suction and washed with dry ether. This salt dis- 
 solves readily in water to a clear solution, ^ich is slightly 
 alkaline to litmus. 
 
 Lead Benzyl Arsenate t The lead salt of benzyl arsonic acid was 
 prepared by adding a solution of lead acetate or nitrate to a 
 solution of the mono-sodium salt of benzyl arsonic acid, A 
 heavy curdy white precipitate was obtained. 
 
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57 
 
 Decomp osition on Heating : Since the nature of the products of 
 
 decomposition of benzyl ar sonic acid might prove of value in 
 studying tne possible tautoraerism, the following experiment was f 
 carried out : j 
 
 50 g. of re cry stall! zed benzyl arsonic acid was heated 5 
 in a small flask over a free flame until decomposition commenced. 
 After the reaction was started, it proceeded without further heat- 
 ing, although at the end the material was heated to insure com- 
 plete decomposition. The product of the reaction consisted of 
 whits arseni c trioxide, and a clear oil. The weight of the solid 
 vsupied from 34-37 grams, and the liquid from 13-19 g. The latter 
 
 was washed out with ether and fractionally distilled. The main 
 
 0 
 
 product boiled from 300-310 ; then the thermometer rose to 380 
 
 and a fraction was collected from 380° to 300°. The higher 
 
 fraction amounted to about 10^- of the liquid product. 
 
 It was apparent that no considerable amount of benzal- 
 dehyde was formed, since the thermometer rose immediately to the 
 
 boiling point of banzyl alcohol and nothing passed over at 180°, 
 
 From the 300-310° fraction on redistillation, a main fraction was 
 
 obtained boiling from 303°-307°, which was shoTO to be benzyl 
 
 alcohol by conversion into the p-nitrobenzoyl derivative, ra.p, 
 
 83°. (33.5°-S4.5° in the literature). I 
 
 In order to investigate the higher boiling fraction, 
 
 the combined 380°-300° fractions from the deooraposition of 300 g. 
 of benzyl arsonic acid were redistilled, and a sainple of pure 
 material boiling from 398°-302° was collected. The latter was 
 purified by two distillations and was then used for the determin- 
 
58 
 
 ation of physical constants. The analysis of the high boiling 
 
 material is reported by Dehn and McGrath, and checks satisfactorily 
 for dibenzyl ether: 
 
 Calculated for C14H14O: C « 84.85^; H - 7.07fo. 
 
 Found, (by Dehn and McGrath): C • 84.65^; H - 7,95‘fo, 
 Physical Constants: Decomposition Product Dibenzyl Ether 
 
 Specific Gravity 1,04 
 
 Refractive Index 1.5593 
 
 Boiling Point 298®-303® 
 
 1.036 
 
 1.5597 
 
 295^-298° 
 
 The above evidence proves that the high boiling fraction is not a 
 
 mixture of benzyl alcohol and stilbene, but pure dibenzyl ether’ 
 Dehn and McGrath state that their product decolorized bromine 
 water, but we were unable to confirm this. A sample of high boil- 
 ing material prepared according to their procedure failed to de- 
 colorize bromine water, and our sample of dibenzyl ether did not 
 decolorize this reagent. 
 
 In order to see whether benzaldehyde might be formed 
 under some other circumstances, a sa^rple of benzyl arsonic acid 
 was moistened with water and heated in a 200 cc. flask over a free 
 flame. An ill-smelling gas was formed dtoring the reaction, and 
 the distillate consisted of water and an oil, smelling strongly 
 
 of benzaldehyde. The water was separated from the heavier oil, 
 and the latter was shaken with sodium bisulfite solution and 
 
 ether added to take up the insoluble portion. The bisulfite j 
 
 * In order to show that the dibenzyl ether obtained was 
 
 not formed by a secondary reaction from benzyl alcohol 
 and arsenic trioxldc, 7b g.of benzyl alcohol and an equal 
 
 weight of areenic trioxido were boiled together for 45 
 minutes under reflux. The mixture after cooling and extract- 
 ion with ether was distilled and no dIbenzyl ether was 
 
 found . 
 
'•f)v ‘ 
 
 •• • ' *♦■ 
 
 . ■ "• i ‘^ ^ ■ . 
 
