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Quaternary salt formation of cinnolines Powell, Rees Kenneth 1951-12-31

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QU/. T E R N A R Y  S A L T  F O M A T I ON  OF  C I N N O L I N E S  R E E S A  T H E S I S  K E N N E T H  S U B M I T T E D  T H E  I N  R E Q U I R E M E N T S M A S T E R  i n  t h e  POWELL  P A R T I A L  F U L F I L M E N T  FOR  DEGREE  OF  THE  OF  OF  A R T S  d e p a r t m e n t o f  •  We  a c c e p t  s t a n d a r d d e g r e e  M e m b e r s  THE  t h i s ,  C H E M I S T R Y  t h e s i s  r e q u i r e d  o f  M A S T E R  o f  t h e  U N I V E R S I T Y A p r i l ,  a s  f r o m O F  c o n f o r m i n g  c a n d i d a t e s  O F ' B R I T I S H 51  f o r  t h e t h e  A R T S .  D e p a r t m e n t  19  t o  o f  C h e m i s t r y .  C O L U M B I A  ABSTRACT  QUATERNARY SALT FORMATION OF CINNOLINE  T h i s study was i n i t i a l l y undertaken with a view to p r e p a r i n g quaternary s a l t s o f c i n n o l i n e s i m u l a t i n g the structmre o f the a l k a l o i d  papaverine.  T h i s would be p o s s i b l e by the s y n t h e s i s o f two compounds, v i z . , 6,7-dimethoxycinnoline dimethoxybenzyl-chloridei been encountered and  and 3 , 4 -  Some d i f f i c u l t y has  i n the s y n t h e s i s o f the former  from experimental evidence now a t hand the-  l a t t e r can be c o n s i d e r e d to be u n s t a b l e . Some new examples o f quaternary  salts  o f 4-methycinnoline are r e p o r t e d but i n general i s o l a t i o n o f s a l t s from 4-methycinnoline and b e n z y l - h a l i d e s has been found ,due  impractical  to t h e i r h y g r o s c o p i c p r o p e r t i e s .  AGOOWIiEDGEMENTS  The  author g r a t e f u l l y  willing  and  who  during  has  able  acknowledges;  assistance  the  o f Mr.  who  H.M.  Erlendson,  prepared  Valuable B.  Garvie,  some o f t h e  investigation.  a l s o The  National  for material assistance  form o f a b u r s a r y . by  G.G.S. D u t t o n  course o f the i n v e s t i g a t i o n  b e e n a most h e l p f u l a d v i s o r ; Research Council  the  a i d was and  G.  in  the  provided Kilgour  compounds u s e d  in this  CONTENTS  INTRODUCTION  THEORETICAL I  II  Cinnoline formation.  Quaternary  salt  formation  DISCUSSION  EXPERIMENTAL  SUPPLEMENT S y n t h e s i s o f some o r t h o - and para hydroxy s u b s t i t u t e d BIBLIOGRAPHY  aryl-phenones  BrTRODTTGTIOK  The  quest  possessing activity  f o r new  and  v a r y i n g degrees o f  dates  greatest  compounds, however, due  The  plant  storehouse  to the  of  great  strides  i n organic  an  i n c r e a s i n g number o f a c t i v e s y n t h e t i c  ever  synthesis  molecules  pharmacological  back to a n t i q u i t y .  a l k a l o i d s have b e e n t h e active  improved  i n more r e c e n t  times,,  41 compounds i s b e i n g put  reported.  King  forth a plausible structure for  cholride activity poisons  (A) and  a quaternary  salt  i n part responsible  o f the  South American  (A)  I  has  recently  d-tuboeurariiB  having  eurariform  f o r the  Indians.  arrow  Greig  i n h i s accoa n t  i n . t a b u l a r f o r m 58  of curariform  pages o f  activity  q u a t e r n a r y ammonium  the m a j o r i t y  o f w h i c h have c u r a r i f o r m  c l i n i c a l use  of papaverine,  (B)  and  clearly  quinoline  demonstrates the  salts,  activity.  The  i t s substitute  6,7-methylenedio;xy-l-VPyriayl-3-methyl (C)  lists  activity  isoquinoline,  of the  iso-  nucleus.  OCH  3  (01  (B)  Papaverine i t s e l f s l e e p which, d o e s not increased. and  Larger  i n small  become d e e p e r a s  of the  medicine  the  ensue.  light  dose i s  doses produce r e f l e x  some t e t a n i s i n g a c t i o n may  clinical  doses produces  irritability I n modern  i t i s used for i t s paralysing  smooth m u s c l e o f t h e  i n t e s t i n e s and  action  blood  4? vessels. is  Greig  frequently  In p y r i d i n i u m , salts  the  actions  has  shown t h a t  associated  the  benzyl  with paralyzing  strychninium,  coniinium  whereas 1 - b e n z y l i s o q u i n o l i n e s  actions. II  action.  and  H - b e n z y l d e r i v a t i v e s have t h e  group  brucinium  greatest  have  curare  relaxing  In view o f the coincidence quaternary  salts  between a c t i v i t y  and t h e b e n z y l  of  group, t h e s y n t h e s i s  o f a m o d e l compound c o n t a i n i n g t h e i s o q u i n o l i n e l i k e structure, with  a benzyl  n i t r o g e n and h a v i n g  group a t t a c h e d  to a  quaternary  a constitution simulating  p a p a v e r i n e was a t t e m p t e d ,  (D).  ocri  3  (3»  The  only  nary  salt  son  who  w  reference  formation obtained  i n the l i t e r a t u r e  to  quater-  i n the cinnoline series  is^Simp-  t h e m e t h y l and e t h y l i o d i d e s o f  some c i n n o l i n e d e r i v a t i v e s , b u t d i d n o t make any  16 reference account  to possible a c t i v i t y .  o f the c h e m i s t r y  Leonard  in his  o f c i n n o l i n e s r e p o r t s no  suggested use f o r c i n n o l i n e s as m e d i c i n a l s . A l t h o u g h t h e compound an  (D) h a s n o t been  prepared  e x p l a n a t i o n o f the d i f f i c u l t i e s i n v o l v e d i n the  synthesis  o f such  number o f new  s t r u c t u r e s i s s e t out, and a  cinnoline salts  III  are reported.  T H E O R E T I C A L  Cinnoline the  I  i s a hetrocyclic binuciear  same n u m b e r i n g a s q u i n o l i n e  v i c i n a l nitrogen of the four  atoms.  isomeric  base h a v i n g  and c o n t a i n i n g  two  I t i s t h e l e a s t w e l l knowi  structures.  00 oo 00 Quinoxaline  The d i s c o v e r y when v o n R i c h t e r  of cinnoline 1  Phthalazine  d a t e s b a c k t o 1883  c l a i m e d t o have o b t a i n e d a  a t i v e o f the di^-nitrogen base. derivatives received  little  Quinazoline  deriv-  The compound o r i t s  attention u n t i l  when S i m p s o n a t t e m p t e d t o p r e p a r e compounds  1945 contain-  ing the c i n n o l i n e nucleus having a n t i m a l a r i a l The d i s c o u r a g i n g  factor i n cinnoline  c h e m i s t r y has  d o u b t l e s s b e e n t h e l a c k o f a c o n v e n i e n t method preparation isomeric  i n contrast  activity.  t o t h e more r e a d i l y  of  accessible  compounds.  To d a t e s i x m a i n methods f o r t h e p r e p a r a t i o n c i n n o l i n e s have been quoted. Richter  involves  The method o f v o n  the c y c l i z a t i o n o f d i a z o t i s e d  aminophenylpropiolic acids, (1).  1  of  o-  (1)  A somewhat easier route to the cinnoline r i n g system 2  was explored by Stoermer and Fincke discovered by Widman  using a reaction  involving the c y c l i z a t i o n . o f  diazotised o-aminoarylethylenes responding 4 - a r y l c i n n o l i n e s .  to produce the corThe requisite d i - a r y l -  ethylenes being obtained from the appropriate diary1ketones and Grig&nard reagent, followed by dehydCration of the r e s u l t i n g carbinols. ( 2 ) .  