Open Collections

UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

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

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata

Download

Media
831-UBC_1947_A8 H23 S6.pdf [ 4.35MB ]
Metadata
JSON: 831-1.0062444.json
JSON-LD: 831-1.0062444-ld.json
RDF/XML (Pretty): 831-1.0062444-rdf.xml
RDF/JSON: 831-1.0062444-rdf.json
Turtle: 831-1.0062444-turtle.txt
N-Triples: 831-1.0062444-rdf-ntriples.txt
Original Record: 831-1.0062444-source.json
Full Text
831-1.0062444-fulltext.txt
Citation
831-1.0062444.ris

Full Text

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 t h e s i s submitted i n p a r t i a l  fulfillment  of the requirements f o r the degree o f MASTER OF ARTS i n t h e Department o f CHEMISTRY.  The U n i v e r s i t y o f 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 v e r t e d to benzoyl  o f three  syntheses Y a n i l l i n i s eon-  v a n i l l i c a c i d , then s u c c e s s i v e l y to t h e  a c y l c h l o r i d e , cyanide w i t h subsequent r e d u c t i o n to the amine. The  second method i n v o l v e s the s y n t h e s i s o f v a n i l l i n  cyanohy&rin f o l l o w e d by r e d u c t i o n to the amine. The  t h i r d method i n v o l v e s the F r i e s rearrangement  of g u a i a c o l a c e t a t e f o l l o w e d by bromination. one  and conversion  t o the amine.  of the acetophen-  ACOOWLEDGEMMT  I would l i k e t o express my s i n c e r e a p p r e c i a t i o n , t o Dr. R; H. C l a r k f o r h i s i n v a l u a b l e a s s i s t a n c e i n t h i s problem. To Dr* R, F . P a t t e r s o n ,  o f the P o w e l l R i v e r Company L i m i t e d ,  a l s o go my g r a t e f u l thanks f o r c a r r y i n g out the h i g h hylrogenations Mr.  and f o r h e l p f u l s u g g e s t i o n s .  pressure  Thanks go a l s o t o  R. Stewart, Mr. R. F. Robertson and Mr. R. W. A. A t t r e e ,  my a s s o c i a t e i n t h i s problem d u r i n g the p a s t  e i g h t e e n months,  who took p a r t i n many d i s c u s s i o n s and o f f e r e d c o n s t r u c t i v e criticisms.  FOREWORD  Mr* A t t r e e ' s t h e s i s ,  i n which he d e s c r i b e s h i s  e f f o r t s t o s y n t h e s i z e the same end product  using  different  methods o f approach, should be read p r i o r t o o r f o l l o w i n g t h e reading of t h i s t h e s i s , picture  i n o r d e r t o o b t a i n a c l e a r and complete  o f 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 d i s c u s s i o n of Sympathomimetic Agents  1  The Beta phenethylamine D i s c u s s i o n as to why  2  skeleton  t h i s compound should have 3  Sympathomimetic p r o p e r t i e s Reasons f o r h i g h r e a c t i v i t y of V a n i l l i n  4  Mesomeric s t r u c t u r e of V a n i l l i n  3  Resume of g e n e r a l methods employed i n t h i s type of r e s e a r c h D i s c u s s i o n of the t h r e e methods attempted i n t h i s  6  problem  9  Experimental  13  Equations f o r . a c y l  13  cyanide method  S y n t h e s i s of V a n i l l i c a c i d  13  B e n z o y l a t i o n of V a n i l l i c a c i d  16  S y n t h e s i s of Benzoyl v a n i l l y l c h l o r i d e  17  Attempted  s y n t h e s i s o f Benzoyl V a n i l l y l cyanide  u s i n g KCN  18  (b) u s i n g anhydrous HON  20  (o) u s i n g Hg(CN)  21  2  22  (cl) u s i n g AgCN Equations f o r the Cyanohydrin  s y n t h e s i s (bottom)  22  M i s c e l l a n e o u s r e d u c t i o n s of cyanohydrin  24  High p r e s s u r e hydrogenation of cyanohydrin  23  Graphs of h i g h p r e s s u r e runs between pages F r i e s Rearrangement  23 27  26  TABLE OF CONTEMIS (Cont'd.) Page Equations f o r F r i e s Rearrangement  28  D i s c u s s i o n of r e s u l t s  29  Conclusion  31  Suggestions Bibliography  f o r further research  32 33  SOME INTERMEDIATES FOR THE SYNTHESIS OF ft - (-3-METHOXY-4-HYDROXY-PHENYL) -ft -  HYDROXYETHYLAMINE  INTRODUCTION  T h i s i n v e s t i g a t i o n , was an attempt t o s y n t h e s i z e compound whose s t r u c t u r e was s i m i l a r t o a d r e n a l i n e .  a  I t was  thought t h a t by a v a r i a t i o n o f some o f the s u b s t i t u e n t s i n the parent epinephrine  ( a d r e n a l i n e ) n u c l e u s the t o x i c e f f e c t s  c o u l d be l e s s e n e d  and the b e n e f i c i a l e f f e c t s r a i s e d , hence  i n c r e a s i n g the Therapeutic  R a t i o o f the oompound.  B a r g e r and  D a l e ^ ) showed t h a t c e r t a i n o f these amines w i t h the b e t a phenethylamine s k e l e t o n would cause e f f e c t s g e n e r a l l y resembling those produced by s t i m u l a t i o n o f the so c a l l e d Sympathetic System o f n e r v e s .  Hence came the name t h a t i s commonly used  f o r t h i s type o f compound - "Sympathomimetic A g e n t " , ( ) 2  General D i s c u s s i o n The  o f t h i s type o f Compound  b e t a phenethylamine s k e l e t o n p r e v i o u s l y mentioned  was e a r l y observed t o be one o f the minimal e s s e n t i a l r e q u i r e ments f o r p r e s s o r  activity.  -AA  <>  Y, , ~ Q_ —  I <  ttkjl  — JSIN  2.  P  ^ r v y l Noel  Amino  6ra»p  Gt-.vp  The most u s e f u l compounds known to-day possess  this  s k e l e t o n and i t oan r e a d i l y be seen from the diagram t h a t i n t h i s s t r u c t u r e t h e r e a r e many p o s s i b i l i t i e s f o r s u b s t i t u t i o n . (a) Three p o s i t i o n s i n the phenyl n u c l e u s w i t h many combinations. (b) On t h e a l p h a and b e t a carbon atoms o f the s i d e c h a i n . (c) On the amino n i t r o g e n group. I t has been demonstrated  that many s u b s t i t u t i o n s may  be made without d e s t r o y i n g the Sympathomimetic p r o p e r t i e s . T h i s i n i t s e l f i s v e r y remarkable, f o r i n so many i n s t a n c e s , a p h y s i o l o g i c a l l y a c t i v e molecule does not permit much change without d e s t r o y i n g i t s B i o l o g i c a l p r o p e r t i e s . When the d e s i r e d end product o f t h i s problem i s compared w i t h e p i n e p h r i n e , ephedrine and benzedrine, i t i s r e a d i l y seen that they do n o t d i f f e r w i d e l y i n s t r u c t u r e .  0 i  CHCHj I  Epinephrine  E-phaH^'nt  De.&ired  Product  2.  D i s c u s s i o n as to why  t h i s Compound should have  Sympathomimetic P r o p e r t i e s In  t h i s s y n t h e s i s the s u b s t i t u t i o n was  c o n f i n e d to  the metaO) p o s i t i o n i n the phenyl nueleus and to the r e p l a c e able hydrogens on the amino group, the a l p h a and b e t a atoms were l e f t  as i n e p i n e p h r i n e .  carbon  In the meta p o s i t i o n i n the  r i n g the h y d r o x y l group o f a d r e n a l i n e has been r e p l a c e d w i t h a methoxy group, and i n the amino group the two hydrogens have been l e f t u n s u b s t i t u t e d , whereas i n the e p i n e p h r i n e s k e l e t o n , one has been r e p l a c e d w i t h a methyl group.  E x p e r i e n c e has shown  that i t i s the meta h y d r o x y l group i n e p i n e p h r i n e t h a t i s r e s p o n s i b l e f o r i t s g r e a t 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 p r e s s o r a c t i v i t y both the meta and the p a r a h y d r o x y l groups should be p r e s e n t . ( ) 2  The h y d r o x y l group p r e s e n t on the  b e t a carbon atom decreased the t o x i c i t y and i n c r e a s e s the p r e s s o r a c t i v i t y , thereby i n c r e a s i n g the t h e r a p e u t i c r a t i o o f 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  d e t r i m e n t a l e f f e c t on the p h y s i c a l p r o p e r t i e s o f the  the  molecule,  such as a decrease i n s t a b i l i t y and a l o w e r i n g of the vapour pressure.  