The Preparation and Pyrolytic Molecular Rearrangment of the 8-Ethers of Caffeine; and Their Conversion to 8-Methyl and 8-Ethylcaffeine A Thesis Submitted to the Faculty o f Michigan State College in Partial Fulfillment of the Requirem ents for the D egree of Doctor of Philosophy by W I N S T O N F. A L L E N D e p a r tm e n t of C h e m is tr y 1932 P ro Q u e s t N u m b e r: 1 0 0 0 8 2 4 7 A ll rig h ts re s e rv e d IN F O R M A T IO N T O A L L U S E R S T h e q u a lity o f th is re p ro d u c tio n is d e p e n d e n t upo n th e q u a lity o f th e c o p y s u b m itte d . In th e u n lik e ly e v e n t th a t th e a u th o r d id n ot s e n d a c o m p le te m a n u s c rip t and th e re a re m issin g p ag es, th e s e w ill be note d. A lso , if m a te ria l had to be re m o v e d , a n o te w ill in d ic a te th e d e le tio n . uest P ro Q u e s t 1 0 0 0 8 2 4 7 P u b lis h e d by P ro Q u e s t L LC (2 0 1 6 ). C o p y rig h t o f th e D is s e rta tio n is held by th e A u th o r. A ll rig h ts re se rve d . T h is w o rk is p ro te c te d a g a in s t u n a u th o riz e d c o p y in g u n d e r T itle 17, U n ite d S ta te s C o d e M ic ro fo rm E d itio n © P ro Q u e s t LLC . P ro Q u e s t LLC . 789 E a st E is e n h o w e r P a rk w a y P.O . B o x 1346 A n n A rb o r, M l 4 8 1 0 6 - 1346 ACKNOWLEDGMENT The w r i t e r w ishes to e x p re s s h i s g r a t i t u d e f o r th e h e lp f u l and i n s p i r i n g c o u n se l g iv e n by D r. R. C. H uston, P r o f e s s o r o f O rganic C hem istry a t M ichigan S ta te C o lle g e , w h ile c a r r y in g on t h i s work. T h is r e s e a r c h was made p o s s ib l e by th e e s t a b l i s h ­ ment o f a F e llo w sh ip in C h em istry a t M ichigan S t a t e C o lle g e from 1929 to 193^ by th e K e llo g g Company. As th e h o ld e r o f th e F e llo w s h ip , t h e w r i t e r acknow ledges h i s in d e b te d n e s s to t h i s Company, and a p p r e c ia t e s th e i n t e r e s t and c o o p e ra tio n o f Mr. H, K. W ild e r, D i r e c t o r o f R e se a rc h a t th e K e llo g g Company, : m 5 9 8 TABLES OF CONTENTS INTRODUCTION Page 1 -2 HISTORICAL AND DESCRIPTIVE 3 - kl A rev iew o f th e c h e m is try o f u r i c a c id s and x a n th in e s EXPERIMENTAL I. H a lo g e n a tio n o f c a f f e in e I I . P r e p a r a tio n o f th e 2 - e th e r c a f f e i n e compounds I I I . P y r o l y s i s and m o le c u la r rea rra n g e m e n t o f th e e th e r c a f f e i n e compounds IV. P r e p a r a tio n o f two S - a lk y lc a f f e in e d e r i v a t i v e s SUMMARY AND DISCUSSION 1+2-20 1+2—1+5 L5-63 63—75 75-80 21-29 CONCLUSIONS 90 ADDENDA I. P r e p a r a tio n o f o th e r c a f f e in e d e r i v a ti v e s I I . T o x ic ity e x p e rim e n ts w ith c a f f e in e and some o f i t s d e r i v a ti v e s III.M o th p r o o fin g t e s t s w ith c a f f e in e and some o f i t s d e r i v a ti v e s 91-101 91-95 9 5 -9 8 9 2 -1 0 1 1 INTRODUCTION Prom 1SS2 to 1906, Em il F is c h e r and h i s a s s o c i a t e s c a r r i e d on t h e i r e x te n s iv e i n v e s t i g a t i o n s and s y n th e s e s o f compounds in th e p u r in e gro u p . S in c e t h a t tim e t h e r e h a s b e e n c o m p a ra tiv e ly l i t t l e a c co m p lish e d in th e l i n e o f s y n th e s is o f many p o s s i b l e de­ r i v a t i v e s o f t h i s im p o rta n t c l a s s o f compounds, (l) N = i i C-H ( 6 ) (2JH-C (5 ) C - N-H (7 ) " « NC-H(S) (3 ) N - (U)C - / ( 9 ) P u rin e CH3-N - C = 0 i t 0=C C - N-CH3 i " XC-E CH3-N - C - N* C a ffe in e The s tu d y o f th e p u r in e compounds w hich in c lu d e s o v e r one h u n d red and f i f t y s y n t h e t i c and n a t u r a l l y o c c u rr in g compounds, s u g g e s ts i n t e r e s t i n g p o s s i b i l i t i e s o f th e s y n th e s is o f many more compounds i n t h i s g ro u p . T his can be v e ry r e a d i l y s e e n , a s t h e r e a r e s e v e r a l p o s i t i o n s on th e m o lecu le w here atom s o r r a d i c a l s can b e s u b s t i t u t e d . S t a r t ­ in g w ith p u r i n e , i t i s found t h a t th e hydrogen i n th e s i x t h p o s i t i o n i s th e f i r s t to be r e p la c e d by a n o th e r atom o r r a d i c a l . The one on p o s i t i o n (2 ) i s n e x t, fo llo w e d b y num bers (7 ) and (S) r e s p e c t i v e l y . Thus we f in d t h a t w itli c a f f e in e a l l o f th e h y drogens a tta c h e d to th e r i n g h av e b een re p la c e d by m ethyl groups ex cep t th e one i n p o s i t i o n ( S ) , Prom th e p h y s i o l o g i c a l s ta n d p o in t i t h as been found t h a t th e two m eth y l groups a tt a c h e d to p o s i t i o n s ( l ) and ( 3 ) a s w ith th e o p h y llin e s have a more pronounced e f f e c t on th e c e n t r a l n e rv o u s sy stem th a n when two m eth y l groups a r e a tta c h e d to p o s i t i o n s ( 3 ) and ( 7 ) a s i n th e c a s e o f th eo b ro m in e . On th e o t h e r h an d , th e l a t t e r compound i s a s tr o n g e r d i u r e t i c th a n th e fo rm e r. The in tr o d u c ti o n o f t h r e e m eth y l groups i n p o s it i o n s ( l ) , ( 3 ) , and ( 7 ) r e s u l t s i n a compound p o s s e s s in g a pronounced s tim u la to r y e f f e c t on th e c e n t r a l n e rv o u s sy ste m , w h ile i f th e th r e e m ethyl g ro u p s a r e on p o s i t i o n s ( l ) , ( 7 ) , and ( 9 ) th e n e rv e s t i m u la ti n g e f f e c t i s s l i g h t l y l e s s . I t would b e i n t e r e s t i n g t h e r e f o r e to s tu d y th e p h y s io l o g i c a l e f f e c t o f p u r in e compounds c o n ta in in g f o u r m ethyl g ro u p s such as S - m e th y lc a ff e in e o r t e t r a m e th y l - u r i c a c id . I t seems w orthy to s tu d y s i m i l a r l y th e e f f e c t o f in tr o d u c in g e t h y l , p r o p y l, b u t y l , b e n z y l, and o th e r groups i n t o th e c a f f e in e m o le c u le . In p r e p a r in g and s tu d y in g th e p r o p e r t i e s o f th e v a r io u s c a f f e in e d e r i v a t i v e s , i t m ust be k e p t i n mind t h a t th e p o s i t i o n o f th e s e r a d i c a l s on th e p u r in e n u c le u s i s o f te n o f more im p o rta n c e th a n th e m ere s u b s t i t u t i o n o f th e r a d i c a l i n th e m o le c u le . The r e s u l t s o f th e e x p e rim e n ts g iv e n i n th e f o llo w in g p ag es a r e l i m i t e d to th e s y n th e s i s o f some o f th e d e r i v a t i v e s o f c a f f e i n e . The s t a r t i n g p o in t i n th e s y n th e s i s o f many o f th e p u r in e compounds d e s c r ib e d by Em il F is c h e r was u r i c a c id . T h is was un­ d o u b te d ly due to th e f a c t t h a t i t was th e c h e a p e s t p u r in e compound o b ta in a b le a t t h a t tim e . A lso much i n t e r e s t c e n te r e d aro u n d u r i c a c id b e c au se o f i t s p h y s io lo g ic a l im p o rt­ a n c e. At th e p r e s e n t tim e , how ever, c a f f e i n e i s u n d o u b te d ly th e c h e a p e s t p u r in e compound on th e m a rk e t. T h is h a s d e v e lo p e d b e c a u s e o f th e in c r e a s i n g consum ption o f d e c a f f e i n a te d c o ff e e by th e p u b l ic , r e s u l t i n g i n th e a c c u m u la tio n o f th e e x tr a c t e d c a f f e in e . B ecause o f th e f a c t t h a t c a f f e in e i s a h e te r o c y c l ic confound c o n ta in in g two c lo s e d r i n g s , t h e r e e x i s t p o s s i b i l i t i e s o f many d e r i v a t i v e s o f t h i s compound a s w e ll a s numer­ ous p r o d u c ts form ed from th e p a r t i a l d e c o m p o sitio n by v a r io u s a g e n c ie s . The p r e p a r a ti o n o f th e e t h e r compounds o f c a f f e i n e opens up an i n t e r e s t i n g a s w e ll a s im p o rta n t c l a s s o f c a f f e i n e d e r i v a t i v e s . These compounds a r e r a t h e r e a s i l y p re p a re d and th e y i e l d s a re v e ry good. 'The p r e p a r a ti o n o f o th e r c a f f e i n e d e r i v a t i v e s from th e s e e t h e r compounds, m a in ly by p y r o l y s i s , e i t h e r a lo n e o r in th e p re s e n c e o f some o t h e r s u b s ta n c e , s u g g e s ts th e p o s s i b i l i t y o f many compounds o f t h e o r e t i c a l a s w e ll a s p r a c t i c a l im p o rta n c e . The r e s u lt s o f th e work undertaken in t h is d ir e c t io n may w e ll "be d iv id ed in to fou r p a rts : (1 ) The p r e p a r a ti o n o f th e S -m o n o h a lo c affe in e compounds. (2 ) The p r e p a r a ti o n o f s ix t e e n o f th e S -m onoether o r o x y c a ff e in e compounds. ( 3 ) The m o le c u la r rea rra n g e m e n t o f some o f th e e th e r compounds by h e a t a lo n e to 1 , 3 , 7 - t r i m e t h y l , 9 - a lk y 1 o r a r y l - u r i c a c id compounds. (*+) The c o n v e rs io n o f th e e th e r c a f f e i n e compounds to two 2 - a l k y l c a f f e i n e de­ r i v a t i v e s by h e a t i n th e p re s e n c e o f a l i p h a t i c a c id a n h y d rid e s , and e th e rs . lilSl'QHICAL A1ID DESCRIPTIVE A Review of the Chemistry o f U ric A cids and X an thines. 3 I . THE URIC ACITS. A. UEIC ACID/2, 6, S-TRIHYDROXT-PURINE), CsH^Os. U ric a c id was d is c o v e re d i n 1776 "by S ch eele in u r i n a r y c a l c u l i and in th e human u rin e . L a te r i t was found hy Foucroy and V au q u elin i n th e N = C-OH excrem ent o f b i r d s . Guano, w hich i s found in some p a r t s 1 1 o f th e t r o p i c s , c o n s is t s m ain ly o f ammonium u r a t e . I t was HO-C C- IT—II d e p o s ite d f o r c e n tu r ie s by b i r d s i n h a b i t i n g th e same " 11 C-OH ground, and now f u r n is h e s th e p r i n c i p a l s o u rc e o f u r i c U - Ca c id . U ric A c id ( e n o l) I t was n o t u n t i l 1S3^ t h a t th e f i r s t d e f i n i t e p r o ­ g r e s s was made i n p u r in e c h e m is try , when L ie b e g made th e f i r s t e le m e n ta ry a n a ly s i s o f u r i c a c id . W ohler and L ie b eg in 1838 p u b lis h e d t h e i r c l a s s ­ i c a l work on u r i c a c id , th u s s t a r t i n g an im p o rta n t c h a p te r o f c h e m is try and b io lo g y . These two a u th o r s p la c e d em phasis on th e f in d in g s o f d ry d i s t i l l a t i o n and o x id a tio n e x p e rim e n ts f o r th e i n t e r p r e t a t i o n o f th e s t r u c t u r e o f u r i c a c id . T hus, a l l a n t o i n , u re a , o x a li c a c i d , and c arb o n d io x id e were i d e n t i f i e d . They d isc o v e re d t h a t a ll o x a n t i n was one o f th e o x id ­ a t i o n p r o d u c ts when u r i c a c id was t r e a t e d w ith d i l u t e n i t r i c a c id , and a llo x a n was form ed i n th e same m anner w ith s tr o n g n i t r i c a c id . By more e n e r g e ti c o x id a tio n th e y a l s o o b t a i n ­ ed p a ra b a m ic a c id . I n I 8 6 3 , B aeyer p u b lis h e d th e f i r s t p a p e r on th e s t r u c t u r e o f u r i c a c id . H is c o n tr i b u ti o n s to th e c h e m is try o f u r i c a c id c o n s is te d i n c o r r e l a t i n g a l l o f th e known sub­ s ta n c e s o f th e a llo x a n group to b a r b i t u r i c a c id , and a l l o f th o s e o f th e parab am ic a c id gro u p to u r e i d o a c e t i c a c id .. B aeyer a ls o s y n th e s iz e d b a r b i t u r i c a c id and h y d a n to in . I n th e y e a r 1875* M edicus p r e s e n te d th e s t r u c t u r a l fo rm u la o f u r i c a c id a s i t i s a c c e p te d to d a y . F i t t i g g , i n 1877* p ro p o se d an a l t e r n a t e fo rm u la f o r t h i s compound. The f i n a l d e c is io n re g a r d in g th e s t r u c t u r e o f u r i c a c id was f u r n is h e d by th e lo n g and in g e n io u s work o f Em il F is c h e r . He p ro v ed t h a t th e s t r u c t u r e o f t h i s compound a s p r o ­ p o se d by M edicus was th e most p l a u s i b l e o n e . F i s c h e r ’s c o n tr i b u ti o n s to th e th e o r y o f th e s t r u c t u r e o f u r i c a c id a r e th e fo llo w in g : He s y n th e s iz e d u r i c a c id by a method t h a t i n ­ d i c a t e s a u n io n o f th e second u r e a to ca rb o n atoms (4) and ( 5 ) o f th e p y rim id in e n u c le u s . He s y n th e s iz e d a l l o f th e mono, d i , and tr im e th y l d e r i v a ti v e s o f u r i c a c id t h a t a re p o s t ­ u l a t e d by th e th e o ry o f s t r u c t u r e e x p re s s e d by th e fo rm u la o f M edicus. He d e m o n s tra te d th e p re s e n c e o f a double bond betw een c arb o n atoms ( 4 ) and (5)» c o n v e rte d u r i c a c id i n t o t r i c h i o r p u r i n e . F in a lly , he c o n v e rte d u r i c a c id i n to p u r in e , th e n u c le u s o f a l l n a t u r a l l y o c c u r r in g s u b s ta n c e s r e l a t e d to p u r in e . U ric a c id i s a w h ite c r y s t a l l i n e pow der, v e ry s p a r in g ly s o lu b le in h o t w a te r and p r a c t i c a l l y i n s o lu b le in c o ld w a te r. I t does n o t m e lt. I t a c ts as a d i b a s i c a c id , th e hydrogen i n th e t h i r d p o s i t i o n b e in g m ost a c i d i c . By th e o x id a tio n o f u r i c a c id a greatd e a l was le a r n e d r e g a r d in g i t s s t r u c t u r e . W ith m oderate o x id a tio n w ith n i t r i c a c id , a llo x a n i s u-rned. (l): 0. P i l o t y , Ann. 333* 2 2, 1904. B er. 37* 2686, 1904. Am. C ,J . 3^* ° 6l , 1 ;0 ; h- n I 1 nh2 I 0=0 I 0=0 I H-N - 0=0 - c=o i 1 HNO3 0=0 t o=c I C - N-H " y0=0 H-J - C - N-H nh2 R educing a g e n ts + HOH (2 m o le c u le s ) R e a c tio n s ( a llo x a n ) in v o lv e d in th e M urexide t e s t . - N-H t H-N - 0=0 A llo x a n U ric A cid O2 A lk a lin e i KMNO^ I H-N 1 0=0 9 0 1 1 0=0 HD-C-0-C it 1 1 + CO2 C - -N-H 1 ' ^ 0=0 H-N - C - N-H H * H-N - H-N - U rea 0=0 A llo x a n tin I 0=0 c - N-H HO J lH . M urexide, ( o r th e Ammonium S a l t o f p u r p u r ic a c id ) A l l a n t o in W ith a l k a l i n e p erm anganate carbon d io x id e i s s p l i t o f f and a l l a n t o i n i s form ed, I'bus i t i s p ro v e n t h a t u r i c a c id c o n ta in s a p y rm id in e r i n g and th e f i v e membered im id a z o le r in g . U r ic a c i d i n th e e n o l form r e a c t s w ith phosphorus o x y c h lo rid e ( 1 ) y i e l d in g f i r s t , 2 , 6 - d i c h l o r 8 -o x y p u rin e and f i n a l l y 2 , 6 , 8 - t r i c h l o r - p u r i n e , a s f o llo w s : N - C-OH N = C-01 1 1 1 N = C-Cl 1 I 1 Cl-C II C - N-H ► Cl-C C - N-H (PCOls)* II " \j-0 H " ' c -0 1 N - 0 - H' N - C - N' 2 , 6 - d i c h l o r - 8 -h y d ro x y -p u rin e 2 , 6 , 8 - t r i c h l o r - p u r i n e C - N-E (POCI3 ) .C-OH N - C - N U r ic A cid ( e n o l) H0-C 11 2 C2 H5 0Na H-N - 0=0 N = C-OCjjHe 1 1 1 1 C - N-H r e d u c tio n w ith HI 0=0 C - N-H ^ 1 11 « 'C - C l " VC-H N - 0 - N* H-N - 0 - N“ X an th in e C2 H5 O—C The c h l o r i n e atoms a re v e ry r e a c t i v e and a r e r e a d i l y exchanged f o r e th o x y , h y d ro x y , t h i o , animo g ro u p s, i o d in e , and in p a r t by hydrogen. Thus many d e r i v a t i v e s o f u r i c a c id a r e p o s s i b l e , su ch as x a n th in e , g u a n in e and a d e n in e . ( l ) : E. F i s c h e r . Ann. 175> 3.^75- 5 The s im p le s t method, f o r th e s y n th e s i s o f u r i c a c id i s t h a t o f F is c h e r and A ch(1 ) c o n s i s t i n g o f th e i n te r m e d ia te fo rm a tio n o f p s e u d o -u r ic a c id in th e f o llo w in g m anner: U rea H 0 H-N + H0-& I ' 0=0 ch 2 I I H-N HO-C fi 0 M alonic a c id H-N - C=0 ' ' 0=C CH2 I I H-N - C ------------------- > > 0 B a rb itu ric a c id r e d u c tio n H-N - 0=0 1 ^H 0=0 C-NH2 • l KCN0 ------------> H-N - 0=0 B. -Ha 0 H-N - 0=0 1 ' > 0=0 C - N-H I I SQsQ H-N- 0=0 P s e u d o -u ric a c id THE MONO-METHYL-URIC ACIDS. 1. H-N- 0=0 > *JL H 0 0=0 0 - ^ - C-NH2 I I H-N - C=0 » ' 0=0 C=N0H ' • H-N - C=0 i I H-N - C - N-H U ric a c id C6H8N4 03 . 3 - ^ e t h y l - u r i c A cid. T h is compound i s p r e p a r e d ^ ) by s h a k in g an a l k a l i n e s o l u t i o n o f u r i c a c id w ith m eth y l io d id e a t JO to 100°. N = C-OH i t N = C-OH i t NaO-C C - N-H + CHSI CH3 -O-C C - N-H » " ^C-OH ----------- * " " NC-0H N - C - N* N - C - N* U ric a c i d 3 -M e th y l-u ric a c i d (e n o l) H-N - 0=0 i t or 0 -0 0 - N-H ' 11 NC=0 CH3-N - C - N-H 3 - M e th y l- u r ic a c i d ( k e to ) ^ 3 -M e th y l-u ric A cid i s i d e n t i f i e d by o x id iz in g i t to 3"meth y l - a l l o x a n and u r e a . a s i m i l a r m anner th e o th e r m e th y la te d u r i c a c id s a r e i d e n t i f i e d . 2, 9- M e th y l- u r ic A c i d . In ^3) In th e p r e p a r a ti o n o f 3-me t h y l - u r i c a c i d , d e s c rib e d ab o v e, a v e r y sm a ll amount o f th e 9 - m e th y l- u r ic a c id i s p ro d u ce d . I t i s s e p a r a te d by b e in g l e s s s o lu b le i n h o t w a te r 9 and i t s g r e a t e r s t a b i l i t y tow ard ammonium s a l t s . I t i s u s u a l l y p r e p a r e d from 9 -is e th y lt r i c h l o r - p u r i n e o r 9 -m e th .y l-g -o x y - 2 , 6 - d ic h l o r - p u r i n e by h e a tin g w ith c o n c e n tra te d h y d r o c h lo r ic a c id . ( 1 ) : B e r. 28, 2 k j 3 , 1895. ( 2 ) : E. F is c h e r . Chem. Z e n t r a l b l a t t I I , 157 u , ^56 (S .2 2 S ), 1897. ( 3 ) : B e r. 17, 3 3 2 , u . 1777. 