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UBC Theses and Dissertations

Some intermediaries for the synthesis of [beta]-(-3-methoxy-4-hydroxy-phenyl)-[beta]-hydroxyethylamine.… Hamilton, John Kelvin 1947

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SOME INTERMEDIATES FOR THE SYNTHESIS OF  ft - ( - 3-METHOXY- 4- HYDROXY- PHEDTYL)-ft ~ HYDROXYETHYLAMIITS PART I by J. K e l v i n Hamilton A thesis submitted i n p a r t i a l f u l f i l l m e n t of the requirements f o r the degree of MASTER OF ARTS i n the Department of CHEMISTRY. The University of B r i t i s h Columbia A p r i l , 1947. • ABSTRACT on SOME INTERMEDIATES FOR THE SYNTHESIS OF ft - ( - 3-METHOXY- 4- HYDROXY- PHENYL) - ft -HYDROXYETHYLAMINE PART I by J. K e l v i n Hamilton In the f i r s t of three syntheses Y a n i l l i n i s eon-verted to benzoyl v a n i l l i c acid, then successively to the acyl chloride, cyanide with subsequent reduction to the amine. The second method involves the synthesis of v a n i l l i n cyanohy&rin followed by reduction to the amine. The t h i r d method involves the F r i e s rearrangement of guaiacol acetate followed by bromination. of the acetophen-one and conversion to the amine. ACOOWLEDGEMMT I would l i k e to express my sincere appreciation, to Dr. R; H. Clark f o r h i s invaluable assistance i n t h i s problem. To Dr* R, F. Patterson, of the Powell River Company Limited, also go my gra t e f u l thanks f o r carrying out the high pressure hylrogenations and f o r h e l p f u l suggestions. Thanks go also to Mr. R. Stewart, Mr. R. F. Robertson and Mr. R. W. A. Attree, my associate i n t h i s problem during the past eighteen months, who took part i n many discussions and offered constructive c r i t i c i s m s . FOREWORD Mr* Attree's thesis, i n which he describes h i s e f f o r t s to synthesize the same end product using d i f f e r e n t methods of approach, should be read p r i o r to or following the reading of t h i s thesis, i n order to obtain a cle a r and complete picture of a l l the syntheses c a r r i e d out i n the search f o r t h i s compound. TABLE OF CONTENTS Page Introduction 1 General discussion of Sympathomimetic Agents 1 The Beta phenethylamine skeleton 2 Discussion as to why t h i s compound should have Sympathomimetic properties 3 Reasons f o r high r e a c t i v i t y of V a n i l l i n 4 Mesomeric structure of V a n i l l i n 3 Resume of general methods employed i n t h i s type of research 6 Discussion of the three methods attempted i n this problem 9 Experimental 13 Equations f o r . a c y l cyanide method 13 Synthesis of V a n i l l i c acid 13 Benzoylation of V a n i l l i c acid 16 Synthesis of Benzoyl v a n i l l y l chloride 17 Attempted synthesis of Benzoyl V a n i l l y l cyanide using KCN 18 (b) using anhydrous HON 20 (o) using Hg(CN) 2 21 (cl) using AgCN 22 Equations f o r the Cyanohydrin synthesis (bottom) 22 Miscellaneous reductions of cyanohydrin 24 High pressure hydrogenation of cyanohydrin 23 Graphs of high pressure runs between pages 23 - 26 F r i e s Rearrangement 27 TABLE OF CONTEMIS (Cont'd.) Page Equations f o r F r i e s Rearrangement 28 Discussion of r e s u l t s 29 Conclusion 31 Suggestions f o r further research 32 Bibliography 33 SOME INTERMEDIATES FOR THE SYNTHESIS OF  ft - (-3-METHOXY-4-HYDROXY-PHENYL) -ft - HYDROXYETHYLAMINE INTRODUCTION This investigation, was an attempt to synthesize a compound whose structure was s i m i l a r to adrenaline. It was thought that by a v a r i a t i o n of some of the substituents i n the parent epinephrine (adrenaline) nucleus the toxic e f f e c t s could be lessened and the b e n e f i c i a l e f f e c t s raised, hence increasing the Therapeutic Ratio of the oompound. Barger and D a l e ^ ) showed that certain of these amines with the beta phenethylamine skeleton would cause e f f e c t s generally resembling those produced by stimulation of the so c a l l e d Sympathetic System of nerves. Hence came the name that i s commonly used f o r t h i s type of compound - "Sympathomimetic Agent",( 2) General Discussion of t h i s type of Compound The beta phenethylamine skeleton previously mentioned was early observed to be one of the minimal e s s e n t i a l require-ments f o r pressor a c t i v i t y . 2. -A-A <> P ^rvyl Noel Y , , ~ Q_ — — JSIN A m i n o 6ra»p I < t t k j l G t - . v p The most useful compounds known to-day possess t h i s skeleton and i t oan r e a d i l y be seen from the diagram that i n t h i s structure there are many p o s s i b i l i t i e s f o r su b s t i t u t i o n . (a) Three positions i n the phenyl nucleus with many combinations. (b) On the alpha and beta carbon atoms of the side chain. (c) On the amino nitrogen group. I t has been demonstrated that many substitutions may be made without destroying the Sympathomimetic properties. This i n i t s e l f i s very remarkable, f o r i n so many instances, a p h y s i o l o g i c a l l y active molecule does not permit much change without destroying i t s B i o l o g i c a l properties. When the desired end product of t h i s problem i s compared with epinephrine, ephedrine and benzedrine, i t i s re a d i l y seen that they do not d i f f e r widely i n structure. 0 E p i n e p h r i n e E-phaH^'nt i C H C H j I De.&ired P r o d u c t 2. Discussion as to why t h i s Compound should have  Sympathomimetic Properties In t h i s synthesis the substitution was confined to the metaO) po s i t i o n i n the phenyl nueleus and to the replace-able hydrogens on the amino group, the alpha and beta carbon atoms were l e f t as i n epinephrine. In the meta p o s i t i o n i n the r i n g the hydroxyl group of adrenaline has been replaced with a methoxy group, and i n the amino group the two hydrogens have been l e f t unsubstituted, whereas i n the epinephrine skeleton, one has been replaced with a methyl group. Experience has shown that i t i s the meta hydroxyl group i n epinephrine that i s re-sponsible f o r i t s great p h y s i o l o g i c a l a c t i v i t y , however f o r maximum pressor a c t i v i t y both the meta and the para hydroxyl groups should be present.