S t o l l e " and Becker  i n an attempt  to,prepare N-amino  i s a t i n synthesized 3-phenylcinnoline-4-carboxylic a c i d by the f o i l i n g s e r i e s o f r e a c t i o n s . (3)  In 1941 Borsche  and H e r b e r t  0  d i s c o v e r e d the acetpphenone  s y n t h e s i s o f 4 - h y d r o x y c i n n o l i n e by d i a z o t i s a t i o n o f o-aminoacetophenone. (4)  Janeeke  In 1942 P f a n n s t i l l and  obtained h i g h l y s u b s t i t u t e d c i n n o l i n e s by  dehydration o f an o-carboxyphenylhydrazine, y i e l d s obtained were very p o r r .  but t h e i r  It i s well to state  here that i n a l l examples mentioned, except  i n the  case o f von R i c h t e r , the formation o f ""the c i n n o l i n e  3  was  i n c i d e n t a l to the main purpose of the 7  In 1947  Jacobs et a l .  investigation.  R and  Simpson  obtained 4-methylcinnoline  hy the Widman-Stoermer r e a c t i o n . They s t a r t e d from r e a d i l y a c c e s s i b l e methylanthranilate bromide and and  and  by treatment w i t h methylmagnesium  dehydration, f o l l o w e d  c y c l i z a t i o n of the  by d i a z o t i s a t i o n  r e s u l t i n g o-iso  propenylaniline  obtained 4-methylcinnoline i n o v e r a l l y i e l d o f 70$.(5).  This was  the  r i n g was  f r e e from f u n c t i o n a l groups thereby opening  the way  first  synthesis  o f a c i n n o l i n e where the  f o r a study o f the b a s i c p r o p e r t i e s  cinnoline Of the  the  nucleus. s i x methods a v a i l a b l e f o r the 9  o f the  of  c i n n o l i n e nucleus, Simpson  they a l l proceed by the  preparation (  has  same mechanism.  shown that He has  t h a t c i n n o l i n e formation i s dependent on a h i g h l y p o s i t i v e diazonium k a t i o n and  4  at the  same time,  found  on the a v a i l a b i l i t y of the  ortho  o f e l e c t r o n s at the  ^-carbon atom  substituted chain.  C o n s i d e r a t i o n o f the mechanism of the R i c h t e r r e a c t i o n shows t h t t the c a r b o x y l of the acid, and,  ( 6 ) , has at the  a r e l a t i v e l y negative  same time,  o-aminopropriolic  ^-carbon atom  the i n d u c t i v e e f f e c t  c a r b o x y l group on the r i n g i n c r e a s e s ' t h e charge on the diazonium k a t i o n and is  o f the  positive  so c i n n o l i n e formation  favoured.  (6) In order to e l u c i d a t e the mechanism of the Widman-Stoermer r e a c t i o n Simpson ^ s t u d i e d the i n 1  f l u e n c e o f s u b s t i t u e n t s Ra  and Rb,  (7),  with-respect  to the ease with which o-aminoarylethylenes c l o s e d to give c i n n o l i n e s .  Stoermer and  d i s c o v e r e d that o-aminocinnamic a c i d , R b r COOH, does not y i e l d a c i n n o l i n e . more evidence negative  ring Gaus  ( 7 ) , Ra=H, Considerably  i s a v a i l a b l e to show that when Rb  c i n n o l i n e formation  Pschorr r e a c t i o n , ( 7 ) , Ra=  H,  is inhibited. Rb=Ph,  1 1  is  In the  Rc=C00H,  (7)  R d = H ,  d i a z o t i s a t i o n  b o x y l i c  a c i d .  a n d t o  R b ^ H , t h e  i s  a n y  s u c h  c i n n o l i n e  a b s e n c e  c a r b o u . R a =  I n  l e a d s  o f  t h e  H o w e v e r  COOH,  Rb  a v a i l a b l e  i n  = H ,  now  p h e n a n t h r e n e ~ 9 - c a r -  r e a c t i o n  w h e r e  f o r m a t i o n  i s  n e c e s s a r y  h y d r o g e n  c o m p o u n d s  Rc  and  t o  = P h , t h e  o f  i m p o s s i b l e  t h e  o n  a n d  R a , o w i n g  t h e  t y p e ,  R d = m e t h y l ,  P s c h o r r  b o t h  ^~  ( 7 ) ,  T h i s  h y d r o g e n  W i d m a n - S t o e r m e r 12  r e a c t i o n s h a v e  s h o w n  y i e l d s  The  a r e  t h a t  M a y e r  d i a z o t i s a t i o n  n o n - f o r m a t i o n  t h e  p o s s i b l e .  o f  a n d  t h i s  B a l l e  l a t t e r  2 - m e t h y l p h e n a n t h r e n e - l O - r c a r b o x y l i c  t r i b u t a b l e o r  b o t h  e i t h e r  c a r b o x y l  o f  c i n n o l i n e  t o  the  o n  t h e  a r y l  i n  t h e s e  r e s i d u e  ^ - c a r b o n  o r  a c i d ,  c a s e s  o n  t o  e t h y l e n e  t h e  (8)  i s  .  a t -  ^ - c a r b o n  b o t h .  F u r i b h e r  1 3 S a c h s i n  a n d  w h i c h  H i l p e r t b o t h  h y d r o g e n s  h a v e , s h o w n  <*--and  d e c o m p o s e  t h a t  < i > - e t h y l e n i c on  2 - a m i n o s t i l b e n e s  c a r b o n  d i a z o t i s a t i o n .  a t o m s  c a r r y  H o w e v e r ,  14 R u g g l i  a n d  d e r i v a t i v e s c a n  be  S t a u b  h a v e  s h o w n  a n d  i f  t h e  c i s  o b t a i n e d  i n  8 0 $  y i e l d .  6  t h e s e  f o r m s  a r e  w e r e u s e d  R u g g l i  a n d  t r a n s p h e n a n t h r e n e D i n g e r  1  5  .  h a v e  d i a z o t i s e d  h a v e  i n n o  c a s e  c o m p o u n d s . f o r m a t i o n n e g a t i v e  o t h e r  i s o l a t e d  We i s  c i s -  must  a n y  a n d  ,  w h e n , R a =  t r a n s - s t i l b e n e s  n i t r o g e n  t h e r e f o r e  i n h i b i t e d  g r o u p  a n d  H,  c o n t a i n i n g  c o n c l u d e  (9),  t h a t  R h =  o r  a n d  a r y l  c i n n o l i n e o r  o t h e r  COOH.  I  (9) T h i s  i s  a n i s m ,  i n  a g r e e m e n t  v i z ,  t h a t  w i t h  t h e  S i m p s o n ' s  \ i - c a r b o n  s u g g e s t e d  a t o m  m u s t  b e  m e c h r e l a t i v e l y  n e g a t i v e . The  m e c h a n i s m  d i s c o v e r e d a n d  so  D u r i n g  e n o l i z a t i o n i n  u s e d  s u p p o r t e d t h e  o r d e r  t h e  a c e i d e n t l y  a p t l y  f u r t h e r  o f  b y  4 - h y d r o x y c i n n o l i n e  b y  S i m p s o n  S i m p s o n ' s  d i a z o t i s a t i o n o f  t h a t  t h e  B o r s c h e  k e t o n e  c y c l i z a t i o n  a n d  a n d co  t h e o r y  o f  s y n t h e s i s ,  H e r b e r t , w o r k e r s ,  o f  ( f o o t n o t e ) h a s  c i n n o l i n e  f o r m a t i o n .  o - a r n i n o a c e t o p h e n o n e s ,  m u s t may  o c c u r t a k e  a t  spme  p l a c e ,  s t a g e (10).  OH  (10)  footnote:  They were c a r r y i n g o u t t h e San&meyer  to  o-Br-acetophenone.  obtain  reaction  Leonard  16  has  suggested that the r e a c t i o n may  involve  an i n t r a m o l e c u l a r c o u p l i n g of the diazonium k a t i o n with an enolate  anion, t h i s would be a k i n to the  coupl-  ing r e a c t i o n of diazonium s a l t s with phenoxide ions to form azo dyes.  T h i s mechanism i s h i g h l y untenable  as c i n n o l i n e c y c l i z a t i o n takes p l a c e  in  concentrated  a c i d whereas diazonium c o u p l i n g takes place i n b a s i c ' „ ' 17 solution. F u r t h e r Hodgson and Marsden have s t a t e d that i n the  c o u p l i n g r e a c t i o n o f diazomium s a l t s under  a l k a l i n e c o n d i t i o n s the r e a c t i v e species i s not the . 18 simple diazohium i o n . Wa tson sets out the accepted t  mechanism f o r a c i d - c a t a l y s e d e n o l i z a t i o n o f a  carb-  19 onyl group and  Simpson  has  ism of c i n n o l i n e formation transformations,  (11).  