The  exchanging  of the a c t i v e hydrogen of the amino  group w i t h a methyl group, as a r u l e , lowers the t h e r a p e u t i c r a t i o * however i t p r o b a b l y g i v e s a c e r t a i n amount of  stability  (2)  to  the  structure. The  v  s t a r t i n g m a t e r i a l i n n e a r l y a l l of the  syntheses i n t h i s problem was pulp and paper i n d u s t r y .  attempted  v a n i l l i n - a b i - p r o d u c t of the  There were two  reasons f o r t h i s ,  one,'  v a n i l l i n as y e t has no great commercial  v a l u e and, secondly  i t has the s u b s t i t u e n t s i n i t s phenyl n u c l e u s t h a t are d e s i r e d i n the f i n a l compound. for  In o t h e r experiments g u a i a c o l was  used  the same reason as was v a n i l l i n - namely the n e c e s s a r y  s u b s t i t u e n t s i n the phenyl, n u c l e u s were a l r e a d y p r e s e n t .  From  the p r e c e d i n g d i s c u s s i o n i t would be expected t h a t the c o r r e s 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 o f g r e a t e r t h e r a p e u t i c v a l u e than the compound attempted  i n this research  - due t o i t s meta h y d r o x y l group.  Compovn^  desire. J  ComfunJ  Reported  T h i s compound from i s o v a n i l l i n has been r e c e n t l y s y n t h e s i z e d by two Russian workers. (3)  The reason f o r the s y n t h e s i s was not g i v e n so i t i s a matter of c o n j e c t u r e as t o whether or not i t was f o r t h e r a p e u t i c use, however the t e s t i n g o f t h i s  com-  pound f o r i t s Sympathomimetic A c t i v i t y should not be o v e r l o o k e d . Reasons F o r the High R e a c t i v i t y of V a n i l l i n The v a n i l l i n n u c l e u s i s v e r y d i f f i c u l t to work w i t h due to the f a c t t h a t i t has a h y d r o x y l group p a r a to the c a r b o n y l group  ^^C^^"  t h a t f r e e h y d r o x y l groups a t t a c h e d to the benzene n u c l e u s ( e x - v a n i l l i n , p. hydroxy benzaldehyde)  have a r e t a r d i n g i n -  f l u e n c e on o x i d a t i o n o f the aldehyde.  The f a c t that  vanillin  does n o t undergo a Cannizzaro r e a c t i o n bears t h i s o u t , Benzaldehyde  undergoes t h i s simultaneous o x i d a t i o n r e d u c t i o n  r e a d i l y and meta hydroxy benzaldehyde at room temperature.  undergoes the r e a c t i o n  I f , however, ortho o r p a r a h y d r o x y l  groups a r e i n the r i n g no such r e a c t i o n takes p l a c e . case o f v a n i l l i n and o t h e r ortho or p a r a s u b s t i t u t e d  In the aldehydes  t h i s may be due t o the f a c t t h a t they can perhaps e x i s t i n another mesomeric form under the c o n d i t i o n s of these r e a c t i o n s  I f t h i s i s the case i t i s no l o n g e r an aldehyde and t h e r e f o r e i t s r e a c t i o n s would not be t y p i c a l o f an aromatic  aldehyde.  Thus the Cannizzaro r e a c t i o n does not take p l a c e when h y d r o x y l groups a r e ortho or para to the c a r b o n y l group. (3»4)  cLi-hydroxy benzaldehyde  behaves l i k e p hydroxy  benzalde-  hyde, s i n c e the Cannizzaro r e a c t i o n takes p l a c e when the meta h y d r o x y l group i s p r e s e n t , i t must be the a d d i t i o n o f a second h y d r o x y l group i n the p a r a p o s i t i o n i n t h i s compound which hinders the reaction.  T h e r e f o r e , v a n i l l i n and i s o v a n i l l i n  would be expected to r e a c t 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 w i t h i t s h y d r o x y l group p a r a t o  the c a r b o n y l group, does not undergo the Cannizzaro r e a c t i o n , w h i l s t i s o v a n i l l i n w i t h i t s h y d r o x y l i n the meta p o s i t i o n v e r a t r a l d e h y d e - w i t h no h y d r o x y l s but two do ( 9 ) .  and  methoxyl groups  I t i s e v i d e n t then from the p r e c e d i n g d i s c u s s i o n , t h a t  v a n i l l i n although o f t e n c l a s s i f i e d as a t y p i c a l aldehyde r e a c t s a t y p i c a l l y ;  aromatic  i n f a c t , t y p i c a l r e a c t i o n s of  v a n i l l i n are the e x c e p t i o n r a t h e r than the  rule.  Many compounds of t h e r a p e u t i c v a l u e have been synt h e s i z e d d u r i n g the l a s t f o r t y y e a r s .  Some have proved  e f f i c a c i o u s w h i l s t many of l e s s e r importance and perhaps some of prime importance have been excluded i n the s c r e e n i n g procedure.  The methods employed i n most cases by the r e s e a r c h  chemists were g e n e r a l s y n t h e t i c procedures  while others  invol-  ved v e r y ingenious and i n t r i c a t e mechanisms t o get to the d e s i r e d compounds.  General Methods Employed i n t h i s type of Research A resume of the v a r i o u s methods t h a t c o u l d be used i n s y n t h e s i z i n g t h i s compound and t h a t have been u t i l i z e d i n s y n t h e s i z i n g s i m i l a r compounds w i l l now (l)  The  be o u t l i n e d .  s y n t h e s i s of the n i t r o s t y r e n e d e r i v a t i v e from  v a n i l l i n u s i n g nitromethane  and methylamine f o l l o w i n g the  method of Knoevenagel and W a l t h e r ^ ^ ) and subsequent  treatment  of t h i s product by the method of R e i c h e r t and K o c h ^ ) • 1 1  CpHsOH R--  CH = CH - F 0 + B r —*R RCH0HCHBrW02 2  2  - CHBrCHBrNOg  » 5  7. K  0  >  H  R - C0CH N0 2  CH3OH  -  2  H 2  +  P  t  °  v  2  R.CH0H.CH m 2  i n C2H5OH  .  ^  * 1 mole (C00H) (2)  2  The b e t a hydroxy phenethylamine s y n t h e s i s as o u t l i n e d  by B a l t z l y and Buck c o u l d a l s o be u t i l i z e d , ^ K u l z and Hornung RCOCH3  (a)  .  2  .  B r  ^  t h e method o f  also.^ ^) 1  2 » R - COCH Br RCH0H0H NH 2  ^ R 0CH HH  (CH )6K4  2  PtO? H  1 2  2  C  2  2  2  2  (b)  RCHO.+ BrCH C00C H5 2  • RCH0HCH C00C H3  2  2  RCHOH. C H . COTgH^ — M P j 2  R - CH  'CH  2  HCl  2  . NHg.B"H ^ 2  > JR.CHOH.CH 00.N^ 2  + R.CHOH.CH ,NH 2  2  1—0 — C - U - H  u  0  (3)  The s y n t h e s i s o f the oyanohydrin and subsequent r e -  d u c t i o n has proved v e r y s u c c e s s f u l f o r compounds o f t h i s A r t e r o n o l , c l o s e l y a l l i e d t o epinephrine way  type.  has been made t h i s  by r e d u c t i o n o f protocatechualdehyde cyanohydrin u s i n g  sodium amalgam. 0-4»1J>) M o d i f i c a t i o n s o f t h i s s y n t h e s i s a r e discussed i n (16). (4)  The epinephrine  s y n t h e s i s o f N a g a i ^ ? ) c o u l d be 1  u t i l i z e d here by condensing a c e t y l v a n i l l i n w i t h nitromethane and  subsequent r e d u c t i o n u s i n g  z i n c and a c e t i c a c i d i n the  presence o f formaldehyde. a c e t y l - R - CHO + CH^E0 (3)  2  9-lk,. „  R  _ CH0HCH NHCH .HC1  The s y n t h e s i s o f the a c y l cyanide  2  5  from the a c y l  c h l o r i d e and subsequent r e d u c t i o n i s a method t h a t i s f r e q u e n t l y used.  There a r e many s l i g h t m o d i f i c a t i o n s t o t h i s procedure  8. and these w i l l now be l i s t e d . The g e n e r a l equation f o r r e d u c t i o n i s R - C:OC:N + 3 H  > RCH0HCH NH  2  2  2  The most obvious method i s t r e a t i n g the a c y l c h l o r i d e w i t h KCN  and H C l i n e t h e r s o l u t i o n . R. :0C:N  (a) R.C:O.Cl • K C N — S S i ^  - (  C  L 8  )  (b) A method i n v o l v i n g a l i t t l e more technique but e q u a l l y as good as (a) i s t h a t o f u s i n g anhydrous HOT. was u t i l i z e d  by Maunthner^ ^) ± 1  benzoyl cyanide from v e r a t r o y l RC0C1 • HON  F  y r 5ft i n e  n  This  s y n t h e s i z i n g 3, 4, dimethoxy  chloride.  *  R.COCN • H C l  Ether  (e) B e a r b i t e t , R o s e n t h a l ^ ) 20  and V o r l a n d e r ^ )  used  2 1  mercuric cyanide t o convert the a c y l c h l o r i d e t o the c y a n i d e . (d) S i l v e r cyanide has been used i n the c o n v e r s i o n o f the a c y l c h l o r i d e to the cyanide.^- '' 22  (e) A. Maihle transformed a c i d c h l o r i d e s i n t o the c o r r e s - ponding n i t r i l e s by means o f an A l 0 3 c a t a l y s t and gaseous 2  ammonia a t temperatures  c l o s e to 300°C.t 5)  (6) The F r i e s rearrangement  2  has been used t o g i v e the  corresponding omega h a l o a c e t y l g u a i a c o l and t r e a t i n g t h i s w i t h a primary a l i p h a t i c amine and subsequent  r e d u c t i o n t o secondary  a l c o h o l g i v e s products o f t h e r a p e u t i c v a l u e .  T h i s method i s  used commercially i n the s y n t h e s i s o f a d r e n a l i n e . (  S e e  24,  23, 26, 27) A second method a v a i l a b l e f o r t h e s y n t h e s i s o f s i m i l a r compounds i s the F r i e d e l - O r a f t s r e a c t i o n , i n which a phenol, or an e t h e r o f a phenol, i s condensed w i t h an a c i d  chloride  o r an a c i d anhydride i n the presence of aluminum c h l o r i d e . The  s i x methods mentioned have a l l been used a t  one  time or another to produce compounds t h a t have been used t h e r a p e u t i c a l l y due  to t h e i r p h y s i o l o g i c a l a c t i o n .  In this  r e s e a r c h the methods attempted were l i m i t e d to t h r e e , the a c y l cyanide  s y n t h e s i s , the cyanohydrin  and v a r i o u s m o d i f i c a t i o n s  and l a s t l y the F r i e s rearrangement of g u a i a c o l a c e t a t e . Mr.  R. W.  A. A t t r e e has been attempting  the  synthesis  of the same compound u s i n g the method of R e i c h e r t and  Ko  and a l s o t r e a t i n g the a c y l c h l o r i d e w i t h diazomethane  and  r e d u c i n g the product  to a secondary a l c o h o l .  DISCUSSION OF THE The  first  one  THREE SYNTHESES ATTEMPTED  to be d i s c u s s e d i s the s y n t h e s i s o f  the d e s i r e d compound f o l l o w i n g the a c y l cyanide method. v a n i l l i n was  The  o x i d i z e d to v a n i l l i c a c i d f o l l o w i n g the method  of I . A. P e a r l ( ^ ) . 2  An attempt was  made to s y n t h e s i z e  the  a c y l c h l o r i d e from the a c i d by u s i n g t h i o n y l c h l o r i d e , however t h i s proved u n s u c c e s s f u l .  The  r e s u l t i n g compound was  not  s o l u b l e i n ten common s o l v e n t s and d i d not melt when taken as h i g h as 223°C.  From these r e s u l t s i t was.thought t h a t due  the f a c t t h a t the p. h y d r o x y l group was pound could have polymerized  as f o l l o w s  not blocked,  to  the com-  10. The b l o c k i n g o f the p . h y d r o x y l group was next a f f e c t e d by b e n z o y l a t i o n . a c i d M.P.178 was f i r s t  T h i s substance, b e n z o y l  vanillic  o b t a i n e d by Tiemann and KrazC 2 ?) by  o x i d a t i o n o f benzoyl eugenol.  Heap and Robinson(30) m o d i f i e d  the procedure somewhat and o b t a i n e d the product by b e n z o y l a t i o n of v a n i l l i c a c i d - M » P . l 6 l - l 6 4 - i n y i e l d s o f approximately  38.4%.  T h e i r method was f o l l o w e d i n t h i s l a b o r a t o r y and i t  was found e x p e r i m e n t a l l y t h a t by adding a l a r g e excess o f b e n z o y l c h l o r i d e the y i e l d c o u l d be g r e a t l y improved.  When  s e p a r a t i n g the benzoic a c i d from t h e b e n z o y l v a n i l l i c  acid,  i f the pH i s taken to 6.4, t h e amount o f b e n z o i c a c i d p r e s e n t 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 .  Yields ran  about 70%. The next step was the s y n t h e s i s o f the a c y l  chloride.  Heap and Robinson(30a) s y n t h e s i z e d t h i s i n 1926 u s i n g phosphorous p e n t a c h l o r i d e , t h e i r y i e l d s r a n approximately 87% however t h e i r method was v e r y cumbersome.  T h i o n y l c h l o r i d e was found  v e r y s u c c e s s f u l t o use when used i n excess.  The y i e l d s were  q u a n t i t a t i v e and no vacuum d i s t i l l a t i o n was n e c e s s a r y , ( s e e experimental). The s y n t h e s i s o f t h e a c y l cyanide from t h e a c y l c h l o r i d e was next attempted.  On t r e a t i n g w i t h KCN and H C l  f o l l o w i n g the g e n e r a l method o f s y n t h e s i z i n g cyanides(l8) and i s o l a t i n g t h e product, the M.P. was 94-97 w h i l e that o f the a c y l c h l o r i d e i t s e l f i s 96-98°C.  A r e d u c t i o n o f t h i s product  was attempted u s i n g sodium and a b s o l u t e a l c o h o l , however p r o d u c t s were not c h a r a c t e r i z e d .  An attempted p u r i f i c a t i o n o f  11. the  end product of one  o f these runs ended i n p r o b a b l e dimer-  i z a t i o n of the p r o d u c t . dark grey on h e a t i n g 94-97°C-  ever no  two  i n a solvent  above s y n t h e s i s was  of L i g r o i n - M.P.  and  was  conditions  always o b t a i n e d .  added to the  and  may  one  occasion chloride  the r e a c t i o n medium took  on a b e a u t i f u l r o y a l p u r p l e c o l o r a t i o n . s i n c e and  On  e t h e r s o l u t i o n of the  p r i o r t o the a d d i t i o n of the HCl,  b e f o r e nor  original  o r d e r of a d d i t i o n of r e a c t a n t s were v a r i e d  a t e s t f o r c h l o r i n e was  when the KCN  of  d u p l i c a t e d many times, how-  r e a c t i o n s were e v e r i d e n t i c a l ,  concentrations but  p r e c i p i t a t e went from white to  l60°C.  of f i n a l The  The  have been due  T h i s was  never n o t e d  to a quinone  structure  f o l l o w i n g h y d r o l y s i s of b e n z o y l group.  However as the  s o l u t i o n i s b a s i c due  to the h y d r o l y s i s  KCTT, i t would not  occur as a tautomer but  a migration  electron.  of an  of  as a mesomer w i t h  12 The KCH.  same s y n t h e s i s was tried, u s i n g HOT i n p l a c e o f  The HON was s y n t h e s i z e d under c o n d i t i o n s such t h a t i t  was anhydrous.(19)  Two runs were made.  In the f i r s t , g a s i n  exeess was bubbled i n t o a p y r i d i n e e t h e r s o l u t i o n o f the c h l o r i d e w i t h no r e s u l t .  On t h e second r u n approximately  ljj  c c . anhydrous HCF l i q u i d (excess) were c o l l e c t e d and s l o w l y bubbled i n t o the s o l u t i o n o f the a c y l c h l o r i d e i n p y r i d i n e . The  r e s u l t i n g product  for C l  2  had a m e l t i n g p o i n t o f l67°C.  I t tested  and gave no t e s t f o r B^. Again f o l l o w i n g procedures used f o r the s y n t h e s i s  of a c y l cyanides - H g ( C W ) ^ different reactions.  88-96°  had a M.P.  96-98°.  