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Quaternary salt formation of cinnolines 1951

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Q U / . T E R N A R Y S A L T F O M A T I O N O F C I N N O L I N E S R E E S K E N N E T H P O W E L L A T H E S I S S U B M I T T E D I N P A R T I A L F U L F I L M E N T O F T H E R E Q U I R E M E N T S F O R T H E D E G R E E O F M A S T E R O F A R T S i n t h e d e p a r t m e n t o f • C H E M I S T R Y W e a c c e p t t h i s , t h e s i s a s c o n f o r m i n g t o t h e s t a n d a r d r e q u i r e d f r o m c a n d i d a t e s f o r t h e d e g r e e o f M A S T E R O F A R T S . M e m b e r s o f t h e D e p a r t m e n t o f C h e m i s t r y . T H E U N I V E R S I T Y O F ' B R I T I S H C O L U M B I A A p r i l , 1 9 5 1 ABSTRACT QUATERNARY SALT FORMATION OF CINNOLINE This study was i n i t i a l l y undertaken with a view to preparing quaternary salts of cinnoline simulating the structmre of the a l k a l o i d papaverine. This would be possible by the synthesis of two compounds, v i z . , 6,7-dimethoxycinnoline and 3,4- dimethoxybenzyl-chloridei Some d i f f i c u l t y has been encountered i n the synthesis of the former and from experimental evidence now at hand the- l a t t e r can be considered to be unstable. Some new examples of quaternary s a l t s of 4-methycinnoline are reported but i n general i s o l a t i o n of salt s from 4-methycinnoline and benzyl-halides has been found impractical ,due to t h e i r hygroscopic properties. A G O O W I i E D G E M E N T S The author g r a t e f u l l y acknowledges; the w i l l i n g and able a s s i s t a n c e o f Mr. G.G.S. Dutton who has d u r i n g the course o f the i n v e s t i g a t i o n been a most h e l p f u l a d v i s o r ; a l s o The N a t i o n a l Research C o u n c i l f o r m a t e r i a l a s s i s t a n c e i n the form o f a b u r s a r y . V a l u a b l e a i d was p r o v i d e d by H.M. E r l e n d s o n , B. G a r v i e , and G. K i l g o u r who prepared some o f the compounds used i n t h i s i n v e s t i g a t i o n . CONTENTS INTRODUCTION THEORETICAL I Cinnoline formation. II Quaternary s a l t formation DISCUSSION EXPERIMENTAL SUPPLEMENT Synthesis of some ortho- and para hydroxy substituted aryl-phenones BIBLIOGRAPHY BrTRODTTGTIOK The quest f o r new and improved molecules p o s s e s s i n g v a r y i n g degrees o f p h a r m a c o l o g i c a l a c t i v i t y dates back to a n t i q u i t y . The p l a n t a l k a l o i d s have been the g r e a t e s t storehouse o f a c t i v e compounds, however, due to the great s t r i d e s i n organic s y n t h e s i s i n more r e c e n t times,, an ever 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 41 compounds i s b e i n g r e p o r t e d . K i n g has r e c e n t l y put f o r t h a p l a u s i b l e s t r u c t u r e f o r d-tuboeurariiB c h o l r i d e (A) a quaternary s a l t h a v i n g e u r a r i f o r m a c t i v i t y and i n p a r t r e s p o n s i b l e f o r the arrow poisons o f the South American I n d i a n s . (A) I G r e i g i n h i s accoa nt o f c u r a r i f o r m a c t i v i t y l i s t s i n .tabular form 58 pages of quaternary ammonium s a l t s , the m a j o r i t y of which have c u r a r i f o r m a c t i v i t y . The c l i n i c a l use o f papaverine, (B) and i t s s u b s t i t u t e 6,7-methylenedio;xy-l-VPyriayl-3-methyl i s o q u i n o l i n e , (C) c l e a r l y demonstrates the a c t i v i t y o f the i s o - q u i n o l i n e n u c l e u s . OCH3 (B) (01 Papaverine i t s e l f i n s m a l l doses produces l i g h t s l e e p which, does not become deeper as the dose i s i n c r e a s e d . L a r g e r doses produce r e f l e x i r r i t a b i l i t y and some t e t a n i s i n g a c t i o n may ensue. In modern c l i n i c a l medicine i t i s used f o r i t s p a r a l y s i n g a c t i o n of the smooth muscle o f the i n t e s t i n e s and b l o o d 4? v e s s e l s . G r e i g has shown that the b e n z y l group i s f r e q u e n t l y a s s o c i a t e d w i t h p a r a l y z i n g a c t i o n . In p y r i d i n i u m , strychninium, c o n i i n i u m and brucinium s a l t s the H-benzyl d e r i v a t i v e s have the g r e a t e s t curare a c t i o n s whereas 1 - b e n z y l i s o q u i n o l i n e s have r e l a x i n g a c t i o n s . I I In view o f the c o i n c i d e n c e between a c t i v i t y o f quaternary s a l t s and the b e n z y l group, the s y n t h e s i s o f a model compound c o n t a i n i n g the i s o q u i n o l i n e l i k e s t r u c t u r e , with a b e n z y l group a t t a c h e d to a quaternary n i t r o g e n and having a c o n s t i t u t i o n s i m u l a t i n g papaverine was attempted, (D). The o n l y r e f e r e n c e i n the l i t e r a t u r e to quater- nary s a l t formation i n the c i n n o l i n e s e r i e s is^Simp- son w who obtained the methyl 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 , but d i d not make any 16 r e f e r e n c e to p o s s i b l e a c t i v i t y . Leonard i n h i s account o f the chemistry of 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 . Although the compound (D) has not been prepared an 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 s y n t h e s i s o f such s t r u c t u r e s i s set out, and a number o f new c i n n o l i n e s a l t s are r e p o r t e d . ocri3 (3» III T H E O R E T I C A L I C i n n o l i n e i s a h e t r o c y c l i c b i n u c i e a r base h a v i n g the same numbering as q u i n o l i n e and c o n t a i n i n g two v i c i n a l n i t r o g e n atoms. I t i s the l e a s t w e l l knowi o f t h e f o u r i s o m e r i c s t r u c t u r e s . 00 oo 00 Q u i n o x a l i n e P h t h a l a z i n e Q u i n a z o l i n e The d i s c o v e r y o f c i n n o l i n e d a t e s back t o 1883 when von R i c h t e r 1 c l a i m e d to have o b t a i n e d a d e r i v - a t i v e o f t h e d i ^ - n i t r o g e n b a s e . The compound o r i t s d e r i v a t i v e s r e c e i v e d l i t t l e a t t e n t i o n u n t i l 1945 when Simpson a t t e m p t e d t o p r e p a r e compounds c o n t a i n - i n g the c i n n o l i n e n u c l e u s h a v i n g a n t i m a l a r i a l a c t i v i t y . The d i s c o u r a g i n g f a c t o r i n c i n n o l i n e c h e m i s t r y has d o u b t l e s s been the l a c k o f a c o n v e n i e n t method o f p r e p a r a t i o n i n c o n t r a s t to t h e more r e a d i l y a c c e s s i b l e i s o m e r i c compounds. To date s i x main methods f o r the p r e p a r a t i o n o f c i n n o l i n e s have been quoted. The method o f von R i c h t e r i n v o l v e s the c y c l i z a t i o n o f d i a z o t i s e d o- a m i n o p h e n y l p r o p i o l i c a c i d s , ( 1 ) . 