( 2) The hydroxyl group present on the beta carbon atom decreased the t o x i c i t y and increases the pressor a c t i v i t y , thereby increasing the therapeutic r a t i o of the molecule. These b e n e f i c i a l e f f e c t s more than o f f s e t the detrimental effect on the physical properties of the molecule, such as a decrease i n s t a b i l i t y and a lowering of the vapour pressure. The exchanging of the active hydrogen of the amino group with a methyl group, as a rule, lowers the therapeutic r a t i o * however i t probably gives a c e r t a i n amount of s t a b i l i t y ( 2 ) to the structure. v The s t a r t i n g material i n nearly a l l of the attempted syntheses i n t h i s problem was v a n i l l i n - a bi-product of the pulp and paper industry. There were two reasons f o r t h i s , one,' v a n i l l i n as yet has no great commercial value and, secondly i t has the substituents i n i t s phenyl nucleus that are desired i n the f i n a l compound. In other experiments guaiacol was used f o r the same reason as was v a n i l l i n - namely the necessary substituents i n the phenyl, nucleus were already present. From the preceding discussion i t would be expected that the corres-ponding compound from i s o v a n i l l i n beta-(-3-hydroxy-4-methoxy-phenyl)-beta-hydroxyethylamine would perhaps be of greater therapeutic value than the compound attempted i n t h i s research - due to i t s meta hydroxyl group. C o m f u n J R e p o r t e d This compound from iso v a n i l l i n has been recently synthesized by two Russian workers. (3) The reason f o r the synthesis was not given so i t i s a matter of conjecture as to whether or not i t was f o r therapeutic use, however the t e s t i n g of t h i s com-pound f o r i t s Sympathomimetic A c t i v i t y should not be overlooked. Compovn^ desire. J Reasons For the High Reactivity of V a n i l l i n The v a n i l l i n nucleus i s very d i f f i c u l t to work with due to the fa c t that i t has a hydroxyl group para to the carbonyl group ^^C^^" that free hydroxyl groups attached to the benzene nucleus ( e x - v a n i l l i n , p. hydroxy benzaldehyde) have a retarding i n -fluence on oxidation of the aldehyde. The f a c t that v a n i l l i n does not undergo a Cannizzaro reaction bears t h i s out, Benzaldehyde undergoes t h i s simultaneous oxidation reduction r e a d i l y and meta hydroxy benzaldehyde undergoes the reaction at room temperature. I f , however, ortho or para hydroxyl groups are i n the r i n g no such reaction takes place. In the case of v a n i l l i n and other ortho or para substituted aldehydes t h i s may be due to the f a c t that they can perhaps exist i n another mesomeric form under the conditions of these reactions I f t h i s i s the case i t i s no longer an aldehyde and therefore i t s reactions would not be t y p i c a l of an aromatic aldehyde. when hydroxyl groups are ortho or para to the carbonyl group. (3»4) cLi-hydroxy benzaldehyde behaves l i k e p hydroxy benzalde-hyde, since the Cannizzaro reaction takes place when the meta hydroxyl group i s present, i t must be the addition of a second hydroxyl group i n the para p o s i t i o n i n t h i s compound which hinders the reaction. Therefore, v a n i l l i n and iso v a n i l l i n would be expected to react d i f f e r e n t l y and t h i s i s borne out experimentally. ( 8 ) V a n i l l i n with i t s hydroxyl group para to Thus the Cannizzaro reaction does not take place the carbonyl group, does not undergo the Cannizzaro reaction, whilst iso v a n i l l i n with i t s hydroxyl i n the meta p o s i t i o n and veratraldehyde - with no hydroxyls but two methoxyl groups do (9). I t i s evident then from the preceding discussion, that v a n i l l i n although often c l a s s i f i e d as a t y p i c a l aromatic aldehyde reacts a t y p i c a l l y ; i n f a c t , t y p i c a l reactions of v a n i l l i n are the exception rather than the r u l e . Many compounds of therapeutic value have been syn-thesized during the l a s t f o r t y years. Some have proved e f f i c a c i o u s whilst many of l e s s e r importance and perhaps some of prime importance have been excluded i n the screening procedure. The methods employed i n most cases by the research chemists were general synthetic procedures while others i n v o l -ved very ingenious and i n t r i c a t e mechanisms to get to the desired compounds. General Methods Employed i n t h i s type of Research A resume of the various methods that could be used i n synthesizing t h i s compound and that have been u t i l i z e d i n synthesizing similar compounds w i l l now be outlined. ( l ) The synthesis of the n i t r o styrene derivative from v a n i l l i n using nitromethane and methylamine following the method of Knoevenagel and Walther^^) and subsequent treatment of t h i s product by the method of Reichert and Koch^ 1 1)• CpHsOH R-- CH = CH - F 0 2 + B r 2 —*R - CHBrCHBrNOg » 5 RCH0HCHBrW02 7. K 0 H > R - C0CH 2N0 2 - H 2 + P t ° 2 v R.CH0H.CH2m2 CH3OH . i n C 2 H 5 O H ^ . * 1 mole (C00H) 2 ( 2 ) The beta hydroxy phenethylamine synthesis as outlined by B a l t z l y and Buck could also be u t i l i z e d , ^ 1 2 ^ the method of Kulz and Hornung also.^ 1^) (a) RCOCH3 B r 2 » R - COCH2Br (CH 2)6K4 ^ R C0CH 2HH 2 . PtO? H 2 RCH0H0H2NH2 (b) RCHO.+ BrCH2C00C2H5 • RCH0HCH2C00C2H3 . NHg.B"H2 ^  RCHOH. CH 2 . COTgH^ —MPj > JR.CHOH.CH200.N^ R - CH 'CH2 HCl + R.CHOH.CH2,NH2 1—0 —C-U-H u 0 (3) The synthesis of the oyanohydrin and subsequent re-duction has proved very successful f o r compounds of t h i s type. Arteronol, c l o s e l y a l l i e d to epinephrine has been made t h i s way by reduction of protocatechualdehyde cyanohydrin using sodium amalgam. 0-4»1J>) Modifications of t h i s synthesis are discussed i n (16). ( 4 ) The epinephrine synthesis of Nagai^ 1?) could be u t i l i z e d here by condensing acetyl v a n i l l i n with nitromethane and subsequent reduction using zinc and acetic acid i n the presence of formaldehyde. acetyl - R - CHO + CH^E02 9-lk,. „ R _ CH0HCH2NHCH5.HC1 (3) The synthesis of the acyl cyanide from the ac y l chloride and subsequent reduction i s a method that i s frequently used. There are many s l i g h t modifications to t h i s procedure 8. and these w i l l now be l i s t e d . The general equation f o r reduction i s R - C:OC:N + 3H 2 > RCH0HCH2NH2 The most obvious method i s tr e a t i n g the ac y l chloride with KCN and HCl i n ether sol u t i o n . (a) R.C:O.Cl • K C N — S S i ^ R . C : 0C:N - ( L 8 ) (b) A method involving a l i t t l e more technique but equally as good as (a) i s that of using anhydrous HOT. This was u t i l i z e d by Maunthner^ 1^) ± n synthesizing 3, 4, dimethoxy benzoyl cyanide from verat r o y l chloride. RC0C1 • HON Fy r 5 f t i n e * R.COCN • HCl Ether (e) Bearbitet, Rosenthal^ 2 0) and Vorlander^ 2 1) used mercuric cyanide to convert the acyl chloride to the cyanide. (d) S i l v e r cyanide has been used i n the conversion of the acyl chloride to the cyanide.