8  i n t e r p r e t e d the mechan-  by the f o l l o w i n g s e r i e s o f  He has found t h a t the y i e l d o f c i n n o l i n e from a given d i a z o t i s e d O-aminoacetophenone i s a competition r e a c t ion  o f the diazonium k a t i o n f o r the negative  carbon  atom or the r e a c t i o n o f the diazonium k a t i o n to form a h y d r o x y l group.  In keeping with t h i s theory he has  found a h i g h y i e l d o f c i n n o l i n e u s i n g h i g h a c i d c o n c e n t r a t i o n and low temperature.  Simpson has also •  s t u d i e d the formation o f c i n n o l i n e when groups that w i l l vary the b a s i c i t y o f the amino group a r e present i n the r i n g o f the o-aminoaeetophenone.  Electron  a t t r a c t i v e groups para to the amino group w i l l produce a r e l a t i v e l y weaker base.  On d i a z o t i s a t i o n  these  weak bases w i l l produce a r e l a t i v e l y more p o s i t i v e diazonium k a t i o n , and an expected h i g h e r y i e l d o f the corresponding c i n n o l i n e .  Included i s a t a b l e compiled  from Simpson's separate papers which c l e a r l y out t h i s  bears  theory.  Cinnoline 4-0H  ConAitions 75$ H S 0 2  tt 7-Cl-#0H  4-0H-3-methyl  tt  6- C1-4-0H7-methyl  10$  3.5NHC1, room temp, cone. HOI, 50-60°  42$ 70$  5ir H C I , 0 3.5H" H S 0 , E8 days @ 20 then 70-80° f o r 1 hour cone H C I  30$ 81$ 90$  2B HCI, room temp, cone HCI,  18$ 83$  5N HCI, 70^80° 21 HCI, 70-80°  90$  2  tt  and HAe, 10-90°  4  Yield  9  4  From the f o r e g o i n g c o n s i d e r a t i o n s we  conclude  that  the ease o f formation and the y i e l d s o f c i n n o l i n e depend on two on. the  f a c t o r s , the a v a i l a b i l i t y of e l e c t r o n s  ^-carbon  atom and  the weakness o f the amino  group o f the ortho-amino compound.  THEORETICAL I I  20 Simpson  has  shown t h a t the b a s i c center o f  4-methylcinnolines quaternary  i s at H i .  He attempted to produce  s a l t s o f 4-methylcinnoline  o f t h e i r decomposition  and by a  study  r e a c t i o n s determine the p o s i t i o n  o f attachment o f the quaternary  group thereby  locating  the center o f b a s i c c h a r a c t e r of the compound. The methiodide cinnoline,  obtained from 6-chloro-4-amino-  (11), on treatment  with hot a l k a l i  to be 6 - c h l o r o - l - m e t h y l - 4 - c i n n o l d n e , as the same product  (12),  obtained by treatment  proved  identified of 6-  c h l o r o - 4 - h y d r o x y c i n n o l i n e with methyl s u l p h a t e . Whereas.treatment o f 4 , 6 - d i c h l o r o c i n n o l i n e w i t h sodium methoxide y i e l d e d the isomeric methoxycinnoline,  (13).  10  6-chloro-4.-  (12)  (11a)  The p e s i t i o n o f quaternary  (13) s a l t formation i n 6-chloro-  4-aminocinnoline  i s thus e s t a b l i s h e d at N .  the condensation  o f 4-methylcinnoline  1  p-dimethylaminobenzaldehyde^  1  Further  e t h i o d i d e with  to produce dyes shows  enhanced a c t i v i t y of the 4 p o s i t i o n due to the b a s i c c h a r a c t e r of  Jacobs et a l . ^ 2  w  e  able to condense  4 - m e t h y l c i n n o l i n e with benzaldehyde i n the presence zinc chloride,  of  (14), a r e a c t i o n a k i n to the condensat-  i o n o f benzaldehyde with 2 , 4 - d i n i t r o t o l u e n e , (15).  (14)  (15)  These f a c t s p o i n t to N]_ as the b a s i c center o f 4 s u b s t i t u t e d c i n n o l i n e s , t h i s being the p o s i t i o n of highest e l e c t r o n density. Because the author was o f quaternary  i n t e r e s t e d i n the  formation  salts of cinnoline, a consideration  o f the f a c t o r s a f f e c t i n g quaternary i n g e n e r a l was Menschutkin^  salt  formation  undertaken. 3  s t u d i e d the r e a c t i o n o f t r i e t h y -  11  amine w i t h found the relative  a l k y l - h a l i d e s i n acetone at r e a c t i o n t o be  bimolecular  v e l o c i t y c o f f i c i e n t s are  100  and  given  o.  He  his in  the  following table. methyl  1140.0 10.0  ethyl n-propyl  1.93  n-butyl  1.38  n-heptyl  1.08  n-oetyl  1.0  Long  24  has  measured the  t e r i a r y bases with salts.  His  rates  organic  of interaction of  h a l i d e s to  r e s u l t s were o f t h e  form  cyclic  quaternary  same o r d e r  as  25 Menschutkin s.  Thomas  1  various on  the  alkyl  g r o u p s and  reactivities  organohalides, he  explained  studied  of t e r t i a r y  A modern t h e o r y  I s now  of various  at hand.  aromatic bases the  mode o f t h e  steric  been o f t e n  expand t h e i r v a l e n c e  and halides  said that neon  s h e l l b e y o n d and  d§y,  hindrances.  s u b s t i t u t e d b a s e s and  I t has  with  of  o f r e a c t i o n mechanism  e l e m e n t s l y i n g b e t w e e n h e l i u m and  efforts  substituents  variations in reactivity  s u b s t i t u t e d b a s e s o r h a l i d e s by  reactivity  effects of  some n u c l e a r  however, a s was  any  the  the  cannot octet.  to o b t a i n d e r i v a t i v e s o f 5-covalent  All nitrogen  26 have been u n s u c c e s s f u l . compounds  containing  12  S c h l e n k and  Hotlz  prepared  5 hydrocarbon  groups i e , teramethylammoni\im b e n z y l ,  however they found them to behave as i o n i z e d (CH ) N:' " R t  3  4  .  Attempts  salts  to o b t a i n compounds with  5 simple a l k y l groups by the i n t e r a c t i o n o f quaternary ammonium h a l i d e s w i t h metal a l k y l s were unsuccessful  2 7  .  F u r t h e r i n no case was the a l k y l group d e r i v e d  from the metal found enter the valence s h e l l o f the n i t r o g e n atom.  I t must be assumed then that the  n i t r o g e n atom with i t s 5 valence e l e c t r o n s can coor d i n a t e 3 a l k y l groups; and then w i l l  each donating a n ' " e l e c t r o n ;  share i t s p a i r o f e l e c t r o n s w i t h any  e l e c t r o n seeking reagent, but i t w i l l not coordinate more than 4 groups d i r e c t l y i n i t s valence  shell.  Baker28 has make am\ exhaustive study o f the f a c t o r s a f f e c t i n g quaternary s a l t  formation.  He has shown  the r e a c t i o n o f s u b s t i t u t e d b e n z y l - h a l i d e s w i t h p y r i d i n e to form s a l t s proceeds by two steps, a ) , the a n i o n i s a t i o n o f the halogen and, b ) , c o o r d i n a t i o n o f the n i t r g e n atom with i t s e l e c t r o n paii? to the now e l e c t r o n d e f i c i e n t methylene system. see then that  i n salt  Y/e  formation the e l e c t r o n pair-  o f the n i t r o g e n accepts the f r e e a r y l r e s i d u e only a f t e r a n i o n i s a t i o n has taken p l a c e .  It i s therefore  c l e a r t h a t n u c l e a r s u b s t i t u e n t s i n the h a l i d e which enhance a c c e s s i o n o f e l e c t r o n s to side c h a i n , l e , CHg,  OCHg, w i l l enhance s a l t formation and v i c e v e r s a .  Hence a n i o n i s a t i o n o f the halogen  13  i s the main f a c t o r  in determining relative reactivities of benzyl-halides in reactions with pyridine. Alteration of the halogen atom for any given benzyl;- nucleus introduces a striking anomaly.  