18S^. 6 3. A cid. ^ T h is compound i s p r e p a r e d from th eobrom ine by f i r s t c o n v e rtin g th e l a t t e r to 7 m e th y l-tric h lo r-p u rin e . H. 1- M e th y l- u r ic A c i d . ^ T iiis compound i s p r e p a r e d by th e s y n th e s i s d ev elo p ed by H.Clemm and E. F i s c h e r , s t a r t i n g w ith m onom ethyl-urea and m alo n ic a c id s i m i l a r to th e s y n th e s is o f u r i c a c id by F is c h e r and Ach. C. THE DIMETHYL-URIC ACIDS. («Q C7H8N403. 3 , 9 -D im e th y l-u ric A cid. T his compound i s p r e p a r e d by th e m ethod o f H i l l and M a b e r r y ^ ) hy h e a tin g th e n e u t r a l le a d s a l t o f u r i c a c id w ith m ethyl i o d id e , and a ls o by th e aqueous m e t h y l a t i o n ^ o f u r i c a c id . T h is l a s t m ethod i s s i m i l a r to t h a t u se d f o r th e p r e p a r a ti o n o f 3~1Ee'th y lu r i c a c id . 2. (£ ) 7 , 9 -D im e th y l-u ric A c id .^5) T h is d e r i v a t i v e i s p r e p a re d from 7 . 9 -d im e th y l, S -o s y -2 , 6 - d ic h l o r - p u r i n e by h e a tin g w ith h y d r o c h lo r ic a c id a t I 3 O0. 3. (y ) 1 , 3 - D im e th y l- u ric A cid. T h is i s p r e p a r e d by th e in te r m e d ia te s y n th e s is o f d i m e t h y l - a l l a n t o in and a ls o by th e f u r t h e r m e th y la tio n o f 1 - m e th y l- u r ic a c id by th e aqueous m ethod. I t m e lts a t 370° w ith d e c o m p o sitio n . I t i s r e a d i l y s o lu b le i n h o t w a te r. *+. (£ ) 3 1 7-Dim e t h y l - u r i c A cid. (7 ) E. F is c h e r f i r s t p r e p a r e d t h i s d e r i v a t i v e from th eobrom ine by h e a tin g w ith a l k a l i . I t i s a l s o p r e p a r e d by th e m e th y la tio n o f 7 -met b y l - u r i c a c id , 5. 1 , 7“ D im e th y l-u ric A c i d ( 8 ) i s p re p a re d s y n t h e t i c a l l y from m o n o e th y l-a llo x a n by way o f d im e th y l- p s e u d o - u ric a c id . I t i s c o n v e rte d in to c h lo r - p a r a x a n th in e b y t r e a t ­ m ent w ith p h o sp h o ru s o s y c h lo r id e . (1).(2 ): (3 ): (U ): ( 5 ): (6 ): (7 ): (8 ): B e r, 2 8 , 2H9 2 , 1895. B e r. 3 0 , 3 OS9 . 1897. J . Am. Chan. Soc. 2 , 3 O5 . B e r. 3 2 , 2 6 8 , 1899. B e r. 1 7 . 1780, 188^. B e r. 2 8 . 2 U7 5 , 1895. B e r. 2 8 , 2^80, 1895. B e r. 3 0 . 3095. 1897. 7 6. 1, 9-Dimethyl-uric A c id ,(l) By s t a r t i n g w ith 9"IEe t h y l - 6 , 2“ d io x y -2 - c h lo r ~ p u r in e t h i s compound i s p re p a re d hy form ing th e oxym ethyl compound w ith fo rm a ld e h y d e , th en t r e a t i n g w ith m eth y l io d id e in an aqueous s o l u t i o n . By s p l i t t i n g o f f th e oxym ethyl and c h lo r in e th e r e s u l t i n g compound i s th e 1 , 9- d im e th y l - u r ic a c id . H--H - i H-N -* C= 0 c=0 i ' Cl-C C - IT—H « » )= o 9 8 HCH Cl-c Cl-C 1"1 > II > c=o / =o" . c N - C N-CE3 II - C - 1T-CH3 9-M ethyl U ric a c i d I>. iRIMETHYl-UHIC ACIDS. 1, 1 CH3I CHa I c0 - 1IT-OCHa T-OCH3 » GHg-lT -.. C= 0 1 E educs C - N-E Cl-C C N - 0 CH3 t i o n . 0=C c - N-0CHa 1«1 ^ -II «II '1 > = 0 >=0 (HI) . c c N - C N-CHs E-N H-N -* C N-CES 1 , 9 -E im e th y lU ric a c id . CH3 -N *- c=o 1 7 ( koh ^ J 1 C8H10N4O3. 1, 3 > 7 r T r im e th y l- u r ic Acid o r H y d ro x y c a ffe in e , i'h is compound i s o f c o n s id e ra b le im p o rtan ce i n c o n n e c tio n w ith th e e x p e rim e n ta l work i n t h i s t h e s i s , "because o f th e e a se in w hich i t i s form ed by h e a ti n g th e a lk y l- o x y c a f f e in e d e r i v a t i v e s in d i l u t e h y d r o c h lo r ic a c id , and o f te n by h e a t a lo n e . Hence i t s s y n th e s is and p r o p e r t i e s w i l l be tak e n up i n more d e t a i l th a n th e o th e r u r i c a c i d s . H y d ro x y c a ffe in e i s s y n th e s iz e d from 1 , 3 , 7“ tr im e th y l- p s e u d o - u r ic a c id ( ^ ) by m e re ly h e a tin g i n an aqueous s o lu t i o n o r more r a p i d l y by h e a tin g i n th e p r e s e n c e o f a d i l u t e m in e ra l a c id . I t i s a ls o p re p a re d by th e d i r e c t m e th y la tio n o f u r i c a c id w ith m ethyl i o d id e a t 0 ° . (a ) In th e p r e p a r a tio n o f h y d ro x y c a ffe in e from th e a lk y l e th e r s o f c a f f e in e (3 ) th e f o llo w in g p ro c e d u re may be u s e d : CH3 -IT - C=0 I I 0=C ’ C - N-CK3 " CH3-H - C - N 2 -M o n o e th e rc a ffe in e CHa-lI - c=o I I (10< HCl) ~ — 0=C > 1 C - N-CH3 " + E - Cl > -°H CH3 -E C- N H y d ro x y c a ffe in e Four to f i v e volum es o f 10^ h y d r o c h lo r ic a c id a r e added to th e e t h e r compound, u s u a l l y m ethoxy o r e th o x y c a f f e in e , i n a s u i t a b l e f l a s k o r b e a k e r and h e a te d on a steam b a th f o r tw enty to t h i r t y m in u te s . A f t e r a s h o r t tim e , th e p ro d u c t b e g in s to s e p a r a te o u t in f i n e , w h ite n e e d le s . As soon a s th e e v o lu tio n o f gas ( e th y l c h lo r id e o r m ethyl c h lo r id e ) h as ended, th e s o l u t i o n i s c o o le d and f i l t e r e d by s u c tio n . To r e c r y s t a l l i z e , th e h y d ro x y c a ffe in e i s im m ed iately d is s o lv e d i n f i f t e e n to tw e n ty volum es o f b o i l i n g w a te r, c o o le d slo w ly and f i l t e r e d . I t i s d r ie d a t room te m p e ra tu re , and f i n a l l y i n an oven a t 110° f o r f o u r to f iv e h o u rs. (1 ): (2): ( 3 ): B e r. 3 2 , 2 5 0 , 1893. B e r, 3 0 , 567, 1897. Ann. 215, 2bS, 1822. 3 . F is c h e r . U ntersuchungun in d e r P u rin g ru p p e , p p . 996-9° 8 The f i r s t f i l t r a t e and a ls o t h a t from r e c r y s t a l l i z i n g th e compound i s e v a p o ra te d down to a v e ry sm a ll volume and th u s a seco n d cro p o f c r y s t a l s o b ta in e d . Prom 3^0 b r o m c a f f e in e , an a v e ra g e o f 180 g . o f h y d ro x y c a ffe in e w ere p r o d u c e d ,o r ab out a 75 i° y i e l d , a c c o rd in g to E. F i s c h e r ’s r e s u l t s . (b ). P ro p e rtie s . H y d ro x y c a ffe in e , o r 1 , 3» 7“ t r i m e t h y l - u r i c a c id , i s a r a t h e r s t a b l e c r y s t a l l i n e com­ pound, m e ltin g a t ab o u t 3^ 5° to a d a rk brown l i q u i d and su b lim in g a t t h i s te m p e ra tu re in c o n s id e r a b le am ount. I t i s d i f f i c u l t l y s o lu b le i n c o ld w a te r , a lc o h o l and e t h e r . In h o t w a te r o r a lc o h o l i t i s q u i te r e a d i l y s o lu b l e , and q u ic k ly s e p a r a te s o u t upon c o o lin g i n t o a f e l t - l i k e mass o f lo n g s l e n d e r w h ite n e e d le s . H y d ro x y c a ffe in e i s r e a d i l y s o lu b le i n s tr o n g m in e ra l a c i d s , b u t i t s e p a r a te s o u t a g a in upon d i l u t i o n w ith w a te r, H y d ro x y c a ffe in e d i f f e r s from c a f f e i n e l a r g e l y by i t s a c id p r o p e r t i e s . I t i s r e a d i l y s o lu b le i n ammonia. I t form s u n s ta b le s a l t s w ith a l k a l i e s , a l k a l i n e e a r t h s and s i l v e r compounds. The sodium s a l t i s p r e p a r e d by a d d in g h y d ro x y c a ffe in e to a s m a ll amount o f p u re c a u s t i c so d a (made f r e s h from th e m e t a l) , and th e n s e p a r a ti n g o u t th e s a l t by th e a d d i­ t i o n o f a lc o h o l. T h is s a l t c o n ta in s t h r e e m o le c u le s o f w a te r o f c r y s t a l l i z a t i o n , w hich can be rem oved by h e a tin g s e v e r a l h o u rs a t 100°. I t i s v e ry s o lu b le i n w a te r, and d i s ­ s o lv e s r e a d i l y in c o n c e n tra te d sodium h y d ro x id e . I t s aqueous s o l u t i o n rem ains c l e a r up­ on th e a d d i t i o n o f s i l v e r n i t r a t e , b u t upon b o i l i n g , a p r e c i p i t a t e o f th e s i l v e r compound i s form ed. Upon c o n tin u e d h e a ti n g o f th e B a lt i n c o n c e n tra te d sodium h y d ro x id e i t i s decomposed w ith th e e v o lu tio n o f ammonia and m ethylam ine. The b a riu m s a l t o f h y d ro x y c a ffe in e p o s s e s s e s s i m i l a r p r o p e r t i e s to th o s e o f th e sodium compound s e p a r a tin g o u t w ith t h r e e m o lecu les o f w a te r o f c r y s t a l l i z a t i o n . I t is b e s t o b ta in e d by p u t t i n g h y d ro x y c a ffe in e i n to a warm s o l u t i o n o f b a riu m h y d ro x id e , p r e ­ c i p i t a t i n g th e e x c e ss b a riu m w ith carb o n d io x id e and e v a p o ra tin g th e f i l t r a t e upon th e w a te r b a th . Upon c o o lin g th e v e ry c o n c e n tra te d s o lu tio n ^ v e r y f i n e p ris m s form . T h is p r o d u c t, a f t e r f i l t e r i n g , i s washed w ith a lc o h o l and d r ie d i n a vacuum. The w a te r o f c r y s t a l l i z a t i o n may be removed by h e a tin g many h o u rs a t 1 5 0 °. I t i s v e ry d i f f i c u l t l y s o lu b le i n w a te r and c h lo ro fo rm . The s i l v e r s a l t o f h y d ro x y c a ffe in e i s in s o lu b le i n w a te r. I t i s e a s i e s t o b ta in e d by a d d in g an am m oniacal s o l u t i o n o f h y d ro x y c a ffe in e to an e x c ess o f an ammoniacal s o lu ­ t i o n o f s i l v e r n i t r a t e , and h e a tin g to b o i l i n g . As soon a s most o f th e ammonia h a s e v o lv e d , th e s i l v e r compound s e p a r a te s o u t a s a v e ry f i n e f e l t - l i k e m ass o f n e e d le s , H y d ro x y c a ffe in e i s tra n s fo rm e d b a c k in to e th o x y c a ff e in e by h e a ti n g th e s i l v e r s a l t ( d r i e d a t 1 10°) i n a c lo s e d tu b e w ith e t h y l io d id e f o r tw e lv e h o u rs a t 110°. T h is r e ­ s u l t s i n a c o m p le te change w ith th e fo rm a tio n o f e th o x y c a f f e in e and s i l v e r i o d id e . The raw p ro d u c t i s e x tr a c t e d w ith b o i l i n g a lc o h o l, e v a p o ra te d to d r y n e s s , and f i n a l l y r e ­ c r y s t a l l i z e d from h o t w a te r. H y d ro x y c a ffe in e i s tra n s fo rm e d i n t o c h lo r c a f f e in e by h e a tin g ( a t th e b o i l i n g p o i n t ) two p a r t s w ith fo u r p a r t s o f phosphorus o x y c h lo rid e and th r e e p a r t s o f phosphorus p e n ta c h lo r i d e . Upon th e e v o lu tio n o f h y d r o c h lo r ic a c id a l l b u t a sm a ll amount o f th e s u b s ta n c e goes i n to s o l u t i o n . The f i l t r a t e i s e v a p o ra te d to d ry n e s s on th e steam b a th . I t i s e x tr a c t e d w ith c o ld w a te r to rem ove o th e r i m p u r i t i e s , and th e r e s id u e f i n a l l y e x tr a c t e d w ith h o t w a te r to r e c r y s t a l l i z e th e c h lo r c a f f e i n e . H y d ro x y c a ffe in e i s e n t i r e l y s t a b l e tow ards c o n c e n tra te d h y d r o c h lo r ic and s u l f u r i c a c i d s , and r e s i s t s o x id a tio n s u b s ta n c e s more th a n c a f f e in e i t s e l f . However, c o n c e n tra ­ t e d n i t r i c a c id decomposes t h i s compound i n th e c o ld , a s does a ls o a d i l u t e aqueous s o l u t i o n o f c h lo r in e o r brom ine. 9 I f a s o l u t i o n o f m o d e ra te ly c o n c e n tr a te d h y d r o c h lo r ic a c id and p o ta s s iu m c h lo r a te c o n ta in in g h y d r o x y c a ffe in e i s g e n tly warmed th e l a t t e r s p l i t s s i m i l a r to c a f f e in e u n d e r th e same t r e a tm e n t. The m ain p ro d u c t i s d im e th y la llo x a n w ith a s m a ll amount o f a p o c a f f e i n e , a c c o rd in g to F is c h e r * s r e s u l t s . I f c h lo r in e gas i s ru n i n t o a n i c e c o ld con­ c e n tr a t e d s o l u t i o n o f h y d r o c h lo r ic a c id c o n ta in in g h y d ro x y c a ffe in e a m ix tu re o f a p o c a f f e in e and h y p o c a ff e in e i s o b ta in e d , h u t no a llo x a n . These r e a c ti o n s a r e g iv e n u n d e r th e d e c o m p o sitio n o f c a f f e i n e . In a l l o f th e s e d e c o m p o sitio n r e a c t i o n s th e f i r s t p ro d u c t form ed, i f t a k i n g p la c e e n t i r e l y i n th e ab sen ce o f w a te r , i s s t a b l e and a compound o f c h lo r in e and h y d r o x y c a f fe in e . To p r e p a r e t h i s h a lo g e n a d d it io n p ro d u c t,o n e p a r t o f anhydrous h y d r o x y c a ffe in e i s shaken w ith tw e n ty - f iv e p a r t s o f v e ry c o o l d ry .brom ine, th e n e v a p o ra te d v e ry q u ic k ly on th e w a te r b a t h , w hereupon some hydrobrom ic a c id i s e v o lv e d b e c au se o f a se c o n d a ry r e ­ a c t i o n , The a d d it io n p ro d u c t o f b ro m h y d ro x y caffein e rem ain s a s a r e d c o lo r e d m ass. T h is compound i s much more u n s ta b l e th a n th e brom ine compound o f c a f f e i n e . The l a t t e r i s changed b a c k i n t o c a f f e in e by a l k a l i s o r s u lf u r o u s a c id , w h ile th e b ro m h y d ro x y c a ffe in e i s e a s i l y decomposed i n an aqueous s o l u t i o n i n to s o lu b le compounds. T h is brom ine a d d i­ t i o n p ro d u c t u n d o u b te d ly lias th e fo llo w in g fo rm u la : CaHsN^OaOHBrg. D ie th o x y h y d ro x y c a ffe in e i s p r e p a re d by ad d in g one p a r t o f th e brom ine h y d ro x y c a f­ f e i n e to t e n p a r t s o f c o ld e th y l a lc o h o l and sh a k in g u n t i l th e l a t t e r a l l goes i n t o s o l u t i o n . At th e same tim e t h e r e s e p a r a te s o u t an abundant mass o f c r y s t a l s o f d ie th o x y h y d r o x y c a f fe in e . I t i s m ost e a s i l y made by su sp en d in g one p a r t o f v e ry f i n e an h y d ro u s h y d ro x y c a ffe in e i n f i v e p a r t s o f a b s o lu te a lc o h o l c o o lin g i n i c e and s a l t and th e n a d d in g a s l i g h t e x c e s s (one and o n e - h a lf p a r t s ) o f p u re d ry brom ine. By s h a k in g , and a t th e same tim e a p p ly in g a g e n tle h e a t , a c l e a r s o l u t i o n r e s u l t s . However a lm o st im m e d ia te ly a t h i c k mass o f c r y s t a l s s e p a r a te s o u t. A f te r f i l t e r i n g th e p r o d u c t, i t i s washed w ith^ c o ld a lc o h o l and th e n w ith e t h e r w hich rem oves a l l o f th e c o lo r due to th e b ro m in e. The p ro d u c t i s v e ry p u r e , and th e y i e l d alm o st q u a n t i t a t i v e . The fo llo w in g e q u a tio n s show how th e above compounds a r e form ed: gh3- n « 0=C ch3- h - c=o ch3- u - c=o • * *^B r * * OOaHB C- l^CHa + B r3 v 0=0 C - N-CH3 + 2C2 Hs 0Hx 0=0 C - U_CHa 1 '« C-OH * 1 ’ 0-0H ' ' SC-0H - C- N* CH3-U - C - H * OH3-H - C - H* Br 0—C3H5 Hydro x y c a f f e i ne B i e th o x y h y d ro x y c a ife in e 2. 0=0 1» 3 1 9 - T r im e th y l- u r ic A c id (l)* T h is compound i s p r e p a r e d from 1 , 3 - d im e th y l- u ric a c id by m e th y la tio n o f th e l e a d s a lt. I t i s decomposed by h e a tin g in th e p re s e n c e o f h y d r o c h lo r ic a c id a t I 5O0 to c a r ­ bon d io x id e , m ethylam ine and g ly c o c o l, p r o v id in g t h a t th e m ethyl gro u p i s a tt a c h e d to th e n i n t h p o s i t i o n . I t m e lts a t 3 1 5-320° w ith slow d e c o m p o sitio n and e v o lu tio n o f g a s . I t i s s o lu b le i n ab o u t t h i r t y p a r t s o f h o t w a te r, and d i f f i c u l t l y s o lu b l e i n c o ld w a te r and h o t a lc o h o l. I t i s r e a d i l y s o lu b le i n ammonia. I t g iv e s a s tr o n g m urexide r e a c t i o n , and a l s o re d u c e s an ammoniacal s i l v e r s o l u t i o n when h e a te d . ( 1 ) : B e r. 28, 2 k j 8 , 1895. 10 3. 1 . 