1 (1) A somewhat easier route to the cinnoline ring system 2 was explored by Stoermer and Fincke using a reaction discovered by Widman involving the cyclization.of diazotised o-aminoarylethylenes to produce the cor- responding 4-arylcinnolines. The requisite di-aryl- ethylenes being obtained from the appropriate diary1- ketones and Grig&nard reagent, followed by dehydCration of the resulting carbinols. ( 2 ) . Stolle" and Becker i n an attempt to,prepare N-amino i s a t i n synthesized 3-phenylcinnoline-4-carboxylic acid by the f o i l i n g series of reactions. (3) In 1941 Borsche and Herbert 0 discovered the acetpphenone synthesis of 4-hydroxycinnoline by d i a z o t i s a t i o n of o-aminoacetophenone. (4) In 1942 P f a n n s t i l l and Janeeke obtained highly substituted cinnolines by dehydration of an o-carboxyphenylhydrazine, but t h e i r y i e l d s obtained were very porr. It i s well to state here that i n a l l examples mentioned, except i n the case of von Richter, the formation of ""the cinnoline 3 was i n c i d e n t a l to the main purpose of the investigation. 7 R In 1947 Jacobs et a l . and Simpson obtained 4-methylcinnoline hy the Widman-Stoermer reaction. They started from readily accessible methyl- anthranilate and by treatment with methylmagnesium bromide and dehydration, followed by d i a z o t i s a t i o n and c y c l i z a t i o n of the 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 of 70$.(5). This was the f i r s t synthesis of a cinnoline where the ring was free from functional groups thereby opening the way for a study of the basic properties of the cinnoline nucleus. Of the six methods available for the preparation 9 ( of the cinnoline nucleus, Simpson has shown that they a l l proceed by the same mechanism. He has found that cinnoline formation i s dependent on a highly po s i t i v e diazonium kation and at the same time, 4 on the a v a i l a b i l i t y of electrons at the ^-carbon atom of the ortho substituted chain. Consideration of the mechanism of the Richter reaction shows th t t the carboxyl of the o-aminopropriolic acid, (6), has a r e l a t i v e l y negative ^-carbon atom and, at the same time, the inductive effect of the carboxyl group on the r i n g increases'the pos i t i v e charge on the diazonium kation and so cinnoline formation i s favoured. In order to elucidate the mechanism of the Widman-Stoermer reaction Simpson 1^ studied the i n - fluence of substituents Ra and Rb, ( 7 ) , with-respect to the ease with which o-aminoarylethylenes r i n g closed to give cinnolines. Stoermer and Gaus 1 1 discovered that o-aminocinnamic acid, (7), Ra=H, Rbr COOH, does not y i e l d a cinnoline. Considerably more evidence is available to show that when Rb i s negative cinnoline formation i s i n h i b i t e d . In the Pschorr reaction, (7), Ra= H, Rb=Ph, R c = C 0 0 H , (6) (7) R d = H , d i a z o t i s a t i o n l e a d s t o p h e n a n t h r e n e ~ 9 - c a r - b o x y l i c a c i d . I n a n y s u c h r e a c t i o n w h e r e b o t h R a , a n d R b ^ H , c i n n o l i n e f o r m a t i o n i s i m p o s s i b l e o w i n g t o t h e a b s e n c e o f t h e n e c e s s a r y h y d r o g e n o n t h e ^ ~ c a r b o u . H o w e v e r i n c o m p o u n d s o f t h e t y p e , ( 7 ) , R a = C O O H , R b = H , R c = P h , R d = m e t h y l , T h i s h y d r o g e n i s a v a i l a b l e a n d n o w t h e P s c h o r r a n d W i d m a n - S t o e r m e r 1 2 r e a c t i o n s a r e b o t h p o s s i b l e . M a y e r a n d B a l l e h a v e s h o w n t h a t d i a z o t i s a t i o n o f t h i s l a t t e r e t h y l e n e y i e l d s 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 a c i d , ( 8 ) . T h e n o n - f o r m a t i o n o f c i n n o l i n e i n t h e s e c a s e s i s a t - t r i b u t a b l e e i t h e r t o t h e a r y l r e s i d u e o n t h e ^ - c a r b o n o r t h e c a r b o x y l o n t h e ^ - c a r b o n o r t o b o t h . F u r i b h e r 1 3 S a c h s a n d H i l p e r t h a v e , s h o w n t h a t 2 - a m i n o s t i l b e n e s i n w h i c h b o t h < * - - a n d < i > - e t h y l e n i c c a r b o n a t o m s c a r r y h y d r o g e n s d e c o m p o s e o n d i a z o t i s a t i o n . H o w e v e r , 14 R u g g l i a n d S t a u b h a v e s h o w n t h e s e w e r e t r a n s d e r i v a t i v e s a n d i f t h e c i s f o r m s a r e u s e d p h e n a n t h r e n e c a n b e o b t a i n e d i n 8 0 $ y i e l d . R u g g l i a n d D i n g e r 1 5 . 6 h a v e d i a z o t i s e d o t h e r c i s - a n d t r a n s - s t i l b e n e s a n d h a v e i n n o c a s e i s o l a t e d a n y n i t r o g e n c o n t a i n i n g c o m p o u n d s . W e m u s t t h e r e f o r e c o n c l u d e t h a t c i n n o l i n e f o r m a t i o n i s i n h i b i t e d w h e n , (9) , R h = a r y l o r o t h e r n e g a t i v e g r o u p a n d , R a = H , o r C O O H . I (9) T h i s i s i n a g r e e m e n t w i t h S i m p s o n ' s s u g g e s t e d m e c h - a n i s m , v i z , t h a t t h e \ i - c a r b o n a t o m m u s t b e r e l a t i v e l y n e g a t i v e . T h e m e c h a n i s m o f t h e 4 - h y d r o x y c i n n o l i n e s y n t h e s i s , d i s c o v e r e d a c e i d e n t l y b y B o r s c h e a n d H e r b e r t , ( f o o t n o t e ) a n d s o a p t l y u s e d b y S i m p s o n a n d c o w o r k e r s , h a s f u r t h e r s u p p o r t e d S i m p s o n ' s t h e o r y o f c i n n o l i n e f o r m a t i o n . D u r i n g t h e d i a z o t i s a t i o n o f o - a r n i n o a c e t o p h e n o n e s , e n o l i z a t i o n o f t h e k e t o n e m u s t o c c u r a t s p m e s t a g e i n o r d e r t h a t c y c l i z a t i o n m a y t a k e p l a c e , (10). OH (10) f o o t n o t e : They were c a r r y i n g out the San&meyer r e a c t i o n to o b t a i n o-Br-acetophenone. 