Since  the velocity of the reaction is determined mainly by the ability for anionisation of the halogen i t would be expected to increase in the order of electron affinity K  Br <CI.  for quaternary  However the experimental  order  salt formation is found to be the  reverse C K B r < I ,  This suggests a consideration  as to whether the ease of separation of the halogen atom as a negative ion is necessarily the same as the order of anionic stabilities of the halide ions. Considering again nuclear substituents, Baker^ found that p-methoxybenzyl-halides formed pyridinium salts so fast the velocity could not be measured.  He  suggests that the resonance effect of the p-methoxy group i s strong enough to produce an "icnized salt" from of the halide, (16).  We see then in this case  anionisation"; the rate determing step in the reaction? has occurred even before the pyridine is present. Footnote.  (16) footnote.  See under discussion.  14  As a f u r t h e r c o n s i d e r a t i o n mechanism Baker  i n salt  formation  has shown that a c t i v a t i o n energies  f o r the r e a c t i o n o f "benzyl-bromide w i t h p y r i d i n e are almost i d e n t i c a l with those o f oL-picoline. strength as  I f basic  i s a measure o f e l e c t r o n a v a i l a b i l i t y  then  c t - p i c o l i n e i s ten times as strong a'base as p y r i d -  ine, electron a v a i l a b i l i t y quaternary s a l t f o r m a t i o n .  can have l i t t l e  e f f e c t on  . " " < : • • . . , "  In summary Baker has shown that the r e a c t i o n between b e n z y l - h a l i d e s and  involves  and t e r t i a r y bases i s b i m o l e c u l a r  simultaneous a d d i t i o n and d i s s o c i a t i o n  denoted by the e l e c t r o n c y c l e , ( 1 7 ) .  Although the  (17) energy o f a c t i v a t i o n i s u n a f f e c t e d  by s u b s t i t u e n t  groups i n the a r y l nucleus the v e l o c i t y o f the r e a c t ion i s altered.  E l e c t r o n accession  increases  react-  i o n v e l o c i t y up to a p o i n t but on the other hand electron recession recession  from the s i d e - c h a i n  para-nitro and  Greater  thatu;- that produced by  i n the nucleus, a l t e r s the mechanism  greatly  sidered  decreases the v e l o c i t y .  that  increases  the v e l o c i t y .  I t i s t o be con-  the e l e c t r o n c y c l e above i s to be comp-  l e t e d before s a l t  formation•will  occur, however,  i n i t i a t i o n ' o f t h i s c y c l e can occur by the i n c i p i e n t anionisation  o f the halogen, (a above), or the e l e c t r o -  s t r i c t i o n o f the t e r t i a r y base, (b above).  15  Baker has  found that the  c r i t i c a l p o i n t where the p r o b a b i l i t y  f o r i n i t i a t i o n o f the r e a c t i o n by methods (a)  and  (b)  We  i s equal i s at p a r a - n i t r o b e n z y l - h a l i d e .  can t h e r f o r e  say  that a l l groups i n the  that r e p e l e l e c t r o n s and to p a r a - n i t r o  nucleus  a l l a t t r a c t i n g groups down  r e a c t by method (a) and  a l l more power-  f u l e l e c t r o n a t t r a c t i n g groups r e a c t by method ( b ) . Such a view a l s o accomodated the effecit o f solvent the  on s a l t  formation.  i o n i z i n g power o f f the  w i l l be  the  experimental  solvent  effect of substituent  The  greater  the more pronounced groups i n the  nucleus i n enhancing or r e t a r d i n g the  halide  anionisation  31  o f the h a l i d e i o n .  Baker  influence of a parahitro e x i s t e n t i n 90$ i n the  showed that the  substituent  ethanol but  retarding  is clearly  i s absent i n dry  acetone,  face o f such r e s u l t s i t seems d i f f i c u l t to  longer assume that  i n non  i o n i z i n g solvents,  the  general inductive polar e f f e c t of substituents the h a l i d e nucleus i s concerned with the or p o l a r i z a t i o n o f the  measured h i s r a t e s o f r e a c t i o n by h a l i d e i?6n w i t h s i l i v e r n i t r a t e .  polarizability  t h a t Baker  t i t r a t i o n of He  a t r u e f u n c t i o n of the  concentration  present  The  author has  of i o n i c  16  was halide  found that some  o f these quaternary s a l t s do not behave as salts.  the  t h e r e f o r e made  assumption that the r a t e o f s4.lt formation  in solution.  in  carbon-halogen bond.  The .author would l i k e to p o i n t out  the  any  ionized  DISCUSSION.  In order to s y n t h e s i z e the quaternary s a l t which i s the analogue o f papaverine two products, 6,7,-dimethoxycinnoline and 3,4-dimethOxybenzylchloride are required.  N e i t h e r o f these compounds are r e p o r t e d i n the l i t e r a t u r e and so an attempted compounds was undertaken.  s y n t h e s i s o f these two  (18) and ( 1 9 ) .  E r l e n & s o n ^ has studied the Blanc reaction and side chain ehlorlnation using sulphuryl chloride. Although he d i d not obtain 3,4-dimethoxybenzyl chloride by either of the above methods he d i d obtain the following a l k y l substituted benzyl chlorides.  (19a).  5A  d  (19a)  18  From the t h e o r e t i c a l c o n s i d e r a t i o n s alreadypresented, page 7, i t i s seen t h a t the 2-iso p r o p e n y l 4,5-dimethoxyaniline, p o s i t i v e diazonium yield  (18-P) , w i l l produce a weakly  k a t i o n and an expected  lower  o f c i n n o l i n e than the corresponding u n s u b s t i t u t -  ed d e r i v a t i v e .  Simpson has obtained the ketone,  and has converted  (l8ol) ,  i t to the corresponding 4-0H-6,7-  dimethoxycinnoline.  No r e f e r e n c e has been made to  the r e a c t i o n o f t h i s ketone by the method proposed by the .author.  The ketone has been obtained but  r e d u c t i o n o f the n i t r o group to the amine has c o n s i s t e n t l y g i v e n poor y i e l d s and d i f f i c u l y encountered  has been  i n the r e a c t i o n o f t h i s ketone with  CH^gl  For c o n s i d e r a t i o n s r e g a r d i n g the formation o f s u b s t i t u t e d b e n z y l c h o r i d e s the reader i s r e f e r r e d to H.M. Earlenson*  3  Author prepared  .  He has i n c o n j u n c t i o n with the  a number o f mono- and d i - s u b s t i t u t e d  benzyl-halides.  In g e n e r a l the r e a c t i v i t y  o f the  h a l i d e i n c r e a s e s with Baker's theory o f s u b s t i t u e n t groups i n the nucleus, page (13).  Para-methoxy!.-  b e n z y l - c h l o r i d e was found to be so r e a t t i v e that it The  decomposed even on d i s t i l l a t i o n chloromethylation of  proceeded  a t reduced  pressure.  hydroquinonedimethylether  t o the d i s u b s t i t u t e d product, and the three  stylyl c h l o r i d e s converted t o the corresponding i o d i d e s w i t h sodium i o d i d e were s t a b l e only a few days. t h i s experimental  evidence  dimethoxybenzyl-halides  From  i t would seem t h a t 3,4-  are d i f f i c u l t to o b t a i n and u n s t a b l e .  19  I f Bakers theory is  correct,  and  o f quaternary  (page 15), t h e n ,  relatively  strong  w o u l d he e x p e c t e d  i e , N i of the cinnoline  "base due t o t h e e l e c t r o n  groups i n the n u c l e u s . of  The a n i o n i s a t i o n  the 3,4-dimethoxybenzyl c h l o r i d e  "by e l e c t r o n electron  accession  i n the side  r e l e a s i n g para-methoxyl  formation i n the cinnoline  isa  releasing o f the c h l o r i d e  i s made more  chain  facile  due t o t h e  group.  