7» 9 - fr im e t h y l- u r ic A c i d . ^ F o r th e s y n th e s i s o f t h i s compound, 9 -m e th y l-6 , 8 - d io x y - 2 - c h lo r p u r in e i s m e th y la te d and th e n th e h a lo g e n i s s p l i t o f f w ith h o t c o n c e n tra te d h y d r o c h lo r ic a c id . T h is s y n th ­ e s i s p ro v e s th e s t r u c t u r e o f th e compound. I t s p r o p e r t i e s a r e v e ry s i m i l a r to th o s e o f 1 , 3» 7 - t r i m e t h y l - u r i c a c id (hydroxy­ c a f f e i n e ) . I t m e lts a t 3^8° w ith c o n s id e r a b le foam ing. I t d i s s o l v e s i n ab out n in e te e n p a r t s o f h o t w a te r and c r y s t a l l i z e s o u t i n b u n d le s o f s le n d e r n e e d le s . I t i s a ls o r a t h e r e a s i l y s o lu b le i n h o t a lc o h o l. I t form s a sodium s a l t , s i m i l a r to h y d r o x y c a f fe in e 3 , 7 , 9 - T r im e th y l- u r ic A cid, (^ ) T h is compound i s a ls o made by th e m e th y la tio n o f 7 i 9 -d im e th y l o r th e 3 , 7 -d im e th y lu r i c a c id by u s in g th e le a d s a l t w ith m eth y l io d id e . I t m e lts c o m p le te ly a t 3 U50 i f h e a te d a lo n g tim e . I t u s u a l l y s t a r t s to m elt a t 350° i s c o m p le te ly m e lte d a t 370 to 380® w ith e v o lu tio n o f gas to a d a rk brown l i q u i d . I t d i s s o l v e s i n a b o u t one h u n d red and t h i r t y p a r t s o f h o t w a te r and c r y s t a l l i z e s o u t when c o ld a s sm a ll n e e d le s , w hich a p p e a r a s p rism s u n d e r th e m isc ro s c o p e . I t i s d i f f i c u l t l y s o lu b le i n a lc o h o l. I t r e a d i l y d i s ­ s o lv e s i n s tr o n g h y d r o c h lo r ic a c id . As w ith h y d r o x y c a f fe in e , i t s a l k a l i s a l t s a r e v e ry s o lu b l e . E. TETRAMETHYL-UBIC ACID. 1. P r e p a r a ti o n . T h is compound i s o f s p e c i a l i n t e r e s t i n c o n n e c tio n w ith th e e x p e rim e n ta l work b e ­ c a u se o f th e f a c t t h a t i t was th e f i r s t u r i c a c id to be p re p a re d by th e m o le c u la r r e ­ a rra n g e m e n t o f an e t h e r o f c a f f e i n e . I t i s a ls o o f i n t e r e s t b e c au se a l l o f th e h ydrogen atom s have been r e p la c e d by m eth y l g ro u p s , hence th e t r i - k e t o n i c c o n f ig u r a tio n i s th e o n ly one p o s s i b l e . T e tr a m e th y l- u r ic a c id was f i r s t p r e p a r e d by E. F i s c h e r w ) from th e s i l v e r s a l t o f 3 , 7 , 9 - t r i m e t h y l - u r i c a c i d , and l a t e r by m e th y la tio n o f u r i c a c i d ^ ) , The l a t t e r i s a c c o n p lis h e d by a d d in g one m ole o f u r i c a c id to an aqueous a l k a l i n e s o lu t i o n c o n ta in in g a l i t t l e o v e r f o u r m oles o f a l k a l i , th e n ad d in g f o u r m oles o f m ethyl io d id e . The m ix tu re i s shaken f o r two h o u rs a t a te m p e ra tu re o f 100 to 110°. I t i s a c i d i f i e d w ith a c e t i c a c i d , e v a p o ra te d to d ry n e ss and e x t r a c t e d w ith c h lo ro fo rm . A y i e l d o f 70 to 80$ was ob­ t a i n e d by E. F i s c h e r . By u s in g l e s s a l k a l i and m ethyl io d id e and n o t h e a tin g so lo n g a t 1 0 0 ° t h i s compound i s made from th e 1 , 3 „ 9 - tr im e th y l o r th e 1 , 3 , 7 - t r d m e t h y l - u r i c a c id s . H. B i l t z and S t r u f e ^ ) g iv e th e f o llo w in g d i r e c t i o n s f o r th e p r e p a r a ti o n o f t e t r a raeth y l u r i c a c id from m e th o x y c a ffe in e j M e th o x y c a ffe in e i s h e a te d i n t e s t tu b e s c o n ta in e d in a p a r a f f i n b a th . A m e ltin g tu b e such a s 7/is lic e ra u s and K orber u s e d was n o t found n e c e s s a ry . At I 7 O8 th e compound ( 1 )2 (2 ): ( 3 )2 (4 ): ( 5)2 B er. 32, 250, 1899. B er. 1 7 , 1782, 1884. B er. 17, 1784, 1884. E. F is c h e r , U ntersuchungun in d e r P u rin g ru p p e . Chem. Z e n t r a l b l a t t , I I , 157» 1897. Ann. 413, 1 9 9 -2 0 0 , 1 9 1 7 , 11 s i n t e r s and upon h e a ti n g h i g h e r i t m e lts t o g e t h e r i n to a c l e a r s o l u t i o n . TThen th e tem pp e r a t u r e i s m a in ta in e d a t 2 0 0 ° th e m e lte d mass becomes c lo u d y , a s th e te tr a m e th y l u r i c a c id b e g in s to s e p a r a te o u t. I t th ic k e n s more and more and s o l i d i f i e s c o m p le te ly a f t e r f o r t y to f i f t y m in u te s . A f t e r a llo w in g to c o o l, th e mass i s ta k e n o u t o f th e tu b e and r e c r y s t a l l i z e d from h o t w a te r. The y i e l d o f t h i s is o m e riz e d compound i s q u a n t i t a t i v e . From 73 £ . o f m eth o x y caffein e^ 70 g. o f t e t r a m e t h y l - u r i c a c id was o b ta in e d . M e ltin g p o in t was 228° ( c o r r . ) , w hich i s i n harmony w ith F i s c h e r 's d a ta . 2. P r o p e r t i e s . ^ The m e ltin g p o in t o f t e t r a m e th y l - u r i c a c id was found by E. F is c h e r to b e a ro u n d 2 2 3 .0 ° (2 2 8 .0 ° c o r r . ) . I t h as a v e ry b i t t e r t a s t e . I t d is s o lv e s i n somewhat l e s s th a n t h r e e p a r t s o f w a te r a t 20° and i n ab out t h i r t y - n i n e p a r t s a t 1 0 0 °. I n b o i l i n g a b s o lu te a lc o h o l i t d is s o l v e s in a p p ro x im a te ly tw e n ty -se v e n p a r t s to one o f th e compound. In d e te rm in in g th e s o l u b i l i t y i n w a te r a s g iv e n a b o v e ,th e f i n e l y p u lv e r iz e d compound was shaken f o r f i v e h o u rs i n th e s o lv e n t. In c r y s t a l l i z i n g from w a te r i t f i r s t form s lo n g f i n e n e e d le s . By re m a in in g i n th e s o lv e n t f o r a lo n g tim e th e s e change to m o n o c lin ic p r is m s . T e tr a m e th y l- u r ic a c id i s c o n v e rte d i n t o c h l o r c a f f e i n e ^ by h e a tin g i n a c lo s e d tu b e w ith pho sp h o ru s o x y c h lo rid e a t lo 0 ° f o r t e n h o u rs. T h is r e s u l t s i n th e l i b e r a t i o n o f th e m eth y l group and th e a d ja c e n t oxygen, whereby th e s o lu t i o n becomes a f a i n t brow n. Upon c o o lin g , an ab u n d an t cro p o f c r y s t a l s fo rm s , and v e ry l i t t l e gas i s l i b e r a t e d upon o p en in g th e tu b e , show ing tlxe m eth y l group i s n o t s p l i t o f f a s m ethyl c h lo r i d e . A f t e r e v a p o r a t­ in g o f f th e phosp h o ru s o x y c h lo rid e u n d e r red u ced p r e s s u r e , th e p ro d u c t i s rem oved from th e unchanged t e t r a m e t h y l - u r i c a c id by c r y s t a l l i z i n g o u t o f h o t w a te r , i n w hich i t i s o n ly s l i g h t l y s o lu b le . A y i e l d o f waS o b ta in e d by E. F is c h e r . By r e d u c tio n w ith hydrogen i n p re s e n c e o f a c a t a l y s t i t i s c o n v e rte d i n to c a f f e in e . By t h i s p ro c e d u re u r i c a c id can be d i r e c t l y c o n v e rte d i n to c a f f e i n e , and p ro v e s th e r e l a t i o n s h i p and s t r u c t u r e o f th e s e compounds. T h is d is c o v e ry was made i n I 896 and a t ab o u t th e same tim e t h a t h y d r o x y c a ffe in e was found to b e i d e n t i c a l w ith 1 , 3» 7 - t r i m e t h y l - u r i c a c id . The l a t t e r compound i s more r e a d i l y c o n v e rte d i n t o c h lo r c a f f e i n e w ith p hosphorus o x y c h lo r id e , and a l a r g e r y i e l d i s o b ta in e d th a n w ith t e t r a m e th y l - u r i c a c id . The d e c o m p o sitio n o f t e t r a m e th y l - u r i c a c id to a l l o c a f f e i n e ^ 2 ) i s o f p e c u l i a r i n t e r ­ e s t n o t o n ly b e c au se i t h e lp s to p ro v e th e c o n f ig u r a tio n o f th e fo rm e r compound b u t a ls o b e c a u se th e mechanism o f th e r e a c ti o n h a s n o t been c l e a r l y u n d e rs to o d and t h e r e have beer. d if f e r e n c e s o f o p in io n a s to how i t ta k e s p la c e . F is c h e r ( 3 ) d is c o v e r e d t h a t a l l o c a f f e i n e i s th e m ain p ro d u c t when t e t r a m e th y l - u r i c a c id i s t r e a t e d w ith d i l u t e c h lo r in e w a te r a t 2 5 °. A lso E. Schm idt and E. S c h e l l i n g '^ ) produced a l l o c a f f e i n e by o x id iz in g c a f f e i n e m eth y lh y d ro x id e w ith p o ta s s iu m c h lo r a te and h y d r o c h lo r ic a c id , o r brom ine w a te r. I t was a g re e d by b o th E. F is c h e r and H. B i l t z t h a t th e f i r s t p ro d u c t form ed i s a g ly c o l o f th e m e th y la te d u r i c a c id . The n e x t s te p i s more d i f f i c u l t to u n d e rs ta n d , a s i t in v o lv e s s p l i t t i n g o f f a n itr o g e n atom and form ing a new r in g sy stem . B ecause o f th e f a c t t h a t E. F i s c h e r o b ta in e d a sm a ll amount o f a l l o c a f f e i n e from h y d r o x y c a f fe in e , w hich r e s u l t e d i n th e l i b e r a t i o n o f ammonia and n o t m ethylam ine, he d e c id e d t h a t th e n itr o g e n i n p o s i ­ t i o n ( 9 ) was s p l i t o f f , as t h a t i s th e o n ly n itr o g e n atom t h a t does n o t c o n ta in a m ethyl (1 ): (2 ); (3 ):' ( 4 )1 B e r. H. E B er. Ann. 30, 3OO9 , 1897. E. F i s c h e r , TTntersuchungun i n d e r P u rin g ru p p e , p p . 367 - 3 6 8 . i l t z , B e r. 43, l6 0 0 , 1910. 3 1 , 2159, 1898. 228, 159-1 6 4 , I 8 S 5 . 12 g ro u p . H, B i l t z t r i e d to r e p e a t F i s c h e r 's r e s u l t s , h u t was v e ry c a r e f u l to o b ta in p u re h y d r o x y c a f f e in e . Only a t r a c e o f a l l o c a f f e i n e was fo u n d . Hence h e c o n c lu d e d t h a t th e a l l o c a f f e i n e came from te tr a m e th y l u r i c a c id a s an im p u r ity . H. B i l t z s o lv e d t h i s p ro ­ blem i n a n o th e r way. He p r e p a r e d 1 , 3 - (i i IQe't h y l - c a f f o l i d e -by a m ethod w hereby i t s c o n s t i ­ t u t i o n was q u i te w e ll e s ta b l is h e d . On t h i s compound th e h ydrogen atom o f th e im ido g ro u p , b e c a u s e o f i t s b e in g a d ja c e n t to two c a rb o n y l g ro u p s , i s e a s i l y r e p la c e d by sodium o r s i l v e r . The sodium o r s i l v e r i s r e a d i l y exchanged f o r a m eth y l g ro u p . The r e ­ s u l t i n g t r i m e t h y l c a f f o l i d e was fou n d to b e i d e n t i c a l w ith a l l o c a f f e i n e . Hence th e form ­ a t i o n o f a l l o c a f f e i n e from te tr a m e th y l u r i c a c id ta k e s p la c e a s f o llo w s : ch3- n - c=o ' ' 0=0 C - H-CH3 ' " 0=0 CH3-N - C- N-CHa h2o + ch3- u 02 > (C l 2 w a te r a t 25 ®) T e tr a m e th y l- u r ic a c id - 0=0 CH3-H - c=o ' ' 02 ' « 0=0 HO-C - H-CH3 -----------> 0=0 H0-C - N-CH3 ' ' 0=0 ' • 0=0 CH3 -H - (jj - H-CH3 CH3-H C - N-CH3 OH H 6 T e tr a m e th y l- u r ic a c id G lycol ^ — CH3-N - 0=0 1 t 0=C-0-C - H-CHs ' Nc=o + UH2 CH3 C - IT-CH3 6 A llo c a ffe in e The o p en in g o f th e a llo x a n r in g a t th e 3* ^-b o n d , th e h y d r o ly tic s p l i t t i n g o f f o f m eth y la m in e , and th e new c lo s e d r in g h a v in g a l a c t o n e - l i k e s t r u c t u r e a r e e n t i r e l y a n a lo g ­ ous w ith p r e v io u s work d e s c r ib in g th e c a f f o l i d e d e c o m p o sitio n o f 7 » 9 ” d imet h y l - u r i c a c id . L a t e r e x p e rim e n ts p ro v ed t h a t th e g ly c o l i s form ed a s an in te r m e d ia te . I f th e o x id a tio n i s more m ild o r s to p p e d s o o n e r, d ira e th y l-a llo x a n and sy m m etrical d im e th y l- u r e a a r e o b ta in e d . A l l o c a f f e i n e m e lts a t 205° (206® c o r r . ) w ith o u t decom posi­ tio n . I t i s a l s o p r e p a r e d from a p o c a f f e in e by m e th y la tio n . By h e a tin g a l l o c a f f e i n e a l o n g tim e in w a te r i t i s tra n s fo rm e d i n to a l l o c a f f e i n e a c i d , and c o rre s p o n d s c o m p le te ly w i t h th e tr a n s f o r m a tio n o f 1 , 3 “met h y l - c a f f o l i d e i n to 1 , 3 - ^ m etb y l - 5-o x y b y d a n to y l-a m id e . * 8 CH3 -H - 0=0 CHs-lT - c ' ' heat ' 0=C-0-C - H-CH3 --------------> HO-C ' Nc=o + H2 0 • 0=0 - H-CH3 |j - N-CH3 A llo c a ffe in e + C02 A l l o c a f f u r ic a c id - o r ( l ,3 -d im e th y l-5 -0 3 y h y d a n to y l-m e th y l-am ide) By m ild tre a tm e n t o f a l l o c a f f u r i c a c id w ith barium h y d ro x id e , m e so x a lic a c i d , m eth y l­ am ine and d im e th y l- u re a a r e form ed. 13 E ffect o f A lk ali upon Tetramethyl-uric Acid^l). By sh a k in g th e compound w ith IN . p o ta s s iu m h y d ro x id e (2 m o les) a t 15° f o r s i x h o u rs com plete d e c o m p o sitio n r e s u l t s . I t i s th e n n e u t r a l i z e d to m ethyl o ran g e "by a d d in g s u l ­ f u r i c a c id . T h is c a u se s a s tr o n g e v o lu tio n o f carbon d io x id e . I t i s th e n e v a p o ra te d to d ry n e s s and th e r e s id u e e x t r a c t e d w ith c h lo ro fo rm . The l a t t e r i s e v a p o ra te d o f f and th e r e s id u e i s d is s o lv e d i n w a te r and s a t u r a t e d w ith ammonia, e v a p o ra te d u n d e r re d u c e d p r e s s u r e , and e x t r a c t e d s e v e r a l tim e s w ith c h lo ro fo rm . By e v a p o ra tin g th e s o l v e n t , a sy ru p rem ain s w hich upon lo n g s ta n d in g c r y s t a l l i z e s o u t to a c o n s id e r a b le e x t e n t . The c r y s t a l s a r e p u r i f i e d w ith a c e t i c e s t e r , and f i n a l l y r e c r y s t a l l i z e d o u t o f h o t a c e to n e . The r e a c t i o n i s a s f o llo w s : CH3-N - 0=0 ' • 0=0 C - N'CH3 I » 0=0 CH3-1T - C - N^CHs CH3-N H koh > - 0=0 t c - N^CHa " ^ 0=0 CH3 -9 - C - N-OHs H + C02 E. F is c h e r c a l l s t h i s b a s e t e t r a m e th y l u r e i d in . I t i s a n a la g o u s to c a f f e i d l n pro d u ced from c a f f e in e by th e same tr e a tm e n t. I t m e lts a t 165 - 167 ® ( l 66 - l 6 s ° c o r r . ) and i s r e a d i l y s o lu b l e i n w a te r and a lc o h o l. F. 1 , 3 , 7-TRIMETHYL - 9-ETHYL-URiC ACId / 2 ^ 1 . P r e p a r a ti o n . As w ith t e t r a m e t h y l - u r i c a c id , t h i s compound i s p re p a re d by th e m o le c u la r r e a r r a n g e ­ m ent o f i t s iso m e r, e th o x y c a ff e in e : CH3 -N - 0=0 1 1 0=c 0 - N^CHa ' " c- oc3h 5 CHa-lT - 0 - / E th o x y c a ffe in e 240® CH3-N - 0=0 1 ' 0=0 C - N-CH3 ' " 0=0 CH3-N - 0 - l^CaHs 1 , 3 , 7 -T rim e th y l-9 -e t h y l - u r i c a c id S -E th o x y c a ffe in e i s h e a te d i n a s e a l e d tu b e w ith a l i t t l e a lc o h o l a t 240® f o r f o u r h o u rs when i t changes i n t o th e t r i m e t h y l - 9 - e t h y l - u r i c a c i d , accom pahied by hydroxy­ c a ffe in e . The l a t t e r i s rem oved by n e u t r a l i z i n g w ith b arium h y d ro x id e , th e t e t r a a l k y l d e r i v a t i v e b e in g e x tr a c t e d from th e d r ie d m a te r ia l w ith warm c h lo r o f o n a . A f te r e v a p o r­ a t i n g o f f th e c h lo ro fo rm th e p ro d u c t i s c r y s t a l l i z e d from a lc o h o l. T h is compound, a s p r e p a r e d by W. W islicam us and H. K o rb e r, had a m e ltin g p o in t from 1 9 7 ° to 1 96 ® (203-204® c o r r . ) and gave th e fo llo w in g a n a l y s i s : ( 1 ) : E. F i s c h e r , B e r. 3 0 , 3 OO9 , 1897. ( 2 ) : W. W islicem us and H. K o rb e r, B e r. 35» 1991 1 19^2. H, B i l t z and M. B e r g iu s , Ann. 4 l 4 , 5 ^ -5 7 . 1917* J . Chem. Soc. 1121, 589 - 59 O, 191 7 . 14 C a lcu la ted Carbon Hydrogen N itrogen 50.42fo 5*86^ 2 3 . 53^ Determined 50.1J# 6.02^ 24.00# 2 , P r o p e r tie s , I r im e th y l-9 ”6 t h y l- u r ic a c id m elts at 203-204® ( c o r r .) w ithout d ecom p osition. I t i s m od erately s o lu b le in hot w ater and a lc o h o l from which i t c r y s t a l l i z e s upon c o o lin g as t h in , m o n o clin ic l e a f l e t s . I t d i s t i l l s w ith p a r t ia l decom position and lib e r a t io n o f e th y le n e at about 3 7 0 ° . "/hen tr e a te d w ith c h lo r in e and m ethyl a lc o h o l in th e (I) c o ld , th e a cid y ie ld s 4, 5-dim ethoxy- 1 , 3* 7 - t r im e t h y l- 9 -e t h y lu r ic a c i d . ( l ) This c r y s t a l l i z e s in n o n osym etric, lim p id ta b CH3-N 0=0 l e t s m eltin g at 97.5°* w h ile th e l e s s s ta b le 4 , 5“dietho:xy de1 ' r iv a t iv e m elts at l4 2 ° and i s formed from e th y l a lc o h o l. These 0=C CH3 -O-C - N-CH3 e th er s y i e l d th e parent a c id on heat in .c w ith h y d rio d ic a c id , 1 ' J j =0 '.Then b o ile d w ith d ilu t e HC1 they y i e l d 1 , 7~ 0 =C C - H-CN-CsH e i t HN - 0=0 9“pben y lp se u d o -u r ic a c id HN - c=o 1 » 1 0 =C C - N-H i w C=0 + H2 O / HN - C - N-C6 H5 9 -p b e n y l-u r ic a c id By h e a tin g the phenylpseudo u r ic a c id in 20$ h y d ro ch lo ric a c id s o lu t io n fo r h a l f an hour i t i s con verted in to 9 -p h e n y l-u r ic a c id , r e s u lt in g in a c le a r s o lu t io n . This i s evaporated down to about one th ir d the o r ig in a l volume over an open flam e w ith the a id o f a stro n g stream o f a i r . An abundant crop o f c r y s t a ls f i n a l l y form s. About an 80$ y i e l d can thus be ob tain ed . I t i s fu r th e r p u r ifie d by d is s o lv in g in d i lu t e a l k a l i , c l a r i f y i n g w ith c h a r c o a l, f i l t e r i n g , and r e p r e c ip it a t in g w ith a c id . I t d r ies w ith two m o lecu les o f w a ter, which are removed a t 1 3 0 ° , or in a vacuum d e s s ic a t o r f o r a lo n g tim e, 9 -P h e n y l-u r ic a c id browns a t J20° and carb on izes a t a h ig h er tem perature. I t i s f a i r l y s o lu b le in hot v/ater from which i t c r y s t a l l i z e s as s ilv e r y lu s tr o u s l e a f l e t s . I t i s very s o lu b le in a lc o h o l, but in s o lu b le in e th er. 2. 1, 3 , 7 -T r im e th y l-9 -P h en y l-u r ic A cid, This compound i s prepared by m eth ylation o f 9-phenyl—u r ic a c id in an a lk a lin e s o lu ­ t io n . N = C -O K ' » K O -C C - N^ w * C H 3 -N - C=0 ' ' Q =C C - N -C H 3 3C H 3I ------------- > NC-0K (Aq.KOH) N - c - n - c 6h 5 T ri-p otassiu m s a l t o f 9-P h en ylu r ic A cid. 1 » ^0=0 ch3- n - c - n - c 6h 6 1» 3« 7 -T rim eth y l— 9-phenyl“ u r ic A cid. B r i e f l y , th e procedure c o n s is t s in h e a tin g the 9 -p h en y lu ric a c id w ith th r ee and one' h a l f moles o f IN, potassium hydroxide and fou r m oles o f m eth y lio d id e in a c lo s e d tube a t 85° fo r two h ours. In about th r e e -fo u r th s o f an hour th e m eth y lio d id e has disappeared and tr im e th y l-p h e n y l-u r ic a c id b eg in s to sep arate o u t. I t i s c o o le d to 0 ° , f i l t e r e d , and e x tr a c te d w ith very d ilu t e c o ld a l k a li to fr e e from a l l a c id s and aga in f i l t e r e d . The y i e l d i s about 5 0 $ . For fu r th e r p u r if ic a t io n i t i s r e c r y s t a lliz e d out o f hot a lc o h o l and d r ie d in an oven a t 1 0 0 ° . ( 1 ) : E. F is c h e r , " " B er. 33» 1701, 1900* Untersuchungen in der Puringruppe, pp. 5Ul-5^9® 16 T r im e th y l- 9 - p h e n y lu r ic a c id m e lts a t 25 S to 2 5 9 ° ( 265 - 266 ° c o r r . ) to a c o l o r l e s s S o l u ti o n , and d i s t i l l s a t a h ig h e r te m p e ra tu re w ith v e ry l i t t l e d e c o m p o sitio n . I t c r y s t a l l i z e s i n sm a ll rh o m b ic -lik e p l a t e s ; and d is s o lv e s i n ab o u t 30 p a r t s o f h o t a lc o h o l , b u t i s more s o lu b l e i n c h lo ro fo rm o r g l a c i a l a c e t i c a c id . I t i s r e a d i l y decomposed by h o t a l k a l i w ith e v o lu tio n o f carb o n d io x id e a s i s te tr a m e th y l—u r i c a c id . 