^- 2 2'' (e) A. Maihle transformed acid chlorides into the corres-- ponding n i t r i l e s by means of an Al 2 03catalyst and gaseous ammonia at temperatures close to 300°C.t 25) (6) The F r i e s rearrangement has been used to give the corresponding omega haloacetyl guaiacol and t r e a t i n g t h i s with a primary a l i p h a t i c amine and subsequent reduction to secondary alcohol gives products of therapeutic value. This method i s used commercially i n the synthesis of a d r e n a l i n e . ( S e e 24, 23, 26, 27) A second method available f o r the synthesis of simi-l a r compounds i s the Friedel-Orafts reaction, i n which a phenol, or an ether of a phenol, i s condensed with an aci d chloride or an acid anhydride i n the presence of aluminum chloride. The s i x methods mentioned have a l l been used at one time or another to produce compounds that have been used therapeutically due to t h e i r p h y s i o l o g i c a l action. I n t h i s research the methods attempted were l i m i t e d to three, the acyl cyanide synthesis, the cyanohydrin and various modifications and l a s t l y the F r i e s rearrangement of guaiacol acetate. Mr. R. W. A. Attree has been attempting the synthesis of the same compound using the method of Reichert and Ko and also t r e a t i n g the a c y l chloride with diazomethane and reducing the product to a secondary alcohol. DISCUSSION OF THE THREE SYNTHESES ATTEMPTED The f i r s t one to be discussed i s the synthesis of the desired compound following the acyl cyanide method. The v a n i l l i n was oxidized to v a n i l l i c acid following the method of I. A. P e a r l ( 2 ^ ) . An attempt was made to synthesize the acyl chloride from the acid by using t h i o n y l chloride, however t h i s proved unsuccessful. The r e s u l t i n g compound was not soluble i n ten common solvents and did not melt when taken as high as 223°C. From these r e s u l t s i t was.thought that due to the f a c t that the p. hydroxyl group was not blocked, the com-pound could have polymerized as follows 10. The blocking of the p.hydroxyl group was next affected by benzoylation. This substance, benzoyl v a n i l l i c acid M.P.178 was f i r s t obtained by Tiemann and KrazC 2 ?) by oxidation of benzoyl eugenol. Heap and Robinson(30) modified the procedure somewhat and obtained the product by benzoylation of v a n i l l i c a c i d - M»P.l6l-l64 - i n y i e l d s of approximately 38.4%. Their method was followed i n t h i s laboratory and i t was found experimentally that by adding a large excess of benzoyl chloride the y i e l d could be greatly improved. When separating the benzoic a c i d from the benzoyl v a n i l l i c acid, i f the pH i s taken to 6.4, the amount of benzoic acid present i n the p r e c i p i t a t e i s p r a c t i c a l l y n e g l i g i b l e . Y i e l d s ran about 70%. The next step was the synthesis of the a c y l chloride. Heap and Robinson(30a) synthesized t h i s i n 1926 using phosphor-ous pentachloride, t h e i r y i e l d s ran approximately 87% however t h e i r method was very cumbersome. Thionyl chloride was found very successful to use when used i n excess. The y i e l d s were quantitative and no vacuum d i s t i l l a t i o n was necessary, (see experimental). The synthesis of the acyl cyanide from the ac y l chloride was next attempted. On tr e a t i n g with KCN and HCl following the general method of synthesizing cyanides(l8) and i s o l a t i n g the product, the M.P. was 94-97 while that of the acyl chloride i t s e l f i s 96-98°C. A reduction of t h i s product was attempted using sodium and absolute alcohol, however products were not characterized. An attempted p u r i f i c a t i o n of 11. the end product of one of these runs ended i n probable dimer-i z a t i o n of the product. The p r e c i p i t a t e went from white to dark grey on heating i n a solvent of L i g r o i n - M.P. of o r i g i n a l 94-97°C- of f i n a l l 6 0°C. The above synthesis was duplicated many times, how-ever no two reactions were ever i d e n t i c a l , conditions and concentrations and order of addition of reactants were varied but a test f o r chlorine was always obtained. On one occasion when the KCN was added to the ether solution of the chloride p r i o r to the addition of the HCl, the reaction medium took on a b e a u t i f u l royal purple col o r a t i o n . This was never noted before nor since and may have been due to a quinone structure following hydrolysis of benzoyl group. However as the solution i s basic due to the hydrolysis of KCTT, i t would not occur as a tautomer but as a mesomer with a migration of an electron. 12 The same synthesis was tried, using HOT i n place of KCH. The HON was synthesized under conditions such that i t was anhydrous.(19) Two runs were made. In the f i r s t , g a s i n exeess was bubbled into a pyridine ether solution of the chloride with no r e s u l t . On the second run approximately ljj cc. anhydrous HCF l i q u i d (excess) were c o l l e c t e d and slowly bubbled into the solution of the acyl chloride i n pyridine . The r e s u l t i n g product had a melting point of l67°C. I t tested f o r C l 2 and gave no test f o r B^. Again following procedures used f o r the synthesis of a c y l cyanides - H g ( C W ) ^ 2 0 * a n d AgCK( 2 2) were used i n di f f e r e n t reactions. In the Hg(CN)2 synthesis the end product had a M.P. 88-96° and gave a p o s i t i v e t e s t f o r chlorine and a negative test f o r nitrogen. I t was probably the aci d chloride M.P. 96-98°. A s i m i l a r synthesis using AgCN was attempted -but products although sweet smelling, which i s t y p i c a l of cyanides, were impure and on r e p u r i f i c a t i o n non c r y s t a l l i z a b l e resins were obtained. The second synthesis that was attempted i n t h i s i n v e s t i g a t i o n w i l l now be