16 Leonard has suggested that the reaction may involve an intramolecular coupling of the diazonium kation with an enolate anion, t h i s would be akin to the coupl- ing reaction of diazonium s a l t s with phenoxide ions to form azo dyes. This mechanism is highly untenable as cinnoline c y c l i z a t i o n takes place i n concentrated acid whereas diazonium coupling takes place i n basic ' „ ' 17 solution. Further Hodgson and Marsden have stated that i n the coupling reaction of diazomium s a l t s under alkaline conditions the reactive species i s not the . 18 simple diazohium ion. Wattson sets out the accepted mechanism for acid-catalysed enolization of a carb- 19 onyl group and Simpson has interpreted the mechan- ism of cinnoline formation by the following series of transformations, (11). 8 He has found that the y i e l d of cinnoline from a given diazotised O-aminoacetophenone i s a competition react- ion of the diazonium kation for the negative carbon atom or the reaction of the diazonium kation to form a hydroxyl group. In keeping with t h i s theory he has found a high y i e l d of cinnoline using high acid concentration and low temperature. Simpson has also • studied the formation of cinnoline when groups that w i l l vary the b a s i c i t y of the amino group are present i n the ri n g of 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 dia 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 posit i v e diazonium kation, and an expected higher y i e l d of the corresponding cinnoline. Included is a table compiled from Simpson's separate papers which c l e a r l y bears out t h i s theory. Cinnoline ConAitions Yield 4-0H 75$ H 2S0 4 and HAe, 10-90° 10$ 3.5NHC1, room temp, cone. HOI, 50-60° 42$ 70$ tt 7-Cl-#0H 5ir H C I , 3.5H" H 2 S 0 4 , E8 days @ 20 then 70-80° for 1 hour cone H C I 0 30$ tt 81$ 90$ 4-0H-3-methyl 2B HCI, room temp, cone HCI, 18$ 83$ tt 6- C1-4-0H- 7- methyl 5N HCI, 70^80° 21 HCI, 70-80° 90$ 9 From the foregoing considerations we conclude that the ease of formation and the y i e l d s of cinnoline depend on two factors, the a v a i l a b i l i t y of electrons on. the ^-carbon atom and the weakness of the amino group of the ortho-amino compound. THEORETICAL II 20 Simpson has shown that the basic center of 4-methylcinnolines i s at H i . He attempted to produce quaternary salts of 4-methylcinnoline and by a study of t h e i r decomposition reactions determine the position of attachment of the quaternary group thereby locating the center of basic character of the compound. The methiodide obtained from 6-chloro-4-amino- cinnoline, (11), on treatment with hot a l k a l i proved to be 6-chloro-l-methyl-4-cinnoldne, (12), i d e n t i f i e d as the same product obtained by treatment of 6- chloro-4-hydroxycinnoline with methyl sulphate. Whereas.treatment of 4,6-dichlorocinnoline with sodium methoxide yielded the isomeric 6-chloro-4.- methoxycinnoline, (13). 10 (11a) (12) (13) The p e s i t i o n of quaternary s a l t formation i n 6-chloro- 4-aminocinnoline i s thus established at N 1. Further the condensation of 4-methylcinnoline ethiodide with p-dimethylaminobenzaldehyde^ 1 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 basic character of Jacobs et al.^2 w e able to condense 4-methylcinnoline with benzaldehyde i n the presence of zinc chloride, (14), a reaction akin to the condensat- ion of benzaldehyde with 2,4-dinitrotoluene, (15). (14) (15) These facts point to N]_ as the basic center of 4 - substituted cinnolines, t h i s being the position of highest electron density. Because the author was interested i n the formation of quaternary salts of cinnoline, a consideration of the factors a f f e c t i n g quaternary s a l t formation i n general was undertaken. Menschutkin^ 3 studied the reaction of t r i e t h y - 11 amine wit h a l k y l - h a l i d e s i n acetone at 100 o. He found the r e a c t i o n to be b i m o l e c u l a r and h i s r e l a t i v e v e l o c i t y c o f f i c i e n t s are g i v e n i n the f o l l o w i n g t a b l e . methyl 1140.0 e t h y l 10.0 n-propyl 1.93 n - b u t y l 1.38 n - h e p t y l 1.08 n - o e t y l 24 1.0 Long has measured the r a t e s o f i n t e r a c t i o n o f c y c l i c t e r i a r y bases wi t h o r g a n i c h a l i d e s to form quaternary s a l t s . H i s r e s u l t s were o f the same order as 25 M e n s c h u t k i n 1 s . Thomas s t u d i e d the e f f e c t s o f v a r i o u s a l k y l groups and some n u c l e a r s u b s t i t u e n t s on the r e a c t i v i t i e s o f t e r t i a r y aromatic bases w i t h o r g a n o h a l i d e s , however, as was the mode o f the d§y, he e x p l a i n e d any v a r i a t i o n s i n r e a c t i v i t y o f s u b s t i t u t e d bases or h a l i d e s by s t e r i c h i n d r a n c e s . A modern theory o f r e a c t i o n mechanism and r e a c t i v i t y o f v a r i o u s s u b s t i t u t e d bases and h a l i d e s I s now a t hand. I t has been o f t e n s a i d t h a t the elements l y i n g between helium and neon cannot expand t h e i r valence s h e l l beyond and o c t e t . A l l e f f o r t s to o b t a i n d e r i v a t i v e s o f 5-covalent n i t r o g e n 26 have been u n s u c c e s s f u l . Schlenk and H o t l z prepared compounds c o n t a i n i n g 12 5 hydrocarbon groups i e , teramethylammoni\im benzyl, however they found them to behave as ionized s a l t s (CH3)4N:'t" R . Attempts to obtain compounds with 5 simple a l k y l groups by the inte r a c t i o n of quater- nary ammonium halides with metal a l k y l s were unsuccess- f u l 2 7 . Further i n no case was the a l k y l group derived from the metal found enter the valence s h e l l of the nitrogen atom. It must be assumed then that the nitrogen atom with i t s 5 valence electrons can coo- rdinate 3 a l k y l groups; each donating an'"electron; and then w i l l share i t s pair of electrons with any electron 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 s h e l l . Baker28 has make am\ exhaustive study of the factors a f f e c t i n g quaternary salt formation. He has shown the reaction of substituted benzyl-halides with pyridine to form salts proceeds by two steps, a), the anionisation of the halogen and, b), coordinat- ion of the nitrgen atom with i t s electron paii? to the now electron d e f i c i e n t methylene system. Y/e see then that i n salt formation the electron pair- of the nitrogen accepts the free a r y l residue only a f t e r anionisation has taken place. It i s therefore clear that nuclear substituents i n the halide which enhance accession of electrons to side chain, l e , CHg, OCHg, w i l l enhance salt formation and vice versa. Hence anionisation of the halogen i s the main factor 13 in determining relative reactivities of benzyl-halides 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. However the experimental order for quaternary 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 is 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. in reactions with pyridine. (16) footnote. See under discussion. 