3* 7 -® e n z y l-3 , 9“ <:ii™e t h y l - u r i c A cid. ) («0 F o r th e p r e p a r a ti o n o f t h i s compound 2 p a r t s o f (d ) 3 * 9 - d im e th y l- u r ic a c id , lU p a r t s o f IN . p o ta s s iu m h y d ro x id e , k2 p a r t s o f w a te r, and 1 ,6 p a r t s o f b e n z y l c h lo r id e a r e d ig e s te d u n d e r a r e f l u x c o n d e n se r f o r one h o u r. D u rin g th e o p e r a tio n a p r e c i p i t a t e fo rm s. A f t e r c o o lin g , th e p ro d u c t i s f i l t e r e d and r e c r y s t a l l i z e d o u t o f h o t a lc o h o l. I t m e lts a t 282 to 2 2 3 °, d is s o lv e s in ab o u t 3 OO p a r t s o f h o t a lc o h o l and c r y s t a l ­ l i z e s o u t upon c o o lin g i n th e form o f sm a ll s h in y l e a f l e t s , 1+, 7 -B en zy l - 1 , 3* 9 -T rim e th y l-u 'ric A cid . One p a r t o f (£ ) 1 , 3« 9 - 1 dim eth y l u r i c a c id , 4-. 7 p a r t s o f IN. p o ta ssiu m h y d ro x id e and 0 . 7 p a r t o f b e n z y l c h lo r id e ( p lu s enough w a te r to d i s s o l v e ) a r e d ig e s te d u n d e r a r e ­ f l u x c o n d e n se r f o r one h o u r a t 100°. D uring t h i s o p e r a tio n th e new p ro d u c t b e in g s to c r y s t a l l i z e o u t. I t i s n e x t e x tr a c t e d w ith d i l u t e ammonia and th e r e s id u e r e c r y s t a l l i z e d o u t o f h o t a lc o h o l. The y i e l d i s about S0)o o f th e t r i m e t h y l - u r i c a c id u s e d . B enzyl—t r i m e t h y l - u r i c a c id form s l a r g e w edge-shaped c r y s t a l s from a lc o h o l. I t m e lts a t 171 to 173 ® i n s o lu b le i n a l k a l i . II. THE XANTHINES. A. XANTHINE OE 2 , 6 -DIOXYPURINE. HN - C=0 1 1 o=c c - nh and » XCH HN-C-N^ (K eto) 1 N = C-OH 1 1 HO-C C - # " " VCH N - C - N * (E nol) X a n th in e was found i n 1817 by Von M arcet i n th e u r i n e o f man and in many lo w er a n im a ls , and i s th e norm al c o n s ti tu e n t o f many anim al t i s s u e s . I t may be s y n th e s iz e d from u r i c a c id by way o f t r i c h l o r - p u r i n e ( 3 ) and. a ls o by t r e a t i n g u r i c a c id w ith fo rm ic a c i d , th u s s p l i t t i n g o f f carb o n d io x id e and w a te r (1 ): (2 ): (3 ): E . F is c h e r . E. F is c h e r . E. F i s c h e r . H. 7 6 , *+8 6 , Untersuchungen in der Puringruppe, p. 23 O; B er. 3 O, 2226, IS 9 7 . Untersuchungun in der Puringruppe, p. 23 O. B e r, 3 0 , 2226, 1297. 1912; C. I . l U l l , 1911. 17 N = C-Cl 1 * HOC2 H5 31-0 C - N-H --------------- ^ " » c -c i N - C - N ^ I r i ch i 0 r -p u r in e NN == C-OC 56 N = C-OH C- 0 C22HH »1 '1 HCL 1 1 C2 H HsO— 5 0-C G C c - N-H -------------- > HD-C C - N-H "it "II Nc -c i " " Nc - c i NC-I NN - -C c- N N - C - N* - s^ ' HI+PH4I VN = 0 -•OH 1 HO-C 11 1 c - N-H (I CH N - c - N Xanthine Guanine i s converted in to xanthine by th e a c tio n o f n itr o u s a c id , s p l i t t i n g o f f n itr o g e n and w ater. I t i s a ls o prepared from c a ffe in e by c h lo r in a tin g w ith phosphorus o x y c h lo rid e p lu s f r e e c h lo r in e in a c lo s e d tube at lbO° and f i r s t o b ta in in g t e t r a c h lo r c a f f e in e . By t r e a t in g t h is compound w ith a c e t ic a c id , 8 -c h lo r -x a n th in e i s o b ta in ed and i s reduced by h y d r io d ic a c id to xan th in e. Xanthine i s sy n th e siz e d by \7. Traube's m e t h o d ^ as fo llo w s : HNH H0-C=0 1 1 0=C + CH2 ' ' HNH C S it Urea HIT - C=0 N - C=0 HN - C=0 * * rearrangement ' * HN02 * • 0=C CH2 -----------------------> C CH2 > 0=C 0-NQH ' ' ( i n a lk a li) ' ' » • heh 0 3 N BN - C=NH HN - C=NH Cyanac e t i c _Acid_______ __ ___________________________ | f R e d u c t i o n H-1T - 0=0 H-N - C=0 H-N - C=0 1 1 1 1 h 1 1 0=C C-NHa HC00 H 0 =C C - N -c ' a l k a li 0=C C - N-H ' " * ' " VN0 heat ^ " ^CH H-N - C-NH2 H-N - 0 -NH3 H-N - c - N* X a n th in e X anthine i s an amorphous powder very s p a r in g ly so lu b le in w ater. I t has one m olecule o f w ater which i s lib e r a t e d on ly when heated at 1 2 5 ® to I 3 O0 . I t i s very s l i g h t l y s o lu b le in a lc o h o l, and in s o lu b le in e th er . I t i s r e a d ily s o lu b le in a l k a l i , but w ith a very sm a ll amount o f sodium hydroxide i t forms a d i f f i c u l t l y s o lu b le primary sodium s a l t , which i s sometimes used to r e c r y s t a ll iz e and p u r ify the compound. X anthine d is s o lv e s r e a d ily in stro n g h y d r o c h lo r ic a c id forming th e h y d ro ch lo rid e, which i s decomposed by w ater. I t p r e c ip it a t e s out upon adding s i l v e r n it r a t e in a voluminous p r e c ip it a t e o f s i l v e r s a l t o f x a n th in e. Xanthine i s s c a r c e ly a ffe c te d by h e a tin g in sa tu ra te d barium hydroxide s o lu t io n , but when heated in concentrated h y d ro ch lo ric a c id a t about 220° i t i s co m p letely broken down, form ing carbon d io x id e , carbon monoxide, ammonia, and g ly c o c o l correspond ing to about th r e e -fo u r th s o f the n itr o g e n atoms con tain ed in th e m olecu le. By warming w ith h y d ro ch lo ric a cid and potassium c h lo r a te , a llo x a n and urea are formed. I t g iv e s th e murexide r e a c tio n by evaporating w ith c h lo r in e w ater and adding ammonia. By h e a tin g xan th in e w ith bromine in a c lo se d tube a t 100°, 8-brom oxanthine i s formed. T h is, by m e th y la tio n , forms S-b rom ocaffein e, and o th er d e r iv a t iv e s may be formed from the l a t t e r by replacem ent o f the halogen by va rio u s r a d ic a ls . X anthine can be ( 1 ) : B e r. 3 3. 1371. 3 °3 5 . 1 9 ° ° . A lso Ann, 331 , Gk, 19O3 . IS d is tin g u is h e d from u r ic a c id by i t s g r e a te r s t a b i l i t y toward n i t r i c a c id ^ ^ . I t d i s s o l ­ v e s m hot d i lu t e n i t r i c a c id w ithout an e v o lu tio n o f g a s , and by evap oratin g to d ryness i t le a v e s an orange y e llo w c o lo r , which changes to a deep red upon th e a d d itio n o f p otassiu m h yd roxid e, R. 1T IE M O N C -M E T H Y L -X A N T H IK E S . 1 , 1 -M e th y l-x a n th in e , t h is compound i s found alon g w ith xanthine in th e u r in e o f man in sm all amounts. I t c r y s t a l l i z e s out o f a c e t ic a c id as s ix - s id e d l e a f l e t s . In th e v a rio u s s o lv e n t s i t i s s l i g h t l y more s o lu b le than x a n th in e. I t a c ts as a very weak d iu r e t ic . 2, 3 “^ e t k y l - x a n th in e . the f i r s t s y n th e s is o f t h is d e r iv a tiv e was d isco v e r e d by E. F is c h e r and F, A c h ^ ) from 3“r-iethyl—u r ic a c id . I t may be sy n th e siz e d by Traube’ s method s t a r t in g w ith monon e th y l-u r e a and c y a n a c e tic a c id . I t i s o n ly found in the u r in e a f t e r e x c e s s amounts o f c a ff e in e or theobromine have been in g e s t e d . I t decomposes above 3^0°* ^ra't does not m e lt. I t g iv e s th e m urexide r e ­ a c t io n . T hree-m ethyl—xanthine d is s o lv e s r e a d ily in d i lu t e a l k a l i . I t does not a c t as a d iu r e t ic w ith d ogs, but does a c t s tr o n g ly w ith c a ts . 3, 7“le t h y l-x a n th in e or H eteroxan th ine. This xan th in e d e r iv a tiv e i s a ls o found in the u r in e o f man, and in c r e a se s when c a f f e in e or theobromine are taken in to th e body. I t was prepared by F« F is c h e r (3 ) from 3 , 7 ”,d in e th y l-x a n th in e (theobrom ine) by h e a tin g w ith phosphorus o x y c h lo rid e and phosphorus p e n ta c h lo r id e . By t h is r e a c tio n a m ethyl group i s s p l i t o f f and a l l o f the hydroxy groups are re p la c e d by c h lo r in e atoms. The l a t t e r are rep laced by such groups as eth oxy w hich in turn are converted to hydroxy groups by means o f con cen trated m ineral a c id s . E eteroxan th in e m elts at 3 8 -° w ith e v o lu tio n o f g a s. I t d is s o lv e s in about 1 ho p a r ts o f hot water, and g iv e s the murexide r e a c tio n . U. S-M ethylxanthine, In th e s y n th e s is o f S -m e th y l-c a ffe in e , th e o p h y llin e , and c a f f e in e from u r ic a c id , g -m e th y l-x a n th in e i s the f i r s t product formed. The procedure c o n s is t s in h e a tin g u r ic a c id w ith a c e t i c anhydride in a c lo s e d tube a t ISO to I S 5 0 or w ithout p ressu re in th e p resen ce o f p y r id in e ,q u in o lin e , or d im e th y l-a n ilin e . (1 ): (2 ): (3 ) : (*4): K o h le r, L ie b ig . Ann. 26, 3U1 , 1838. Ber. 3 1 , 1980, 1898. B er. 3 0 , 1S3 9 . 1897. B ehringer & Sohne, D.R.P. 1 2 1 ,22h, C. I I I I , 1901. E, ’.7aser, Synthese der Organischen A r z n e im itte l, p. 20U. 19 N = C-OH ' « ,0 HO-C C - N-H + xC-CH3 " " ^C-OH °SJ-CH3 N - C- N 8 U ric a c id ( e n o l) H-N - C=0 • ' ---------------------- ^ 0=C C - u_h ' " 'C-CH3 + CHsCOOH + COa H-N - C - N 7 8 -M e th y l-X a n th in e (K eto) 180 - 185 ® 8 -M e th y l-x a n th in e c r y s t a l l i z e s out o f h o t w a te r i n th e form o f p ris m s o r p l a t e s . At 3 SO0 i t hrownfl, and decomposes ahove 400°, I t i s s o lu b le in ab o u t 3 3 ^ p a r t s o f h o t w a te r , b u t i s e a s i l y s o lu b le i n a l k a l i , d i l u t e ammonia and i n warm d i l u t e h y d r o c h lo r ic a c id . I t i s n o t p r e c i p i t a t e d o u t o f a s o lu t i o n o f c o n c e n tra te d s u l f u r i c a c id by a d d in g w a te r. I t g iv e s th e m urexide r e a c ti o n . I t s m onopotassium s a l t form s sm a ll n e e d le s . I n an am m oniacal s o l u t i o n o f s i l v e r n i t r a t e a g e la tin o u s s i l v e r s a l t r e s u l t s w hich becom es s t a b l e w ith b o i l i n g . The s o l u t i o n o f 8 -m e th y l-x a n th in e w ith s i l v e r n i t r a t e i n d i l u t e n i t r i c a c id g iv e s a c o l o r l e s s f lo c c u le n t s a l t . In a s o lu t i o n o f c o n c e n tr a te d h y d ro ­ c h l o r i c a c i d , a h y d ro c h lo r id e c r y s t a l l i z e s out upon c o o lin g a s c o l o r l e s s n e e d le s w hich a r e decomposed i n w a te r. 5. 9 -M e th y l-x a n th in e does n o t o c c u r n a t u r a l l y , b u t may b e s y n th e s iz e d ^ a s fo llo w s & 0 H-N -- c=o H-N -. 0=0 1 1 «H »H H / 0=C C - N-C=S 0-NHa + CS=C=NCH3 — — > o=c r / « 1 1 N-H | ch3 H-N -- c=o H-N -Hs 0 (HCl) i - c=o 1 1 H-N - C=0 h- n o=c I C - N HUOs C-SH H-N - C - N-CH3 C - N, .CH H-N - C - N-CH3 9-M ethy 1 -X a n th in e . o=c I I t form s sm a ll n e e d le s , m e lts a t 38 *+° w ith d e c o m p o sitio n , and i s s o lu b le i n ab o u t 280 p a r t s o f h o t w a te r. I t r e a d i l y g iv e s th e m urexide r e a c t i o n . C. THE DIMETHYL-XANTHINES. 1. 1 , 3 - D im e th y l- x a n th in e , o r T h e o p h y llin e . T h is compound was i s o l a t e d by K ossel i n 1888 by a lc o h o l ic e x t r a c t i o n o f t e a le a v e s However i t may be more r e a d i l y o b ta in e d by s y n th e t ic m ethods. ( 1 ) : B o h rin g e r & Sohne, D .R .P. 1 2 0 ,^ 3 7 , C. I , . 1219, 1901. ( 2 ) : E. F i s c h e r & F. Ach, B e r. 28, 3135**39» 1895. E. F i s c h e r , B e r. 3°* 55:>» 1897. W. T ra u b e, B e r. 3 3 , 30 UI, 3O5 2 , 19 OO. B ayer & Co. Mfg. D .R .P. I 3 8 M H ; C . I . , 370, 1903. 20 When ( ! ) a n aqueous IN. p o ta s s iu m h y d ro x id e s o l u t i o n o f 1 -m e th y l x a n th in e i s t r e a t e d w ith m e th y l i o d id e th e r e s u l t i n g p ro d u c t i s th e o p h y l li n e . T h e o p h y llin e can be s y n th e s iz e d a c c o r d in g to th e f o llo w in g r e a c t i o n s : H-N - 0=0 CH3-N • 1 M eth ylation 1 0=C C - N -H :-----------> 0=C • " Jj-H * CHa-N - C-NHs0 CHa-N - C=0 CH3-N - C=0 1 -H20 * • C - N-H ----------------> 0=C 0- - N-H " C-H (HC1) » M 'c -H C-NH2 0 CH3-N - 0 - NX T h e o p h y llin e The g r e a t e s t amount o f t h e o p h y llin e i s p r e p a r e d c o m m e rc ially from -uric a c i d ^ ^ ^y h e a t i n g w ith a c e t i c a n h y d rid e and f i r s t fo rm in g 8 -me th y 1- x a n t h i n e a s d e s c r ib e d ab o v e. H-N i 0=0 i j 0 =C C - N-H + y CH3 C l ' H V cH 3 H-N - C - N 8 M ethyl x a n th in e CH3-N - C=0 i i c - N-CH3 + 0 HC1 ‘ 11 'c -C H s CH3-N - C 8 M ethyl c a f f e i n e 0 =C S0 2 C12 i n n itr o - b e n z e n e + I 2 ( c a t a l y s t ) CH3-N - C=0 H2 » ' 9- c i + 3H2o 0=C C - N ' " / C-CSC13 (H e a t) CHg-N - C - n ' T etra ch lo m e t h y lc a f f e in e CH3-N - C=0 « « > 0=C C - N-H ' " ^C-H CH3-N - C - N / T h eop h yllin e T h e o p h y llin e may a l s o b e p r e p a r e d by th e c h l o r i n a t i o n o f c a f f e i n e a t 100®, o r b e t t e r by th e m ethod o f Y e isu k e Y o s k ito m io ) d e s c r ib e d l a t e r , g iv in g 7 , 8- d i c h l o r c a f f e i n e . By h y d ro ly B is th e l a t t e r i s c o n v e rte d sim p ly by b o i l i n g w a te r i n to c h lo r t h e o p h y l li n e . Upon r e d u c t io n b y h y d ro g en g a s i n th e p re s e n c e o f a c a t a l y s t , su ch a s c o l l o i d a l p a lla d iu m 9 th e c h l o r i n e i s r e p la c e d by hy d ro g en and th e o p h y llin e i s form ed. ch 3- n - c=o ch3- n - c=o ch 3- n - c=o I I H20 ' » h2 • • 0=C C - N-CH2 C1----------- > 0=C C - N-H ---------------- » 0=C C - N-H • " ^C -C l * n ( r e d u c ti o n ) ' " 'c -H CH3-N - C - N CH3-N - C -N CH3-N - C - N* 7 , 8- d ic h l o r c a f f e in e 8- c h l o r th e o p h y ll i n e T h e o p h y llin e T h e o p h y llin e c r y s t a l l i z e s o u t o f h o t w a te r w ith one m o le c u le o f w a te r o f c r y s t a l ­ l i z a t i o n in th e form o f c o l o r l e s s p l a t e s . T h is i s l i b e r a t e d a t 110®. I t m e lts a t 2b8'®. I t i s d i f f i c u l t l y s o lu b le i n c o ld w a te r, b u t r e a d i l y s o lu b le i n h o t w a te r o r d i l u t e ammonia* T h e o p h y llin e i s n e u t r a l in r e a c t i o n . I t g iv e s th e m urexide r e a c t i o n . Thin ( 1 ) : M. K ru g e r, B e r. 3 ^ 5 . 1900. ( 2 ) : B o h rin g e r & Sohne, D .R .P . 151,133*. 0. I , 1 U3O, 190U. ( 3 ) : J . Pharm . Soc. J a p a n . No. 5°8» ^6 0 -4 6 9 , 192^ . 21 compound i s a v e ry p ronounced d i u r e t i c , b u t h a s v e ry l i t t l e e f f e c t upon th e c e n t r a l n e r ­ vous sy stem . I t i s a n e u t r a l compound and form s a c id as w e ll a s b a s ic s a l t s . I t is p r e c ip ita te d a s a s i l v e r s a l t w ith s i l v e r n i t r a t e in an ammoniacal s o l u t i o n . An e th y l diam ine s a l t o f t h e o p h y llin e i s u s e d i n m e d ic in e f o r in tr a m u s c u la r i n j e c t i o n , and i s known as " E u p h y llin " . The s o l u b i l i t y o f th e o p h y llin e i s in c r e a s e d by making o rg a n ic a c id s a l t com plexes w ith t h e o p h y l l i n e , such as sodium b e n z o a te . By th e a c t i o n o f c h l o r i n e ^ in an aqueous s o l u t i o n o f th e o p h y llin e th e r e i s soon form ed 1 , 3 - dim e t h y l - u r i c a c id g ly c o l, CHa-N - 0=0 CHa-l'I - C=0 • • H20 ' 'OH 0=0 C - N-H ------------ > 0=C C - N-H ' " ) j- H ( C l2 ) ' ' 'C=0 CH3-N - c - n ' CH3-N - c - N-H OH T h e o p h y llin e 1 , J - ^ n ^ t h y l u r i c a c id g ly c o l jCsHgOH. ( 0 1 a ) CHa-N - 0=0 ' 'H O 0=0 C — N-C-Q-CsHs • ' o - c 2h s ch3- n - c 0L* E th o x y -d im e th y l—u ra m il-N c a r b o n ic a c id e s t e r , 2 , 1 , 7 -I)i niet h y l - x a n t h i n e , o r P a r a x a n th in e , i s found in th e u r i n e o f man. I t i s r e a d i l y s y n th e s iz e d by c h l o r i n a t i n g c a f f e i n e ^ ) w ith p hosphorus o x jrc h lo rid e and p h o sp h o r­ u s p e n ta c h lo r id e a t l60® o r w ith f r e e c h lo r in e a t 200° g iv in g 3» 8 - d i c h l o r - c a f f e i n e . By h y d r o ly s is and r e d u c tio n o f th e l a t t e r , p a ra x a n th in e i s o b ta in e d i n a s i m i l a r m anner to th e p r e p a r a t i o n o f th e o p h y llin e from 7« 8 - d i c h l o r c a f f e i n e . I t can a ls o be o b ta in e d by th e c h l o r i n a t i o n and m e th y la tio n o f h e te r o x a n th in e . '3 ? By t r e a t i n g 1 , 7“ < iira e th y l-u ric a c i d ^ ) w ith phosp h o ru s o x y c h lo rid e and th e n re d u c ­ in g th e r e s u l t i n g c h lo r p a ra x a n th in e w ith h y d r io d ic a c id , p a ra x a n th in e i s p re p a re d . P a r a x a n th in e m e lts a t 298 to 299 ° . I t i s d i f f i c u l t l y s o lu b le i n c o ld w a te r , and d i s s o l v e s i n ab o u t 2k p a r t s o f h o t w a te r from w hich i t c r y s t a l l i z e s upon c o o lin g a s g la s s y c o l o r ­ l e s s c r y s t a l s . I n an e x c e s s o f c o ld sodium h y d ro x id e s o l u t i o n i t form s a c h a r a c t e r i s t i c ­ a l l y d i f f i c u l t l y s o lu b le sodium s a l t . By t r e a t i n g an aqueous a l k a l i n e s o l u t i o n o f p a ra x a n th in e w ith m eth y l io d id e a t 100® i t i s tra n s fo rm e d i n t o c a f f e i n e . P a T ax an th in e i s a s tr o n g d i u r e t i c . 