but products  * a n d A g C K ( ) were used i n 22  I n t h e Hg(CN)2 s y n t h e s i s the end product  and gave a p o s i t i v e t e s t f o r c h l o r i n e and a  negative t e s t f o r nitrogen. M.P.  2 0  I t was probably  the a c i d c h l o r i d e  A s i m i l a r s y n t h e s i s u s i n g AgCN was attempted although  sweet s m e l l i n g , which i s t y p i c a l o f  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 r e s i n s were The  obtained. second s y n t h e s i s t h a t 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 d i s c u s s e d . the most obvious,  T h i s method i s perhaps  however, i t . i s not as simple  as i t appears  on paper due t o the d i f f i c u l t i e s one encounters on r e d u c t i o n . V a n i l l i n apparently  does not r e a c t t y p i c a l l y  with  NaHSO^^ ) however when i t i s d i s s o l v e d i n NaHSO^ i t does under2  go a r e a c t i o n w i t h KCU to g i v e the cyanohydrin(1-5) •  The r e -  d u c t i o n of t h i s compound has been t r i e d by many methods, none of which have been s u c c e s s f u l thus f a r .  Hydrogen was bubbled  13. i n t o a s o l u t i o n of the cyanohydrin i n g l a o i a l a c e t i c  acid  u s i n g P t as the c a t a l y s t , however the product was non c h a r a c t e r i z a b l e due t o the f a c t that i t was a b l a c k p u r p l e resin.  A b s o l u t e a l c o h o l and m e t a l l i c sodium and 2$ sodium  amalgam have been t r i e d without s u c c e s s . F i n a l l y an attempt was made t o reduce t h i s compound to the d e s i r e d end product u s i n g h i g h p r e s s u r e hydrogen and Raney n i c k e l c a t a l y s t .  The graphs a r e i n c l u d e d and a d i s c u s -  s i o n o f the procedure employed i n t h e e x p e r i m e n t a l s e c t i o n . In t h e hydrogenation o f 3(0^0) 4(0H) C^H CH0HOT 4  t h e r e are many d i f f i c u l t i e s to contend w i t h .  According to  (32) H. Adkins  cyanides a r e hydrogenated  nickel catalysts. 13© C. 0  t o p r i m a r y amines over  The p r e f e r r e d temperature  range i s 100 -  An important s i d e r e a c t i o n i n the hydrogenation o f  cyanides and oximes i s the f o r m a t i o n o f secondary amines. They a r e a p p a r e n t l y formed as the r e s u l t o f t h e i n t e r a c t i o n of an immine w i t h the primary amine. (23) R.C5N * H  » R.CH:NH + H  2  R.CHtNH * R.CH ]JH 2  2  » R.CH NH  2  2  • R.CH.NH.CH R • H 2  2  2  ^  fc  2  R.CH .UHCH .R * HH3 < 2  2  ±^2  R.CHs-IT.CHfc.R • HH3  The best method of m i n i m i z i n g the f o r m a t i o n o f secondary amines i s t o c a r r y out the h y d r o g e n a t i o n as r a p i d l y as p o s s i b l e .  T h i s i s accomplished by u s i n g cyanide completely  f r e e o f halogen, a r e l a t i v e l y h i g h r a t i o o f c a t a l y s t and a temperature  and p r e s s u r e s u f f i c i e n t l y h i g h t o b r i n g  r e a c t i o n w i t h i n an hour or two.  abput  14. A new reported I t has  method f o r the r e d u c t i o n  was  i n December 1946,(^4) u s i n g l i t h i u m aluminum  hydride.  been s u c c e s s f u l l y used to reduce a r y l n i t r o compounds  to the c o r r e s p o n d i n g azo The  reduction  may  be  d e r i v a t i v e s and n i t r i l e s to amines.  i s noted f o r i t s cleanness and  c a r r i e d out i n ether  I t was  the f a c t that i t  s o l u t i o n at room temperature w i t h  h i g h y i e l d s i s a l s o another p o i n t  and  of n i t r i l e s  i n i t s favor.  thought t h a t by b e n z o y l a t i n g  both the  secondary a l c o h o l i c h y d r o x y l g r o u p s ^ ^ ) r e d u c t i o n  facilitated  more r e a d i l y , and  be removed by h y d r o l y s i s .  phenolic could  be  the b l o c k i n g groups c o u l d e a s i l y  T h i s method was  not  successful, for  the p r o d u c t s i s o l a t e d were e i t h e r o i l s or p u t t y l i k e masses which a f t e r s i x months had The  not  crystallized.  t h i r d method attempted was  rearrangement of a c e t y l g u a i a c o l and T h i s r e a c t i o n c o n s i s t s i n the  t h a t of the F r i e s  chloracetyl guaiacol.  conversion  of an e s t e r of a  phenol t o an ortho o r p a r a hydroxyketonej or a mixture of both by treatment w i t h aluminum c h l o r i d e .  As mentioned p r e v i o u s l y ,  the F r i e d a l - C r a f t s r e a c t i o n can a l s o be  employed to  synthesize  s i m i l a r compounds, however, d e s p i t e the f a c t t h a t the F r i e s r e a c t i o n r e q u i r e s two and  steps - the p r e p a r a t i o n  ester  the rearrangement to the hydroxyketone - as compared to  s i n g l e step  i n the F r i e d a l - C r a f t s s y n t h e s i s ,  i s u s u a l l y p r e f e r r e d f o r the p r e p a r a t i o n The  of the  y i e l d s are o r d i n a r i l y b e t t e r and  does not have to be m o d i f i e d of e s t e r s .  the  the F r i e s method  of p h e n o l i c  ketones  the experimental procedure  g r e a t l y to adapt i t to a v a r i e t y  15.  EXPERIMENTAL  S y n t h e s i s Number 1. The  a c y l cyanide method.  f S * ^ / ^ CW c. t  t»  Step 1.  i,  • soc/,. —* f-|*\_J>«-"-«J <  CH,«,  o  '  HCM  o  \  e  7  The p r e p a r a t i o n o f the v a n i l l i c a c i d f o l l o w i n g the  method o f I . A. P e a r l ^ ? ) 2  30.4  w  a  s  c a r r i e d out.  gms. (.2 moles) of v a n i l l i n were added w i t h  v i g o r o u s s t i r r i n g to 400 c c . HgO i n which were d i s s o l v e d 48 gms. (1.2 moles) of NaOH. to 55°C.  The r e s u l t i n g s o l u t i o n was heated  With continued a g i t a t i o n a s o l u t i o n o f 34 gms.  (.2 moles) AgN03 i n 130 c c . H^O - at a temperature of 55°C were added a l l a t once.  Both s o l u t i o n s were at a temperature  .  -  16.  of j>5°C when the AgNO^ was u n t i l the temperature was  added.  Outside heat was  63°(ll) when the r e a c t i o n went  spontaneously and the temperature rose t o 75°(il)C. r e a c t i o n mixture was  M.P.  The  then f i l t e r e d t o remove the f r e e Ag° and  the f i l t r a t e a c i d i f i e d by b u b b l i n g i n S 0 acid precipitated.  applied  2  u n t i l the v a n i l l i c  The a c i d was f i l t e r e d , washed, d r i e d -  210-11°C. I t was  found e x p e r i m e n t a l l y t h a t  i f too much water  was added i n d i s s o l v i n g e i t h e r the NaOH or the AgNOj, the v a n i l l i c a c i d d i d 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 w i t h S 0  2  but went a deep p u r p l e c o l o r g i v i n g the i n d i c a t i o n t h a t perr- > haps n i t r o v a n i l l i c a c i d was the main p r o d u c t .  I t was  also  found that i f the NaOH was not pure (Na C0^) or had absorbed 2  H0 2  and the c o n c e n t r a t i o n i n the r e a c t i n g medium was  too low,  the temperature would have to be r a i s e d t o 80-90°C b e f o r e the r e a c t i o n would  commence*  The v a n i l l i c a c i d o b t a i n e d from these  r e a c t i o n s was never as pure as when the r e a c t i o n at a lower temperature.  Pearl  s t a t e d that  the r e a c t i o n went  spontaneously a t j>5°C and that the y i e l d s were however these r e s u l t s were never d u p l i c a t e d Step 2.  quantitative  in this  laboratory.  The method employed i n the b e n z o y l a t i o n of the v a n i l -  l i c a c i d was  as  follows:  24 gms NaOH were d i s s o l v e d were added 25 gms gms  took p l a c e  (32cc) was  of v a n i l l i c a c i d *  added  '  i n 400 c c . H 0 2  and t o t h i s  Bensoyl c h l o r i d e -  38.4  and the mixture s t i r r e d m e c h a n i c a l l y  f o r 40 minutes, w h i l e kept i n an i c e b a t h . time the mixture was a white s o l i d .  At the end of t h i s  Upon warming to room  1  temperature t h i s went i n t o s o l u t i o n . was 10.5.  The pH a t t h i s  7-  point  T h i s was taken t o 6.6 u s i n g 6JSHC1 - where a d u l l  gray p r e c i p i t a t e formed.  