A l m o s t no work h a s "been r e p o r t e d salt  formation  6,7-dimethoxycinnoline  3,4-dimethoxy"benzyl c h l o r i d e  to r e a d i l y form a s a l t ,  salt  on quaternary  series  2 0  .  While  the  attempted synthesis  o f 6,7-dimethoxycinnoline  and  3 , 4 - d i m e t h o x y b e n z y l c h l o r i d e was b e i n g u n d e r -  t a k e n t h e a u t h o r made a s t u d y o f s a l t  formation  o f t h e r e a d i l y a v a i l a b l e 4 - m e t h y l c i n n o l i n e a n d some o f the  more common o r g a n i c - h a l i d e s .  i n v e s t i g a t i o n a r e summarized shows f o r t h e m a j o r i t y  The r e s u l t s o f t h i s  i n the table,  ( 2 0 ) , and  o f a r y l - h a l i d e s used f o r  r e a c t i o n with 4-methyleinnoline,  c o m p a r a t i v e l y few  s a l t s were i s o l a t e d i n a c r y s t a l l i n e  condition.  ?8 Baker"  studied  the rates  halides  with pyridine  prevent  errors  of reaction  i n dry acetone.  o f benzylIn order to  i n h i s r e s u l t s from h y d r o l y s i s  o f the  "i unused b e n z y l - h a l i d e s the  solvent  quaternary  due t o t h e p r e s e n c e o f m o i s t u r e i n  he u s e d t h e h y g r o s c o p i c p r o p e r t i e s  o f the  s a l t s t o d r y the acetone b e f o r e u s e . 20  He  ...  T a b l e (20)  base  halide  color  Qjuinoline  CH I  clear-yellow  1  C H I  clear-pale  2  benzylchloride  clear-red  3  benzylbromide  clear-cream  4  benzyliodide  olear-yellow  5  p-UOg-benzylbromide  clear-red  6  2,6-dimethyl-  CHgl  yellow  7  quinoline  CgHgl  yellow-red  8  benzylchloride  no  9  4-methyl-  CHgl  yellow-orange  10  cinnoline  C2H5I  yellow-red  11  n-C^gBr  yellow-green  12  benzylchloride  yellow-green  13  b enzylbromide  yellow-brown  14  benzyliodide  yellow-red  15  3-Me-benzylchloride  no  16  n tt  n tt tt  n  n t»  n tt tt tt tt  2  5  yellow  white  reaction  reaction  2-Me-benzylchloride yellow-blue 4-Me-benzylchloride no r e a c t i o n 2-0H-4-H02-benzylchloride yellow-green  17 18 19  3,4-diMe-benzylchloride  yellow-green  20  2,4-diMe-benzylohloride  yellow-blue  21  n  1,4-diMe-benzylohloride  yellow-blue  22  n  O-Cl-benzylchloride  yellow-dark  specks  23  n  p-Cl-benzylchloride  yellow-dark  specks  24  »  2 4-diCl-benzylchloride  yellow-blue  25  3,4-^diCl-benzyl c h l o r i d e  no  26  p-NOg-benzylbromide  yellow-pink-white  n n tt  2  S  change  tt it  t  21  reaction  27  time  form of s a l t  mp.°C.  remarks  1  £ hour  fine yellow needles  135  reported 133  .2  8 days  fine yellow prisms  14 5d  "  3  reflux 24 hours  coarse red prisms  113  « 65 & 170  tt  coarse cream prisms  192.5d  5  n.  coarse yellow needles  156  reported 135  6  n  red prisms  198  turns yellow at  7  3 dfiys  yellow white needles  240  reported  8  10 (lays  9  10 days  10  •§• hour  orange needles  196d  reported 169  11  4 hours  red needles  154  12  8 days  green s o l i d  13  90 (lays  green o i l  14  18 hours  yellow needles  15  3 hours  yellow red needles  16  8 days  17  8 (lays  18  Id days  19  30 seconds  green prisms  20  8 days  green o i l  21  8 days  blue prisms  22  4 days  clear blue prisms  23  8 days  dark scales  24  8 days  blue green prisms  25  8 days  clear prisms  91  26  8 days  27  3 hours  fine green needles  202  4  158  "  237  154  hygroscopic  hygroscopic n  clear blue prisms  hygroscopic  76  hygroscopic under 50  n  decomposition  22  ifeygroscppio  d i d not i s o l a t e halide  any o f t h e s a l t s h u t m e r e l y  i o n a t v a r i o u s t i m e s w i t h aqueous s i l v e r  The  i n t h e t a b l e a r e so h y g r o s c o p i c t h a t  i s o l a t i o n as c r y s t a l l i n e Further  i n a l l eases  h y d r a t e d o i l from this  needle  salt  formation has  due t o t h e s e p a r a t i o n o f a  t h e o r i g i n a l homogeneous  solution.  i s s o i s seen i n t h e f o r m a t i o n o f y e l l o w  like  crystals  from  a solution  o f 4-methylcinn-  and b e n z y l - i o d i d e i n d r y e t h e r i n a s e a l e d ampoule.  These c r y s t a l s  liquify  the atmosphere. has  their  compounds i s n o t f e a s i b l e .  i t i s considered that  occurred  oline  nitrate.  author b e l i e v e s t h a t c e r t a i n o f the s a l t s  described  That  t i t r a t e d the  t o a g r e e n o i l on e x p o s u r e  As f u r t h e r evidence t h a t  salt  to  formation  o c c u r r e d t h e a u t h o r p r e s e n t s t h e f o l l o w i n g ex-  perimental evidence.  The p r e c i p i t a t i o n o f s i l v e r  h a l i d e s on a d d i t i o n o f a q u e o u s s i l v e r n i t r a t e t o etheral far  s o l u t i o n s o f the o i l s  exceeding the r a t e o f h y d r o l y s i s o f the f r e e  organ!c-halides.  T h i s would i n d i c a t e  o f an i o n i z e d h a l i d e alkali oils  takes place a t a v e l o c i t y  to both  results  ion.  isolated  the presence  The a d d i t i o n o f a q u e o u s  crystalline  s a l t s and h y d r a t e d  i n the f o r m a t i o n o f b l u e dyes  o f q u a t e r n a r y ammonium  hydroxides,4®.,  23  indicative  It  has already  studied  "been s t a t e d , page  Baker  the rates o f r e a c t i o n o f benzyl-halides  electron repelling constituent. attracting  In order  t o examine t h e e f f e c t  s u b s t i t u e n t s an attempted  following reactions,  synthesis  of electron o f 6-  was u n d e r t a k e n by way o f t h e  (21).  c o m p l e t e d a s i t was f e l t  This  that  c o u l d n o t be i s o l a t e d ,  to expect  the l e s s  reactive  s y n t h e s i s was n o t  i f salts  cinnoline  form s a l t s  with  groups i n t h e n u c l e u s o f t h e b a s i c  nitro-4-methylcinnoline  would  (13),  there  o f 4-methyli s no r e a s o n  6-nitro-4-methylcinnoline  c a p a b l e o f i s o l a t i o n and a n a l y s i s .  COOCH  CH COCl  3  3  o  NH-&CH,  JHN0  3  CH,  COOH  HfcS0/M 4  T  I  NHC-CH,  -R.0  CH,  CH,  r  COOCH,  (21)  CH M,I  HONO  3  CH,  NO,  i oH  NH  NH,  2  24  EXPERIMENTAL  o-isopropene-aniline A  s o l u t i o n o f 50g. o f m e t h y l a n t h r a n i l a t e i n  5 0 0 c c . o f e t h e r was a d d e d d u r i n g s t i r r i n g h o u r t o CHgMgl, ether  750oc.,  (made f r o m Mg. 4 0 g . ,  yellow  "below 0 ° C .  suspension  5 hours.  C H g l 240g.  4 m o l e s o f G-rignard a r e r e q u i r e d f o r  e a c h mole o f e s t e r u s e d . maintained  o v e r f-  ).  The t e m p e r a t u r e was  d u r i n g t h e a d d i t i o n and t h e  was t h e n h e a t e d  under r e f l u x  The m i x t u r e was c o o l e d a n d p o u r e d  for  into  NH4CI a n d i c e a n d e t h e r l a y e r a l l o w e d t o s e p a r a t e . The  w a t e r l a y e r was f u r t h e r e x t r a c t e d w i t h  fresh  e t h e r a n d the combined e x t r a c t s d r i e d o v e r  anhydrous  MgSC>4 a n d t h e s o l v e n t removed by d i s t i l l a t i o n . of the o i l y  c a r b i n o l was r e c o v e r e d .  