14 As a further consideration i n salt formation mechanism Baker has shown that a c t i v a t i o n energies for the reaction of "benzyl-bromide with pyridine are almost i d e n t i c a l with those of oL-picoline. I f basic strength i s a measure of electron a v a i l a b i l i t y then as ct-picoline i s ten times as strong a'base as pyrid- ine, electron a v a i l a b i l i t y can have l i t t l e effect on quaternary s a l t formation. ."<:•.-," In summary Baker has shown that the reaction between benzyl-halides and t e r t i a r y bases i s bimolecular and involves simultaneous addition and di s s o c i a t i o n denoted by the electron cycle, (17). Although the energy of ac t i v a t i o n i s unaffected by substituent groups i n the a r y l nucleus the v e l o c i t y of the react- ion i s altered . Electron accession increases react- ion v e l o c i t y up to a point but on the other hand electron recession decreases the v e l o c i t y . Greater recession from the side-chain thatu;- that produced by para-nitro i n the nucleus, a l t e r s the mechanism and greatly increases the v e l o c i t y . It i s to be con- sidered that the electron cycle above i s to be comp- leted before salt formation•will occur, however, i n i t i a t i o n ' o f t h i s cycle can occur by the incipient anionisation of the halogen, (a above), or the electro- s t r i c t i o n of the t e r t i a r y base, (b above). Baker has (17) 15 found that the c r i t i c a l point where the probability for i n i t i a t i o n of the reaction by methods (a) and (b) i s equal i s at para-nitrobenzyl-halide. We can therfore say that a l l groups i n the nucleus that repel electrons and a l l a t t r a c t i n g groups down to para-nitro react by method (a) and a l l more power- f u l electron a t t r a c t i n g groups react by method (b). Such a view also accomodated the experimental effecit of solvent on s a l t formation. The greater the i o n i z i n g power o f f the solvent the more pronounced w i l l be the effect of substituent groups i n the halide nucleus i n enhancing or retarding the anionisation 31 of the halide ion. Baker showed that the retarding influence of a parahitro substituent i s c l e a r l y existent i n 90$ ethanol but i s absent i n dry acetone, i n the face of such r e s u l t s i t seems d i f f i c u l t to any longer assume that i n non i o n i z i n g solvents, the general inductive polar effect of substituents i n the halide nucleus i s concerned with the p o l a r i z a b i l i t y or p o l a r i z a t i o n of the carbon-halogen bond. The .author would l i k e to point out that Baker measured his rates of reaction by t i t r a t i o n of the halide i?6n with s i l i v e r n i t r a t e . He therefore made the assumption that the rate of s4.lt formation was a true function of the concentration of ionic halide present i n solution. The author has found that some of these quaternary sa l t s do not behave as ionized s a l t s . 16 DISCUSSION. In order to synthesize the quaternary s a l t which i s the analogue of papaverine two products, 6,7,-di- methoxycinnoline and 3,4-dimethOxybenzylchloride are required. Neither of these compounds are reported i n the l i t - erature and so an attempted synthesis of these two compounds was undertaken. (18) and (19). Erlen&son^ has studied the Blanc reaction and side chain ehlorlnation using sulphuryl chloride. Although he did not obtain 3,4-dimethoxybenzyl chlor- ide by either of the above methods he did obtain the following alkyl substituted benzyl chlorides. (19a). 5Ad (19a) 18 From the the o r e t i c a l considerations already- presented, page 7, i t i s seen that the 2-iso propenyl- 4,5-dimethoxyaniline, (18-P) , w i l l produce a weakly positi v e diazonium kation and an expected lower y i e l d of cinnoline than the corresponding unsubstitut- ed derivative. Simpson has obtained the ketone, (l8ol) , and has converted i t to the corresponding 4-0H-6,7- dimethoxycinnoline. No reference has been made to the reaction of t h i s ketone by the method proposed by the .author. The ketone has been obtained but reduction of the ni t r o group to the amine has consist- ently given poor y i e l d s and d i f f i c u l y has been encountered i n the reaction of t h i s ketone with CH^gl For considerations regarding the formation of substituted benzylchorides the reader i s referred to H.M. Earlenson* 3 . He has i n conjunction with the Author prepared a number of mono- and di-substituted benzyl-halides. In general the r e a c t i v i t y of the halide increases with Baker's theory of substituent groups i n the nucleus, page (13). Para-methoxy!.- benzyl-chloride was found to be so reattive that i t decomposed even on d i s t i l l a t i o n at reduced pressure. The chloromethylation of hydroquinonedimethylether proceeded to the disubstituted product, and the three stylyl chlorides converted to the corresponding iodides with sodium iodide were stable only a few days. From t h i s experimental evidence i t would seem that 3,4- dimethoxybenzyl-halides are d i f f i c u l t to obtain and unstable. 19 I f Bakers theory o f quaternary s a l t f o r m a t i o n i s c o r r e c t , (page 15), then, 6,7-dimethoxycinnoline and 3,4-dimethoxy"benzyl c h l o r i d e would he expected to r e a d i l y form a s a l t , i e , N i of the c i n n o l i n e i s a r e l a t i v e l y s t r o n g "base due to the e l e c t r o n r e l e a s i n g groups i n the n u c l e u s . The a n i o n i s a t i o n o f the c h l o r i d e of the 3,4-dimethoxybenzyl c h l o r i d e i s made more f a c i l e "by e l e c t r o n a c c e s s i o n i n the side c h a i n due to the e l e c t r o n r e l e a s i n g para-methoxyl group. Almost no work has "been r e p o r t e d on quaternary s a l t f ormation i n the c i n n o l i n e s e r i e s 2 0 . While the attempted s y n t h e s i s o f 6,7-dimethoxycinnoline and 3,4-dimethoxybenzyl c h l o r i d e was b e i n g under- taken the author made a study o f s a l t f o r m a t i o n o f the r e a d i l y a v a i l a b l e 4-methylcinnoline and some o f the more common o r g a n i c - h a l i d e s . The r e s u l t s o f t h i s i n v e s t i g a t i o n are summarized i n the t a b l e , (20), and shows f o r the m a j o r i t y 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 w i t h 4-methyleinnoline, comparatively 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 c o n d i t i o n . ? 