T h i s was f i l t e r e d ,  and t h e f i l t r a t e  was a c i d i f i e d s t i l l more, t o pH 6.5 - where a voluminous p r e c i p i t a t i o n occurred.  T h i s 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 a t pH 6;4. The  f i r s t p r e c i p i t a t e was washed w i t h 4 x 100 c c .  b o i l i n g H 0, d r i e d and weighed. 2  The second and t h i r d p r e c i -  p i t a t e s were combined and added t o 500 c c . b o i l i n g H 0 2  f i l t e r e d - d r i e d - weighed. Wt. o f Ppte. I - 4.5 gms. - ppted © pH 6.6 - M.P. - 162-66°C uncorrected - Theoretical Wt. o f P p t e . I I  - 161-4.  (2nd and 3rd; - 24 gms - ppted O pH 6.5-6.4 M.P. - 160-65°C - u n c o r r e c t e d .  T o t a l weight - 28.5 gms. Theoretical  - 40.5 gms.  i  - 70.35%  Yield  Y i e l d s as h i g h and h i g h e r than t h i s have been d u p l i cated by Mr. R. W. A* A t t r e e Step 3.  i n this  laboratory..  Conversion of the benzoyl v a n i l l i c  a c i d to benzoyl  vanillyl chloride. The  t h i o n y l c h l o r i d e used i n t h i s p r e p a r a t i o n was  purified following from l i n s e e d  t h e g e n e r a l manner from q u i n o l i n e  oil(35)  and then  #  20 grams p u r i f i e d t h i o n y l c h l o r i d e were added to 10 grams b e n z o y l v a n i l l i c until  a c i d and the mixture s l o w l y  s o l u t i o n o c c u r r e d , and then f o r 10 minutes more.  refluxed The  18 f l a s k was  allowed to o o o l s l i g h t l y and then 40 c c . L i g r o i n were  added and the mixture r e f l u x e d f o r 5 minutes, to  then  transferred  a beaker and c o o l e d i n a mixture of dry i c e and  whereupon the b e n z o y l v a n i l l y l  alcohol,  c h l o r i d e c r y s t a l l i z e d ,- was  f i l t e r e d - d r i e d - weighed. or 9 5 • 2 % - mother l i q u o r was  Y i e l d 1 0 . 2 gms. evaporated  so y i e l d s are p r o b a b l y  quantitative.  Step 4.  S y n t h e s i s of b e n z o y l v a n i l l y l cyanide from  vanillyl  chloride.  (a) ( i ) u s i n g KCT  and  • 7 5 gms.  of b e n z o y l v a n i l l y l c h l o r i d e were d i s s o l v e d . 5 gms.  KCW  dissolved i n 4 cc.  To t h i s , l c c . c o n c e n t r a t e d HCl was  f l a s k was  benzoyl  HCl.  i n 8 c c . e t h y l e t h e r and added.  a l s o added.  obtained. Yield  T h i s product was .70  gms.  or  9 6 . 5 % .  product  M.P.  9 5  0  97°C  -  attempted  - uncorrected.  u s i n g metal-  sodium and a b s o l u t e e t h e r , however no p r o d u c t s were i s o l a t e d . ( i i ) The above s y n t h e s i s was  a c y l c h l o r i d e and 4 . 5 gms.  KCH.  r e p e a t e d u s i n g 1 0 gms.  of the  Y i e l d 9 gms.  M.P.  or 9 3 % -  93°C. uncorrected.  As the range of the m e l t i n g p o i n t was was  was  d r i e d i n vacuo.  Reduction of t h i s product was  88 -  The  The e t h e r l a y e r  then separated and on e v a p o r a t i o n a white c r y s t a l l i n e  lic  HgO  stoppered and v i g o r o u s l y shaken f o r 2 5 minutes,  keeping the s o l u t i o n c o o l a l l the w h i l e .  was  not  d e c i d e d to p u r i f y the p r o d u c t .  so g r e a t i t  To the 9 gms.  of supposed  cyanide, 1 0 0 c c . L i g r o i n were added and the mixture heated b o i l i n g when suddenly the y e l l o w white c r y s t a l l i n e m a t e r i a l  to  19. darkened, momentarily became a dark c o l o r e d o i l and s e t t l e d out i n f i n e gray b l a c k c r y s t a l s . d r i e d - M.P.  T h i s was  l60°C ( s t a r t s t o decompose).  then filtered,  T h i s product  may  be a dimer. ( i i i ) S y n t h e s i s ( i ) was the r e a c t i o n mixture was  repeated, however on t h i s o c c a s i o n  took on a deep p u r p l e c o l o r a t i o n , which  found to be p r e s e n t i n the water l a y e r , the e t h e r l a y e r  being c o l o r l e s s .  On e v a p o r a t i o n and c r y s t a l l i z a t i o n from the  e t h e r l a y e r an impure product was An attempt was  36-72°C.  o b t a i n e d - M.P.  made to p u r i f y t h i s product, however t h i s  was  u n s u c c e s s f u l and the m a t e r i a l remained as a heavy t h i c k orange r e s i n which d i d not c r y s t a l l i z e on s t a n d i n g .  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 ( i v ) The  polymers.  s y n t h e s i s was  repeated u s i n g 4 gms.  of the  c h l o r i d e the only d i f f e r e n c e between t h i s method and and i i i KOT  i s t h a t the HCl was  solution.  acyl  i , i i  added p r i o r to the a d d i t i o n of the  The mixture was  worked up as u s u a l and  white c r y s t a l s obtained were d r i e d .  M.P.  the  91-94°C u n c o r r e c t e d .  Q u a l i t a t i v e A n a l y s i s - Ho B 2 - C l g p r e s e n t .  Microscopic  a n a l y s i s of the c r y s t a l s of the a c y l c h l o r i d e and the supposed a c y l cyanide were v e r y s i m i l a r .  I t i s w e l l w i t h i n the  realm  of p r o b a b i l i t y t h a t the r e a c t i o n d i d not go and the a c y l c h l o r i d e was  o b t a i n e d back again i n a s l i g h t l y impure form as i n d i c a t e d  by the m e l t i n g p o i n t and the q u a l i t a t i v e , a n a l y s i s . (b) R e a c t i o n of benzoyl v a n i l l y l c h l o r i d e w i t h anhydrous HOT.  20. The HON was prepared by t r e a t i n g KGB w i t h 18BT H S0 2  4  ( f o l l o w i n g Method i n P a r t i n g t o n ) ( 2 6 ) . KCN + H S 0 — 2  * KHS0  4  I t was d r i e d by p a s s i n g over C a C l  2  4  * HON  and PgO^*  ( i ) 4.1 gms. of b e n z o y l v a n i l l y l c h l o r i d e were taken i n t o s o l u t i o n u s i n g 150 c c . o f a b s o l u t e e t h e r . was condensed  The HCN produced  i n a f l a s k , secured, and then u s i n g a v e r y low  flame was evaporated s l o w l y and bubbled i n t o the c h l o r i d e ether s o l u t i o n .  T h i s s o l u t i o n was s t i r r e d m e c h a n i c a l l y and  kept (anhydrous) f r e e from the atmosphere by use o f a mercury s e a l and a C a C l s  i n i c e water.  2  d r y i n g tube.  The f l a s k i t s e l f was immersed  The t o t a l time f o r the r e a c t i o n was 35 minutes.  The r e s u l t i n g e t h e r e a l s o l u t i o n was evaporated t o a s m a l l volume and on c o o l i n g white c r y s t a l s formed - d r i e d - M.P. 94-97°C»  Qualitative Analysis - C l  2  present U  2  absent.  ( i i ) The above procedure was d u p l i c a t e d except t h a t i n p l a c e of 150 c c . a b s o l u t e ether, 75 c c . a b s o l u t e e t h e r and 75 cc* anhydrous p y r i d i n e were used. A word o f c a u t i o n i s opportune a t t h i s p o i n t .  Traps  were always s e t up on e i t h e r s i d e o f the r e a c t i o n f l a s k and they were n e c e s s a r y i n both runs.  There i s a heat o f r e a c t i o n i n  the  HCTT g e n e r a t o r and when i t c o o l s down a p a r t i a l vacuum i s  set  up - sucking back the contents o f the R e a c t i o n f l a s k and  on one o c c a s i o n the mercury from the mercury  seal.  The r e a c t i o n mixture was d i s t i l l e d i n vacuo mm.  a t 16  t i l l bumping commenced, then the mixture was allowed t o c o o l  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  ••• • was  filtered,  i t was  - 21.  and on exposure to the a i r was  found to  sublime,  probably p y r i d i n e h y d r o c h l o r i d e * On a l l o w i n g the mother l i q u o r to evaporate  p r e c i p i t a t e formed. shaken w i t h R" 0,  T h i s was  f i r s t 100  2  d i s s o l v e d i n 100  a yellow  c c . ether  c c . then two p o r t i o n s of 50  and  cc.  each, i n order to remove i m p u r i t i e s such as p y r i d i n e hydrochloride.  