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 extract made alkaline with sodium oarhonate, and steam dis- 
 tilled, when a clear white oil having the odor of hen2Ealdehyde 
 passed over. This was extracted with ether and identified as the 
 phenyl hydrazone, m.p, 154°-155®, (m.p, 155°-156°, of phenyl hydra- 
 
 zone from known benzaldehyde) , A mixed melting point of these two | 
 
 i 
 
 substances was unaltered. This proves conclusively that benzalde- 
 hyde can be formed when benzyl arsonic acid is decomposed by heat, 
 but it is not one of the main products of the reaction. The 
 following equation is suggested for its formation: 
 
 3 CsHsCHgAsOsHg SCqHsCHO + AsgOs + A 3 H 3 + 3HgO 
 
 The arsine formed in this reaction accoiJints for the ill-smelling 
 
 gas which is evolved, and its decomposition by heat would account 
 for the deposit of metallic arsenic observed in the flask and con- 
 denser tube. 
 
 Deoomoosition by Mineral Acids : Concentrated hydrochloric acid 
 decomposes benzyl arsonic acid in the cold with the formation of 
 benzyl chloride and arsenic chloride. Strong sulfurio acid decom- 
 poses it in the cold with the formation of arsenious acid and a 
 
 gummy material. If the benzyl arsonic acid is dissolved in hot 
 water and a few cc. of strong sulfurio acid added and the mixture 
 'ooiled for a short while, the decomposition is quantitative, as 
 
 stated bv Dehn and McGra,th: 
 
 1000 
 
 CeHBCHjAsOsHj CsHbCHsOH + H3ASO3 
 
 sulfuric 
 
 By using the follomng procedure it was found that a simple quan- 
 titative determination of benzyl arsonic acid could be made.- 
 Samples of pure benzyl arsonic acid weighing 0,2 to 
 0.4 g. were placed in a 500 cc. erlenraeyer flask, lOO cc. of water 
 
added and the acid dissolved by boiling on a wire gauze. After 
 cooling, 10 oc. of concentrated sulfuric acid were added and the 
 solution boiled gently for 30 - 30 minutes. It was then cooled, 
 neutralized with alkali and faintly acidified with sulfuric acid. 
 Sodium bicarbonate was then added and the arsenious acid titrated 
 with standard iodine in the usual way. 
 
 Weight of Sample Iodine Solution Arsenic Found 
 
 0.4134 g. 52.6 3 cc 34.88 fo 
 
 0.2109 g. 33.54 cc 34.73 fo 
 
 0.1732 g. 21.73 cc 34.33 $ 
 
 0.1874 g. 33.53 cc 34.34 
 
 0.2013 g. 25.33 CC 34.39 ^ 
 
 0.2435 g. 30.58 cc 34.30 i 
 
 Calculated for Benzyl Arsonic acid 34.72 ‘^o 
 
 Average of six determinations above 34,73 ^ 
 
 Iodine solution * 0,0736 Normal, 
 
 Using this method, the solubility of benzyl arsonic acid in water 
 at 35® was found to be 0.369 g, per 100 cc, of solution, Dehn 
 and McGrath found 0.34 g. at 23.5® and 0,39 at 27°. Interpolation 
 of their results for 35® gives 0.368 g. per 100 cc,, which is in 
 close agreement with the above result. 
 
 Benzyl Arsine 
 
 This substance is described by Dehn, who obtained it 
 in the usual manner by the reduction of the arsonic acid with 
 amalgamated zinc and strong hydrochloric acid. In practice it 
 was found advisable to mix the benzyl arsenic acid with water, so 
 
' r 
 
 ^ ► p 
 
 li?i: 
 
 i € 
 
 A 
 
61 
 
 that the acid used ivould not he sufficiently strong to decompose it. 
 
 Preparation : In a flask provided with a mechanical stirrer and an 
 efficient hulhed reflux condenser were placed 100 g. of pure benzyl 
 
 ! 
 
 arsonic acid, 750 g. of amalgamated zinc dust, 500 co. of water and j 
 500 cc. of ether. This mixture was stirred vigorously and concen- ! 
 trated hydrochloric acid was allowed to run in slowly from a drop- 
 ping funnel, and ether was added from time to time to maintain the 
 original amount of about 500 cc, After two or tliree days the 
 ethereal layer was drawn off into a 350 cc, Claissen flask from 
 which it was distilled in portions. The residue consisted of 
 benzyl arsine and water, and was distilled under reduced pressure 
 in an atmosphere of nitrogen. Water first distills off and then 
 the benzyl arsine comes over as a clear white liquid, gradually 
 
 0 
 
 becoming yellow on standing. The boiling points observed were 95 
 at 30 mm,, and 90^ at 24 ram. Dehn reported 140^ at 360 ram. The 
 yield was 37 -^ g, which is 50“;^ of the theoretical amount . 
 
 Reaction with Benzaldehyde: 37|- g, of benzyl arsine was mixed 
 
 with 47 g. of benzaldehyde (3 moles) and a few drops of strong 
 hydrochloric acid. The mixture became quite warm and formed a 
 pasty mass. The latter was washed with dry ether, but only an 
 insoluble red product, benzaldehyde, and benzyl arsonic acid could 
 be identified in the mixture. A repetition of the reaction gave 
 the same results. 
 