8 Baker" s t u d i e d the r a t e s o f r e a c t i o n o f 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 i n dry acetone. In order to prevent e r r o r s 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 due to the presence o f moisture i n the s o l v e n t he used the hy g r o s c o p i c p r o p e r t i e s o f the quaternary s a l t s to dry the acetone before use. He 20 ... T a b l e (20) base h a l i d e c o l o r change Qjuinoline C H S I c l e a r - y e l l o w 1 n C 2 H 5 I c l e a r - p a l e y e l l o w 2 tt b e n z y l c h l o r i d e c l e a r - r e d 3 n benzylbromide c l e a r - c r e a m 4 tt b e n z y l i o d i d e o l e a r - y e l l o w 5 tt p-UOg-benzylbromide c l e a r - r e d 6 2,6-dimethyl- CHgl y e l l o w white 7 q u i n o l i n e CgHgl y e l l o w - r e d 8 n b e n z y l c h l o r i d e no r e a c t i o n 9 4-methyl- CHgl yellow-orange 10 c i n n o l i n e C2H5I y e l l o w - r e d 1 1 n n - C ^ g B r ye l l o w - g r e e n 12 t» b e n z y l c h l o r i d e y e l l o w - g r e e n 13 n b enzylbromide yellow-brown 14 tt b e n z y l i o d i d e y e l l o w - r e d 15 tt 3-Me-benzylchloride no r e a c t i o n 16 tt tt n 2-Me-benzylchloride 4-Me-benzylchloride 2 - 0 H - 4 - H 0 2 - b e n z y l c h l o r i d e y e l l o w - b l u e no r e a c t i o n y e l l o w - g r e e n 17 18 19 n 3,4-diMe-benzylchloride y e l l o w - g r e e n 20 tt 2,4-diMe-benzylohloride y e l l o w - b l u e 21 n 1,4-diMe-benzylohloride y e l l o w - b l u e 22 n O - C l - b e n z y l c h l o r i d e yellow-dark specks 23 n p - C l - b e n z y l c h l o r i d e y ellow-dark specks 24 2 » 2 t 4 - d i C l - b e n z y l c h l o r i d e y e l l o w - b l u e 25 tt 3,4-^diCl-benzyl c h l o r i d e no r e a c t i o n 26 it p-NOg-benzylbromide yellow - p i n k - w h i t e 27 21 time form of salt mp.°C. remarks 1 £ hour fine yellow needles 135 reported 133 .2 8 days fine yellow prisms 14 5d " 158 3 reflux coarse red prisms 113 « 65 & 170 24 hours 4 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 237 8 10 (lays 9 10 days 10 •§• hour orange needles 196d reported 169 11 4 hours red needles 154 " 154 12 8 days green solid hygroscopic 13 90 (lays green o i l 14 18 hours yellow needles hygroscopic 15 3 hours yellow red needles n 16 8 days 17 8 (lays clear blue prisms hygroscopic 18 Id days 19 30 seconds green prisms 76 20 8 days green o i l 21 8 days blue prisms hygroscopic 22 4 days clear blue prisms under 50 n 23 8 days dark scales decomposition 24 8 days blue green prisms ifeygroscppio 25 8 days clear prisms 91 26 8 days 27 3 hours fine green needles 202 22 d i d not i s o l a t e any o f the s a l t s hut merely t i t r a t e d the h a l i d e i o n a t v a r i o u s times with aqueous s i l v e r n i t r a t e . The 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 d e s c r i b e d i n the t a b l e are so h y g r o s c o p i c t h a t t h e i r i s o l a t i o n as c r y s t a l l i n e compounds i s not f e a s i b l e . F u r t h e r i t i s c o n s i d e r e d that s a l t f o r m a t i o n has oc c u r r e d i n a l l eases due to the s e p a r a t i o n o f a hydrated o i l from the o r i g i n a l homogeneous s o l u t i o n . That t h i s i s so i s seen i n the formation o f y e l l o w needle l i k e c r y s t a l s from a s o l u t i o n o f 4-methylcinn- o l i n e and b e n z y l - i o d i d e i n dry e t h e r i n a s e a l e d ampoule. These c r y s t a l s l i q u i f y to a green o i l on exposure to the atmosphere. As f u r t h e r evidence t h a t s a l t f o rmation has o c c u r r e d the author p r e s e n t s the f o l l o w i n g ex- p e r i m e n t a l e v i d e n c e . 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 aqueous s i l v e r n i t r a t e to e t h e r a l s o l u t i o n s o f the o i l s takes p l a c e a t a v e l o c i t y f a r 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 o r g a n ! c - h a l i d e s . T h i s would i n d i c a t e the presence of an i o n i z e d h a l i d e i o n . The a d d i t i o n o f aqueous a l k a l i to both i s o l a t e d c r y s t a l l i n e s a l t s and hydrated o i l s r e s u l t s i n the formation of blue dyes i n d i c a t i v e o f quaternary ammonium hydroxides,4®., 23 I t has a l r e a d y "been s t a t e d , page (13), Baker s t u d i e d the r a t e s o f r e a c t i o n o f b e n z y l - h a l i d e s w i t h e l e c t r o n r e p e l l i n g groups i n the nucleus o f the b a s i c c o n s t i t u e n t . In or d e r t o examine the e f f e c t of e l e c t r o n a t t r a c t i n g s u b s t i t u e n t s an attempted s y n t h e s i s o f 6- n i t r o - 4 - m e t h y l c i n n o l i n e was undertaken by way o f the f o l l o w i n g r e a c t i o n s , (21). T h i s s y n t h e s i s was not completed as i t was f e l t t h a t i f s a l t s o f 4-methyl- c i n n o l i n e c o u l d not be i s o l a t e d , there i s no reason to expect the l e s s r e a c t i v e 6 - n i t r o - 4 - m e t h y l c i n n o l i n e would form s a l t s capable o f i s o l a t i o n and a n a l y s i s . C H 3 C O C l COOCH 3 o NH-&CH, COOH HfcS04/MT COOCH, JHN03 CH, NHC-CH, (21) I -R.0 CH, rCH, NH, CH3M,I CH, N O , i oH NH 2 HONO 24 EXPERIMENTAL o - i s o p r o p e n e - a n i l i n e 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 500cc. o f ether was added d u r i n g s t i r r i n g over f- hour to CHgMgl, (made from Mg. 40g., CHgl 240g. eth e r 750oc., 4 moles o f G-rignard are r e q u i r e d f o r each mole o f e s t e r used. ) . The temperature was maintained "below 0°C. d u r i n g the a d d i t i o n and the y e l l o w suspension was then heated under r e f l u x f o r 5 hours. The mixture was cooled and poured i n t o NH4CI and i c e and ether l a y e r allowed to separate. The water l a y e r was f u r t h e r e x t r a c t e d with f r e s h ether and the combined e x t r a c t s d r i e d over anhydrous MgSC>4 and the s o l v e n t removed by d i s t i l l a t i o n . 