The  ether l a y e r was  then evaporated  c r y s t a l l i n e p r e c i p i t a t e obtained. 170°C. u n c o r r e c t e d .  c h l o r i d e w i t h Hg(CN) . 2  s y n t h e s i z e d a c c o r d i n g to the method  40  gms.  of benzoyl v a n i l l y l  c h l o r i d e and  2  i n a H2SO4 bath and  d r y i n g tube.  The  shaken f r e q u e n t l y w h i l e the  of  A great d e a l o f the m a t e r i a l was evaporated  minutes.  then cooled and a gray p r e c i p i t a t e was  e x t r a c t e d w i t h ether u s i n g 25,  15,  10,  10  insoluble.  which the Hg(CN)  on  This material  cc. p o r t i o n s . The e t h e r e x t r a c t  e x t r a c t e d w i t h petroleum 2  i s insoluble.  e t h e r (benzine)  On c o n c e n t r a t i n g the  s o l u t i o n and c o o l i n g , a white c r y s t a l l i n e p r e c i p i t a t e T h i s was  uncorrected.  left  and on c o o l i n g gave a y e l l o w orange p r e c i p i t a t e .  T h i s i n t u r n was  obtained.  kept  temperature  h e l d f o r 30  the bottom w i t h a dark v i s c o u s o i l on top of i t .  was  gms.  r e a c t i o n f l a s k was  s l o w l y r a i s e d to 135°C where i t was  The f l a s k was  was  2.6  were i n t i m a t e l y mixed and p l a c e d i n a r e a c t i o n f l a s k  f i t t e d with a C a C l  was  was  2  Gay^ ^.  ( i ) 2.9 2  2  168-  N .  2  The Hg(CN)  Hg(CN)  d r i e d - M.P.  Q u a l i t a t i v e A n a l y s i s No G l - No  (c) R e a c t i o n of benzoyl v a n i l l y l  of Rupp and  T h i s was  and a white  filtered  and d r i e d .  Qualitative analysis - C l  M.P. 2  in  benzine was  88-90°C -  present, N  2  absent.  (&) R e a c t i o n  of benzoyl v a n i l l y l c h l o r i d e and AgCF.  The AgCH used i n t h i s experiment was  made f o l l o w i n g  the method o u t l i n e d i n Partington.(3&) ( i ) 3 gms.  o f benzoyl v a n i l l y l c h l o r i d e and  2 gms.  (excess) were mixed i n t i m a t e l y and heated s l o w l y u n t i l e n t i r e mass went i n t o s o l u t i o n . 30 minutes and  T h i s was  ml. of e t h e r .  The  on a deep y e l l o w c o l o r a t i o n and had  the  refluxed gently for  on c o o l i n g formed a dark s o l i d mass.  e x t r a c t e d w i t h 100  AgCN  This  was  e t h e r e a l s o l u t i o n took  some s o l i d m a t e r i a l  j suspended i n i t , and  t h i s was  f i l t e r e d out.  the r e s u l t i n g product was  r e f u s e d to c r y s t a l l i z e .  f o r t h r e e weeks when i t was The  e t h e r was  removed  a v i s c o u s dark orange o i l ,  The m a t e r i a l had a v e r y sweet  that has been noted b e f o r e .  had taken p l a c e ;  The  I t was  which  smell  l e f t i n the r e f r i g e r a t o r  noted t h a t p a r t i a l  e n t i r e mass was  crystallization  extracted with alcohol,  however, only a s m a l l p o r t i o n went i n t o s o l u t i o n , the r e s t remaining as an i n s o l u b l e r e d brown amorphous mass M.P. 103  C.  The  volume and  a l c o h o l i c e x t r a c t was  evaporated to a  63-83°C.  T h i s was  R e p u r i f i c a t i o n proved of no  as the m a t e r i a l s t i l l remained i n a non state.  small  cooled, whereupon a dark brown amorphous mass,  s i m i l a r to the above, p r e c i p i t a t e d out. d r i e d , M.P.  63-  filtered, assistance  c r y s t a l l i n e semi  solid  23. S y n t h e s i s Number  was  The  Cyanohydrin S y n t h e s i s .  The  synthesis  c a r r i e d out  reduction  2.  of 3 nethoxy 4 hydroxy  following  the method of Buck, ("^t  of t h i s compound was  hydrogen was  extracting  semi s o l i d m a t e r i a l  a l c o h o l and  was  and  hydrogen.  o n l y r e s u l t was  on  a dark v i s c o u s  a l s o attempted u s i n g a b s o l u t e  m e t a l l i c sodium (Mendius R e a c t i o n ) . gms.  of the m a n d e l o n i t r i l e  c c . a b s o l u t e e t h a n o l and  amounts.  solvent  At f i r s t the  were d i s s o l v e d  m e t a l l i c sodium was  in  added i n small  s o l u t i o n took on a p i n k c o l o r a t i o n ,  however, on the a d d i t i o n of more sodium t h i s c l e a r e d up the  the  h i g h l y r e m i n i s c e n t of a polymer.  reduction  1.02 50  A  bubbled i n f o r e i g h t hours, however,  and p u r i f y i n g , the  The  38)  attempted u s i n g P l a t i n u m as  c a t a l y s t , g l a c i a l a c e t i c a c i d as the The  mandelonitrile  s o l u t i o n became cloudy, more sodium was  added and  and  the  r e a c t i o n a l l o w e d 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. down completely by s o l u t i o n was t e r e d out.  c e n t r i f u g a t i o n and  pipetted The  The  o f f and  On  thrown  supernatant a l c o h o l i c  t e s t e d by  fil-  i g n i t i o n f o r sodium  t e s t i n g w i t h HNOg f o r a  primary amine, the r e s u l t s were a l s o The  the  the white p r e c i p i t a t e was  p r e c i p i t a t e was  but r e s u l t s were i n c o n c l u s i v e .  p r e c i p i t a t e was  inconclusive.  p r e c i p i t a t e on treatment w i t h 6NH2SO4 formed  i n t o white c r y s t a l s . M.P.  of compound  -  M.P.  of cyanohydrin-  82.5 83  0  -  83.  0  24.  M.P.  of v a n i l l i n  -  81°  The above r e s u l t s show t h a t the compound probably i s a mixture  of the cyanohydrin  odour o f v a n i l l i n was  and. v a n i l l i n i t s e l f , as a s t r o n g  noted at t h i s p o i n t .  The r e d u c t i o n was  a g a i n attempted u s i n g m e t a l l i c  sodium and a b s o l u t e e t h a n o l .  Product  on t h i s o c c a s i o n  a dark v i s c o u s mass i n d i c a t i n g probable HCH  was  polymers.  Sodium and a b s o l u t e amyl a l o o h o l was  also tried  as  a r e d u c i n g agent, however t h i s d i d not prove anymore s u c c e s s f u l . Reduction, e t h a n o l was  tried.  u s i n g a 27. sodium amalgam and  absolute  On t r e a t i n g the r e s u l t i n g p r e c i p i t a t e  w i t h 6HH2SO4 a moderate r e a c t i o n took p l a c e and a y e l l o w o i l was  formed which on c o o l i n g gave a p a l e y e l l o w  solid.  The  c r y s t a l s t r u c t u r e and odour of t h i s compound were h i g h l y 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  h y d r o x y l group and the p h e n o l i c h y d r o x y l group were both b l o c k e d the compound c o u l d be hydrogenated m o r e ' r e a d i l y without  so much danger o f the s i d e c h a i n b e i n g  and  completely  reduced. These syntheses  d i d not prove s a t i s f a c t o r y .  d i a c e t y l d e r i v a t i v e of the cyanohydrin so the d i benzoyl d e r i v a t i v e was method o f A l o y and R o b o u t . ^ ^ 1  c o u l d not be  isolated  attempted f o l l o w i n g the T h e i r procedure was  e x a c t l y but on each o c c a s i o n the end product was tallizable  The  an  followed uncrys-  o i l , or at l e a s t on s t a n d i n g s i x months f a i l e d  crystallize.  The  o n l y product  t h a t was  *  ever i s o l a t e d i n  to  23. voluminous  q u a n t i t i e s and i n pure form was  T h i s procedure was  benzoic a c i d .  t r i e d many times, s u c c e s s f u l r e s u l t s were  never o b t a i n e d so the i d e a was d i s c a r d e d . The r e d u c t i o n o f the 3 methoxy 4 hydroxy  mandeloni-  t r i l e was next attempted u s i n g h i g h p r e s s u r e hydrogen Raney n i c k e l .  The r e d u c t i o n was  P a t t e r s o n and h i s co-workers  c a r r i e d out by Dr. R.  cc.  gms.  