c o l d A c £ 0 gave a s o l i d  48g.  Acetylation,-with  derivative after  hour,  y recrtstallization mp.  f r o m b e n z e n e - l i g r o i n gave  1 4 6 ° , Simpson, The  tertiary  Dean a n d S t a r k  mp.  146-147°.  a l c o h o l was t h e n tube w i t h  needles,  dehydrated  i na  the a i d o f 250cc. o f d r y  toluene  and a s m a l l  crystal  of iodine.  retical  amount o f w a t e r was o b t a i n e d  The t h e o -  i n4  hours.  The  toluene  was removed u n d e r r e d u c e d p r e s s u r e a n d  the  residue  d i s t i l l e d using a mirror  Vigreux  jacketed  column, b p . o f t h e o l e f i n 8 4 ° / 4 m m . J a c o b s  et a l l  b p . 83.5 - 87.5 /i-gmm/'^SSg. ij t h e o r e t i c a l was r e c o v e r e d . 25  79$ o f t h e  4-methylcinnoline 30g.  o f t h e o l e f i n was  o f 60ec.  o f c o n e . HC1  u t i o n was  dissolved  i n 200cc.  was  immediately  The  c l e a r d a r k g r e e n s o l u t i o n was  a positive  obtained with starch-iodide  and warmed d u r i n g and h e l d at that  diluted  temperature  till  the  $-naphthol  t o a deep r e d .  The  200cc.  collected which.is a n e l i g i b l e  connected to  o f gas were  for 3  e t h e r e x t r a c t s were d r i e d and  the  ether y i e l d e d y e l l o w green c r y s t a l s . f r o m hexane gave mp.  Jacobs  mp.  et a l .  72.5  the e t h e r r e s i d u e under  calc.  - 74°.  / 3mm.  A  Distillation  b p . 1 3 3 ° /4mm.  sample  of  50$  Jacobs  Recrystallization  f o u n d 18.9$.  a n t h r a n i l a t e u s e d was  days.  72 - 7 4 ° .  gave g r e y - y e l l o w n e e d l e s rap. 7 4 ° . 19.4$.  extracted  reduced pressure y i e l d e d  o f a grey green s o l i d , 135-137°  sol-  evaporation of  recrystallized  hexane  The  made b a s i c w i t h aqueous NaOH a n d  The  et a l bp.  deaminat-  amount.  with ether i n a continuous extractor  24g.  bath  changed  t h e amount o f  i o n o c e u r i n g i n the r e a c t i o n ;  400cc.  became n e g a t i v e .  s y s t e m was  a gas b u r e t t e t o d e t e r m i n e  test  coupling  stage the r e a c t i o n m i x t u r e had  u t i o n was  sol-  paprer.  to  h o u r t o 5 0 ° on a w a t e r  reaction with alkaline  color  The  c o o l e d t o 5° a n d the s u s p e n s i o n o b t a i n e d  d i a z o t i s e d w i t h 20$ NaNOg u n t i l  this  solution  o f water.  was  At  in a  Yield o f the  26  from  from •  Nitrogen methyl-  theoretical.  Aeetoveratrone 62g.  of a c e t y l chloride  vertrole conical  i n 260ce. o f f l a s k cooled  was  added to lOOg.  carbon d i s u l p h i d e to below - 1 0 ° .  powdered A l C T g  ( p r a c t i c a l g r a d e ) , was  small  with  portions  proceeded the in  The  and  addition  of  ered glass using  a filter  separated.  water  The  extracts  As  the  reaction out  was  evolved.  w h o l e was  a i d and  the  on  63$  of  the  the  Perkin  Oxime  137.5  3 3  -  ,  bp.  a  the  residue  27  the  sint-  layer w i t h CHCI3 emulsificat-  o v e r MgS04 was  of  theoretical.  The  oil  a white  mp.  50  solid,  and  distilled  clear o i l  1 6 0 - 1 6 2 ° /10mm.,  138°  decanted  through  oily  drying  f  collodial  extracted  Y i e l d 83g.  s t a n d i n g to  K o e p f l i and  was  o i l whereupon On  solvent  under reduced pressure. 1 2 7 - 1 3 0 ° / 1mm.  o f CS2  filtered  l a y e r was  added to  e v a p o r a t i o n of the  a water b a t h f o r  l a y e r and  o i l took p l a c e .  crystallized  in  c r u s h e d i c e decomposed  The  mp.  on  resulting clear layer  Al(OH)3 l a y e r .  i o n o f the  added  complex s e t t l e d  50°  complex g i v i n g a brown o i l y  the  of  hydrogen c h l o r i d e  heated under r e f l u x to  hour.  and  lOOg.  liter  AICI3 h a d b e e n a d d e d t o r e a c t i o n m i x t u r e  a l l the  the  in a 1  shaking.  magenta c o l o r e d  r o u n d r o u g h s t o n e s and  After was  constant  of  bp,  °.  6-nitroacetoveratrone 54g. added  o f powdered o f l i q u i d  i n small portions to a mechanioally  mixture the  of  HNO3  the a d d i t i o n .  been added.  up  4  (80ec.)  between - 5 ° a n d - 3 ° d u r i n g  after  The m i x t u r e  the l a s t  o f the ketone had  was s t i r r e d  at the r e a c t i o n  f o r a f u r t h e r -jjf h o u r a n d t h e mass was  poured i n t o water.  The n i t r o - c o m p o u n d was w o r k e d  i n t h e u s u a l way a n d r e c r y s t a l l i z e d  51g.  stirred  The n i t r o k e t o n e u s u a l l y b u t n o t a l w a y s  began t o c r y s t a l l i z e  temperature  was  ( 8 8 c c . d 1.42 ) a n d o o n c . H g S 0  temperature maintained  then  acetoveratrone  o f long golden  mp. 1 3 3 - 1 3 5 ° .  needles  Yield  from  mp. 1 3 2 - 1 3 4 ° .  ethanol. Simpson,  3 4  75$ o f t h e t h e o r e t i c a l .  6-aminoacetoveratrone. a.  5g. o f 6 - n i t r o a c e t o v e r a t r o n e  ( 4 0 c o . ) was h e a t e d 7.5g.  on a steam b a t h  with  iron  added i n s m a l l p o r t i o n s d u r i n g 1 hour  frequent  shaking.  hour.  After a total  diluted with  colored. solvent  powder with  o f t h e r e a c t i o n and a f t e r  o f 1-J- h o u r s t h e m i x t u r e ^ a s  50$ s o d i u m a c e t a t e  extracted with  acid  Addition o f lOcc. portions o f  w a t e r were made a t t h e s t a r t f  i n acetic  CHClg t i l l  till  cloudy and  e x t r a c t s were no l o n g e r  The E x t r a c t s were d r i e d w i t h KgCOg removed on a steam b a t h ,  Darco and  d i l u t e NaOH. 3 g . o f y e l l o w  28  e  t h e r e s i d u e was  t a k e n u p i n d i l u t e HC1, t r e a t e d w i t h p r e c i p i t a t e d with  ^  crystal-  line  m a t e r i a l were o b t a i n e d .  A sample  recrtstallized  f r o m e t h e r gave y e l l o w brown n e e d l e s mp. Simpson  b.  3 4  mp.  100-104°.  103-105°.  R e d u c t i o n o f 6 - n i t r o a c e t o v e r a t r o n e w i t h am. Adam's  m a c h i n e u s i n g Raney n i c k e l  c a t a l y s t was  attempted  w i t h v a r y i n g p r e s s u r e s and t e m p e r a t u r e s , h o w e v e r no good y i e l d s were o b t a i n e d and i n a l l c a s e s t h e p r o d u c t was c o n t a m i n a t e d be r e m o v e d by  c.  with dark m a t e r i a l which  could  only  distillation.  R e d u c t i o n off t h e n i t r o  compound was  attempted  35 u s i n g t h e method o f West methanol.  by i r o n powder i n HCI a n d  However r e d u c t i o n was i n c o m p l e t e by t h i s  method. Note;  a l l the aminoacetoveratrone  s e v e r a l r u n s was d i s t i l l e d u n d e r p r e s s u r e when a t o t a l  obtained i n  greatly  o f SOg. o f y e l l o w  reduced crystalline  S o l i d was o b t a i n e d , b p . 1 5 0 ° /O.lmm. (2-amino-4,5-dimethoxyrpheny3^-dimethyl-carbinol. (19.5g.  .1 mole) o f 6 - a m i n o a c e t o v e r a t r o n e i n  l O O c c . o f t o l u e n e was a d d e d d u r i n g s t i r r i n g t o CHgMgl The  temperature  dition A  (.31 m o l e s ) made f r o m Mg. and  was m a i n t a i n e d a t 0 ° d u r i n g t h e a d -  and a yewllow  further  200cc.  