48g. of the o i l y c a r b i n o l was re c o v e r e d . Acetylation,-with c o l d Ac£0 gave a s o l i d d e r i v a t i v e a f t e r hour, y r e c r t s t a l l i z a t i o n from b e n z e n e - l i g r o i n gave needles, mp. 146° , Simpson, mp. 146-147°. The t e r t i a r y a l c o h o l was then dehydrated i n a Dean and Stark tube with the a i d o f 250cc. o f dry toluene and a small c r y s t a l o f i o d i n e . The theo- r e t i c a l amount o f water was obtained i n 4 hours. The toluene was removed under reduced pressure and the r e s i d u e d i s t i l l e d u s i n g a m i r r o r j a c k e t e d V i g r e u x column, bp. o f the o l e f i n 84°/4mm. Jacobs et a l l bp. 83.5 - 87.5 /i-gmm/'^SSg. 79$ o f the ij t h e o r e t i c a l was r e c o v e r e d . 25 4 - m e t h y l c i n n o l i n e 30g. o f the o l e f i n was d i s s o l v e d i n a s o l u t i o n o f 60ec. o f cone. HC1 i n 200cc. o f water. The s o l - u t i o n was c o o l e d to 5° and the suspension obtained was d i a z o t i s e d w i t h 20$ NaNOg u n t i l a p o s i t i v e t e s t was immediately o b t a i n e d w i t h s t a r c h - i o d i d e p a p rer. The c l e a r dark green s o l u t i o n was d i l u t e d to 400cc. and warmed d u r i n g hour to 50° on a water bath and h e l d at that temperature t i l l the c o u p l i n g r e a c t i o n w i t h a l k a l i n e $-naphthol became n e g a t i v e . At t h i s stage the r e a c t i o n mixture had changed c o l o r to a deep r e d . The system was connected to a gas b u r e t t e to determine the amount o f deaminat- i o n o c e u r i n g i n the r e a c t i o n ; 200cc. o f gas were c o l l e c t e d w hich.is a n e l i g i b l e amount. The s o l - u t i o n was made b a s i c with aqueous NaOH and e x t r a c t e d w i t h e t h e r i n a continuous e x t r a c t o r f o r 3 days. The e t h e r e x t r a c t s were d r i e d and e v a p o r a t i o n o f the ether y i e l d e d y e l l o w green c r y s t a l s . A sample r e c r y s t a l l i z e d from hexane gave mp. 72 - 74°. Jacobs et a l . mp. 72.5 - 74°. D i s t i l l a t i o n o f the e t h e r r e s i d u e under reduced pressure y i e l d e d 24g. o f a grey green s o l i d , bp. 133° /4mm. Jacobs et a l bp. 135-137° / 3mm. R e c r y s t a l l i z a t i o n from • hexane gave grey-yellow needles rap. 7 4 ° . N i t r o g e n c a l c . 19.4$. found 18.9$. Y i e l d from methyl- a n t h r a n i l a t e used was 50$ o f the t h e o r e t i c a l . 26 Aeetoveratrone 62g. o f a c e t y l c h l o r i d e was added to lOOg. o f v e r t r o l e i n 260ce. o f carbon d i s u l p h i d e i n a 1 l i t e r c o n i c a l f l a s k c o o l e d to below - 1 0 ° . lOOg. o f powdered AlCTg ( p r a c t i c a l grade), was added i n s m a l l p o r t i o n s with constant shaking. As the r e a c t i o n proceeded the magenta c o l o r e d complex s e t t l e d out i n round rough stones and hydrogen c h l o r i d e was e v o l v e d . A f t e r a l l the AICI3 had been added to r e a c t i o n mixture was heated under r e f l u x to 50° on a water bath f o r f hour. The r e s u l t i n g c l e a r l a y e r o f CS2 was decanted and t h e a d d i t i o n o f crushed i c e decomposed the complex g i v i n g a brown o i l y l a y e r and a c o l l o d i a l Al(OH)3 l a y e r . The whole was f i l t e r e d through s i n t - ered g l a s s u s i n g a f i l t e r a i d and the o i l y l a y e r s e p a r a t e d . The water l a y e r was e x t r a c t e d w i t h CHCI3 and the e x t r a c t s added to the o i l whereupon e m u l s i f i c a t - i o n o f the o i l took p l a c e . On d r y i n g over MgS04 and e v a p o r a t i o n o f the s o l v e n t the r e s i d u e was d i s t i l l e d under reduced p r e s s u r e . Y i e l d 83g. o f c l e a r o i l bp, 127-130° / 1mm. 63$ o f the t h e o r e t i c a l . The o i l c r y s t a l l i z e d on s t a n d i n g to a white s o l i d , mp. 50 °. K o e p f l i and P e r k i n 3 3 , bp. 160-162° /10mm., Oxime mp. 137.5 - 138° 27 6 - n i t r o a c e t o v e r a t r o n e 54g. o f powdered o f l i q u i d a c e t o v e r a t r o n e was added i n small p o r t i o n s to a mechanioally s t i r r e d mixture o f HNO3 (88cc. d 1.42 ) and oonc. HgS0 4 (80ec.) the temperature maintained between -5° and -3° d u r i n g the a d d i t i o n . The n i t r o k e t o n e u s u a l l y but not always began to c r y s t a l l i z e a f t e r the l a s t o f the ketone had been added. The mixture was s t i r r e d at the r e a c t i o n temperature f o r a f u r t h e r -jjf hour and the mass was then poured i n t o water. The nitro-compound was worked up i n the u s u a l way and r e c r y s t a l l i z e d from e t h a n o l . 51g. o f l o n g golden needles mp. 132-134°. S i m p s o n , 3 4 mp. 133-135°. Y i e l d 75$ o f the 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 i n a c e t i c a c i d (40co.) was heated on a steam bath with i r o n powder 7.5g. added i n small p o r t i o n s d u r i n g 1 hour wi t h f r e q u e n t shaking. A d d i t i o n o f l O c c . p o r t i o n s o f water were made at the s t a r t o f the r e a c t i o n and a f t e r f hour. A f t e r a t o t a l o f 1-J- hours the mixture ^ a s d i l u t e d w i t h 50$ sodium a c e t a t e t i l l cloudy and e x t r a c t e d w i t h CHClg t i l l e x t r a c t s were no l o n g e r c o l o r e d . The E x t r a c t s were d r i e d w i t h KgCOg ^ e s o l v e n t removed on a steam bath, the r e s i d u e was taken up i n d i l u t e HC1, t r e a t e d w i t h Darco and p r e c i p i t a t e d with d i l u t e NaOH. 3g. o f y e l l o w c r y s t a l - 28 l i n e m a t e r i a l were o b t a i n e d . A sample r e c r t s t a l l i z e d from e t h e r gave y e l l o w brown needles mp. 100-104°. S i m p s o n 3 4 mp. 103-105°. b. Reduction 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 machine u s i n g Raney n i c k e l c a t a l y s t was attempted with v a r y i n g p r e s s u r e s and temperatures, however no good y i e l d s were o b t a i n e d and i n a l l cases the product was contaminated with dark m a t e r i a l which c o u l d only be removed by d i s t i l l a t i o n . c. Reduction off the n i t r o compound was attempted 35 u s i n g the method o f West by i r o n powder i n HCI and methanol. However r e d u c t i o n was incomplete by t h i s method. Note; a l l the aminoacetoveratrone o b t a i n e d i n s e v e r a l runs was d i s t i