3* 3 , 7 -D im e th y l-x a n th in e o r Theobrom ine. Theobrom ine was d is c o v e re d by W askresensky in 18^2 in th e cacao bean a lo n g w ith c a f f e i n e . I t o c c u rs to th e e x te n t o f about 1 ,2 to 1 .8 $ in th e cacao b e a n , (1 ): (2)j (3 ) : "but form s a c r y s t a l l i n e s u b lim a te a t 29 0 °, I t d is s o lv e s i n ab o u t l6 0 0 p a r t s o f w a te r a t 13.0® C and i n lUO p a r t s a t 100®C, I t i s i n s o lu b le i n carbon t e t r a c h l o r i d e and e t h e r . By o x id a tio n w ith h y d r o c h lo r ic a c id and p o ta s s iu m c h lo ra te ^ th e o b ro m in e b re a k s down in to m o n o m eth y lallo x an and m onom ethylurea, th u s f u r n i s h in g one o f th e p ro o fs o f i t s s t r u c t u r e , fro m th e above o x id a tio n to m e th y l- a llo x a n i t r e a d i l y g iv e s th e m ure 3d.de t e s t w ith ammonia. I t i s r e a d i l y c h lo r i n a t e d i n a c h lo ro fo rm s o l u t i o n a t room te m p e ra tu re to 8 - c h l o r th e o b ro m in e . In th e p re s e n c e o f c o n c e n tra te d h y d r o c h lo r ic a c id a t 20 0 °, t h e o ­ brom ine i s b ro k en down to s a r c o s i n , am m onia.and m ethylam ine. The same p ro d u c ts r e s u l t upon lo n g h e a ti n g w ith bariu m h y d ro x id e s o l u t i o n . In com parison w ith c a ffe in e ^ h o w e v e r, i t i s more r e s i s t a n t to d eco m p o sitio n by a l k a l i . Theobrom ine i s m e th y la te d to c a f f e in e by sh a k in g an a l k a l i n e s o l u t i o n w ith an e x c e s s o f m e t h y l- s u lf a te . Theobrom ine i s l i k e th e o p h y llin e i n b e in g a n e u t r a l compound and form ing b o th a c id and b a s ic s a l t s , and in a l s o b e in g more s o lu b le i n an a c id o r a l k a l i n e s o lu t i o n th a n in a n e u t r a l s o l u t i o n . The s a l t s form ed a r e a l l r e a d i l y decomposed i n an aqueous s o l u t i o n . The l it h iu m s a l t o f th eo b ro m in e d is s o l v e s i n ab o u t h a l f i t s w e ig h t o f w a te r and i s u se d in m e d ic in e . I f add­ ed to an am m oniacal s i l v e r n i t r a t e s o l u t i o n theobrom ine p r e c i p i t a t e s o u t a s a g e la tin o u s mass w hich form s a c r y s t a l l i n e in s o l u b l e p r e c i p i t a t e i f h e a te d in ammonia. T h is form a­ t i o n o f an i n s o l u b l e s i l v e r s a l t i s made u s e o f in s e v e r a l m ethods f o r th e q u a n t i t a t i v e d e te r m in a tio n o f th eo b ro m in e. The o l d e s t and most u se d p r e p a r a tio n o f theobrom ine to d ay i s " d i u r e t i n " o r th eo b ro m in e sodium s a l i c y l a t e . I t i s a v e ry s o lu b le a d d it io n compound, e a s i l y h y d ro ly z e d i n an aqueous s o l u t i o n . D. THE TRI-ALKYL-XAiTTHIBES. 1. Is 3» 7 -T rim e th y l- x a n th in e o r C a f fe in e . ( a ) . O ccurrence and P r e p a r a tio n . C a f fe in e was d is c o v e re d in c o ff e e by Robequet and P e l l e t i e r and C aventou in 1821. However th e a c ti v e p r i n c i p l e c a l l e d " c o f f e e b ase" was d e s c r ib e d by F e rd . Runge in 1820. The i d e n t i t y o f c a f f e in e w ith " th e in e " o f t e a was d is c o v e re d by a n a ly s i s in I 838 by J o b s t. C o ffee b ean s c o n ta in from 1 .0 0 to 1 .2 0 $ and t e a le a v e s from 1 . 5 to 3«5^ c a f f e in e and co co a ab o u t 0 . 1 to O .^o. C om m ercially, c a f f e in e h a s b een s y n th e s iz e d i n c o n s id e r a b le q u a n t i t i e s from u r i c a c id by th e 8 - m e th y l- x a n th in e m e th o d '4 ' . The l a t t e r I s p re p a re d w ith a c e t i c a n h y d r i d e and u r i c a c id a s d e s c r ib e d u n d e r S -m e th y l-x a n th in e . (1 ); (2): (3)* (U)s E. F is c h e r . Ann. 215, 3 1 1 , 1882. B o h r in g e r .& Sohne. D .R .P. 1 5 1 ,1 3 3 ; C. , 1 . , 7 . T raube. B e r. 3 3 , 3 0 5 0 , 19 OO. B o h rin g e r & Sohne. D .R .P. 1 5 1 ,1 3 3 , C. , 1 . , 1 U3 O, 190 U. 1 ^ 0 , 190 U. 23 H-N - C=0 CH3-N - 0=0 ' ' 3CH3 C1 » * 0=0 0 - N-H > 0=c C - N-CH3 ' " C-CH3 ' " ^C-CH3 H-N - C - NX CH3-N - C - N/ 8 -m e th y lx a n th in e 8 - m e th y lc a f f e in e $ S^iST i--------------------CHs-H - C=0 OHs-N - C=0 1 ' h 3o ' • 0=C C - N-CH3 =► o=c c - n -g h 3 t » ^C-C-C1 3 Heat ' ' ^C-H CH3-N - C - N/ CH3-N - C - N 1 i 3 » 7 - t r i m e t h y l 8- t r i c h l o r m e t h y l c a f f e in e x a n th in e An o l d e r m ethod f o r th e p r e p a r a ti o n o f c a f f e in e from u r i c a c id c o n s is t s m e th y la tin g th e l a t t e r , "by s h a k in g w ith m ethyl io d id e i n an a l k a l i n e s o l u t i o n , to t e r r a ­ ine th y l- u r i c a c id . T h is i s t r e a t e d w ith phosphorus o ^ r c h lo r id e w hich rem oves th e im ^hyl group i n th e n i n t h p o s i t i o n and r e p la c e s th e h y d ro sy l group i n th e e ig h th p o s i t i o n w i t h a c h lo r in e atom . T h is r e s u l t s i n 8- c h l o r c a f f e i n e w hich i s r e a d i l y re d u c e d to c a f f e i n e in p re s e n c e o f hy d ro g en gas and a c a t a l y s t . T here a r e two g e n e ra l m ethods f o r th e s y n th e s is o f c a f f e in e w hich h e lp to p ro v e i t s s t r u c t u r e . The f i r s t one, by E . F i s c h e r , (2 ) c o n s is t s i n f i r s t p r e p a r in g th e 1 , 3 - d i ­ m eth y l u r i c a c id by s t a r t i n g w ith d im e th y l- u re a and m a lo n ic a c id ( s i m i l a r to th e s y n th e s i s d e s c r ib e d u n d e r u r i c a c i d ) . The 1 , 3 - d im e th y l- u r ic a c id i s c o n v e rte d i n t o S - c h lo r th e o p h y l l i n e by means o f p h osphorus o x y c h lo rid e , The c h lo r th e o p h y llin e i s re d u c e d to th e o ­ p h y l l i n e , th e n m e th y la te d to c a f f e in e . The seco n d m ethod i s t h a t o f 17. T r a u b e 's ^ ) t>y s t a r t i n g w ith d im e th y l- u re a and c y a n a c e tic a c id and i s s i m i l a r to th e s y n th e s is o f x a n th in e by T ra u b e 's m ethod. CH3 -N-H i C=C + i CH3 -I'T-H D im eth y l-U re a f CH3 -IT - ho-c= o ch3- n - 0=0 » > i C=H2 C=H2 ---------?• 0=0 i i i C^N CH3-N-H C=N C y a n a c e tic A cid 0=0 • ' red u ctio n 0=0 C-N-0H ---------------- > ' ' (M 4 ) 3 S CH3 -N - C=N-H ( 1 ) : E. ( 2 ) : E. ( 3 ) : W. re a rra n g e m e n t --------------------- > (by a l k a l i ) CH3-N - 0=0 ' » 0=0 C-H2 * 1 CH3-N - C=N-H HNOa CH3-N - 0=0 CH3 -N - 0=0 » 1 HC00H • ' H H 0=0 C - N=H2 ---------- > 0=0 C - N-C=0 ' " » " CH3-N - C - N-H2 CH3-N - 0 - N-H2 J h ea t in p r e CH3 -IT - 0=0 sen ce o f 1 ' a lk a lin e s o ln . 0=0 0 - N-CH3 o f CH3 I • " )C-H CH3-!T - C - N / C a ffe in e F i s c h e r . B er. 3^* 3^ 1 0 ( 1897* F i s c h e r . B e r. 2 8, 3135* 1895. T rau b e. B e r. 33* 3 ^ 2 - 5 ^ , 1900. 24 b . P h y s ic a l P r o p e r tie s o f C a ffe in e , ( l ) C a ffe in e c r y s t a l l i z e s out o f w ater as s i l k y , h a i r li k e n e e d le s h avin g the form ula CqHiq1T4 0 2 .H 2 0 . The compound l o s e s i t s H20 p a r t ly upon lo n g sta n d in g in the a i r and c o m p le te ly i f h ea ted s e v e r a l hours at 1 1 0 °, Anhydrous c a f f e in e m elts a t 2 3 6 . 5 ° (C o r r .) . At a c o n s id e r a b le low er tem perature, i t b e g in s to sublim e. This p rop erty o f su b lim a tio n i s a ls o known to tak e p la c e in d r ied p la n t m a te r ia l c o n ta in in g c a f f e in e . I t sublim es more r e a d ily than the l e s s m ethylated x a n th in e s. Hence i t may be concluded th a t the a d d itio n o f m ethyl groups to th e xanthine m olecule in c r e a s e s the r a te o f su b lim a tio n , low ers th e m e ltin g p o in c , in c r e a s e s s o l u b i l i t y in w ater as w e ll as in many organ ic s o l ­ v e n ts and a id s in th e form ation o f d e f in i t e c r y s t a l s . By t h is g r e a te r v o l a t i l i t y and c o n sid e r a b ly g r e a te r s o lu b il i t y ^ c a f f e i n e i s d i s t i n ­ gu ish ed and sep a r a te d from theobrom ine. A sa tu r a te d aqueous s o lu tio n o f c a f f e in e con­ t a in s 4 6 ,5 S ' P er 100 g. o f s o lu t io n at 6 5 ° and 2 . l 4 g. a t 2 5 °. In chloroform at 2 5 ° a sa tu r a te d s o lu t io n c o n ta in s 11 g . c a ff e in e per 100 g . o f s o lv e n t . E ther sa tu r a te d w ith c a f f e in e a t 2 5 ® c o n ta in s 0 ,2 7 g . per 100 g . A b solu te e th y l a lc o h o l sa tu r a te d w ith c a f f e in e at 1 5 to 1 7 ° r e q u ir e s 1 6 5 p a r ts o f th e so lv e n t f o r one p art o f c a ff e in e and 3 ^ p a r ts a t th e b o i li n g p o in t. For the s o l u b i l i t y o f c a f f e in e in v a r io u s s o lv e n ts one may r e f e r to A lle n 's Commercial Organic A n a ly sis V ol. V II, p . 3H * C a ffein e i s o d o r le s s and g iv e s a n e u tr a l r e a c t io n . I t has a m oderately b i t t e r t a s t e . c„ Chemical P r o p e r tie s and D ecom position o f C a ffein e . 1. O xidation o f c a f f e in e . (o) CH3 -IT - C=0 I t CK3 —IT — C—0 1 1 KCIO3 ( in HC1 s o lu tio n ) C=C C - IT-CEa I » ^C-E CH3 -H - C - IT7 C a ffe in e KCIO3 Below in HC1 5 O0 1 HoO 0=C C- N-CHs ---------• " NC=0 Heat CH3 -U - C - 1T-H H ydroxycaffeine (m. p. 3^5°) c=o + I I CH3 -IT - c=0 D im eth y l-a llo x a n c=o I 1T=HS Monomethyl-urea or Bromine w ater ch3-it - C= 0 1 o=c 50« H-IT-CK3 I CH3 -H - 0=0 1 o=c 1 C - IT-CH3 » H0/ ' ^C=0 CH3 -K - C - N-H OH H ydroxycaffeine g ly c o l CE3-47 - C=0 t 1 C-O-C » I + ch 3 nh 3 N-CHa >=0 1T-H A p o ca ffein e (m. p. 144-14-5°) ( 1 ) : V. Meyer & P. Jacobson - Lehrbuch der Organischen Chemie. V ol. II C y c lic Compounds pp. 1293-95* ( 2 ) : H. B i l t z . B er. 43, l 6 lS - 2 2 , 1910; Ber. 46, 3 4 0 7 , 1 9 1 3 , E. F is c h e r . Ann. 2 1 5 , 2 5 3 , 1SS2; U ntersuchungen, p . 8 S. 25 H CH3-N - C=0 c h 3- n - c = 0 I I +ch 3 nh 2 c -o -c - n -ch 3 " « ^c=o 0 C - N-H fl A p o ca ffein e (m .p . l 4 4 - l 4 5 ° ) H OH3 -N - C=0 1 1 HI HO-C - H-CH3 ' ^C=0 C - N-H 6 C a ffu ric Acid (m .p. 2 1 0 - 2 2 0 ° ) Ba(OH); H2=C - N-CH3 \ I ■^c=o C - N-H H-C t N-CH3 ^C=0 C - N-E 6 H ydrocaffuric a c id 1 -m eth y l-h y d a n to in I t may "be observed th a t th e mechanism o f th e se r e a c tio n s i s v e r y s im ila r to th e o x id a tio n o f te tr a m e th y l-u r ic a c id to a l lo c a f f e in e and f i n a l l y the break in g down to d i m eth y l-h y d a n to in . I t f a m is h e s one o f th e p ro o fs fo r the str u c tu r e o f c a ff e in e as a c c ep te d tod ay. H. B i l t z upon more recen t in v e s t ig a t io n s d id not reach the same c o n c lu sio n s as d id 2 . F is c h e r regard in g th e decom position o f c a f f e in e or h y d ro x y ca ffein e to h y p o c a ffe in e and c a f f o l i n . F is c h e r gave th e em p irica l form ula o f h y p o c a ffe in e , prepared by h e a tin g h y d r o x y c a ffe in e w ith b a s ic le a d a c e t a t e , as C6 H7 O3 N3 . He prepared c a f f o l i n which he gave th e form ula CsH9 0 2 N3 , by h e a tin g a p o c a ffe in e w ith barium hydroxyide which r e s u lt e d in th e lib e r a t io n o f one mole o f carbon d io x id e . B i l t z prepared h y p o c a ffe in e ' ' by p a s s in g dry h y d r o c h lo r ic a c id gas in to an a b s o lu te e th y l a lc o h o l s o lu t io n o f th e d i e t h y l e th er o f h y d r o x y c a ffe in e g l y c o l . A fte r becoming sa tu r a te d w ith h y d r o c h lo r ic a c id i t was d ig e s t e d over a f r e e flam e. A fte r se p a r a tin g and p u r ify in g the r e s u lt in g crop o f c r y s t ­ a l s he o b ta in ed h y p o c a ffe in e C8 H1 0 O4 N4 which m elted at 1 8 5 - 1 ^6 ° . For the p rep a ra tio n o f c a f f o l i n ,B i l t z h eated a co n cen tra ted barium hydroxide s o lu ­ t io n c o n ta in in g h y p o c a ffe in e . The r e s u lt in g compound gave th e form ula C7 H i 2 0 3 ^ 4 » m elted a t 1 9 7 ° • By h e a tin g c a f f o l in w ith a c e t i c anhydride under a r e f lu x condenser f o r f i f t e e n hours and evap oratin g th e s o lu tio n to dryness by h e a tin g in a vacuum, B i l t z o b ta in ed a c e c a f f e in e , m eltin g a t 191°. The r e a c tio n s in v o lv e d in the p re p a r a tio n o f t h e s e th r ee compounds are as fo llo w s : CHs-N - C=0 CHs-N - c=o ' '0C2 Hb HC1 gas « ' Ba(0H ) 2 0=C C - N-CH3 ---------------------------0=C C - N-CH3 --------------------> » ' ^p-OH (C2 H5 0H) ' ' 'c-OH CH3-N - C - N and heat CH3 -N CJ - i f 0 o c 2 h5 D ie th y l- e th e r o f h y d ro x y ca ffein e H ypocaffeine or Oxy-trim e t h y l- u r ic a c id g ly c o l (m.p, 1 8 5 - 1 8 6 ° ) -co 2 + v CHs-N - C=0 • *H 0=C 0 - N-CH3 1/ h2 o a c e t i c anhydride >=° CHs-H JM fe C a ffo lin or 1 , 3» 6 - t r im e t h y l- a lla n t o in (m .p. I 9 I 0 ) ( 1 ) : S . F is c h e r . Ann. 215-2 9 2 , 1882. ( 2 ) : H. B i l t z . B er. 4 4 , 282-2 9 8 , 1911. CH3-N - C=0 1 *H H > 0=0C- N-CH3 '/ CH3-E A c e c a ffe in e or 1 , 3- i c a c id m ix tu r e , ch olestrop h an e i s produced, thus: ch3- n I 0=0 lc acid or with a chrom- CH3 -I-I - 0=0 HN03 ' > o=c + CH3 IIH2 + COa & o th e r p roducts I CH3-N - 0=0 Cholestrophane or dimethylparabar&c a c id (m. p. 1 U5 . 5 0 ) I o=c I 0 - N-CHa // C-H CHS-N - 0 - N C h olestrophane i s r e a d ily decomposed "by a l k a li in to sym m etrical dim ethyl-carbam ide (m. p . 97-100® ) and o x a lic a c id . Hence on adding ammonia and calcium c h lo r id e to i t s aqueous s o lu t i o n , and warming th e l i q u i d , calcium o x a la te i s p r e c ip it a t e d . By h e a tin g c a f f e in e at 2^0-250® w ith con cen trated h y d r o c h lo r ic a c id i t i s com plete­ l y broken down to carbon d io x id e , ammonium c h lo r id e , m ethyl am ine, and o th e r su b sta n c e s. The Mure s id e r e a c t io n ( l ) i s g iv e n by c a f f e in e , though to a l e s s degree than does u r i c a c id , Murexoin i s formed in s te a d o f m urexide. CH3 -N - c=o '» « 02 2 C a ffe in e -> (HH0 3 ) 2, 0=0 I c=o I 1 — CH3 -H - 0=0 D im eth y l-a llo x a n c=o *0H 0 =C I ch3- n N ? o=c 1 N-CH3 I 0=0 A J 9 H0 Am alie A cid (orange y e llo w ) 0 + NH4 OH Mureoxin 2 , D ecom position o f C a ffein e in the P resen ce o f A lk a li. (b r ig h t red) (2 ) C a f f e i d i n e ^ ) i s formed by d ig e s t in g c a ff e in e in a sa tu r a te d s o lu t io n h yd roxid e f o r s e v e r a l d ays, or i n 2 N. sodium hydroxide a t room tem perature. H H CH3-17 CH3-13 - 0=0 CH3 -N - 0=0 » ' Ba(0H ) 2 Heat ' » H20 > H0-^ C— N-CH3 0=0 C - H-CH3 ---------------''CH o r 211. UaOH 0: " N.C-H Heat H jr a t 25®. CHa-N - C - N^ CH3 -N CHs -N - C - N C a ffein e C a ffe id in e Carbonic Acid o f barium 0=0 I C - N-CH3 +C02 " >"H C- N C a ffe id in e (m. p . ( 1 ) : 0. P i l o t y . Ann. 3 3 3 , 2 2 , 190 U. Slummer & S t i e g l i t z , Am, Chem, J. 31» 6 6 l, 190U» M ohlar. B e r. 37» 2 6 s6 , 190U. ( 2 ) : M aly, A ndreasch. M. k, 369-3 7 0 , 1883; & T a s s e ly , B l. ( 3 ) 1 7 . 598, 1897, E. P i s c h e r & -Bromberg. B e r. 3 0, 219, 1897. H. B i l t z & S tr a fe . Ann. b o k , 1 I+3 , 1 9 1 I+. H. B i l t z & H. R ak ett. B er. 6 lB , 1^ 09-22, 1928. ( 3 ) : S t r e c k e r . Ann. 1 2 3 , 3°0« 9 ^®) 27 C a f f e id in e may be m e th y la te d r e a d i l y to th e m e th y l-a n d d i m e t h y l ,c a f f e id i n e . Upon f u r t h e r h e a t i n g o r w ith a s t r o n g e r a l k a l i , c a f f e i n e i s decomposed to ammonia m e th y la m in e , foxm ic a c id ^ a n d s a r c o s i n , 9 Ha H2 0 B-IT - C -C-OH S a r c o s in 3, S a lts o f C a f f e i n e .