 Substituted Benzyl Arsonic Acids 
 The instability of benzyl arsonic acid toward mineral 
 
 acids limits the reactions which can be applied to this substance 
 
or. !; j;. i r_ir 
 
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 a.nd therefor© it was decided to try certain substituted benzyl 
 halides in Meyer's reaction, to obtain the desired derivatives. 
 
 Experiments with ra-nitrobenzyl chloride, p-nitrobenzyl 
 chloride, diphenyl chloromethane, and 1-phenyl -1-bromoethane did 
 not lead to the desired ar sonic acids, but the halogenated benzyl 
 halides were found to give the corresponding halogenated benzyl 
 arsonic acids in good yields, 
 
 4-Chlorobenzyl Arsonic Acid 
 
 Preparation : p-Chlorobenzyl chloride was prepared by the action 
 
 of chlorine in the s'onlight on an excess of pure p-chlorotoluene, 
 heated to boiling. The product was purified by distillation under 
 atmospheric pressure and then in vacuo. The reaction was carried 
 out as described for benzyl arsenic acid, except that a 30*^ excess 
 of the sodium arsenite was used. The product separated out as a 
 mass of fluffy white crystals, in a yield of 60 per cent of the 
 thebretical amount. p-Chlorobenzyl arsonic acid may be crystal- 
 lized from water or dilute alcohol; it is quite soluble in hot 
 95^ alcohol and does not separate on cooling; it is insoluble in 
 ether and organic solvents, m.p, 184^. 
 
 Analysis: (Robertson* s method) 
 
 Subs. 0.3482, 0.2475 g. ; required 24.52, 34.23 cc 0,0808 N I. 
 
 Calc, for C^HgOjClAs: As = 29.92fo; Found: As = 29.93fn. 
 
 This acid is decomposed by warm mineral acids in the same way as 
 benzyl arsonic acid; with strong hydrochloric acid, p-chlorobenzyl 
 chloride is formed. 
 
63 
 
 2~Clilorobgnzyl Araonic Acid 
 
 In considering the preparation of the halogen substi- 
 tuted benzyl arsonic acids it was no'ied that the halogenated benzyl 
 bromides were more easily prepared than the chlorides, and since 
 the former react equally well with sodium arsenite, it was decided 
 to use them. A great deal of difficulty is experienced in handling 
 these substances since they are very powerful lachrymators, and to 
 avoid this a simplified method was employed. 
 
 General Procedure : One mole of the pure halogenated toluene was 
 heated to boiling in the sunlight, and slightly 5-ess than one mole 
 of bromine was slowly added through a dropping funnel. The reac- 
 tion mixture after addition of all of the bromine was allowed to 
 cool, and the product washed with ice water. This sometimes 
 caused the material to solidify. The water was separated by de- 
 cantation, and the washing repeated. The crude halogenated benzyl 
 bromide was then treated with a solution of 1,2 moles of sodium 
 arsenite, and boiled under reflux with good stirring. The heating 
 was continued for 6 to 8 hours, and the course of the reaction 
 followed by titration of saiKples of the solution from time to 
 time. The reaction is 60^ to 75^ complete after the time mentioned. 
 
 After cooling, the reaction mixture was extracted with 
 benzene to remove the oily layer and the alkaline solution was 
 treated with decolorizing charcoal and filtered. The clear fil- 
 trate on acidification with 20 % sulfuric acid* gave a white curdy 
 
 Sulfupio acid Is used 
 
 i n 
 
 p r e f 0 r e 
 
 nee 
 
 t o 
 
 hydr o« h 1 or 
 
 I c 
 
 acid, since a trace of t 
 
 h « 
 
 latter 
 
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 removed by 
 
 
 the washing, will cause 
 
 the 
 
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 laohrymat I 
 
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64 
 
 prscipit?Lte of the halogenated oensyl arsonic acid. 
 
 Preparation : Pure o-chlorotoluene waa converted to o-chlorohenzyl 
 bromide and reacted with sodium arsenite according to the general 
 directions. The reaction was 60^ complete after four hours, and 
 no appreciable decrease of iodine titration was observed after an 
 additional four hours heating. The o-chlorobenzyl arsonic acid 
 separated out as white crystalline flakes, which may be recrystal- 
 lized from water or dilute alcohol. From water it is obtained in 
 small whits plates, m,p, 157-158°. 
 
 Subs, 0.3008, 0.1970 g. required 17.98, 17.66 co.0.0892l N I 
 Calc, for CvHeOaClAs: As = 39.93f^. Found: 30. 00fo,30. 37fo. 
 