l l e d under g r e a t l y reduced p r e s s u r e when a t o t a l o f SOg. o f y e l l o w c r y s t a l l i n e S o l i d was obtained, bp. 150° /O.lmm. (2-amino-4,5-dimethoxyrpheny3^-dimethyl-carbinol. (19.5g. .1 mole) o f 6-aminoacetoveratrone i n lOOcc. o f toluene was added d u r i n g s t i r r i n g to CHgMgl (.31 moles) made from Mg. and CH3I i n e t h e r . The temperature was maintained at 0° d u r i n g the ad- d i t i o n and a yewllow green suspension was o b t a i n e d . A f u r t h e r 200cc. o f toluene was added and the mixture It 29 warmed and the et h e r removed by d i s t i l l a t i o n . When a l l o f the ether had been d r i v e n o f f the mixture was r e f l u x e d f o r 2 hours, c o o l e d and poured i n t o i c e and KH 4C1. The toluene l a y e r was separated and the water l a y e r made n e u t r a l with sodium a c e t a t e , and e x t r a c t e d w i t h CHClg. The toluene and CHClg l a y e r s were s e p a r a t e l y evaporated and the r e s i d u e from both taken up. i n d i l . HCI, f i l t e r e d through Darco and on making b a s i c w i t h d i l . Na0H.3g. of a white s o l i d was o b t a i n e d . The d i f f i c u l t y i n t h i s r e a c t i o n i s the s l i g h t s o l u b i l i t y off the amino-ketone i n s o l v e n t s s u i t a b l e f o r the Grignard r e a c t i o n . K - a c e t y l - m e t h y l a n t h r a n i l a t e 1 mole of methyl a n t h r a n i l a t e was added to 1.1 moles o f a c e t i c anhydride and warmed to j u s t below the b o i l i n g p o i n t f o r 1 hour. The mixture was then c o o l e d and poured i n t o d i l u t e sodium a c e t a t e and the white c r y s t a l l i n e s o l i d r e c r y s t a l l i z e d from e t h a n o l . 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 mpJLOO0 was ob t a i n e d , y i e l d 9 3 $ o f the t h e o r e t i c a l . 5 - n i t r o - N - a c e t y l - m e t h y l a n t h r a n i l a t e N i t r a t i o n o f N-acetyl-methyl a n t h r a n i l a t e was 36 c a r r i e d out u s i n g the method o f Vogel , The crude nitro-cpmpound was r e c r y s t a l l i z e d from et h a n o l , mp.l62°. 30 Note: I t was hoped to c a r r y out a G r i g n a r d r e a c t i o n w i t h t h i s n i t r o compound as the t a b l e ( E l ) shows. However the n i t r o compound i s i n s o l u b l e i n Grignard r e a c t i o n s o l v e n t s and so i t was deci d e d to h y d r o l i z e the n i t r o compound to the corresponding amino-acid and estenttfy and then to t r y the Gr i g n a r d r e a c t i o n on the more s o l u b l e amino e s t e r . 5 - n i t r o - a n t h r a n i l i c a c i d . The h y d r o l y s i s o f the amide ( 5 - n i t r o - N - a e e t y l - m e t h y l a n t h r a n i l a t e ) was c a r r i e d out i n 70$ H2S0 4 u s i n g the 37 method o f Vogel . D i f f i c u l t y was encountered i n r e c o v e r i n g the amino a c i d from the 70$ H2SO4. The best method was to d i l u t e the a c i d s o l u t i o n w i t h an equal volume o f water and on c o o l i n g i n an i c e bath a y e l l o w sludge s e t t l e d out. T h i s sludge was c o l l e c t e d 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 a i d , and was d i s s o l v e d from the f i l t e r cafee usmng b o i l i n g e t h a n o l . E v a p o r a t i o n o f some o f the s o l v e n t gave f i n e y e l l o w needles mp. 265°, Reported S 8 280° (£63°) Quaternary S a l t s A l l s a l t s were majie by mixing equal molar quant- i t i e s o f base and h a l i d e i n dry e t h e r and allowed to stand a t room temp, t i l l s a l t f o r m a t i o n had o c c u r r e d . When p o s s i b l e they were r e c r y s t a l l i z e d from e t h e r c o n t a i n i n g a l i t t l e e t h a n o l . NoteM In most cases r e f l u x i n g t o i n c r e a s e the r a t e o f r e a c t i o n l e a d to ' '.31 !: decomposition. B e n z y l c h l o r i d e 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 under reduced p r e s s u r e and the f r a c t i o n b o i l i n g at 46.5° / 7mm. was c o l l e c t e d . B e n z y l bromide 2 moles o f bromine was added,through a dropping f u n n e l to 2.1 moles o f b o i l i n g toluene i r r a d i a t e d w i t h a 150 watt lamp. A f t e r a d d i t i o n o f the bromine was complete ( 1 hour ) the mixture was r e f l u x e d t i l l the e v o l u t i o n o f HBr had ceased. The mixture was then d i s t i l l e d and a f t e r " f o r e r u n o f toluene the be n z y l bromide was c o l l e c t e d bp. 195-205°. Schramm 3 9 198°. and 127°/80mm. R e d i s t i l l a t i o n through a short column gave 220g. o f c l e a r l i q u i d bp. 68° / 5mm. Y i e l d o f pure product 65$ o f the; t h e o r e t i c a l . Benzyl i o d i d e To lOOg. o f sodium i o d i d e i n 500g. o f acetone was added 63g. o f r e d i s t i l l e d b e n z y l c h l o r i d e . The s o l u t i o n was r e f l u x e d f o r 4 hours, cooled and the p r e c i p i t a t e o f sodium c h l o r i d e f i l t e r e d o f f . The acetone was removed and the ben z y l i o d i d e d i s t i l l e d undeijreduced p r e s s u r e bp. 82° / 7mm. The d i s t i l l a t e was shaken w i t h a small p o r t i o n o f mercury to remove t r a c e s o f i o d i n e and then r e d i s t i l l e d , bp. 83° / 7mm. H e i l b r o n 4 0 S 3 0 /10 mm. 32 SUPPLEMENT In an i n v e s t i g a t i o n b e i n g c a r r i e d out by Mr. G.G.S.. Button i t was r e q u i r e d to s y n t h e s i z e a l l the 0- and p-hydroxy-n-alkyl-phenols w i t h a l k y i groups c o n t a i n i n g from 1 to 7 carbons. T h i s supplement r e p r e s e n t s a p o r t i o n o f the experimental work done by the author d u r i n g the p e r i o d i n which the main t h e s i s was being prepared. 33 A d a C h l o r i d e s The a c i d c h l o r i d e s o f a l l a c i d s used to make e s t e r s were made i n the f o l l o w i n g way. 1 mole o f the a c i d was added slowly through a dropping f u n n e l to 1.1 moles o f r e d i s t i l l e d t h i o n y l c h l r o i d e c o o l e d to 0°C. The r e a c t i o n mixture was shaken p e r i o d i c a l y and when a l l o f the a c i d had been added the mixture was warmed t i l l the e v o l u t i o n o f HC1 was complete and then heated under r e f l u x f o r 1 hour. The mixture was then d i s t i l l e d and the f o r e r u n o f t h i o n y l c h l o r i d e c o l l e c t e d and then the crude a c i d c h l o r i d e . R e d i s t i l l a t i o n through a short column gave a c i d c h l o r i d e o f a p u r i t y s u i t a b l e f o r u s e . Y i e l d s range 70-90$. Phenyl e s t e r s Phenyl esteBS were prepared i n the f o l l o w i n g manner• 1. mole o f the a c i d c h l o r i d e was poured i n a t h i n stream onto 1.1 moles o f phenol. The mixture was heated u n t i l the e v o l u t i o n o f hydrogen c h l o r i d e was complete ana the e s t e r d i s t i l l e d . I f a l a r g e b o i l i n g range was observed the e s t e r was r e d i s t i l l e d through a short column. Y i e l d s ranged 80-90$. 