discussed. This method i s perhaps the most obvious, however, i t . i s not as simple as i t appears on paper due to the d i f f i c u l t i e s one encounters on reduction. V a n i l l i n apparently does not react t y p i c a l l y with NaHSO^^ 2) however when i t i s dissolved i n NaHSO^ i t does under-go a reaction with KCU to give the cyanohydrin(1-5) • The re-duction of t h i s compound has been t r i e d by many methods, none of which have been successful thus f a r . Hydrogen was bubbled 13. into a solution of the cyanohydrin i n g l a o i a l acetic a c i d using Pt as the catalyst, however the product was non characterizable due to the fac t that i t was a black purple r e s i n . Absolute alcohol and meta l l i c sodium and 2$ sodium amalgam have been t r i e d without success. F i n a l l y an attempt was made to reduce t h i s compound to the desired end product using high pressure hydrogen and Raney n i c k e l c a t a l y s t . The graphs are included and a discus-sion of the procedure employed i n the experimental section. In the hydrogenation of 3(0^0) 4(0H) C^H4CH0HOT there are many d i f f i c u l t i e s to contend with. According to (32) H. Adkins cyanides are hydrogenated to primary amines over n i c k e l c a t a l y s t s . The preferred temperature range i s 100 -13© 0C. An important side reaction i n the hydrogenation of cyanides and oximes i s the formation of secondary amines. They are apparently formed as the re s u l t of the i n t e r a c t i o n of an immine with the primary amine. (23) R.C5N * H 2 » R.CH:NH + H 2 » R.CH2NH2 R.CHtNH * R.CH2]JH2 • R.CH.NH.CH2R • H 2 ^ fc2 R.CH2.UHCH2.R * HH3 < ±^ 2 R.CHs-IT.CHfc.R • HH3 The best method of minimizing the formation of secondary amines i s to carry out the hydrogenation as rap i d l y as possi b l e . This i s accomplished by using cyanide completely free of halogen, a r e l a t i v e l y high r a t i o of catalyst and a temperature and pressure s u f f i c i e n t l y high to bring abput reaction within an hour or two. 14. A new method f o r the reduction of n i t r i l e s was reported i n December 1946,(^4) using l i t h i u m aluminum hydride. It has been successfully used to reduce a r y l n i t r o compounds to the corresponding azo derivatives and n i t r i l e s to amines. The reduction i s noted f o r i t s cleanness and the f a c t that i t may be c a r r i e d out i n ether solution at room temperature with high y i e l d s i s also another point i n i t s favor. I t was thought that by benzoylating both the phenolic and secondary a l c o h o l i c hydroxyl groups^^) reduction could be f a c i l i t a t e d more r e a d i l y , and the blocking groups could e a s i l y be removed by hydrolysis. This method was not successful, f o r the products i s o l a t e d were either o i l s or putty l i k e masses -which a f t e r six months had not c r y s t a l l i z e d . The t h i r d method attempted was that of the F r i e s rearrangement of acetyl guaiacol and c h l o r a c e t y l guaiacol. This reaction consists i n the conversion of an ester of a phenol to an ortho or para hydroxyketonej or a mixture of both by treatment with aluminum chloride. As mentioned previously, the F r i e d a l - C r a f t s reaction can also be employed to synthesize s i m i l a r compounds, however, despite the f a c t that the F r i e s reaction requires two steps - the preparation of the ester and the rearrangement to the hydroxyketone - as compared to the single step i n the F r i e d a l - C r a f t s synthesis, the F r i e s method i s u s u a l ly preferred f o r the preparation of phenolic ketones The y i e l d s are o r d i n a r i l y better and the experimental procedure does not have to be modified greatly to adapt i t to a v a r i e t y of esters. 15. EXPERIMENTAL Synthesis Number 1. The acyl cyanide method. f S * ^ / ^ • soc/,. —* <f-|*\_J>«-"-«J CWtc. i, o C H , « , e t» ' HCM o \ 7 Step 1. The preparation of the v a n i l l i c acid following the method of I. A. Pearl^ 2?) w a s c a r r i e d out. 30.4 gms. (.2 moles) of v a n i l l i n were added with vigorous s t i r r i n g to 400 cc. HgO i n which were dissolved 48 gms. (1.2 moles) of NaOH. The r e s u l t i n g solution was heated to 55°C. With continued a g i t a t i o n a solution of 34 gms. (.2 moles) AgN03 i n 130 cc. H^ O - at a temperature of 55°C were added a l l at once. Both solutions were at a temperature . - 16. of j>5°C when the AgNO^ was added. Outside heat was applied u n t i l the temperature was 63°(ll) when the reaction went spontaneously and the temperature rose to 75°(il)C. The reaction mixture was then f i l t e r e d to remove the free Ag° and the f i l t r a t e a c i d i f i e d by bubbling i n S0 2 u n t i l the v a n i l l i c a cid p r e c i p i t a t e d . The acid was f i l t e r e d , washed, d r i e d -M.P. 210-11°C. It was found experimentally that i f too much water was added i n d i s s o l v i n g either the NaOH or the AgNOj, the v a n i l l i c acid did not p r e c i p i t a t e on n e u t r a l i z a t i o n with S0 2 but went a deep purple color g i v i n g the i n d i c a t i o n that perr- > haps n i t r o v a n i l l i c acid was the main product. I t was also found that i f the NaOH was not pure (Na2C0^) or had absorbed H 20 and the concentration i n the reacting medium was too low, the temperature would have to be raised to 80-90°C before the reaction would commence* The v a n i l l i c a c i d obtained from these reactions was never as pure as when the reaction took place at a lower temperature. Pearl stated that the reaction went spontaneously at j>5°C and that the y i e l d s were quantitative however these re s u l t s were never duplicated i n t h i s laboratory. Step 2. The method employed i n the benzoylation of the v a n i l -l i c acid was as follows: 24 gms NaOH were dissolved i n 400 cc. H 20 and to t h i s were added 25 gms of v a n i l l i c acid* Bensoyl chloride - 38.4 gms (32cc) was added ' and the mixture s t i r r e d mechanically f o r 40 minutes, while kept i n an i c e bath. At the end of t h i s time the mixture was a white s o l i d . Upon warming to room 17-temperature t h i s went into solution. The pH at t h i s point was 10.5. This was taken to 6.6 using 6JSHC1 - where a d u l l gray p r e c i p i t a t e formed. This was f i l t e r e d , and the f i l t