A.  a t the r e s e a r c h l a b o r a t o r y of  the P o w e l l R i v e r Company L i m i t e d , P o w e l l R i v e r , B. 16  and  C.  of the m a n d e l o n i t r i l e were sent up i n 620  of 93% e t h a n o l . £ of t h i s s o l u t i o n was  hydrogenated under the  c o n d i t i o n s g i v e n on data sheet No.(l).. c a t a l y s t used was  The Raney n i c k e l  f r e s h l y prepared and i t s a c t i v i t y t e s t e d  by  the hydrogenation of 2 moles of acetone t o i s o p r o p a n o l . Fo decrease i n p r e s s u r e was noted d u r i n g the hydrogenation o f the m a n d e l o n i t r i l e , nor d i d any decrease i n the c a l c u l a t e d number of moles of hydrogen  take p l a c e .  This  cHd not n e c e s s a r i l y i n d i c a t e t h a t no hydrogenation had o c c u r r e d . In  the f i r s t p l a c e the vapor p r e s s u r e of the e t h a n o l had n o t  been taken i n t o c o n s i d e r a t i o n ; secondly, the t o t a l a b s o r p t i o n r e q u i r e d t h e o r e t i c a l l y was  hydrogen  v e r y small and the  p r e s s u r e gauge was not extremely s e n s i t i v e , and f i n a l l y ,  the  l i b e r a t e d ammonia would tend to minimize the o b s e r v a b l e pressure l o s s * The hydrogenation of cyanides over n i c k e l  almost  always g i v e s r i s e to some secondary amines and ammonia so t h a t the s m e l l of ammonia i n the hydrogenated produet expected and was  noted.  was  .15  mm IS -5o  t-2-5  IS*  \JS Z.oo Z.lS ISO  2.7s-  3.00  26. The remaining •£• o f the s o l u t i o n was hydrogenated under the c o n d i t i o n s g i v e n on the hydrogenation d a t a sheet Mb. 2.  I n o r d e r t o reduce t o as low as p o s s i b l e the. f o r m a t i o n  of a secondary amine, the bomb and contents- were heated t o 50°C b e f o r e the admission of the h i g h p r e s s u r e hydrogen.  In  t h i s way the low temperature hydrogenation was reduced somewhat.  The temperature was kept somewhat lower and t h e time  of hydrogenation s h o r t e r than i n r u n No. 1. R e f r a c t i v e I n d i c e s - O r i g i n a l s o l u t i o n 1.3713 Hydrogenation N o . l - I.3683 Hydrogenation No.2 - 1.3678 On comparing  the r e f r a c t i v e i n d i c e s i t i s q u i t e  evident t h a t something took p l a c e d u r i n g t h e hydrogenation. Assuming the f o r m a t i o n o f both p r i m a r y and secondary amine, the s o l u t i o n may now c o n t a i n t h e s t a r t i n g m a t e r i a l (assuming t h i s t o have been pure) and both the amines,  The  problem now beeomes one of s e p a r a t i o n o f these two c o n s t i t u e n t s . The b e s t method o f s e p a r a t i o n i n t h i s case i s probably that o f Hinsberg.  T h i s s e p a r a t i o n i s based on the f a c t t h a  t h a t primary aromatic amines r e a c t w i t h p a r a t o l u e n e s u l p h o n y l c h l o r i d e t o form an i n n e r s a l t o r Z w i t t e r i o n which i s s o l u b l e i n NaOH - whereas t h e secondary amine, h a v i n g no a c t i v e hydrogen, i s unable t o form t h i s type of s a l t and i s t h e r e f o r e i n s o l u b l e i n NaOH.  T h i s problem i s a t a s t a n d s t i l l a t p r e s e n t  due to the f a c t t h a t no para t o l u e n e s u l p h o n y l c h l o r i d e i s a v a i l a b l e i n the department.  The m a t e r i a l has been ordered  and when i t a r r i v e s t h e problem w i l l be immediately c o n t i n u e d .  27 Synthesis  Number 3. F r i e s Rearrangement. The  t h i r d method attempted i n the s y n t h e s i s of  beta - (-3-methoxy-4-hydroxy-phenyl)-beta-hydroxyethylamine was the F r i e s Rearrangement u s i n g g u a i a c o l as t h e s t a r t i n g  material.O-3,24,25,26,27) Step 1.  Synthesis  o f c h l o r a c e t y l g u a i a c o l f o l l o w i n g the  Schotten Baumann method. (a) 4 gms. NaOH were d i s s o l v e d i n 100 c c . H 0 and t o 2  t h i s was added 12.4 gms. g u a i a c o l .  The c h l o r a c e t y l c h l o r i d e  was next added w i t h v i g o r o u s 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 c o o l i n g .  p u r i f i e d from hot ethanol M.P. 36-39°C-uncorrected.  The p r o d u c t was  and the r e s u l t i n g product d r i e d . T h e o r e t i c a l - 38-39°C.  (b) Attempted F r i e s Rearrangement o f the c h l o r a c e t y l g u a i a c o l f o l l o w i n g procedures o u t l i n e d i n Organic  Reactions,  Volume I . ^ ) 2 6  The using and  a c y l g u a i a c o l s have been f r e q u e n t l y  rearranged  t h i s method t o g i v e the c o r r e s p o n d i n g acetophenones  i t was thought t h a t the c h l o r a c e t y l g u a i a c o l would r e -  arrange s i m i l a r l y t o g i v e the omega chloroacetophenone. i s the case i n the commercial a d r e n a l i n e  synthesis  This  where  c a t e c h o l and c h l o r a c e t y l c h l o r i d e are r e a r r a n g e d . i n the presence o f POCl^ to g i v e the corresponding omega chloroacetophenone. The  conditions followed  i n t h i s were those g i v i n g  the maximum y i e l d of the p a r a isomer..  28. j> gms. o f c h l o r a c e t y l g u a i a c o l were d i s s o l v e d i n 25 gms. o f n i t r o b e n z e n e .  To t h i s was added 6.7 gms. o f 1  anhydrous A l C l ^ . left  The mixture was shaken f o r one hour and  s t a n d i n g f o r twenty-four hours.  The s o l u t i o n was next  e x t r a c t e d w i t h e t h e r and the e t h e r e a l s o l u t i o n shaken up w i t h d i l u t e NaOH.  The NaOH s o l u t i o n was a c i d i f i e d w i t h H S 0 2  4  - b u t w i t h 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 d e c i d e d that a more c e r t a i n method would be to s y n t h e s i z e the a c e t y l g u a i a c o l and rearrange i t and then t r e a t the aeetovanillone with B r to give the corresponding 2  omega bromoacetophenone. G u a i a c o l a c e t a t e was s y n t h e s i z e d u s i n g the Schotten Baumann method. The procedure was the same as the above w i t h the e x c e p t i o n that a c e t y l c h l o r i d e was used i n p l a c e of c h l o r a c e t y l 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 a t 12 mm.  The f r a c t i o n t h a t  came over between 106-112°C. a t 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  o f t h i s compound i s under way a t  the present time and the f o l l o w i n g equations o u t l i n e the procedure  t o be f o l l o w e d t o a t t a i n the d e s i r e d end p r o d u c t . ,  2?  DISCUSSION OF RESULTS  The r e s u l t s of t h i s r e s e a r c h have not been v e r y gratifying.  T h i s i s p r o b a b l y due i n p a r t , to the l a c k of  experience on the p a r t of the r e s e a r c h worker and a l s o i n p a r t to the f a c t that v a n i l l i n i s not the e a s i e s t m a t e r i a l w i t h which to d e a l .  The presence of the h y d r o x y l  group p a r a  to the c a r b o n y l group makes t h i s s t a r t i n g m a t e r i a l r e a c t i v e and g i v e s u n p r e d i c t a b l e In the f i r s t  results i n typical  s y n t h e s i s , the c o n v e r s i o n  highly reactions.  of the a c y l  c h l o r i d e to the a c y l cyanide was never found to be s u c c e s s f u l . Many r e f e r e n c e s  are* g i v e n i n the l i t e r a t u r e t o the r e a c t i o n s  of a c y l c h l o r i d e s w i t h KCN, HON, compounds very  Hg(CN)  s i m i l a r to v a n i l l i n .  2  and AgCN, u s i n g  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 t e s t f o r n i t r o g e n and a n e g a t i v e  test f o r chlorine.  