34 p-hydroxyacetophenone To 272g. o f p h e n y l a c e t a t e i n 1140cc. o f p u r i f i e d nitrobenzene i n a f l a s k c o o l e d to below 20°C. was added 400g. o f powdered A l C l g ( p r a c t i c a l grade) w i t h shaking. The tomperature was maintained below 20°G. d u r i n g the a d d i t i o n and the r e s u l t i n g brown suspension allowed to stand overnight at room temperature. The s o l u t i o n was then warmed on a water bath to 50°C. f o r 1 hour, c o o l e d and poured i n t o i c e and HCI. The nitrobenaene was removed by steam d i s t i l l a t i o n and the r e s i d u e c r y s t a l l i z e d from the water on c o o l i n g . Y i e l d o f crude product EOOg. The product was found d i f f i c u l t to p u r i f y without l o s s o f m a t e r i a l . D i s t i l l a t i o n under reduced p r e s s u r e gave a pink o i l b.p. 155-160°C /2mm. w h i c h ' s o l i d i f i e d on s t a n d i n g . Treatment o f the crude product w i t h NaOH, c h a r c o a l and a f i l t e r a i d , f o l l o w e d by a c i d i f i c a t i o n y i e l d e d y e l l o w c r y s t a l s , m.p. 106-107°C. m.p. ef the pure compound 1098c. In 4 runs the y i e l d s v a r i e d from 50-60$. 35 o-and p-hydroxyacetophenone, 120g. o f phenylacetate was added i n small p o r t i o n s to 180g. o f A l C l g ( p r a c t i c a l grade) which had he en preheated to 70°C. The e v o l u t i o n o f HC1 was very r a p i d and the temperature of the mixture rose t o afeout 130°C. Heat was a p p l i e d to maintain the temperature a t 140°C. f o r -f hour. The r e a c t i o n mixture was cooled somewhat and a mixture o f 500cc. o f cone. HC1 i n 500cc. o f water was added i n p o r t i o n s to the f l a s k . A v i o l e n t r e a c t i o n f o l l o w e d and the dark complex gave way to a r e d o i l . # The o i l was separated and washed with 50$ HC1 and w i t h warm water. The water l a y e r and washings were co o l e d and e x t r a c t e d w i t h two lOOcc. p o r t i o n s o f e t h e r . The ether e x t r a c t s were added t o the o i l and the ether and water removed a t the pump. D i s t i l l a t i o n o f the r e s i d u a l o i l gave 34g. 28$, of c l e a r o i l hp. 77-80°C. /1mm* and 50g. 50$, o f a pink s o l i d hp. 155-160°C. / 1mm. #. I t would he more p r o f i t a b l e to h y d r o l y z e lower members o f the s e r i e s with i c e and HC1 due t o thE r a t e o f h y d r o l y s i s . 36 0- and p-hydroxybutyrlphenone lOOg. (.6 moles) o f the e s t e r was added i n small p o r t i o n s to 119g. (.8 moles) o f A l C l g which had "been preheated t o 70°. The e v o l u t i o n o f HCI was r a p i d and the temperature of the mixture rose to about 155°. Heat was a p p l i e d to m a i n t a i n the temperature a t 140° f o r f hour. The r e a c t i o n mixture was c o o l e d to 30° and a mixture o f 300cc. o f cone. HCI and 450cc. o f warm water was added i n p o r t i o n s to the r e a c t i o n m i x t u r e. The y e l l o w grey complex d i s s o l v e d and gave way to a b r i g h t r e d o i l . The mixture was a g a i n cooled to 30° and the o i l separated, washed wi t h 50$ HCI and wi t h warm water. The wet o i l was d i s t i l l e d and a f t e r removal o f the water 32g. 32$ o f c l e a r o i l , bp. 105° /2mm., and 40g. 40$ pf a white s o l i d , bp 160- 173° /2mm. were o b t a i n e d . o- and p-hydroxy-n-valerophenone 89g. o f e s t e r a t 70° was added i n a t h i n stream to 90g. o f A I C I 3 ( p r a c t i c a l grade) preheated to 50° and t h e temperature rose to 140°. The mixture was then heated to 150°-160° f o r f hour and then c o o l e d to 4 0 ° . 250cc. o f cone. HCI i n 250g. o f water was poured onto the orange mass. The mixture was warmed u n t i l the complex decomposed and while s t i l l hot the brown o i l was separated, washed wi t h warm 50$ HCI and then w i t h warm water. The wet o i l on 37 d i s t i l l a t i o n y i e l e d 39g. 44$, o f the ortho isomer bp. 125° / 3mm. and 40g. 45$, o f the para isomer bp. 185-190° /2.5mm. The para isomer c r y s t a l l i z e d on s t a n d i n g . o- and p-hydroxy i s o valerophenone 178g. (1 mole) of the e s t e r and 195g. (1.3 moles) o f AICI3 was t r e a t e d i n the same manner as f o r n- valerophenones. D i s t i l l a t i o n under reduced p r e s s u r e y i e l d e d 63ce. 34$, of the ortho isomer bp, 101-103° / 1mm. and 50cc. 41$ o f the para isomer bp. 160-168° / 1 mm. Hote: T h i s work i s s t i l l under way and the constants f o r the d e r i v a t i v e s has not been completed although 2 , 4 - d i n i t r o p h e n y l h y d r a z i n e s , semicarbazones and hydantoins. o f a l l the compounds l i s t e d have been made • 38 BIBLIOGRAPHY 1. von R i c h t e r , (Ber. 16_ 677 11883)). 2. Stoermer and Fineke, (Ber. 42_ 3115 (1909)). 3. Widman, (Ber. 16_ 677 (1883)). 4. S t o l l e and Becker, (Ber. 57 1123 (1924)). 5. Borache and H e r b e r t , (Ann. J546 293 (1941)). 6. P f a n n s t i l l and Janecke, (Ber. 75 1096 (1942)). 7. Jacobs et a l . , (J.A.C.S. 68 1310 •.; (1947)). 8. Simpson, (J.S.C. 1947 809 ). 9. Simpson, (J.C.S. 1942 and sate,.}. 10. 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Erlendson, (Unpublished). 33. K o e p f l i and P e r k i n , (J.C.S. 1928 2989). 34. Simpson, (J.C.S. 1946 9 6 ) . 35. West R.W., (J.C.S. 1925 494). 36. Vogel, ( P r a c t i c a l Organic Chem., page 558.). 37. Vogel, ( P r a c t i c a l Organic Chem^ page 558.). 38. H e l l b r o n , ( D i c t i o n a r y o f Org, Compds., I l l 91.) 39. Schramm, (Ber., 18 608 (1885)). 40. H e i l b r o n , ( D i c t i o n a r y Org. Compds., I 247). 41. K i n g , (J.C.S. 1935 138; 1948 265). 42. G r e i g , (Chem. Rev. .42 285 (1947)). 43. W a l l s , (J.C.S. 1944 and Subq.). 40

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