r a t e was a c i d i f i e d s t i l l more, to pH 6.5 - where a voluminous p r e c i p i t a t i o n occurred. This was f i l t e r e d o f f and more HCl added and a t h i r d p r e c i p i t a t e formed at pH 6;4. The f i r s t p r e c i p i t a t e was washed with 4 x 100 cc. b o i l i n g H20, dried and weighed. The second and t h i r d p r e c i -p i t a t e s were combined and added to 500 cc. b o i l i n g H20 -f i l t e r e d - dried - weighed. Wt. of Ppte. I - 4.5 gms. - ppted © pH 6.6 - M.P. - 162-66°C uncorrected - Theoretical - 161-4. Wt. of Ppte.II (2nd and 3rd; - 24 gms - ppted O pH 6.5-6.4 -M.P. - 160-65°C - uncorrected. Total weight - 28.5 gms. Theoretical - 40.5 gms. i Y i e l d - 70.35% Yields as high and higher than t h i s have been d u p l i -cated by Mr. R. W. A* Attree i n t h i s laboratory.. Step 3. Conversion of the benzoyl v a n i l l i c acid to benzoyl v a n i l l y l chloride. The t h i o n y l chloride used i n t h i s preparation was p u r i f i e d following the general manner from quinoline and then from linseed oil(35) # 20 grams p u r i f i e d t h i o n y l chloride were added to 10 grams benzoyl v a n i l l i c acid and the mixture slowly refluxed u n t i l solution occurred, and then f o r 10 minutes more. The 18 f l a s k was allowed to oool s l i g h t l y and then 40 cc. L i g r o i n were added and the mixture refluxed f o r 5 minutes, then transferred to a beaker and cooled i n a mixture of dry ice and alcohol, whereupon the benzoyl v a n i l l y l chloride c r y s t a l l i z e d ,- was f i l t e r e d - dried - weighed. Y i e l d 1 0 . 2 gms. or 9 5 • 2 % - mother l i q u o r was not evaporated so y i e l d s are probably quantitative. Step 4. Synthesis of benzoyl v a n i l l y l cyanide from benzoyl v a n i l l y l chloride. (a) ( i ) using KCT and HCl. • 7 5 gms. of benzoyl v a n i l l y l chloride were dissolved i n 8 cc. ethyl ether and . 5 gms. KCW dissolved i n 4 cc. HgO added. To t h i s , l cc. concentrated HCl was also added. The f l a s k was stoppered and vigorously shaken f o r 2 5 minutes, keeping the solution cool a l l the while. The ether l a y e r was then separated and on evaporation a white c r y s t a l l i n e product was obtained. This product was dried i n vacuo. Y i e l d . 7 0 gms. or 9 6 . 5 % . M.P. 9 5 0 - 9 7°C - uncorrected. Reduction of t h i s product was attempted using metal-l i c sodium and absolute ether, however no products were i s o l a t e d . ( i i ) The above synthesis was repeated using 1 0 gms. of the acyl chloride and 4 . 5 gms. KCH. Y i e l d 9 gms. or 9 3 % - M.P. 88 - 9 3°C. uncorrected. As the range of the melting point was so great i t was decided to p u r i f y the product. To the 9 gms. of supposed cyanide, 1 0 0 cc. L i g r o i n were added and the mixture heated to b o i l i n g when suddenly the yellow white c r y s t a l l i n e material 19. darkened, momentarily became a dark colored o i l and then s e t t l e d out i n f i n e gray black c r y s t a l s . This was f i l t e r e d , d r i e d - M.P. l60°C ( s t a r t s to decompose). This product may be a dimer. ( i i i ) Synthesis ( i ) was repeated, however on t h i s occasion the reaction mixture took on a deep purple coloration, which was found to be present i n the water layer, the ether layer being c o l o r l e s s . On evaporation and c r y s t a l l i z a t i o n from the ether l a y e r an impure product was obtained - M.P. 36-72°C. An attempt was made to p u r i f y t h i s product, however t h i s was unsuccessful and the material remained as a heavy thick orange r e s i n which did not c r y s t a l l i z e on standing. The water l a y e r on standing, became cloudy and had a brown p r e c i p i t a t e i n i t s i m i l a r to HCN polymers. (iv) The synthesis was repeated using 4 gms. of the acyl chloride the only difference between t h i s method and i , i i and i i i i s that the HCl was added p r i o r to the addition of the KOT solution. The mixture was worked up as usual and the white c r y s t a l s obtained were dried. M.P. 91-94°C uncorrected. Qualitative Analysis - Ho B 2 - Clg present. Microscopic analysis of the c r y s t a l s of the acyl chloride and the supposed acyl cyanide were very s i m i l a r . I t i s w e l l within the realm of p r o b a b i l i t y that the reaction did not go and the a c y l chloride was obtained back again i n a s l i g h t l y impure form as indicated by the melting point and the qualitative, analysis. (b) Reaction of benzoyl v a n i l l y l chloride with anhydrous HOT. 20. The HON was prepared by t r e a t i n g KGB with 18BT H 2S0 4 (following Method i n Partington)(26). KCN + H 2S0 4 — * KHS0 4 * HON It was dried by passing over C a C l 2 and PgO^* (i ) 4.1 gms. of benzoyl v a n i l l y l chloride were taken into solution using 150 cc. of absolute ether. The HCN produced was condensed i n a f l a s k , secured, and then using a very low flame was evaporated slowly and bubbled into the chloride ether solution. This solution was s t i r r e d mechanically and kept (anhydrous) free from the atmosphere by use of a mercury seal and a C a C l 2 drying tube. The f l a s k i t s e l f was immersed s i n i c e water. The t o t a l time f o r the reaction was 35 minutes. The r e s u l t i n g ethereal solution was evaporated to a small volume and on cooling white c r y s t a l s formed - dried - M.P. 94-97°C» Qualitative Analysis - C l 2 present U 2 absent. ( i i ) The above procedure was duplicated except that i n place of 150 cc. absolute ether, 75 cc. absolute ether and 75 cc* anhydrous pyridine were used. A word of caution i s opportune at t h i s point. Traps were always set up on either side of the reaction f l a s k and they were necessary i n both runs. There i s a heat of reaction i n the HCTT generator and when i t cools down a p a r t i a l vacuum i s set up - sucking back the contents of the Reaction f l a s k and on one occasion the mercury from the mercury s e a l . The reaction mixture was d i s t i l l e d i n vacuo at 16 mm. t i l l bumping commenced, then the mixture was allowed to cool and a f i n e white c r y s t a l l i n e p r e c i p i t a t e s e t t l e d out. This • • • • - 21. was f i l t e r e d , and on exposure to the a i r was found to sublime, i t was probably pyridine hydrochloride* On allowing the mother l i q u o r