^ C a f fe in e a c t s a s a v e ry f e e b le b a se and fo n n s a d d i t i o n compounds w ith many a c id s and a c id s a l t s . I n g e n e r a l th e y a r e r e a d i l y p re p a re d and a r e e a s i l y b ro k e n down to c a f f e i n e and t h e f r e e a c id s by m e re ly d i s s o l v in g i n w a te r , o r som etim es upon c o n tin u e d s ta n d in g i n th e a i r . F o r e x a m p le , c a f f e in e - h y d r o c h lo r id e (C 8H10N4O2 .HCI+ 2H2 O) i s made by a d d in g c a f f e i n e t o c o n c e n tr a te d h y d r o c h lo r ic a c i d and e v a p o ra tin g o f f th e h y d r o c h lo r ic a c i d u n t i l c o l o r ­ l e s s p r is m a t ic c r y s t a l s farm . Upon s ta n d in g i n th e a i r i t g r a d u a lly g iv e s o f f h y d ro ­ c h l o r i c a c id g a s and w a te r. I f h e a te d a t 75° th e f r e e c a f f e i n e i s r e c o v e r e d . However c a f f e i n e - o x a l a t e and s a l i c y l a t e c r y s t a l l i z e o u t o f w a te r unchanged, b e in g b u t s p a r i n g ly s o lu b l e . The c i t r a t e i s v e ry s o lu b l e , b u t w i l l c r y s t a l l i z e o u t o f a c o n c e n tr a te d aqueous s o l u t i o n . I t i s u s e d i n m e d ic in e b ecau se o f i t s in c r e a s e d s o l u b i l i t y i n w a te r. C affeineusodium s a l i c y l a t e and b e n z o a te axe e x te n s i v e l y u s e d i n m e d ic in e when i t i s d e s ir e d to in tr o d u c e c a f f e i n e i n t o th e body by su b c u ta n e o u s i n j e c t i o n . More r e c e n t l y c a f f e i n e a m in o a c id y lp h e n e tid in e h a s been found s u i t a b l e f o r su b c u ta n e o u s i n j e c t i o n , C a f f e i n e - p e r i o d i d e ( 2 ) i s n o tew o rth y b ecau se o f i t s extrem e i n s o l u b i l i t y i n w a te r . I t i s p r e p a r e d by a d d in g c a f f e i n e to an aqueous s o lu t i o n o f io d in e and p o ta s s iu m i o d id e an d a c i d i f i e d w ith h y d r o c h lo r ic a c id . A p r e c i p i t a t e o f C8H10H4 O2 H I. I 4 r e s u l t s . V a rio u s o t h e r c a f f e in e - h a lo g e n s a l t s may lik e w is e be p re p a re d . C a ffe in e i s c o m p le te ly p r e c i p i t a t e d w ith s i l i c o - t u n g s t i c a c i d O ) i n th e p r e s e n c e o f 5$ h y d r o c h lo r ic a c id . C a f fe in e g iv e s a b r i g h t r e d p r e c i p i t a t e w ith f r e s h p o ta ssiu m io d o b is m u th a te p l u s 10$ io d in e s o l u t i o n , W w h ile theobrom ine g iv e s a brown c o l o r , ch a n g in g i n t h i r t y m in u te s to a c h o c o la te brow n. I t i s n o t p r e c i p i t a t e d by n e u t r a l io d iz e d p o ta s s iu m io d id e , th u s d i s t i n g u i s h i n g t h i s a l k a l o i d from o th e r n o n -p u rin e a l k a l o i d s . C a f fe in e - m e r c u ric c h lo r i d e (C aH io^O sH gC lg) p r e c i p i t a t e s o u t a b u n d a n tly a s lo n g f e l t - l i k e c o l o r l e s s n e e d le s when c a f f e in e i n ab o u t 200 p a r t s o f w a te r i s m ixed w ith a s a t u r a t e d m e rc u ric c h lo r id e s o l u t i o n ; I t i s s o lu b le i n ab o u t 260 p a r t s o f c o ld w a te r . ( 1 ) : 2 , S chm idt, Ann. 217, 203; B e r. lU , SlH. ( 2 ) i Oomberg. Am. Chem. Soc. I S , 3^7» IS 96 , (3 ): A. A z a d ian . B u ll. Soc. Chim. Belg. 3 1 , 15, 1922. ( k ) i M, Malmy. J. Pharm, Chim. 2 3 , 89, 1921. 28 (d ) Physiological Properties of Caffeine.^ Caffeine produces three distinct effects when taken into the human body: (1) It stimulates the central nervous system from the head, downward. This is done by lowering the threshold of resistance to messages sent over the synapses of the nerv­ ous system. This results in temporarily overcoming fatigue and drowsiness and increases attentiveness and coordination for a time, if taken in moderate doses from 0,1 to 0.3 gram. A cup of coffee contains from 0.05 g. to 0.15 g. of caffeine. If caffeine is taken in excessive doses it results in convulsions and paralysis. The lethal dose for man is about ten grams. (2) Caffeine increases the heart’s action to a moderate degree. It is one of the safest mild heart stimulants if administered in the proper dosage. It also increases respiration to a moderate extent. This is a secondary effect of the drug. (3) n acts as a diuretic by increasing the permeability of the walls of the kid­ neys. Its action in this respect is somewhat less than theobromine and theophylline. Because of the fact that the major part of the experimental work involves the halogenation and preparation of the ethers of caffeine these subjects will be dealt with later on in the historical and descriptive discussion under separate headings. 2. 3, 7, 8-Trimethylxanthine. This xanthine derivative is obtained by the action of methyl iodide on the dry dipotassium salt of 8-methylxanthine. It forms small needles out of hot water, and darbed prisms from hot alcohol. It sinters at 29 6 ° and melts at 302 to 3^3e» It sub­ limes by continuous heating to fine needles. This compound is soluble in 18 parts of hot water and quite soluble in hot alcohol. 3. 1 , 3 , 8-T rim eth y lx a n th in e, (3) This compound is obtained from 1, 3“dimethylxanthine by heating with acetic anhydride, usually in the presence of pyridine. It forms needles, and melts at 3^5° to a faintly colored liquid and sublimes by continuous heating into small colorless needles. It is soluble in about 40 parts of hot water, rather soluble in hot alcohol, moderately soluble in ammonia and dilute alkali. In concentrated alkali, an alkaline salt separates out in needles. It is readily soluble in dilute mineral acids. (1): Sollmann. Manual of Pharmacology, 2d ed. (W.B. Saunders Co.) pp. 21+1-258. Secher. A. Pth. 77* 8 3 , ^-91^• Schmiedberg. Ber. 3^» 255°, 1901. Riesser. A. Pth. 80, 208, 1916. Sten3trom. Bio. Z. 1+9, 2 2 5 , 1913. Belak, Bio. Z. 8 3 , 1&5» 1917• Means, Newburgh. C. I., 171. 1916. W. Sollant & J , B. Reiger. Dept. Agr. Wash. J . Pharm. 3 , ^+55-i+57W. C. Rose. Physiological Reviews 3* 5^"602, 19 2 3 . V. C, Meyers & E. L, Wardell, J. Biol. Chem. 77* 697-721* 1928. Cushney's Pharmacology and Therapeutics, (Edmunds & Gunn), pp. 3OL-3 I3 . ( 2 ) : Bohringer & Sohne. D.R.P. 1 2 8 , 2 1 2 , C, I., 5^9, 1902. (3 ): Bohringer 8» Sohne. D.R.P. 121,223* C, I., J l , 1901. 29 4 , 1 , 3» 7 - T r i e t h y l x a n t h i n e ^ i s p ro d u ce d ‘by th e r e d u c tio n o f th e t r i e t h y l - 8c h lo r x a n th in e w ith h y d r io d ic a c id and p h o sp h o ru s. I t m e lts a t 1 1 3 °. 5. 1 , 3 , 7 - T r i b u t y l x a n t h i n e ) i s l ik e w is e p ro d u ced "by th e r e d u c tio n o f th e t r i b u t y l 8 - c h l o r x a n t h in e w ith h y d r io d ic a c id and p h o sp h o ru s. I t m e lts a t 4 l - 4 2 ° . I t s h y d r o c h lo r ­ i c a c id s a l t m e lts a t 131-134°. E. THE TETRA-ALKYL AND AEYL-XANTHINES. 1. 1 , 3 , 7 , S -T e tra m e th y lx a n th in e (2 ) o r 8 - M e th y l- C a f fe in e . T h is compound i s p r e p a r e d "by th e m e th y la tio n o f 8 - m e th y l- x a n th in e , 3> 2 - d im e th y lx a n th in e , o r 1 , 3» S - tr i m e th y l - x a n t h i n e , u s in g m eth y l i o d id e . (R e a c tio n s may be found u n d e r p r e p a r a t i o n o f t h e o p h y l l i n e .) I t form s n e e d le s o u t o f w a te r i n w hich i t i s s o lu b le i n a b o u t 1 .6 p a r t s a t 1 0 0 °. I t i s r a t h e r e a s i l y s o lu b le i n a lc o h o l, b e n z en e , and acetonSj an d v e ry s o lu b le i n c h lo ro fo rm . I t m e lts a t 201, 0 to 2 0 8 .5 ° su b lim e s a t a h ig h e r te m p e ra tu re undecom posed to s m a ll n e e d le s . I t i s c la im e d O ) to have s l i g h t l y more s tim u ­ l a t i n g e f f e c t on th e c e n t r a l n e rv o u s system th a n does c a f f e i n e . 2. 1 , 3» 7“ E r ie th y l- 8 - m e th y lx a n th in e ,( 2 ) By t r e a t i n g 8- m e th y lx a n th in e w ith e th y l io d id e , e th y l groups r e p l a c e t h r e e h y d ro ­ gens r e s u l t i n g i n th e above compound. I t form s p r is m s , w hich s i n t e r a t 128° and m e lt a t 1 3 2 - 13 3 ° . I* su b lim e s a t a h ig h e r te m p e ra tu re in to f i n e n e e d le s w ith o u t d e c o m p o s itio n . 3. 1 , 3» 8 -T rim e th y l-7 “ B e n z y lx a n th in e .(2 ) T h is compound i s made by t r e a t i n g 1 , } , 8- tr im e th y l x a n th in e w ith b e n z y lc h lo r id e . I t form s sm a ll n e e d le s t h a t m elt a t 159**l60. 5° . H. B i l t z and J , S a u e r(^ ) have made r e c e n t i n v e s t i g a t i o n s r e g a r d in g th e r e a c t i v i t y o f p o s i t i o n ( 8 ) i n x a n th in e s and is o x a n th in e s u n d e r th e c o n c e p tio n t h a t th e s e compounds a c t a s a ro m a tic s u b s ta n c e s . W ith u r i c a c id s i t i s th e 4 -5 d o u b le bond t h a t i s e s p e c i a l l y r e a c t i v e , w h ile w ith x a n th in e s i t i s th e hydrogen i n p o s i t i o n ( 8 ) t h a t i s . e s p e c i a l l y r e ­ a c tiv e . I s o x a n th in e s can be r e a d i l y m e th y la te d on c arb o n atom ( 8 ) by means o f m eth y l s u lfa te . H-N - C=0 1 1 0=0 0 - N-H ^C-H H-N - C - N* X a n th in e 1 (1 ): (2 ): (3 ) : (4 ): 11 H-N - C=0 i t 0=0 0 - N^ ' " / C-H H-N - 0 - N-H Is o x a n th in e D. W. M acCorquodale. J . Am. Chem. Soc. 51» 2 2 ^ 5 -5 1 , 1929. B o h rin g e r & Sohne. D .R .P , 128,212, 0. I . , 5^9, 1902. S chm iedberg. B e r. 3^5 2 5 5 6 , 1901. B e r. 64 b , 7 5 2 -5 6 , 1931* 0 . A. 2 5, No. 1 5 . p . 2965 - 6 6 , 1931. 30 The x a n th in e s and is o x a n th in e s d i f f e r on m e th y la tio n j o n ly th e l a t t e r can be m e th y la te d a t p o s i t i o n ( 8 ) , w h ile th e is o m e ric 1 , 3 » 7 > 8 - te t r a m e t h y lx a n t h in e can n o t be o b ta in e d from c a f f e i n e , b u t o n ly from 8 -m e th y l x a n th in e by th e B o h rin g e r m ethod, 3 « 9 - T r im e th y lis o x a n th in e i s r e a d i l y m e th y la te d i n th e e ig h t h p o s i t i o n w ith m e th y l s u l f a t e . T h is i s d o u b tle s s a f f e c t e d by a d d it io n o f m ethyl and m ono-m ethyl s v ilf a te r a d i c a l s , a t th e 7 - 2 d o u b le bond and su b se q u e n t e lim in a tio n o f m eth y l h ydrogen s u l f a t e . The m eth y l group i n p o s i t i o n ( 8 ) i n b o th compounds can alw ays be rem oved w ith brom ine w ith th e fo rm a tio n o f th e 8 -b ro m x a n th in e o r is o x a n th in e . O th e r o b s e r v a tio n s le a d to th e c o n c lu s io n t h a t 8 - t h i o u r i c a c id s c o n ta in in g an im ido group n e x t to th e t h i o r e a c t a s 8 - t h i o x a n t h i n e s . The d if f e r e n c e betw een th e u r i e a c id s and th e x a n th in e s i n d i c a t e s t h a t th e l a t t e r , and th e i s o x a n th in e s to an even g r e a t ­ e r d e g re e , h a v e an a ro m a tic c h a r a c te r ; a s th e two d o u b le bonds o f th e five-m em bered r i n g c a n n o t be d e te c te d by a d d i t i o n r e a c t i o n s , w h ile s u b s t i t u t a b i l i t y to a h ig h d e g re e makes i t s a p p e a ra n c e . III. HAL0GENATI0N OF CAFFEINE. CH3-N - C=0 i C l 2 below 100 « c - n -c k 3 0 =C - N-CH3 ---------------------- > 0 =C i i " V ci C-H ( u s u a l ly i n b o i l ch 3 - n - c - n in g CHC13 ) ch 3- n - c - N^ C a f fe in e (POClj (P0C1 3 + PC15 a t l6 0 ° ) o r (C la a t 200 ®) (C l 2 a t 100°) CHa-N - C=0 i t CH3-N - C=0 i i o=c c - n - ch 3 I « ^ c -C l CEaCl-N - C - NX 3, 8-Dichlorcaffeine c e 3- n t c - n -c h 3 " '.C-Cl H-N - C - N 8 -C h lo rp a ra x a n th in e 0=C ^ R e d u c tio n ) CHa-N - C=0 i i c - n -ch 3 o=c C-H H-N - C - N P a r a x a n th in e I c - n -c h 2c i " 'c - c i CHa-N - C - N 7 , 8 - D ic h lo r c a f f e in e o=c I C la a t l 6 o ° ) CHaCl-N - C=0 i i 0 =C C - N-CHaCl • " 'c - C l CH2 C1-N - C - N* T e t r a c h lo r c a f f e i n e I- (A c e tic A c id ) (Hs0) (Ha0) I .CHs-N - C=0 t i - c= o 8 - C h lo r c a f f e in e ch 3- n - c= o I 0=0 C - N-H » " ^G-Cl ch 3- n - c - n / 8-C h lo r th e o p h y l1in e I H-N - 0=0 i i o=c t C - N-H " C-Cl H-N - C - N" 8 -C h lo rx a n th in e |lle d u ct io n ) ^(R ed u ctio n ) CH3-N — c=o I I H-N - C=0 i t 0=c C - N-H i « ^C-H CHs-N - C - N* T h e o p h y llin e 0 =C i C - N-H " ' C_H H-N - C - n ' X an th in e 31 H a lo g e n a tio n o f c a f f e in e u s u a l l y in v o lv e s th e re p la c e m e n t o f th e hydrogen atom in th e e ig h th p o s i t i o n . However, t e t r a c h l o r - c a f f e i n e may he produced hy re p la c e m e n t o f a h y d ro g en i n each m eth y l g ro u p , A scheme show ing th e c h l o r i n a t i o n o f c a f f e i n e hy d i f f e r ­ e n t m ethods fo llo w e d hy t h e i r r e d u c tio n to t h r e e l e s s m e th y la te d x a n th in e s i s g iv e n on page 30. A. THE PREPARATION OP THE 8-HALOCAFFEINE COMPOUNDS. 1. 8 - C h lo r c a f f e in e was p r e p a re d hy R o c h le d e r^ 2 ) hy th e a c ti o n o f g a se o u s c h lo r i n e on c a f f e i n e su sp en d e d i n w a te r. I n a s i m i l a r m anner th e same p ro d u ct was o b ta in e d when a h y d r o c h lo r ic a c id s o l u t i o n c o n ta in in g c a f f e in e w ith p o ta s s iu m c h lo r a te was h e a te d t o 5^ °^ . T hese m ethods w ere n o t v e ry p r a c t i c a l f o r h ig h y i e l d s b e c a u se o f d e c o m p o sitio n r e s u l t i n g from th e e x c e s s o f c h lo r in e p r e s e n t i n th e w a te r s o l u t i o n , P i s c h e r d e s c r ib e s o t h e r m ethods (3 ) f o r p r e p a r in g c h l o r c a f f e i n e . One c o n s i s t s i n p l a c i n g w e ll d r ie d and f i n e l y p u lv e r iz e d c a f f e i n e i n a t h i n l a y e r on a g l a s s p l a t e , th e n p a s s i n g a r a p i d s tre a m o f d ry c h lo r in e gas o v e r i t . The r e a c ti o n s t a r t s when c o ld ; how­ e v e r , a s soon a s much e v o lu tio n o f h y d r o c h lo r ic a c id i s o b s e rv e d , th e te m p e ra tu re r i s e s to 3 0 -4 0 °. When th e r e a c t i o n i s c o m p le te , th e lumpy mass i s f i n e l y p u l v e r i z e d , th en wanned on an o i l h a th a t 75” 2 0 °. C h lo r in a tio n i s c o n tin u e d u n t i l h y d r o c h lo r ic a c id g as i s no lo n g e r e v o lv e d . The s l i g h t l y c o lo r e d raw p ro d u c t i s f r e e d from e x c e s s c h lo r in e hy a d d in g a c o n c e n tr a te d s o lu t i o n o f s u lf u r o u s a c id a f t e r d i s s o l v in g th e c h l o r c a f f e i n e i n c o n c e n tr a te d h y d r o c h lo r ic a c id . By th e a d d it io n o f w a te ^ most o f th e c h lo r c a f f e i n e p r e c i p i t a t e s o u t i n w h ite , m ic ro s c o p ic c r y s t a l s , w h ile th e unchanged c a f f e in e rem ain s in s o l u t i o n . By e v a p o ra tin g t h e h y d r o c h lo r ic a c id from th e f i l t r a t e , th e n r e d i s s o lv i n g th e r e s id u e i n h o t w a te r, a se co n d c ro p o f c r y s t a l s may he o b ta in e d . P o r com plete p u r i f i c a t i o n , th e p ro d u c t i s r e ­ c r y s t a l l i z e d from h o t w a te r. In c o o p e ra tio n w ith R e e se , F is c h e r ( 4 ) dev elo p ed a s t i l l b e t t e r m ethod f o r p r e p a r in g c h l o r c a f f e i n e . One p a r t o f c a f f e in e ( d r i e d a t 120°) i s d is s o lv e d in e ig h t p a r t s o f d ry c h lo ro fo rm . T h is s o l u t i o n i s th e n p la c e d i n a f l a s k f i t t e d w ith a r e f l u x c o n d e n se r, an d c h l o r i n a t e d by p a s s in g i n d ry c h lo r in e g as w h ile th e c h lo ro fo rm i s k e p t a t th e b o i l i n g p o i n t . In o r d e r to in s u r e th e c h lo r in e b e in g f r e e from watery th e g as i s p a s s e d t h r u c o n c e n tr a te d s u l f u r i c a c id th e n phosphorus p e n to x id e . A f t e r a s h o r t tim e , some h y d ro ­ c h l o r i c a c id s a l t o f c a f f e in e b e g in s to s e p a r a te o u t o f th e c h lo ro fo rm s o l u t i o n . Upon c o n tin u in g th e c h l o r i n a t i o n , th e p r e c i p i t a t e g r a d u a lly d i s a p p e a r s , r e s u l t i n g i n a v i g o r ­ ous e v o lu tio n o f h y d r o c h lo r ic a c id gas e s c a p in g th ro u g h th e c o n d e n se r. The c h lo r c a f f e i n e , b e in g a v e ry weak b a s e , i s n o t a b le to combine and h o ld b ack th e h y d r o c h lo r ic a c id g a s . As soon a s th e e v o lu tio n o f h y d r o c h lo r ic a c id gas s to p s and th e s o l u t i o n a g a in becomes c l e a r , th e r e a c t i o n i s c o m p le te . F i f t y grams o f c a ff e in e w e r e c h lo r i n a t e d in t h i s way in t h i r t y m in u te s . One can o f c o u rs e u s e any g r e a t e r amount i n p r a c t i s e w ith a s e f f i c i e n t r e s u l t s . The c h lo ro fo rm i s d i s t i l l e d o f f on a w a te r h a th . The d i s t i l l a t e i s fo u n d s u i t a b le to u s e d i r e c t l y f o r a second c h lo r i n a t io n i f d e s ir e d . The c h l o r c a f f e i n e rem a in s a s a w h ite , c r y s t a l l i n e mass upon e v a p o ra tin g o f f th e c h lo ro fo rm , and i s f r e e d from t r a c e s o f th e s o lv e n t by h e a tin g i n a sh a llo w d is h . I t i s f i n a l l y d ig e s te d i n a sm a ll q u a n ti ty o f w a te r. The1 p ro d u c t so o b ta in e d by F is c h e r and R eese was snow w h ite and c h e m ic a lly p u r e . The y i e l d was n e a r l y q u a n t i t a t i v e . (1 ): (2 ): (3 ): (4 ); E. F is c h e r & F . Ach. B e r. 3 9. 4-23, 1906. J a h r e s b e r . f . Chem. U. S. w. f . 435, 1850. E. F i s c h e r . Ann. 2 1 5 , 2 5 3 , 1882, E. F i s c h e r ,a n d R eese. Ann. 221, 3 3 6 , I 883 . 32 F o r th e t r a n s f o r m a tio n o f c h lo r c a f f e i n e i n to e th o x y and h y d ro x y c a ffe in e th e same m ethods were recommended a s a r e u se d i n th e c a se o f b ro m c a ffe in e . The p r e p a r a t i o n o f th e s e compounds was c o n s id e r a b ly s im p l if ie d "by th e u s e o f th e s e m ethods em ploying c h l o r c a f f e i n e . A n other m ethod d e s c r ib e d by Fischer^-*-) c o n s i s t s i n h e a t ­ i n g an h y d ro u s c a f f e i n e w ith t h r e e volum es o f pho sp h o ru s p e n ta c h lo r id e i n an o i l b a th a t 1 5 0 - l6 0 o \ m t i l a l l o f th e pho sp h o ru s p e n ta c h lo r id e h as d i s t i l l e d o f f . A r e s id u e rem ain ­ in g c o n s i s t s f o r th e m ost p a r t o f c h l o r c a f f e i n e . C h lo r c a f f e in e m e lts a t 188®. I t I s e a s i l y s o lu b le i n s tr o n g a c id s b u t i s a g a in p r e c i p i t a t e d u n changed by th e a d d it io n o f w a te r . In c o ld w a te r and i n e t h e r i t i s v e r y d i f f i c u l t l y s o l u b l e , b u t i t i s more s o lu b le i n h o t w a te r and s t i l l more s o lu b le i n h o t a lc o h o l . C h l o r c a f f e i n e i s tra n s fo rm e d back to c a f f e in e by n a s c e n t hydrogen i n an a c id s o lu ­ t i o n . T h is i s a c c o m p lish e d by d i s s o l v in g c h lo r c a f f e i n e i n 20^ h y d r o c h lo r ic a c id and a d d in g a s m a ll amount o f z in c d u s t w h ile sh a k in g u n t i l a t e s t shown by a d d in g w a te r f a i l s to g iv e a p r e c i p i t a t e . 