CH3I i n e t h e r .  g r e e n s u s p e n s i o n was o b t a i n e d .  o f t o l u e n e was a d d e d and t h e m i x t u r e It  29  warmed a n d t h e e t h e r removed b y d i s t i l l a t i o n . all  o f the ether had been d r i v e n o f f the mixture  refluxed  f o r 2 hours,  KH C1.  The t o l u e n e  4  cooled  with  CHClg.  sodium a c e t a t e ,  The t o l u e n e  HCI,  filtered  dil.  Na0H.3g. o f a w h i t e  solubility  and t h e w a t e r and e x t r a c t e d  s o l i d was  i n this  separately  f r o m b o t h t a k e n up. i n d i l .  t h r o u g h D a r c o a n d on m a k i n g b a s i c  difficulty  was  i n t o i c e and  a n d C H C l g l a y e r s were  e v a p o r a t e d and t h e r e s i d u e  The  and poured  l a y e r was s e p a r a t e d  l a y e r made n e u t r a l w i t h  the  When  with  obtained.  r e a c t i o n i s the s l i g h t  off t h e a m i n o - k e t o n e i n s o l v e n t s s u i t a b l e f o r  Grignard  reaction.  K-acetyl-methyl  anthranilate  1 m o l e o f m e t h y l a n t h r a n i l a t e was a d d e d t o 1.1 m o l e s o f a c e t i c a n h y d r i d e and warmed t o j u s t the b o i l i n g p o i n t  f o r 1 hour.  cooled  into dilute  and p o u r e d  solid  The m i x t u r e was sodium a c e t a t e  white  crystalline  180g.  o f r e c r y s t a l l i z e d m a t e r i a l mpJLOO  recrystallized  from  yield  9 3 $ o f the t h e o r e t i c a l .  0  5-nitro-N-acetyl-methyl Nitration  below  was  then  and the ethanol. obtained,  anthranilate  o f N-acetyl-methyl  a n t h r a n i l a t e was 36  carried  out u s i n g  t h e method o f V o g e l  n i t r o - c p m p o u n d was r e c r y s t a l l i z e d mp.l62°. 30  from  ,  The c r u d e  ethanol,  Note: with  I t was h o p e d t o c a r r y o u t a G r i g n a r d r e a c t i o n this nitro  However  compound  the n i t r o  as the t a b l e  compound  ( E l ) shows.  i s insoluble i n Grignard  r e a c t i o n s o l v e n t s a n d so i t was d e c i d e d t o h y d r o l i z e the n i t r o and  compound  to the corresponding  amino-acid  estenttfy and t h e n t o t r y t h e G r i g n a r d r e a c t i o n  on t h e more  s o l u b l e amino e s t e r .  5-nitro- anthranilic  acid.  The h y d r o l y s i s o f t h e amide a n t h r a n i l a t e ) was  carried  (5-nitro-N-aeetyl-methyl  o u t i n 70$ H 2 S 0  4  u s i n g the  37 method o f V o g e l  .  D i f f i c u l t y was  encountered  r e c o v e r i n g t h e amino a c i d  f r o m t h e 70$ H2SO4.  b e s t method was  the a c i d  to d i l u t e  in The  s o l u t i o n w i t h an  e q u a l volume o f w a t e r and on c o o l i n g i n a n i c e b a t h a yellow  sludge  settled  out.  This  s l u d g e was  on a s i n t e r e d g l a s s f u n n e l u s i n g a f i l t e r was d i s s o l v e d f r o m t h e f i l t e r ethanol.  Evaporation  fine yellow Quaternary All ities  needles  mp.  cafee usmng  collected  a i d , and boiling  o f some o f t h e s o l v e n t gave 265°, Reported  280°  (£63°)  equal molar  quant-  S  8  Salts  s a l t s were majie by m i x i n g  o f base and h a l i d e i n d r y e t h e r and a l l o w e d t o  stand a t room temp, t i l l  salt  f o r m a t i o n had  When p o s s i b l e t h e y were r e c r y s t a l l i z e d containing a l i t t l e  ethanol.  NoteM  occurred.  from  I n most  ether cases  r e f l u x i n g to increase the r a t e o f r e a c t i o n l e a d to ' '.31 decomposition. !:  Benzyl  chloride  B.D.H. b e n z y l c h l o r i d e was d i s t i l l e d u n d e r r e d u c e d p r e s s u r e a n d t h e f r a c t i o n b o i l i n g a t 46.5° /  7mm. was c o l l e c t e d .  Benzyl  bromide  2 m o l e s o f b r o m i n e was a d d e d , t h r o u g h a d r o p p i n g f u n n e l t o 2.1 m o l e s o f b o i l i n g t o l u e n e a 150 w a t t lamp. was  complete  the  evolution  After  ( 1 hour  irradiated with  a d d i t i o n o f t h e bromine  ) t h e m i x t u r e was r e f l u x e d  o f HBr h a d c e a s e d .  till  The m i x t u r e was  t h e n d i s t i l l e d and a f t e r " f o r e r u n o f t o l u e n e t h e b e n z y l b r o m i d e was c o l l e c t e d b p . 1 9 5 - 2 0 5 ° . 198°.  and 127°/80mm.  short  column  Yield  o f pure product  Benzyl  gave  Redistillation  5mm.  65$ o f the; t h e o r e t i c a l .  i n 500g. o f a c e t o n e  added 63g. o f r e d i s t i l l e d  precipitate  benzyl chloride.  filtered  and t h e b e n z y l  shaken w i t h a s m a l l p o r t i o n  Heilbron  4 0  S3  0  mm.  32  The  distilled  The d i s t i l l a t e  o f m e r c u r y t o remove  and t h e n r e d i s t i l l e d , /10  off.  iodide  u n d e i j r e d u c e d p r e s s u r e b p . 8 2 ° / 7mm.  o f iodine  The  f o r 4 hours, c o o l e d and the  o f sodium c h l o r i d e  a c e t o n e was removed  traces  bp. 68° /  iodide  s o l u t i o n was r e f l u x e d  was  39  through a  220g. o f c l e a r l i q u i d  To l O O g . o f sodium i o d i d e was  Schramm  bp. 83° /  7mm.  SUPPLEMENT  In an  investigation being carried  G.G.S.. B u t t o n 0-  and  i t was  from  1 to 7 c a r b o n s .  r e p r e s e n t s a p o r t i o n o f the  being  prepared.  33  groups  T h i s supplement  e x p e r i m e n t a l work done  the a u t h o r d u r i n g the p e r i o d  t h e s i s was  Mr.  r e q u i r e d to s y n t h e s i z e a l l the  p-hydroxy-n-alkyl-phenols with a l k y i  containing  by  o u t by  i n which the  main  A d a  Chlorides  The esters  acid  chlorides  o f a l l acids used  were made i n t h e f o l l o w i n g  1 mole o f t h e a c i d was added  t o make  way.  slowly through a  d r o p p i n g f u n n e l t o 1.1 m o l e s o f r e d i s t i l l e d chlroide shaken  cooled to 0°C.  periodicaly  The r e a c t i o n m i x t u r e was  and when a l l o f t h e a c i d h a d b e e n  a d d e d t h e m i x t u r e was warmed t i l l HC1 was c o m p l e t e 1 hour.  a  and t h e n h e a t e d u n d e r  of thionyl chloride  crude a c i d c h l o r i d e .  short  for  column gave a c i d  use.  Phenyl  the evolution o f reflux f o r  The m i x t u r e was t h e n d i s t i l l e d a n d t h e  forerun the  thionyl  Yields  range  c o l l e c t e d and t h e n Redistillation  chloride  through  o f a purity  suitable  70-90$.  esters  P h e n y l esteBS were p r e p a r e d i n t h e f o l l o w i n g manner• 1. mole o f t h e a c i d thin  stream onto  was  heated u n t i l  was  complete  boiling  c h l o r i d e was p o u r e d  1.1 m o l e s o f p h e n o l . the evolution  ana the e s t e r  through a short  column.  34  The m i x t u r e  o f hydrogen  distilled.  r a n g e was o b s e r v e d t h e e s t e r Yields  ina  chloride  I f a large was  ranged  redistilled 80-90$.  p-hydroxyacetophenone To  272g. o f p h e n y l a c e t a t e i n 1 1 4 0 c c . o f  purified 2 0 ° C . was  nitrobenzene  i n a flask  c o o l e d to below  a d d e d 4 0 0 g . o f powdered A l C l g  grade) w i t h s h a k i n g .  The  tomperature  b e l o w 2 0 ° G . d u r i n g t h e a d d i t i o n and brown s u s p e n s i o n a l l o w e d t o temperature.  The  ice  and H C I .  