to evaporate a yellow p r e c i p i t a t e formed. This was dissolved i n 100 cc. ether and shaken with R"20, f i r s t 100 cc. then two portions of 50 cc. each, i n order to remove impurities such as pyridine hydro-chloride. The ether layer was then evaporated and a white c r y s t a l l i n e p r e c i p i t a t e obtained. This was dried - M.P. 168-170°C. uncorrected. Qualitative Analysis No G l 2 - No N 2. (c) Reaction of benzoyl v a n i l l y l chloride with Hg(CN) 2. The Hg(CN) 2 was synthesized according to the method of Rupp and Gay^ 4 0^. ( i ) 2.9 gms. of benzoyl v a n i l l y l chloride and 2.6 gms. of Hg(CN) 2 were intimately mixed and placed i n a reaction f l a s k f i t t e d with a C a C l 2 drying tube. The reaction f l a s k was kept i n a H2SO4 bath and shaken frequently while the temperature was slowly raised to 135°C where i t was held f o r 30 minutes. The f l a s k was then cooled and a gray p r e c i p i t a t e was l e f t on the bottom with a dark viscous o i l on top of i t . This material was extracted with ether using 25, 15, 10, 10 cc. portions. A great deal of the material was i n s o l u b l e . The ether extract was evaporated and on cooling gave a yellow orange p r e c i p i t a t e . This i n turn was extracted with petroleum ether (benzine) i n which the Hg(CN) 2 i s insoluble. On concentrating the benzine solution and cooling, a white c r y s t a l l i n e p r e c i p i t a t e was obtained. This was f i l t e r e d and dried. M.P. 88-90°C -uncorrected. Qualitative analysis - C l 2 present, N 2 absent. (&) Reaction of benzoyl v a n i l l y l chloride and AgCF. The AgCH used i n t h i s experiment was made following the method outlined i n Partington.(3&) ( i ) 3 gms. of benzoyl v a n i l l y l chloride and 2 gms. AgCN (excess) were mixed intimately and heated slowly u n t i l the entire mass went into solution. This was refluxed gently f o r 30 minutes and on cooling formed a dark s o l i d mass. This was extracted with 100 ml. of ether. The ethereal s o l u t i o n took on a deep yellow coloration and had some s o l i d material j suspended i n i t , t h i s was f i l t e r e d out. The ether was removed and the r e s u l t i n g product was a viscous dark orange o i l , which refused to c r y s t a l l i z e . The material had a very sweet smell that has been noted before. I t was l e f t i n the r e f r i g e r a t o r f o r three weeks when i t was noted that p a r t i a l c r y s t a l l i z a t i o n had taken place; The entire mass was extracted with alcohol, however, only a small portion went into solution, the r e s t remaining as an insoluble red brown amorphous mass M.P. 63-103 C. The a l c o h o l i c extract was evaporated to a small volume and cooled, whereupon a dark brown amorphous mass, sim i l a r to the above, p r e c i p i t a t e d out. This was f i l t e r e d , dried, M.P. 63-83°C. Re p u r i f i c a t i o n proved of no assistance as the material s t i l l remained i n a non c r y s t a l l i n e semi s o l i d state. 23. Synthesis Number 2. The Cyanohydrin Synthesis. The synthesis of 3 nethoxy 4 hydroxy mandelonitrile was c a r r i e d out following the method of Buck, ("^ t 38) A reduction of t h i s compound was attempted using Platinum as the c a t a l y s t , g l a c i a l a c e tic a c i d as the solvent and hydrogen. The hydrogen was bubbled i n f o r eight hours, however, on extracting and p u r i f y i n g , the only r e s u l t was a dark viscous semi s o l i d material highly reminiscent of a polymer. The reduction was also attempted using absolute alcohol and m e t a l l i c sodium (Mendius Reaction). 1.02 gms. of the mandelonitrile were dissolved i n 50 cc. absolute ethanol and m e t a l l i c sodium was added i n small amounts. At f i r s t the solution took on a pink coloration, however, on the addition of more sodium t h i s cleared up and the solution became cloudy, more sodium was added and the reaction allowed to proceed f o r approximately 40 minutes when a white p r e c i p i t a t e s e t t l e d out. The p r e c i p i t a t e was thrown down completely by centrifugation and the supernatant a l c o h o l i c solution was pipetted o f f and the white p r e c i p i t a t e was f i l -tered out. The p r e c i p i t a t e was tested by i g n i t i o n f o r sodium but r e s u l t s were inconclusive. On t e s t i n g with HNOg f o r a primary amine, the r e s u l t s were also inconclusive. The p r e c i p i t a t e on treatment with 6NH2SO4 formed into white c r y s t a l s . M.P. of compound - 82.5 - 83.0 M.P. of cyanohydrin- 830 24. M.P. of v a n i l l i n - 81° The above r e s u l t s show that the compound probably i s a mixture of the cyanohydrin and. v a n i l l i n i t s e l f , as a strong odour of v a n i l l i n was noted at t h i s point. The reduction was again attempted using m e t a l l i c sodium and absolute ethanol. Product on t h i s occasion was a dark viscous mass i n d i c a t i n g probable HCH polymers. Sodium and absolute amyl aloohol was also t r i e d as a reducing agent, however t h i s did not prove anymore successful. Reduction, using a 27. sodium amalgam and absolute ethanol was t r i e d . On treating the r e s u l t i n g p r e c i p i t a t e with 6HH2SO4 a moderate reaction took place and a yellow o i l was formed which on cooling gave a pale yellow s o l i d . The c r y s t a l structure and odour of t h i s compound were highly c h a r a c t e r i s t i c of v a n i l l i n . I t was thought that i f the secondary a l c o h o l i c hydroxyl group and the phenolic hydroxyl group were both blocked the compound could be hydrogenated more'readily and without so much danger of the side chain being completely reduced. These syntheses did not prove s a t i s f a c t o r y . The d i a c e t y l derivative of the cyanohydrin could not be i s o l a t e d so the d i benzoyl d e r i v a t i v e was attempted following the * method of Aloy and Robout.