2. S -B ro m c a ffe in e . T h is compound was f i r s t p r e p a re d by 0. S c h u ltz e n by warming c a f f e i n e w ith brom ine on a w a te r b a th . T h is m ethod, how ever, gave a sm all y i e l d as th e te m p e ra tu re was to o low and th e d i f f i c u l t y i n rem oval o f e x c e ss brom ine made t h i s method o f l i t t l e p r a c t i c a l im p o rta n c e . F i s c h e r d e v e lo p e d th e fo llo w in g m e th o d O ) : Ten -p arts o f w e ll d r ie d c a f f e in e a re a,dded by s h a k in g to 50 p a r t s o f c o ld , d ry brom ine. F i r s t , a s was a ls o p o in te d o u t by S h u ltz e n , a d a rk r e d brom ine a d d it io n p ro d u c t i s form ed. A f t e r th e r e a c t i o n i s a llo w e d to b e c o m p le te d i n tw e lv e h o u r s , th e brom ine i s d i s t i l l e d o f f on a w a te r b a th . The r e s i d u e i s h e a te d to I 5O0 on an o i l b a th u n t i l th e m ost o f th e hydro c h l o r i c a c i d i s evolved* The r e s i d u e re m a in in g a s a r e d c o lo re d mass i s t r e a t e d w ith c o n c e n tr a te d s u lf u r o u s a c i d , and w h ile s h a k in g , a r a p id s tre a m o f s u l f u r d io x id e gas i s ru n i n to th e m ix tu re . The p u ro o s e o f t h i s •procedure i s to decompose th e a d d it io n a l p ro d u c t o f b ro m c a ffe in e and b ro m in e . TM s r e d u c tio n i s c o n tin u e d u n t i l th e s o l i d m ass i s e n t i r e l y b ro k en up and th e s o l u t i o n i s c o m p le te ly c o l o r l e s s when wanned on th e w a te r b a th . H ere one must u s e c a re t h a t th e s u lf u r o u s a c id i s in e x c ess i n o r d e r to p re v e n t th e o x id a tio n by th e brom ine in w a te r a t a h i g h e r te m p e ra tu re . The g r e a t e s t p a r t o f th e b ro m c a ffe in e rem ain s by t h i s p ro c e d u re a s a w M te , c r y s t a l l i n e m ass. The p a r t re m a in in g i n s o lu t i o n may b e p r e c i p i t ­ a te d by th e a d d it io n o f w a te r. From 50 p a r t s o f c a f f e in e 5 6 -5 8 p a r t s o f b ro m c a ffe in e w ere o b ta in e d by F is c h e r by t h i s m ethod, o r about SCK o f th e t h e o r e t i c a l y i e l d . T his c ru d e p r o d u c t may b e u s e d d i r e c t l y f o r th e p r e p a r a ti o n o f l a t e r d e s c r ib e d compounds. F o r c o m p le te p u r i f i c a t i o n i t i s b e s t to d i s s o l v e i t in h o t c o n c e n tra te d h y d r o c h lo r ic a c i d , th e n p r e c i p i t a t e i t w ith w a te r. A more r e c e n t m ethod f o r th e p r e p a r a ti o n o f b ro m c a ffe in e i s t h a t d e s c r ib e d by Y e isu k e Y o s k i to m i ^ ) . He u se d c a lc u la t e d am ounts o f brom ine and th u s a v o id e d th e d i f f i ­ c u l t i e s e n c o u n te re d by S c h u ltz e n and F i s c h e r . The p ro c e d u re i s a s f o llo w s ! a t h r e e l i t r e , t h r e e n ecked f l a s k i s f i t t e d w ith a s t i r r e r , s e p a r a to r y f u n n e l, th erm o m eter, and (1 ): (2 ): (3 ): 00: F . F i s c h e r . Ann. 215, 253. 1882. Z e i ts c h r , f . Chem. 6lU , 1,367 . U n tersuchungun i n d e r P u rin g ru p p e , p . 9 3 , J . Pharm. 8 0 c. Ja p an Ho. 5^8, U6o_9, 192^; and C. A, I S , 3 I 7 U, 1 9 ^ . 33 r e f l u x c o n d e n s e r. I n to t h i s f l a s k i s u u t 100 g. o f anhydrous c a f f e i n e , 300 g. o f d ry ca rb o n t e t r a c h l o r i d e , 70 O g, 0f d ry n itr o b e n z e n e . Through th e s e p a r a to r y fu n n e l i s ad d e d , w h ile s t i r r i n g , drop hy d ro o , a m ix tu re o f 9^ g. o f brom ine and 60 g. o f n i t r o ­ b e n z en e a t th e r a t e o f f o u r te e n drons n e r te n se c o n d s. The te m p e ra tu re i s m a in ta in e d a t 1 0 3 °, d u r in g t h i s a d d it io n and f o r one to two h ours a f t e r . Then th e m ix tu re i s steam d is tille d . The l i g h t e r c o lo re d carb o n t e t r a c h l o r i d e goes o v e r f i r s t and th en th e d a n k e r c o lo r e d n itr o b e n z e n e w i l l fo llo w . At t h i s p o in t w h ite c r y s t a l s s e p a r a te o u t. The t>rod u c t i s rem oved on th e s u c tio n f i l t e r and d r ie d . The m o th er l i q u o r i s e v a p o ra te d and a seco n d c ro p o f c r y s t a l s i s s e c u re d . The y i e l d was found to be 85-901. The m e ltin g n o i n t was 20 6 °. T h is f a c t , t o g e t h e r w ith th e s u c c e s s f u l p r e p a r a ti o n o f 8 - e th o x y c a f f e in e by t r e a t i n g th e b ro m c a ffe in e w ith a lc o h o l ic p o ta s h , p ro v e s th e compound to be S-brom c a f f e i n e and th e same compound a s was p r e p a r e d by S c h u ltz e n and F i s c h e r 0 By u s in g t h i s m ethod th e bad o d o r i s n o t e n c o u n te re d , and th e tim e o f r e a c t i o n i s s h o rte n e d . B ro m c a ffe in e m e lts a t 2 0 6 °, I t i s v e ry d i f f i c u l t l y s o lu b le i n h o t w a te r and a lc o h o l . I t i s m ost e a s i l y d is s o lv e d in c o n c e n tra te d h y d r o c h lo r ic a c id o r in g l a c i a l a c e t i c a c id . I t g iv e s th e m urexide r e a c ti o n w ith c h lo r in e w a te r. As w ith c h l o r c a f f e i n e , by t r e a t i n g w ith a l c o h o l i c ammonia in a c lo s e d tu b e , a m in o c a ffe in e i s p ro d u ce d . A lso by t r e a t i n g w ith a lc o h o l ic p o ta s s iu m o r sodium h y d ro x id e , e th o x y c a ffe in e i s form ed. A new d e c o m p o sitio n p r o d u c t o f a h a lo c a f f e in e was made by Y oskitom i and K. M yrana g a (l). In an a tte m p t to p ro d u ce h y d ro x y c a ffe in e from c a f f e in e w ith o u t g o in g th ro u g h e th o x y c a f f e in e , a l k a l i n e tr e a tm e n t u n d e r h ig h p r e s s u r e was t r i e d , B ro m ca ffe in e ( 1 1 .2 g. ) and UO g. o f l .N . p o ta s s iu m h y d ro x id e were h e a te d a t 1^0® in a s e a le d tu b e f o r e ig h t h o u r s . W hite n e e d le s h a v in g a h y d r o x y c a f fe in e - 1 ik e a u p e a ra n c e w ere o b ta in e d , w hich, how ever, m e lte d a t 321® i n s t e a d o f 3^5°» U n lik e th e h y d r o x y c a f fe in e , th e y w ere i n s o l u b l e i n w a te r o r a l k a l i , b u t d is s o lv e d e a s i l y i n a c id s . T h is compound gave no m u rex id e r e ­ a c tio n . I t h a s th e m o le c u la r fo rm u la o f CjoHisUeOs and c o n ta in e d e i t h e r an amino o r im ido g ro u p . ’Then t r e a t e d w ith brom ine i n anhydrous a c e t i c a c id i t gave c h o le s tro p h a n e and ammonium b ro m id e. T h is new compound i s p ro b a b ly h y d ra z o d im e th y lh y d a n to in . H H I I CH3 - N - C C - N - CH \ 3 3 / 0 = C \ CH„ 3 - N - C - N, - N| - C - N H ch3 _ H By r e p e a ti n g t h i s e x p e r i m e n t w i t h h a lo c a f f e in e and 1 N, p o ta s s iu m h y d ro x id e ( l m ole) in an a u to c la v e a t 100-1 ^40° Y oskitom i o b ta in e d h y d ro x y c a ffe in e and a new com­ pound, CgHisHeOs w hich m e lte d a t 321 ®. GH.s-N - G-Q 5 s 0=0 G - I-GH 3 8 " > - g “ CHs CH3 -N - 0 - N M ethylami n o c a ff e in e I t c o n ta in s an amino g ro u p , g iv e s th e m urexide r e a c t i o n , a ls o parab am ic a c id on o x i d a t io n . Hence Y oskitom i c la im s t h i s new compound to be m e th y la m in o c a ffe in e . ( 1 ) j J 0 Pha.:na„ Soc, Ja p an No. 52 7» 1926; G» A. 2 0 , 282b ■] „ 1926 . ( 2 ) ; J . Pharm. Soc. Ja p an No, U9 , 2 5 2 -4 , 1 9 2 9 . 3^ 3. 8-Iodocaffeine. Y o s k i t o m i ^ ) d e v e lo p e d a v e ry s a t i s f a c t o r y m ethod f o r th e p r e p a r a ti o n o f io d o f e i n e . Ten g . o f d ry c a f f e i n e and 17 g . o f d ry i o d in e ( c a l c u l a t e d am ounts a r e 10 g, o f c a f f e i n e to 1 3 . l 6 g. o f io d in e ) a r e p u t i n a c lo s e d tu b e and h e a te d a t 150 ° f o r s i x h o u r s . A f t e r th e tu b e i s opened, and th e p r e s s u r e reduced* th e p u r p li s h - b l a c k c r y s t a l s fo rm . The c r y s t a l s a r e d i s s o lv e d i n a lc o h o l th e n d i s t i l l e d * th e g r e a t e r p a r t o f th e io d in e b e in g d r iv e n o f f w ith t h e a lc o h o l. The r e s id u e i s d r ie d on a p o r c e l a i n p l a t e , th e n w ashed w ith s u lf u r o u s a c id . The w h ite c r y s t a l s a r e s u c ti o n f i l t e r e d and r e c r y s t a l ­ l i z e d from a lc o h o l . W hite, b e a u t i f u l c r y s t a l l i n e n e e d le s a r e o b ta in e d w hich have a m e ltin g p o i n t o f 218 - 219 ®. I f i o d o c a f f e i n e i s t r e a t e d w ith 20° w arn h y d r o c h lo r ic a c id and pow dered p a lla d iu m , th e r e a c t i o n i s r e v e r s e d , and c a f f e in e i s o b ta in e d . When i o d o c a f f e in e iB t r e a t e d w ith a l c o h o l i c p o t a s h , e th o a y c a f f e in e i s p ro d u c e d , a s w ith brom o r c h l o r c a f f e i n e . B. THE DICHLOBCAFFEINE COMPOUNDS. 1. 7s 8 - D i c h l o r c a f f e i n e . For th e p r e p a r a ti o n o f t h i s d e r i v a t i v e , 1 p a r t by w e ig h t o f d ry 8 - c h l o r c a f f e i n e p lu s 0 ,3 9 p a r t by w e ig h t o f c h lo r i n e g as a r e h e a te d i n a c lo s e d tu b e i n th e p r e s e n c e o f a b o u t 4 .3 ^ volum es o f p h o sp h o ru s o s y c h lo r id e a t 100° f o r n in e h o u r s . The p h o sp h o ru s p s y c h l o r i d e i s rem oved by e v a p o ra tin g u n d e r g r e a t l y re d u c e d p r e s s u r e , le a v in g a p r a c t i c a l l y c o l o r l e s s r e s i d u e . T h is i s d is s o lv e d i n a b o u t 17 volum es o f h o t m eth y l a lc o h o l. A f t e r c o o lin g to 0 ° , th e p ro d u c t c r y s t a l l i z e s o u t a s f in e c o l o r l e s s n e e d le s . A f t e r a seco n d r e c r y s t a l l i z a t i o n from m eth y l a lc o h o l, F i s c h e r found th e m e ltin g p o i n t t o b e 1^9-151® ( 15 O. 5 to 1 5 2 .5 c o r r . ) . By e v a p o ra tin g down th e m o th er l i q u o r each tim e , to s e c u re a s e c o n d c ro p , a b o u t a 70$ y i e l d was o b ta in e d . In th e m ethod o f Y iesuke Y o s k ito m i^ ) th e f o llo w in g p ro c e d u re was d e v e lo p e d : C a f f e in e (150 g . d r ie d a t 1 2 0 ° ) 'i s added to a s o lu t i o n o f 750 g . o f d r y carbon t e t r a ­ c h lo r i d e and 750 g . d ry n itr o b e n z e n e and 1 g , o f io d in e a s a c a t a l y s t c o n ta in e d i n a 5 l i t e r t h r e e n eck ed b a llo o n f l a s k f i t t e d w ith a s t i r r i n g a p p a r a tu s . W hile h e a tin g a t th e b o i l i n g p o in t o f th e m ix tu re ( 93 ° ) d ry c h lo r in e g a s i s p a s s e d i n f o r ab o u t t h r e e h o u r s , o r u n t i l th e con ten tsb eco m e r e d d is h brown i n a t r a n s p a r e n t l i q u i d . C a r b o n te tr a c h l o r i d e and n itr o b e n z e n e a r e removed by d i s t i l l i n g u n d e r re d u c e d p r e s s u r e . The r e s id u e c o n s i s t i n g o f th e p ro d u c t and a sm a ll amount o f th e s o lv e n ts i s c r y s t a l l i z e d o u t o f h o t m eth y l a lc o h o l. Y eisuke Y oskitom i fo u n d th e m e ltin g p o i n t to be 1^5° t and y i e l d s from 85 to 90$. I f i t i s d e s ir e d to p r e p a r e S - c h lo r th e o p h y llin e th e s o lv e n ts a r e removed by ste a m d i s t i l l a t i o n w hich h y d ro ly z e s th e J, S - d ic h i o r c a f f e in e . 7 , 8 - d i c h l o r c a f f e l n e m e lts a t 1 5 0 .5 t o 1 5 2 .5 ° ( c o r r , ) . I t i s v e ry r e a d i l y s o lu b le i n g l a c i a l a c e t i c a c id , somewhat more d i f f i c u l t l y s o lu b le i n h o t a lc o h o l (8 p a r t s ) , and s o lu b le i n a b o u t JO p a r t s o f h o t w a te r. I t i s r e a d i l y s o lu b le i n b e n z e n e , b u t v e ry s l i g h t l y s o lu b le i n p e tro le u m e t h e r . I t i s n o t changed by h e a tin g f o r many h o u rs i n m e th y l a lc o h o l to m e th o x y c a ffe in e , b u t a c o n s id e r a b le amount o f c h lo r th e o p h y llin e i s form ed. T h is change ta k e s p l a c e much more r e a d i l y i n an aqueous s o l u t i o n . I t in v o lv e s ( 1 ) : J . Fharm. Soc. Jap an 5OS, h 6 0 -9 , I 92 IJ- 5 ; C.A. 1 8 , 317 U, 192U. ( 2 ) : E. F is c h e r .a n d F, Ach. B er. 3 9 , U2 3 , 1 9 0 6 . ( 3 )2 Y eisu k e Y o sk ito m i, J . Pharm. Soc. J a p a n , No, 5§s ^ 6 0 -9 . 192^S 0. A. I S , 317^, 1 9 2 ^ 35 th e s p l i t t i n g o f f o f th e c h lo im e th y l group "by th e l i b e r a t i o n o f h y d r o c h lo r ic a c id sa d fo rm a ld e h y d e , a s f o llo w s : CH3-N - C=0 ' ' Ha 0 0=C C - N-CHaCl -----' " ,C-C1 ( h e a t) CHs-N - C - n ' 7 . S -d ic h lo rc a ffe in e 2. CH3 -N - C=0 ' » * 0=C C - N-H • " ^C -C l CHs-N - C - N* g - C h lo rth e o p h y llin e H + HC1 + EC=0 3* 8- D i c h l o r c a f f e i n e . ^ Two m ethods were d e v e lo p e d by F i s c h e r and Ach f o r th e p r e p a r a ti o n o f t h i s compound. In th e f i r s t method^ 23 p a r t s o f d ry c h lo r c a f f e i n e and 30 p a r t s ( 1 ,5 m o les) o f ph o sp h o ru s p e n ta c h lo r id e and 100 volum es o f phosphorus o x y c h lo rid e a r e h e a te d i n a c lo s e d tu b e , o r i n an a u to c la v e a t 158 to l 62 ° f o r t e n to tw e lv e h o u rs . A f t e r c o o li n g , t h e r e i s no p r e s s u r e i n th e tu b e and i n th e red -b ro w n s o l u t i o n t h e r e rem a in s 10 to 15 $ o f unchanged 8- c h l o r c a f f e i n e suspended a s c o l o r l e s s n e e d le s . The s o lu ­ t i o n i s f i l t e r e d and e v a p o ra te d u n d e r g r e a t l y reduced p r e s s u r e p r a c t i c a l l y to d r y n e s s . The r e s id u e i s th e n d is s o lv e d i n c h lo ro fo rm . In o rd e r to decompose th e unchanged p h o s­ p h o ru s p e n ta c h lo r i d e , th e c h lo ro fo rm s o l u t i o n i s shaken w ith w a te r and a g a in e v a p o ra te d to a s y ru p . The l a t t e r i s d is s o lv e d i n d ry e t h e r , and c o o le d u n t i l th e d i c h l o r c a f f e i n e s e p a r a te s o u t i n w a rt-s h a p e d c r y s t a l a g g re g a te s . These a r e f r e e d from th e a d h e rin g sy ru p by w ash in g w ith benzene and th u s made c o l o r l e s s . About a 30 $ y i e l d can b e o b ta in e d ,, The seco n d m ethod in v o lv e s th e u s e o f carbon t e t r a c h l o r i d e i n s t e a d o f p h o sp h o ru s o z y c h lo r id e and c h l o r i n a t i o n i s a cco m p lish ed a t th e l a s t by f r e e c h lo r i n e gas i n an open v e s s e l . A v ig o ro u s s tre a m o f c h lo r in e g a s i s p a s se d i n t o th e m e lte d c a f f e i n e w ith c o n s ta n t s t i r r i n g . At f i r s t th e te m p e ra tu re i s h e ld a t 2 0 0 °, l a t e r when th e mass becomes t h i n n e r th e te m p e ra tu re i s lo w e re d to 170®. From 1 ,2 to 1 ,5 m oles o f c h lo r in e i s u s u a l l y n e c e s s a r y , A y i e l d o f 18$ o f th e p u r i f i e d compound was o b ta in e d by F i s c h e r , I t was n o t c o n s id e r e d a s good a p ro c e d u re a s th e f i r s t one d e s c r ib e d , 3 , S - d i c h lo r c a f f e i n e m e lts a t l4 h to 1 ^ 5 ° (lb -5 to l h 6 ° c o r r . ) . I t i s r e a d i l y s o lu b le i n c o ld c h lo ro fo rm , benzene and. a c e to n e and a c e t i c e s t e r , and a l s o i n w arn e t h e r an d a lc o h o l . I t c r y s t a l l i z e s o u t in th e fo n n o f w a r t- s h a p e d ,c o a le s c e d n e e d le s . I t g iv e s th e m urexide r e a c t i o n . The f i l t r a t e a f t e r c r y s t a l l i z i n g o u t o f an e t h e r s o l u t i o n c o n ta in s some t r i c h l o r c a f f e i n e . T h is s e p a r a te s o u t on lo n g s ta n d in g . Upon r e c r y s t a l l i z i n g o u t o f b e n z e n e , c o l o r l e s s n e e d le s a re o b ta in e d o f th e t r i c h l o r c a f f e i n e . By h y d r o ly s i s an d r e d u c t i o n . 3 , 8- d i c h l o r c a f f e i n e i s c o n v e rte d i n to p a r a x a n th in e , C. TETRACHLORCAFFEINE. (2 ) Twenty p a r t s by w eig h t o f 7» 8- d i c h l o r c a f f e i n e , 1 3 . ^ p a r t s by w e ig h t o f c h lo r i n e and 110 volum es o f phosp h o ru s o x y c h lo rid e a r e h e a te d i n ah a u to c la v e f o r tw e lv e h o u rs ©t 160 to 162®. A f t e r c o o lin g , t h e r e i s v e ry l i t t l e p r e s s u r e i n th e a u to c la v e . The m ix tu re i s e v a p o ra te d a t ab o u t ^5° u n d e r ab o u t 15-20 mm. p r e s s u r e . The y e llo w is h brown r e s i d u e i s d is s o lv e d i n h o t b e n z en e . From a r a t h e r c o n c e n tra te d s o lu tio n , l i g h t y e llo w c r y s t a l s ( 1 ) : E. F i s c h e r & F. Ach. ( 2 ) : E. F i s c h e r & F . Ach. B e r. 3 9 , ^ 3 , 1906 . B e r. 3 9 , 1*23, *906. 