distillation w a t e r on The  The and  loss  crude  In  found  was  poured  on  to p u r i f y  35  from  EOOg.  /2mm. of  the  a filter aid,  a c i d i f i c a t i o n yielded yellow  the y i e l d s v a r i e d  the  without  Treatment  the pure  steam  reduced  155-160°C  standing.  ef  from  o f crude product  difficult  into  r e m o v e d by  D i s t i l l a t i o n under  1 0 6 - 1 0 7 ° C . m.p.  4 runs  resulting  t h e n warmed on a w a t e r  p r o d u c t w i t h NaOH, c h a r c o a l and  f o l l o w e d by m.p.  Yield  gave a p i n k o i l b . p .  which'solidified  maintained  the r e s i d u e c r y s t a l l i z e d  of material.  pressure  the  c o o l e d and  nitrobenaene  cooling.  p r o d u c t was  was  s t a n d o v e r n i g h t a t room  s o l u t i o n was  bath t o 50°C. f o r 1 hour,  (practical  crystals,  compound 50-60$.  1098c.  o-and  p-hydroxyacetophenone,  120g. portions  o f p h e n y l a c e t a t e was to  180g.  of AlClg  very r a p i d  i n small  (practical  h a d he en p r e h e a t e d t o 7 0 ° C . was  added  The  evolution of  H e a t was  cooled  A violent gave way  added  to a red oil.# 50$ HC1  The  i n portions  o i l was  and w i t h warm  The w a t e r l a y e r a n d w a s h i n g s were  a n d e x t r a c t e d w i t h two  cooled  lOOcc. portions o f ether.  The  ether  the  e t h e r a n d w a t e r removed a t t h e pump.  e x t r a c t s were a d d e d t o t h e o i l and  of the r e s i d u a l  o i l gave  h p . 7 7 - 8 0 ° C . /1mm* hp. 155-160°C. /  #.  reaction  r e a c t i o n f o l l o w e d and t h e  s e p a r a t e d and washed w i t h water.  The  somewhat and a m i x t u r e o f 5 0 0 c c .  i n 5 0 0 c c . o f w a t e r was  to the f l a s k . d a r k complex  HC1  a p p l i e d t o maintain  t h e t e m p e r a t u r e a t 1 4 0 ° C . f o r -f h o u r .  o f c o n e . HC1  which  and t h e t e m p e r a t u r e o f t h e m i x t u r e  r o s e t o afeout 1 3 0 ° C .  m i x t u r e was  grade)  3 4 g . 28$,  and 5 0 g . 50$,  of clear o i l  o f a pink  solid  1mm.  I t w o u l d he more p r o f i t a b l e  l o w e r members o f t h e s e r i e s w i t h to thE rate  Distillation  of hydrolysis.  36  to hydrolyze i c e a n d HC1  due  0- a n d p - h y d r o x y b u t y r l p h e n o n e lOOg. portions  (.6 m o l e s )  o f t h e e s t e r was a d d e d  t o 1 1 9 g . (.8 m o l e s )  preheated t o 70°. the  temperature  Heat for  was a p p l i e d f hour.  i n small  o f A l C l g w h i c h h a d "been  The e v o l u t i o n o f HCI was r a p i d a n d  o f t h e m i x t u r e r o s e t o about  155°.  t o m a i n t a i n the temperature a t 140°  The r e a c t i o n m i x t u r e was c o o l e d t o 3 0 °  and a m i x t u r e o f 3 0 0 c c . o f c o n e . HCI and 4 5 0 c c . o f warm w a t e r was added mixture.  The y e l l o w g r e y complex  way t o a b r i g h t to  i n p o r t i o n s to the r e a c t i o n  red o i l .  d i s s o l v e d a n d gave  The m i x t u r e was a g a i n c o o l e d  3 0 ° a n d t h e o i l s e p a r a t e d , washed w i t h 50$ HCI a n d  w i t h warm w a t e r .  The wet o i l was d i s t i l l e d  removal o f t h e water  3 2 g . 32$ o f c l e a r  o i l , bp.  1 0 5 ° /2mm., a n d 4 0 g . 40$ pf a w h i t e s o l i d , 1 7 3 ° /2mm.  and a f t e r  bp 160-  were o b t a i n e d .  o- a n d p - h y d r o x y - n - v a l e r o p h e n o n e 89g. to  o f e s t e r a t 7 0 ° was a d d e d  90g. o f A I C I 3  (practical  to  40°.  The m i x t u r e was  f o r f h o u r and t h e n  cooled  2 5 0 c c . o f c o n e . HCI i n 250g. o f w a t e r  was p o u r e d o n t o warmed u n t i l hot  stream  grade) p r e h e a t e d t o 50°  and t h e t e m p e r a t u r e r o s e t o 1 4 0 ° . then h e a t e d t o 150°-160°  i n a thin  the orange  t h e complex  mass.  The m i x t u r e was  decomposed and w h i l e  still  t h e brown o i l was s e p a r a t e d , washed w i t h warm  50$ H C I a n d t h e n w i t h warm w a t e r .  37  The wet o i l on  distillation yieled b p . 1 2 5 ° / 3mm. 185-190°  39g. 44$,  o f the o r t h o  and 4 0 g . 45$,  /2.5mm.  isomer  o f the p a r a isomer  The p a r a i s o m e r c r y s t a l l i z e d  bp.  on  standing.  o- and p - h y d r o x y 178g. of  i s o valerophenone  (1 mole) o f t h e e s t e r and 195g.  A I C I 3 was  treated  valerophenones. yielded  6 3 c e . 34$,  / 1mm. / 1  i n t h e same manner a s f o r n -  Distillation  under  reduced pressure  o f t h e o r t h o i s o m e r bp,  and 5 0 c c . 41$  moles)  o f the p a r a isomer bp.  101-103° 160-168°  mm.  Hote: for  (1.3  T h i s work i s s t i l l  u n d e r way  t h e d e r i v a t i v e s has not been  2,4-dinitrophenylhydrazines,  and t h e c o n s t a n t s  completed although  semicarbazones  h y d a n t o i n s . o f a l l t h e compounds l i s t e d made •  38  have  and been  BIBLIOGRAPHY  1.  von R i c h t e r ,  (Ber.  2.  S t o e r m e r and  Fineke,  3.  Widman,  4.  Stolle  5.  B o r a c h e and H e r b e r t ,  6.  P f a n n s t i l l and  7.  Jacobs  8.  Simpson,  (J.S.C.  1947  9.  Simpson,  (J.C.S.  1942  10.  Simpson,  (J.C.S.  1943  11.  S t o e r m e r and  12.  Mayer and. B a l i e . ,  13.  S a c h s and H i l p e r t ,  14.  R u g g l i and  15.  16_  (Ber.  ( B e r . 16_ and  (Ber.  57  (Ann.  J546  68  1310  809 and  1096  (1942)).  •.; ( 1 9 4 7 ) ) .  ). sate,.}.  45  3104  403_  (Ber.  167  39__  (1912)). 1914)).  899  (1906)).  ( n e l v . c h i m . A c t a . 20  37  ( H e l v . e h i m . A c t a . 24_  16.  Leonard,  (Chem. Rev.  17.  Hodgson and Marsden,  18.  Watson,  37  269  19.  Simpson,  (J.G..S.  1948  1172).  20.  Simpson,  (J.C.S.  1947  1652  21.  Simpson,  (J.O.S. 1947  22.  Jacobs  23.  Mensohutkin,  24.  Long,  (J.S.C.  1652  (J.A.C.S.  68  (Zeit. physikal 19112164).  39  ). 173).  (1945)). 1945  (Modern t h e o r i e s o f O r g .  (J.C.S.  (1941)).  447-9).  (Ann.  Dinger,  et a l . ,  (1924)). 293  75  (Ber.  Staub,  (1909)).  1123  (Ber.  (J.A.C.S.  Gaus,  3115  (1883)).  Janecke,  et a l . ,  11883)). 42_  677  Becker,  R u g g l e and  677  and  207).  Chem. p,  169).  precf.) .  ). 1310 chem.  (1947)). _5_ 589  (1890)).  25.  Thomas,  (J.C.S.  1913  594).  26.  S c h l e n k and H o l t z ,  27.  Marvel  et a l . ,  28.  Baker,  (J.C.S..  1931  2416)  29.  Baker,  (J.C.S.  1931  241$).  30.  Baker,  (J.C.S.  1939 5 1 9 ) .  31.  Baker,  (J.C.S.  1939 5 1 9 ) .  32.  Erlendson,  33.  K o e p f l i and P e r k i n ,  34.  Simpson,  35.  West R.W.,  36.  Vogel,  (Practical  Organic  Chem.,  page  558.).  37.  Vogel,  (Practical  Organic  Chem^  page  558.).  (Ber.,  (J.A.C.S.  49 48  603  (1916)).  2689  (1926)).  and subq.  f  (Unpublished).  (J.C.S.  (J.C.S. 1946  (J.C.S.  (Ber.,  494).  o f O r g , Compds.,  39.  Schramm,  40.  Heilbron,  18  608  41.  King,  42.  Greig,  (Chem. R e v . .42  43.  Walls,  (J.C.S.  1935  O r g . Compds., 138; 285  1948  265).  (1947)).  1944 a n d S u b q . ) .  40  I l l 91.)  (1885)).  (Dictionary  (J.C.S.  2989).  96).  1925  38. H e l l b r o n , ( D i c t i o n a r y  1928  I  247).  

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