^ 1^ Their procedure was followed exactly but on each occasion the end product was an uncrys-t a l l i z a b l e o i l , or at l e a s t on standing s i x months f a i l e d to c r y s t a l l i z e . The only product that was ever i s o l a t e d i n 23. voluminous quantities and i n pure form was benzoic a c i d . This procedure was t r i e d many times, successful r e s u l t s were never obtained so the idea was discarded. The reduction of the 3 methoxy 4 hydroxy mandeloni-t r i l e was next attempted using high pressure hydrogen and Raney n i c k e l . The reduction was carried out by Dr. R. A. Patterson and his co-workers at the research laboratory of the Powell River Company Limited, Powell River, B. C. 16 gms. of the mandelonitrile were sent up i n 620 cc. of 93% ethanol. £ of t h i s solution was hydrogenated under the conditions given on data sheet No.(l).. The Raney n i c k e l catalyst used was f r e s h l y prepared and i t s a c t i v i t y tested by the hydrogenation of 2 moles of acetone to isopropanol. Fo decrease i n pressure was noted during the hydrogenation of the mandelonitrile, nor d i d any decrease i n the calculated number of moles of hydrogen take place. This cHd not necessarily indicate that no hydrogenation had occurred. In the f i r s t place the vapor pressure of the ethanol had not been taken into consideration; secondly, the t o t a l hydrogen absorption required t h e o r e t i c a l l y was very small and the pressure gauge was not extremely sensitive, and f i n a l l y , the l i b e r a t e d ammonia would tend to minimize the observable pressure l o s s * The hydrogenation of cyanides over n i c k e l almost always gives r i s e to some secondary amines and ammonia so that the smell of ammonia i n the hydrogenated produet was expected and was noted. mm .15 -5o IS t-2-5 I S * \JS Z.oo Z.lS ISO 2.7s- 3.00 26. The remaining •£• of the solution was hydrogenated under the conditions given on the hydrogenation data sheet Mb. 2. In order to reduce to as low as possible the. formation of a secondary amine, the bomb and contents- were heated to 50°C before the admission of the high pressure hydrogen. In th i s way the low temperature hydrogenation was reduced some-what. The temperature was kept somewhat lower and the time of hydrogenation shorter than i n run No. 1. Refractive Indices - O r i g i n a l s o l u t i o n 1.3713 Hydrogenation No.l - I.3683 Hydrogenation No.2 - 1.3678 On comparing the r e f r a c t i v e indices i t i s quite evident that something took place during the hydrogenation. Assuming the formation of both primary and secondary amine, the solution may now contain the s t a r t i n g material (assuming t h i s to have been pure) and both the amines, The problem now beeomes one of separation of these two constituents. The best method of separation i n t h i s case i s prob-ably that of Hinsberg. This separation i s based on the fac t tha that primary aromatic amines react with para toluenesulphonyl chloride to form an inner s a l t or Zwitter ion which i s soluble i n NaOH - whereas the secondary amine, having no active hydro-gen, i s unable to form t h i s type of s a l t and i s therefore insoluble i n NaOH. This problem i s at a s t a n d s t i l l at present due to the fac t that no para toluenesulphonyl chloride i s available i n the department. The material has been ordered and when i t arrives the problem w i l l be immediately continued. 27 Synthesis Number 3. Fr i e s Rearrangement. The t h i r d method attempted i n the synthesis of beta - (-3-methoxy-4-hydroxy-phenyl)-beta-hydroxyethylamine was the F r i e s Rearrangement using guaiacol as the s t a r t i n g material.O-3,24,25,26,27) Step 1. Synthesis of chloracetyl guaiacol following the Schotten Baumann method. (a) 4 gms. NaOH were dissolved i n 100 cc. H20 and to th i s was added 12.4 gms. guaiacol. The chloracetyl chloride was next added with vigorous s t i r r i n g and an orange o i l separated out, t h i s c r y s t a l l i z e d on cooling. The product was p u r i f i e d from hot ethanol and the r e s u l t i n g product dried. M.P. 36-39°C-uncorrected. Theoretical - 38-39°C. (b) Attempted F r i e s Rearrangement of the chlo r a c e t y l guaiacol following procedures outlined i n Organic Reactions, Volume I.^ 2 6) The acyl guaiacols have been frequently rearranged using t h i s method to give the corresponding acetophenones and i t was thought that the chloracetyl guaiacol would re-arrange s i m i l a r l y to give the omega chloroacetophenone. This i s the case i n the commercial adrenaline synthesis where catechol and chloracetyl chloride are rearranged.in the presence of POCl^ to give the corresponding omega chloroacetophenone. The conditions followed i n t h i s were those giving the maximum y i e l d of the para isomer.. 28. j> gms. of chloracetyl guaiacol were dissolved i n 25 gms. of nitrobenzene. To t h i s was added 6.7 gms. of 1 anhydrous A l C l ^ . The mixture was shaken f o r one hour and l e f t standing f o r twenty-four hours. The solution was next extracted with ether and the ethereal solu t i o n shaken up with d i l u t e NaOH. The NaOH solution was a c i d i f i e d with H 2S0 4 - but with no r e s u l t - no p r e c i p i t a t e s e t t l e d out even on strong cooling. I t was decided that a more c e r t a i n method would be to synthesize the acetyl guaiacol and rearrange i t and then treat the aeetovanillone with B r 2 to give the corresponding omega bromoacetophenone. Guaiacol acetate was synthesized using the Schotten Baumann method. The procedure was the same as the above with the exception that acetyl chloride was used i n place of chloracetyl chloride. The product t h i s time was an impure o i l which was f r a c t i o n a l l y d i s t i l l e d i n vacuo at 12 mm. The f r a c t i o n that came over between 106-112°C. at 12 mm. was taken as pure. Guaiacol acetate B.P. @ 760 mm. - 241-5°C - 12 mm.l24-5°C Guaiacol B.P. & 76O mm. - 205°C - 24 '» 106°C. A rearrangement of thi s compound i s under way at the present time and the following equations outline the procedure to be followed to a t t a i n the desired end product. , 2? DISCUSSION OF RESULTS The r e s u l t s of t h i s research have not been very g r a t i f y i n g . This i s probably due i n part, to the lack of experience on the part of the research worker and also i n part to the fa c t that v a n i l l i n i s not the easiest material with which to deal. The presence of the hydroxyl group para to the carbonyl group makes t h i s s t a r t i n g material highly reactive and gives unpredictable r e s u l t s i n t y p i c a l reactions. In the f i r s t synthesis, the conversion of the acyl chloride to the acyl cyanide was never found to be