 4-Bromo benzyl Arsonic Acid 
 
 Preparation : Using p-bromotoluene as described in the general 
 procedure, the reaction of the p-bromobenzyl bromide with sodium 
 arsenita was observed to be 75^ complete after eight hours. The 
 p-bromobenzyl arsonic acid was obtained as beautiful white needles 
 from dilute alcohol; m.p, 173°-180°. 
 
 Subs, 0,2497, 0,2500 g, required 19.42, 19.50 cc. 0.0893 M I 
 Calc, for C-^HgOgBrAs: As = 25,42fo. Found: 25.46^, 25.53fo. 
 
 2-Bromo benzyl Arsonic Acid 
 
 Preparation : Starting with o-bromotoluene, the general procedure 
 was followed and the reaction between o-bromo benzyl bromide and 
 sodium arsenits was observed to be 66^ complete after eight hours. 
 The acid was obtained in the usual manner, and was purified by 
 recrystal iizat ion from dilute alcohol, from which it separated in 
 
( t i 
 
66 
 
 SUMMARY 
 
 A convenient method was fcimd for the preparation of 
 large quantities of henzyl arsenic acid, and an interesting ob- 
 servation was made on the melting point of this substance. 
 
 The products of the decomposition of benzyl arsenic 
 acid by heating were investigated and the following equations were 
 found to represent the reactions more accurately than any previous- 
 ly suggested: 
 
 
 
 3 CsHbCHsAsOsHs SCsHsCHaOH + AsgOg + H 2 O 
 
 3 CgHsCHgAsOsHg ■*- (CgH5CHg)20 + ASgOs + 3HgO 
 
 3 CeHsCHsAsOaHa -SCqHsCHO +As20a +AsxHa + 3 H 2 O 
 
 Benzyl arsine was condensed with benaaldehyde, but no 
 
 simple compound of the type, R-As(CHOH-R)^ , could be isolated 
 
 from the reaction mixture. Benzyl arsenic acid and an insoluble 
 
 red product were formed. 
 
 A simple method has been devised for the quantitative 
 determination of arsonic acids of the benzyl series, based on their 
 decomposition by hot aqueous sulfuric acid. 
 
 The follovtring halogen substituted benzyl arsonic acids 
 were prepared: 0- and p-chlorobenzyl arsenic acid, and 0- and p- 
 bromobenzyl arsonic acids. 
 
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67 
 
 BIBLIOGRAPHY 
 
 1. Frankel, "Arzneimittel-Synthsse", 5th Ed,, 19B1 p,699. j 
 
 2. Michaelia and Paetow, Ber.18, 41, (1885); Annalen 60 (1686). | 
 
 3. Mannheim, Annalen 308 (1905). Ii 
 
 4. Dehn and MoGrath, J. Am. Ohem. Soc. 347 (1906). | 
 
 5. Dehn, Am.Chem.J. 113 (1908). 
 
 6. Sachs and Kantorowicz, Bar, ^1, 2767 (1908). 
 
 7. Bert he im, Ber. 48, 350 (1915). 
 
 8. Adams and Palmer, J. Am. Ohem. Soc. 2375 (1920). 
 
 , C.S, Palmer, University of Illinois Thesis, 1921, 
 
 9. Unpublished research, C.S. Palmer. 
 
 10. J.L.Hall, University of Illinois Thesis, 1932. 
 
 Cf. A, J. Quick, University of Illinois Thesis, 1921, pp.57, SO. 
 
 11. Jones and Werner, J. Am. Chern. Soc. JD, 1257 (1918). 
 
 13. Quick and Adams, J. Am, Chem. Soc. _44, 805 (1922). 
 
 General References: 
 
 Bertheira, "Hand’buch der Organ! schen Arsenverbindungsn", 1913. 
 Morgan, "Organic Compounds of Arsenic and Antimony", 1918. 
 
1 
 
 i 
 
 J 
 
 Oi 
 
68 
 
 Vita 
 
 The writer was bom in Chicago, Illinois, on 
 August 9, 1900. He attended the Lincoln School in this 
 city from 1903-1913 and was graduated from the Lane Tech- 
 nical High School in 1916. He attended the Lane Junior 
 College during 1916 and 1917 and entered the University of 
 Illinois in 1917, He was graduated from the latter institu- 
 tion in 1919 with the degree of Bachelor of Science in Chem- 
 istry, and received the degree of Master of Science in 1990. 
 The following appointments were held in the University of 
 Illinois: 
 
 Graduate Assistant In Chemistry, 1919-1920. 
 
 Social Hygiene Board Fellow, 
 
 Carr Fellow in Chemistry, 
 
 1920- 1931. 
 
 1921- 1922.