T h i s may have been  due to f a u l t y technique because on the f a c e of i t t h e r e i s no reason why the b e n z o y l v a n i l l y l c h l o r i d e should not be converted  i n t o the c o r r e s p o n d i n g cyanide, u n l e s s  thermodynamically i m p o s s i b l e .  o f course, i t i s  In a l l of these syntheses the  r e a c t i o n s were d u p l i c a t e d and the c o n d i t i o n s were f o l l o w e d as c l o s e l y as p o s s i b l e to those o u t l i n e d f o r s i m i l a r syntheses of a c y l cyanides.  U n l e s s the a c y l cyanide has a m e l t i n g  point  c l o s e t o t h a t of the c h l o r i d e , which i s u n l i k e l y , i t would be reasonable to say t h a t the above r e a c t i o n does not take p l a c e , at l e a s t not under the c o n d i t i o n s that have been t r i e d i n t h i s  30. laboratory.  Thermodynamically the r e a c t i o n p r o b a b l y goes  r e a d i l y , however the c o n d i t i o n s n e c e s s a r y may  be h i g h l y  specific. The second method attempted i s undoubtedly the most obvious o f the t h r e e , however i t i s not as simple as i t appears on paper due t o the d i f f i c u l t i e s encountered on reduction.  T h i s same method was used i n the s y n t h e s i s o f  the c o r r e s p o n d i n g 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 u n s u c c e s s f u l due t o the f a c t  that  e i t h e r the end p r o d u c t s were non i s o l a t a b l e or were h i g h l y r e m i n i s c e n t of v a n i l l i n , the s t a r t i n g m a t e r i a l .  The  end  products of the h i g h pressure, hydrogenation have n o t y e t been i s o l a t e d and c h a r a c t e r i z e d , but i t appears t h a t  this  r e a c t i o n has proceeded p a r t i a l l y , a t l e a s t , i f the i n d i c e s of r e f r a c t i o n are any  criteria.  The l a s t method attempted i s r e a l l y o n l y i n i t s i n i t i a l phases and v e r y l i t t l e  can be s a i d a t t h i s time as to'  whether or not i t i s going t o be s u c c e s s f u l . arrangement  should not prove too d i f f i c u l t ,  The a c t u a l r e the main problem  w i l l l i e i n the c o n v e r s i o n o f the r e a r r a n g e d product t o the primary amine and subsequent  reduction.  31.  CONCLUSION  None of the three methods attempted has been , f o l l o w e d through to a s u c c e s s f u l c o n c l u s i o n . six  step s y n t h e s i s , was  the a c y l cyanide a two  The f i r s t ,  h a l t e d when a l l attempts to make  ended i n d i s m a l f a i l u r e .  step s y n t h e s i s , i s n e a r i n g completion  The  succeed.  i s the l a c k of h i g h p r e s s u r e  equipment i n the  again we  second method,  and  the method that w i l l f i n a l l y  department.  a  The main  i s probably hindrance  chemistry  Method number t h r e e , i s q u i t e p o s s i b l e but here  have a l o n g s y n t h e s i s , s i x s t e p s , which i s always a  hindrance.  32  SUGGESTIONS FOR  FURTHER RESEARCH  I n v e s t i g a t i o n s should be c o n t i n u e d on the s y n t h e s i s of the a c y l cyanide w i t h c a r e f u l a t t e n t i o n p a i d to the temperature  o f the r e a c t i o n , which should be kept i n the  neighbourhood o f zero degrees  and a l s o t o the time f o r which  the r e a c t i o n i s allowed to proceed. KCN  and HCN  The methods  are the e a s i e s t w i t h which to work and  employing should  g i v e the h i g h e s t y i e l d s . In the case of the cyanohydrin, the r e d u c t i o n u s i n g P a l l a d i u m should be attempted. work due time.  P l a t i n u m was  to the f a c t t h a t p a l l a d i u m was  used i n t h i s  u n a v a i l a b l e a t the  The h i g h p r e s s u r e work should a l s o be c o n t i n u e d i f a t  a l l p o s s i b l e , as t h i s i s the c l e a n e s t and reduce the  s u r e s t way  to  cyanohydrin. The i n v e s t i g a t i o n employing  should be continued.  The  the F r i e s Rearrangement  s t a r t i n g material i n this synthesis  i s g u a i a c o l whereas i n the o t h e r two  syntheses i t i s v a n i l l i n .  Thus, i f the d e s i r e d end product i s i s o l a t e d u s i n g t h i s procedure,  i t w i l l p r o v i d e 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 p h y s i c a l and chemical p r o p e r t i e s , p r o v i d e d of course, t h a t e i t h e r method one or two  i s successful.  33. BIBLIOGRAPHY 1.  Chemistry of the Simpler Bases, B a r g e r and. Dale.  2.  I n d u s t r i a l and E n g i n e e r i n g Chemistry, 37 #2, %  •  126,  1943(Eeb)  —  3. A. I . Vinogradova and V. N. Arkhangel'skaya, Chem. A b s t r a c t s  41, 425, 1947  4. Staudinger and  a l s o J . Gen. Chem.(TT.S.S.R.)  Kon,  Ann.,  384,58,1911.  3. Staudinger, Kene, Prodrom  Ber., 46,3530,1913.  6. Baeyer and  Ber., 31,1569,1900.  7. 8.  Villiger  P r i v a t e communication, Dr. R. A. P a t t e r s o n , P o w e l l R i v e r Company L t d . , F e b . ( l 9 4 7 ) . (a)  Organic Reactions  Can.Jour•Re searoh  (b) H i b b e r t , H. (c)  H i b b e r t , H. and  G.H.  Tomlinson  J.A.CS.,58,345,1936 56,348,1936  (d) i b i d (e) 9.  105.  Vol.II,R.Adams,page  58,340,1936  ibid  Ber., 62,1177,1929.  Lock  Ber., 12» 306,1904. 4  10. Khoevenagel  and Walther  11. R e i c h e r t and Koch 12.  B a l t z l y and Buck  13.  K u l z and Hornung  14.  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.  15.  Buck  J.A.C.S., 2i»3388,1933.  16.  A l o y and Robout  Bull.Chim.de France 11,390,1912.  17.  Nagai,  C A . , 16,990,1922. U.S.,~T,399,144.  18.  F r a n c i s and N e r n s t e i n  Ann.,  582,204,1911.  19.  Maunthner  Ber.,  42,192,1909.  W.N.  (4)  34. BIBLIOGRAPHY  (Cont'd)  20. B a r b i t e t and Rosenthal, L.  Ber., 44,2463,1911.  21. V o r l a n d e r  Ber., 44,2455,1911.  22.  Anschutz,  R.  Ann.,  23. M a i h l e , A.  368,76-88,1909.  Bull.Soc.Chim., 23,380,1918 a l s o C.A., 13_, 321, I9T9. 10,392,1927,  24. R e i c h s t e i n  Helv.Chim.Acta,  25. Rosemund and L o h f e r t  Ber., 61,2601,1928.  26.  Vol.1,  Organic Reactions  27. C o u l t h a r d , M a r s h a l l and Pyman  R.Adams, page343.  J.of Chem.Soc.,Vol.1, 288,1930.  28. P e a r l , I . A .  J.A.C.S., 68,1100,1946.  29.  Ber., 15_,2068,1882.  Teimann and Kraz  30. Heaps, T. and Robinson,  J.C.S., 2342,1926.  R.  (a) i b i d 51. Romeo, G. and P i r r o n e , F.  Ann.Chim.Appliceta, 18,189, 1928, a l s o C.A.,_22,3863, 1928.  32.  Reactions of Hydrogen, Wisconsin Press.  Adkins, H.  53. WInans and Adkins  J.A.C.S., 21,306-12,1932 a l s o C A . 26,969,1932.  34.  Ind. and Eng.Chem.,14 Dec. 1946.  35. Organic 36.  V o l . I I * page 570, ,1941.  Syntheses  I n o r g a n i c Chemistry, by P a r t i n g t o n .  37. Rupp, F. and Gay, S .  Apoth.Ztgs.,23,373T74. a l s o C A . 2,312771908.  38. Zapworth, Manoie and co-workers  J.C.S.,  2533, 1928.  J.CS.,  1976,  1931.  

Cite

Citation Scheme:

        

Citations by CSL (citeproc-js)

Usage Statistics

Share

Embed

Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                        
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            src="{[{embed.src}]}"
                            data-item="{[{embed.item}]}"
                            data-collection="{[{embed.collection}]}"
                            data-metadata="{[{embed.showMetadata}]}"
                            data-width="{[{embed.width}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
http://iiif.library.ubc.ca/presentation/dsp.831.1-0062444/manifest

Comment

Related Items