successful. Many references are* given i n the l i t e r a t u r e to the reactions of a c y l chlorides with KCN, HON, Hg(CN) 2 and AgCN, using compounds very s i m i l a r to v a n i l l i n . In t h i s research, however, no product was ever i s o l a t e d that gave a d e f i n i t e test f o r nitrogen and a negative test f o r chlorine. This may have been due to f a u l t y technique because on the face of i t there i s no reason why the benzoyl v a n i l l y l chloride should not be con-verted into the corresponding cyanide, unless of course, i t i s thermodynamically impossible. In a l l of these syntheses the reactions were duplicated and the conditions were followed as c l o s e l y as possible to those outlined f o r s i m i l a r syntheses of a c y l cyanides. Unless the acyl cyanide has a melting point close to that of the chloride, which i s u n l i k e l y , i t would be reasonable to say that the above reaction does not take place, at l e a s t not under the conditions that have been t r i e d i n t h i s 30. laboratory. Thermodynamically the reaction probably goes re a d i l y , however the conditions necessary may be highly s p e c i f i c . The second method attempted i s undoubtedly the most obvious of the three, however i t i s not as simple as i t appears on paper due to the d i f f i c u l t i e s encountered on reduction. This same method was used i n the synthesis of the corresponding compound from i s o - v a n i l l i n ^ ) . Reductions t r i e d thus f a r have proven unsuccessful due to the f a c t that either the end products were non i s o l a t a b l e or were highly reminiscent of v a n i l l i n , the s t a r t i n g material. The end products of the high pressure, hydrogenation have not yet been i s o l a t e d and characterized, but i t appears that t h i s reaction has proceeded p a r t i a l l y , at l e a s t , i f the indices of r e f r a c t i o n are any c r i t e r i a . The l a s t method attempted i s r e a l l y only i n i t s i n i t i a l phases and very l i t t l e can be said at t h i s time as to' whether or not i t i s going to be successful. The actual re-arrangement should not prove too d i f f i c u l t , the main problem w i l l l i e i n the conversion of the rearranged product to the primary amine and subsequent reduction. 31. CONCLUSION None of the three methods attempted has been , followed through to a successful conclusion. The f i r s t , a s i x step synthesis, was halted when a l l attempts to make the a c y l cyanide ended i n dismal f a i l u r e . The second method, a two step synthesis, i s nearing completion and i s probably the method that w i l l f i n a l l y succeed. The main hindrance i s the lack of high pressure equipment i n the chemistry department. Method number three, i s quite possible but here again we have a long synthesis, six steps, which i s always a hindrance. 32 SUGGESTIONS FOR FURTHER RESEARCH Investigations should be continued on the synthesis of the acyl cyanide with c a r e f u l attention paid to the temperature of the reaction, which should be kept i n the neighbourhood of zero degrees and also to the time f o r which the reaction i s allowed to proceed. The methods employing KCN and HCN are the easiest with which to work and should give the highest y i e l d s . In the case of the cyanohydrin, the reduction using Palladium should be attempted. Platinum was used i n t h i s work due to the f a c t that palladium was unavailable at the time. The high pressure work should also be continued i f at a l l possible, as t h i s i s the cleanest and surest way to reduce the cyanohydrin. The investigation employing the F r i e s Rearrangement should be continued. The s t a r t i n g material i n t h i s synthesis i s guaiacol whereas i n the other two syntheses i t i s v a n i l l i n . Thus, i f the desired end product i s i s o l a t e d using t h i s procedure, i t w i l l provide a means of i d e n t i f i c a t i o n , and also serve as a check as to the physical and chemical properties, provided of course, that either method one or two i s successful. 33. BIBLIOGRAPHY 1. 2. 3. 4. 3. 6. 7. 8. Chemistry of the Simpler Bases, Barger and. Dale. Ind u s t r i a l and Engineering Chemistry, 37 #2, 126, 1943(Eeb) % • — A. I. Vinogradova and V. N. Arkhangel'skaya, Chem. Abstracts 41, 425, 1947 also J . Gen. Chem.(TT.S.S.R.) Staudinger and Kon, Staudinger, Kene, Prodrom Baeyer and V i l l i g e r Ann., 384,58,1911. Ber., 46,3530,1913. Ber., 31,1569,1900. Private communication, Dr. R. A. Patterson, Powell River Company Ltd., Feb .(l947). (a) Organic Reactions (b) Hibbert, H. (c) Hibbert, H. and G.H. Tomlinson (d) i b i d (e) i b i d 9. Lock 10. Khoevenagel and Walther 11. Reichert and Koch 12. B a l t z l y and Buck 13. Kulz and Hornung 14. 15. Buck 16. Aloy and Robout 17. Nagai, W.N. 18. Francis and Nernstein 19. Maunthner Vol.II,R.Adams,page 105. Can.Jour•Re searoh J.A.CS.,58,345,1936 56,348,1936 58,340,1936 Ber., 62,1177,1929. Ber., 12»4306,1904. Ber., _68,B,445,1935. J.A.C.S.,62,164,1940. C. A., 3i,3011,1942 (Ger. 682,394,1939. D. R.P. 193,634. J.A.C.S., 2i»3388,1933. Bull.Chim.de France (4) 11,390,1912. CA., 16,990,1922. U.S.,~T,399,144. Ann., 582,204,1911. Ber., 42,192,1909. 34. BIBLIOGRAPHY (Cont'd) 20. Barbitet and Rosenthal, L. Ber., 44,2463,1911. 21. Vorlander 22. Anschutz, R. 23. Maihle, A. 24. Reichstein 25. Rosemund and Lohfert 26. Organic Reactions 27. Coulthard, Marshall and Pyman 28. Pearl,I.A. 29. Teimann and Kraz 30. Heaps, T. and Robinson, R. (a) i b i d 51. Romeo, G. and Pirrone, F. 32. Adkins, H. 53. WInans and Adkins 34. 35. Organic Syntheses Ber., 44,2455,1911. Ann., 368,76-88,1909. Bull.Soc.Chim., 23,380,1918 also C.A., 13_, 321, I9T9. Helv.Chim.Acta, 10,392,1927, Ber., 61,2601,1928. Vol . 1 , R.Adams, page343. J.of Chem.Soc.,Vol.1, 288,1930. J.A.C.S., 68,1100,1946. Ber., 15_,2068,1882. J.C.S., 2342,1926. Ann.Chim.Appliceta, 18,189, 1928, also C.A.,_22,3863, 1928. Reactions of Hydrogen, Wisconsin Press. J.A.C.S., 21,306-12,1932 also C A. 26,969,1932. Ind. and Eng.Chem.,14 Dec. 1946. Vol.II* page 570, ,1941. 36. Inorganic Chemistry, by Partington. 37. Rupp, F. and Gay, S . Apoth.Ztgs.,23,373T74. also C A . 2,312771908. 38. Zapworth, Manoie and co-workers J.C . S . , 2533, 1928. J . C S . , 1976, 1931. 

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