36 s e p a r a t e o u t upon c o o lin g . These a r e s u c ti o n f i l t e r e d , washed w ith w a te r and d r ie d a t room te m p e r a tu r e . The p ro d u c t i s r a t h e r im p u re. I t i s p u r i f i e d hy d i s s o l v i n g i n a b o u t 10 volum es o f e t h e r and c l a r i f i e d w ith a n im al c h a r c o a l. A f t e r c o n c e n tr a tin g th e s o lu ­ t i o n down somewhat i t i s c o o le d i n i c e . P u re t e t r a c h l o r c a f f e i n e s e p a r a t e s o u t i n s m a ll c o l o r l e s s c r y s t a l s . About a 60$ y i e l d was o b ta in e d by P i s c h e r . P o r a n a l y s i s i t i s n e c e s s a r y to c r y s t a l l i z e th e second tim e o u t o f e th e r an d th e n d ry i n a vacuum d e s s i c a t o r . T e t r a c h l o r c a f f e i n e m e lts a t 1 2 S .0-129.5® ( 129 . 0 - 1 3 0 . 5 ® C o r r .) to a c o l o r l e s s l i q u i d . I t d i s s o l v e s r e a d i l y i n a c e to n e , g l a c i a l a c e t i c a c i d , b e n z e n e , and r a t h e r e a s i l y i n a lc o h o l . I t i s s o lu b le i n a b o u t Uo p a r t s by w eight o f warm e t h e r , and c r y s t a l l i z e s o u t a s m ic ro s c o p ic p l a t e l e t s . I t d is s o lv e s i n about 100 p a r t s o f h o t w a te r w hich soon c a u s e d e c o m p o s itio n w ith th e l i b e r a t i o n o f form alddayde and h y d r o c h lo r ic a c id . llKhen p r e p a r e d d i r e c t l y from S - c h lo r c a f f e in e a s m a lle r y i e l d and a l e s s p u re p r o d u c t i s o b ta in e d . IV. ETHER COMPOUNDS OP CAFPEINE. A. The 8 -M o n o -A lk y l-E th e rs o f C a f fe in e , 1. 8 -M ethoxy c a f f e i n e , o r 1 , 3 . 7“ t r i m e t h y l , 2 , 6 - d io z y , S -m e th o z y -p u rin e was p r e ­ p a r e d by P i s c h e r ( l ) by h e a tin g 8 -brom o r S - c h lo r c a f f e i n e w ith p o ta s s iu m o r sodium h y d ro x id e i n m eth y l a lc o h o l. The d e t a i l s o f th e p ro c e d u re a r e i d e n t i c a l w ith th e p r e ­ p a r a t i o n o f e th o s y c a f f e in e w hich i s d is c u s s e d i n more d e t a i l . T h is compound c r y s t a l l i z e s o u t o f w a te r o r a lc o h o l i n s m a ll, w h ite n e e d le s . The m e ltin g p o in t i s 1 7 ^ °. By warming w ith h y d r o c h lo r ic a c i d , i t i s e a s i l y h y d ro ly z e d by h y d r o z y c a f fe in e . M e th o z y c a f f e in e '^ ) h a s a s tr o n g e r p a r a l y t i c e f f e c t on th e c e n t r a l n e rv o u s sy stem th a n c a f f e i n e . At th e same tim e i t i s l e s s s ti m u la ti n g t o th e r e f l e x e s . P o r c l i n i c a l p u rp o s e s i t i s a s s p e c i f i c a l l y a d a p te d a s e th o z y c a ff e in e f o r n e u r a l g ia and f o r c a s e s i n w h ich s t i m u la ti o n i s c o n tr a in d i c a t e d . CHa-N - C=0 CHg-N - C=0 0=C C - N-CHa » " C-Cl CHa-N - C - n ' 8- c h l o r c a f f e i n e + Na-OCHa (h e a t) CHa-N - 11=0 » » 10$ HC1 0=C C - N-CHa -------------•' \w A/«Vf /1___ "II ^C-OCHa ( h e aA t. „ ch3- n - c - n ^ g -m e th o z y c a ffe in e 0=C C - J^CH 3 ' " / C-OCHa CHa-N - C - N/ 8 -m e th o z y c a ffe in e CHa-N - C=0 0=C C - N-CHa ' • V o -H CHa-N - C - / h y d ro z y c a f f e in e M e th o z y c a ffe in e may a ls o be p re p a re d by m e th y la tio n o f h y d ro z y c a ffe in e (1 ): (2 ): B e r. 1 7 , 1785. 18SU. B e r. 30. 569, 1897. Y. y o s k ito m i, J . Kyoto Med. Soc. 1 9 , No. 8-9» 1921. 37 2, S - E th o x y c a f fe in e ,^ B ro m c a ffe in e o r c h l o r c a f f e i n e upon lo n g h e a tin g i n an aqueous p o ta s s iu m o r sodium h y d ro x id e s o l u t i o n , i s c o m p le te ly decom posed. The r e s u l t i n g p ro d u c ts a r e v e ry s o lu b l e , h u t have n o t "been i n v e s t i g a t e d and i d e n t i f i e d . However, t h e r e i s found no t r a c e o f th e s t a b l e h y d r o x y c a f f e in e . A. s im p le r p ro c e d u re ta k e s p la c e hy th e a c ti o n o f brom o r c h lo r ­ c a f f e i n e w ith a l c o h o l i c p o ta s h r e s u l t i n g i n th e rep la ce m e n t o f th e h a lo g e n hy th e eth o x y g ro u p . F o r th e p r e p a r a ti o n o f e th o s y c a f f e in e , JO g. o f f i n e l y p u lv e r iz e d b ro m c a ffe in e a r e h e a te d w ith 200 g . o f 10 $ a lc o h o l ic s o l u t i o n o f p o ta ssiu m h y d ro x id e a t th e b o i l i n g p o in t o f th e a lc o h o l . I n f i f t e e n to tw enty m in u te s , th e b ro m c a ffe in e d is a p p e a r s and i n i t s p l a c e a p r e c i p i t a t e o f p o ta s s iu m brom ide fo rm s. The h p t s o l u t i o n i s f i l t e r e d . E th o x y c a f f e i n e s e p a r a t e s , by c o n s id e r a b le c o o lin g i n a f r e e z in g m ix tu re , f o r t h e m ost p a r t i n t o c o l o r l e s s n e e d le s . T hese a r e f i l t e r e d and washed w ith a l i t t l e c o ld a lc o h o l. From th e m o th er l i q u o r , th e rem a in d e r o f th e p ro d u c t i s o b ta in e d by c a r e f u l n e u t r a l i z a t i o n w ith h y d r o c h lo r ic a c id and e v a p o ra tio n down to a sm a ll volum e. By a d d in g c o ld w a te r to th e r e s i d u e , th e rem a in d e r o f th e e th o x y c a ffe in e s e p a r a te s o u t a s a f a i n t brown c o lo r e d c r y s t a l l i n e m ass. I f i t i s d e s i r e d t o p r e p a r e h y d r o x y c a f fe in e , th e m o th er l i q u o r i s e v a p o ra te d down a f t e r a d d in g an e x c e s s o f h y d r o c h lo r ic a c id . E th o x y c a f fe in e may a ls o be p r e p a r e d by t r e a t i n g th e s i l v e r s a l t o f h y d ro x y c a ffe in e w ith e th y l- io d i& e . F o r co m p lete p u r i f i c a t i o n , th e e th o x y c a ff e in e i s r e c r y s t a l l i z e d o u t o f h o t a lc o h o l o r h o t w a te r, and f i n a l l y d r i e d a t 10 0 ° . The a n a l y s i s f o r t h i s compound p r e p a r e d by E. F is c h e r was a s f o llo w s : Carbon H ydrogen N itro g e n C a lc u la te d 50.^1 5 .9 2 3 .5 3 D eterm ined 50«07 6 .0 7 2 ^ ,0 6 E th o x y c a f fe in e m e lts a t 1^0° and d i s t i l l s a t a h ig h e r te m p e ra tu re , w ith o u t decomp­ o s itio n . I t i s d i f f i c u l t l y s o lu b le i n c o ld a lc o h o l and e t h e r , b u t e a s i l y s o lu b le i n h o t a l c o h o l . I n b o i l i n g w a te r i t m e lts and d i s s o l v e s i n c o n s id e r a b le am ounts. Upon r a p id c o o lin g , i t s e p a r a te s o u t a s f i n e , o i l y d r o p le t s w hich v e ry soon s o l i d i f y fo rm in g a n e t ­ work o f w h ite n e e d le s . T h is compound p o s s e s s e s s l i g h t b a s i c p r o p e r t i e s . I t d is s o lv e s i n d i l u t e h y d ro ­ c h l o r i c a c i d to a c o n s id e r a b le e x te n t and s e p a r a te s o u t unchanged upon th e a d d it io n o f a lk a li. By h e a tin g th e h y d r o c h lo r ic a c id s o l u t i o n o f e th o x y c a f f e in e , d e c o m p o sitio n ta k e s p la c e r a p i d l y w ith th e fo rm a tio n o f c h lo r e th a n e and h y d r o x y c a f fe in e , i n a s i m i l a r m anner a s g iv e n f o r m e th o x y c a ffe in e . 3. S - I s o - A m y l o x y c a f f e i n e .^ T h is compound i s lik e w is e p re p a re d by h e a tin g c h lo r o r b ro m c a ffe in e w ith sodium o r p o ta s s iu m iS e -a m y la te i n a n e x c e s s o f th e iso -a m y l a lc o h o l. I t c r y s t a l l i z e s o u t o f d i l ( 1 ) : E. F i s c h e r . U n tersu cb u n g en i n d e r P u rin g ru p p e , p p . 95-96. E. F i s c h e r . Ann. 215, 2b6, 1882. W. W isliceran s, X o rb er. B e r. 3 5 , 1992* 1902, S chm iedberg. B e r. 3 ^ , 2 5 5 7 , 1901. H. B i l t z , B e r g iu s . Ann. U l i , 5 1 9 , 1917. ( 2 ) : M agnanim i, P r i v i t m a t t h . 38 u t e a lc o h o l i n th e form o f w h ite , s i l k y , l u s t r o u s n e e d le s . Iso -A m y lo x y c a ffe in e i s v e ry s o lu b le i n c h lo ro fo rm . B. The m e ltin g p o in t i s 1 2 9 .5 ° . THE S-MONO-ARYL ETHERS OF CAYFEIiTE. (1) The phenol in t i o n w ith x y le n e a s p r e p a r a t i o n o f th e s e e th e r s i s a c co m p lish e d hy h e a ti n g c h l o r c a f f e i n e w ith a th e p r e s e n c e o f an e q u iv a le n t amount o f p o ta s s iu m h y d ro x id e in an aqueous s o lu ­ r e f l u x i n g , o r u n d e r p r e s s u r e a t a h ig h e r te m p e ra tu re , and a ls o hy th e u s e o f th e s o lv e n t . 1. 8 -P h e n y lo x y c a ffe in e (C 14H14 O3N4 ) (2 ) p r e pa r e d hy h e a tin g t o g e t h e r i n th e p r o p o r t io n s o f I S . 4 g. c h l o r c a f f e i n e , 5 .0 g. p o ta s s iu m h y d ro x id e , S.O g . p h en o l and 5^ g» w a te r u n d e r a r e f l u x c o n d e n se r f o r s i x h o u r s ; o r hy h e a tin g t o g e th e r f o r one h o u r i n a c lo s e d tu h e a t 1 2 0 ° , 2 ,3 g, c h l o r c a f f e i n e , 0 ,7 5 g . p o ta s s iu m h y d ro x id e , 1 .0 g. p h e n o l, and 5 .0 g. w a te r. T h is compound form s n e e d le s from a l c o h o l , w hich m e lt a t 1 U3 .O 0 . I t i s s l i g h t l y s o lu b l e in w a te r , d i f f i c u l t l y s o lu b le i n c h lo ro fo rm and s o lu b le in c o ld c o n c e n tra te d h y d r o c h lo r ic a c id w ith d e c o m p o sitio n . I t i s s t a b l e a ls o i n h o t 15^ aqueous sodium h y d ro x id e . 2. 8 -G u a ic o lo x y c a f fe in e i s p r e p a r e d by h e a ti n g f o r f o u r h o u rs in a c lo s e d tu b e a t l40® th e f o llo w in g m ix tu re : 2 .3 g. c h l o r c a f f e i n e , 1 .2 4 g. g u a ic o l, 0 .7 5 g. p o ta s s iu m h y d ro x id e , and 5 g. w a te r. I t form s c o l o r l e s s n e e d le s from a b s o lu te a lc o h o l , m e ltin g a t I 5I - I 52 0 . I t i s o d o r le s s and h as a s l i g h t l y b i t t e r t a s t e . 3 . 8 -fh y m o lo x y c a ffe in e ( C i s H a s O a ^ ) ^ ) i s made by h e a ti n g f o r t h r e e and o n e - h a lf h o u rs in an a u to - c la v e a t 155 ° . th e fo llo w in g m ix tu re : 23 g. c h l o r c a f f e i n e , 15 g . th y m o l, 15 g, p o ta s s iu m h y d ro x id e , and 375 g* o f x y le n e . I t c r y s t a l l i z e s o u t o f h o t a lc o h o l a s sm all w h ite n e e d le s , and a s k n o b -sh ap ed c r y s t a l s from l i g r o i n . I t m e lts a t I 3 O -I 3 2 0 . 4. 8 - o - C r e s o lo x y c a f f e in e (C 15H16 O3N4 )T his compound i s p re p a re d by h e a tin g t o ­ g e th e r 2 .3 g. c h l o r c a f f e i n e , 1 .1 g. o - c r e s o l , 1 .5 g. p o ta s s iu m h y d ro x id e , and 5 -g . w a te r i n a c lo s e d tu b e a t I 5O0 f o r two h o u rs . I t c r y s t a l l i z e s o u t o f a lc o h o l a s o d o r le s s , a t lp O - l 51°. / ty\ 5. 8 -m -C re s o lo x y c a ffe in e (C 15H16 O3N4 ) is f o r f o u r h o u rs a t 155 ° th e f o llo w in g m ix tu re : 2 .3 1 . 5 g. p o ta s s iu m h y d ro x id e , and 5*0 g. w a te r. It ne d i e s o u t o f d i l u t e a lc o h o l. The m e ltin g p o in t ( 1 ) : A. Baumann, A. Baumann, G-er. P a te n t ( 2 ) : A. Baumann, A. Baumann, t a s t e l e s s , w h ite n e e d le s , w hich m e lt p re p a re d by h e a tin g i n a c lo s e d tu b e g. c h lo r c a f f e i n e , 1 .0 g . m - c r e s o l, forms w h ite , t a s t e l e s s , and o d o r le s s i s l4 4 -l4 5 ® . C. I I , 2 0 3 6 , 1913. Arb, Pharm. J u s t . U niv. B e r lin 1 0, 127-47 2 6 4 , 3 8 9 , S e p t. 27, 1912, B ayer & Co.Mfg. A rch. Pharm. I n s t , U niv. B e r lin 1 0, 1 27-47. C, I I , 2 O3 6 , 1913- 39 6 . 8 - p - C r e s o lo x y c a f f e in e (C jg H ieO sN ^ )(l) i s prep ared , in th e same way as th e mc r e s o l compound. I t form s c o l o r l e s s n e e d le s out o f d i l u t e a lc o h o l. The m e ltin g p o in t i s 1 3 8 -1 3 9 °. 7. 8 -E u g e n o lo x y c a ffe in e ( C ib H b o O ^ O ^ ) i s o b ta in e d hy h e a tin g i n an a u to c la v e f o r s i x h o u rs a t 14-0° th e fo llo w in g m ix tu re : 3*5 §• e u g e n o l, 4 .6 g. c h l o r c a f f e i n e , 4 ,0 g. p o ta s s iu m h y d ro x id e , and 1 5 .0 g. x y le n e . I t c r y s t a l l i z e s from a b s o lu te a lc o h o l a s c o l o r ­ l e s s , t a s t e l e s s n e e d le s , t h a t m e lt a t 119 - 2 2 0 ° . 8. 8 - C a rv a c r o lo x y c a ff e in e (C i 8H2203 N4 ) ( ^ i s p re p a re d by h e a tin g a m ix tu re o f 1 .5 g . c a r v a c r o l , 2 .3 g. c h l o r c a f f e i n e , 1 .5 g. p o ta ssiu m h y d ro x id e and 1 0 .0 g. x y le n e i n a c lo s e d tu b e a t 170° f o r th r e e h o u rs. I t form s w h ite , t a s t e l e s s and o d o r le s s n e e d le s o u t o f d i l u t e a lc o h o l t h a t m e lt a t l4 5 - l 4 6 ° . 9. S-o-O xyphenyl oxy c a f f e in e i s p r e p a r e d by h e a ti n g a m ix tu re o f 1 .5 g . m e t a l l i c sodium i n 120 g. w a te r, 6 .6 g, p y r o c a te c h o l, and 1 3 .8 g. c h lo r c a f f e i n e u n d e r a r e f l u x c o n d e n se r f o r t h r e e and o n e - h a lf h o u rs. I t form s w h ite n e e d le s o u t o f benzene o r w a te r. I t m e lts a t . 21 5 ° . T his compound i s s o lu b le i n d i l u t e c o ld sodium h y d ro x id e i n c o n tr a s t to th e double compound w hich i s form ­ ed a t th e same tim e . The a c e t a t e (C 16H16 O5N4 ) form s c o l o r l e s s n e e d le s o u t o f b e n z e n e , m e ltin g a t 1 8 6 -1 8 7 °. I t i s o d o r le s s and t a s t e l e s s , and in s o l u b l e in d i l u t e sodium h y d ro x id e . 10, 8 - D i c a f f e i n e E th e r o f P y ro c a te c h o l (C22 H23 O6N8 ) i s o b ta in e d by h e a tin g 1 ,1 g. o f p y r o c a te c h o l, 4 ,6 g. c h lo r c a f f e i n e , 1 .5 g. p o ta ssiu m h y d ro x id e , and 3^*0 g* w a te r f o r e ig h t h o u r s , o r by h e a tin g 1 .5 1 g. o f th e m on o caffein e e t h e r o f p y r o c a te c h o l, l , l 4 g. c h l o r c a f f e i n e , 1 .0 8 g. p o ta ssiu m h y d ro x id e , and 3 ^ .0 g. w a te r u n d e r u n d e r a r e f l u x c o n d e n se r f o r f i v e and o n e - h a lf h o u rs. I t form s c o l o r l e s s n e e d le s out o f c h lo ro fo rm and m e lts a t 2 8 0 -2 8 1 °. I t i s i n s o l u b l e i n d i l u t e sodium h y d ro x id e . 11. 8 -Mono c a f f e in e E th e r of E e s o rc in o l (Ci 4H i 404 lT4 ) ^ ^ i s o b ta in e d by h e a tin g t o ­ g e th e r a s o l u t i o n c o n ta in in g 0 .7 5 g» m e t a l l i c sodium i n 40 g. o f w a te r w ith 3*3 g. r e s o r c i n o l and 6 .9 g . c h l o r c a f f e i n e , f o r s i x h o u rs u n d e r a r e f l u x c o n d e n se r. I t form s w h ite , t a s t e l e s s , o d o r le s s n e e d le s from a lc o h o l w hich m e lt a t 1 9 7 °-1 9 S °. I t i s s o lu b le i n c o ld , d i l u t e sodium h y d ro x id e , a lo n g w ith an eq u al amount o f th e d o u b le compound. The a c e t a t e form s o d o r le s s , c o l o r l e s s , t a s t e l e s s , sm all n e e d le s . They m e lt a t 1 2 3 -1 2 4 °; and a r e in s o l u b l e i n sodium h y d ro x id e . /1\ 12. 8 - D i c a f f e i n e E th e r o f R e s o rc in o l (C22 H23 O6N8 ) i s made i n th e same m anner a s th e d i c a f f e i n e e t h e r o f p y r o c a te c h o l. I t c r y s t a l l i z e s o u t o f x y len e p lu s p e tro le u m e t h e r . The m e ltin g p o in t i s 2 8 8 -2 8 9 °. I t i s in s o lu b le i n c o ld d i l u t e sodium h y d ro x id e . 1 3 , 8 -P a ra h y d ro x y p h e n y lo x y c a ffe in e (Ci4Hi 4 04N4 ) ( l ) i s p re p a re d by h e a tin g a s o l u t i o n c o n ta in in g 0 . 5 g. m e t a l l i c sodium in 40 g. w a te r, 2 ,2 g 8 h y d ro q u in o n e , and 4 .6 g. c h l o r ­ c a f f e i n e u n d e r a r e f l u x c o n d e n se r f o r s i x h o u rs . I t. c r y s t a l l i z e s o u t o f a lc o h o l o r w a te r a s c o l o r l e s s , sm a ll n e e d le s t h a t m e lt a t 206-207°, I t i s s o lu b le i n h o t w a te r and c o ld d i l u t e sodium h y d ro x id e . The a c e t a t e form s c o l o r l e s s , t a s t e l e s s , and o d o r le s s n e e d le s o u t o f a lc o h o l. The m e ltin g p o in t i s 2 1 0 -2 1 1 °. The a c e t a t e i s i n s o l u b l e in sodium h y d ro x id e . ( 1 ) : A0 Baumann, A rch. Pharm. I n s t . U niv. B e r lin 1 0, 127-47', C. I I . , 2037, 1913- 4o 14. 8 —d i c a f f e i n e e t h e r o f Hydroqunnone (C22 d 220 &Na)^ i s o b ta in e d in th e same w anner a s th e d i c a f f e i n e e t h e r o f p y r o c a te c h o l. I t form s w h ite n e e d le s when c r y s t a l l i z e d o u t o f a c e t i c a c id w hich m e lt a t 285°. I t i s in s o lu b le i n h o t w a te r and c o ld d i l u t e sodium h y d ro x id e , 15. S -Q x y c a ffe in e Compound o f P a rao x y -B en zo ic A cid (C 15H14 O5N4 ) T h is compound i s o b ta in e d by h e a ti n g a m ix tu re o f 2 ,8 g . o f p a ra o x y -b e n z o ic a c id , 0 .4 6 g. c h lo r c a f f e in s k 3 . g . p o ta s s iu m h y d ro x id e and 6 0 . g. w a te r u n d e r r e f l u x c o n d e n se r f o r e ig h t h o u rs . I t c r y s t a l l i z e s o u t o f w a te r as w h ite , sm a ll n e e d le s t h a t m e lt a t 243-244®. I t i s s o lu b le in d i lu t e a lk a li. I t i s s li g h t ly b i t t e r in ta s te . The O -oxybenzoic a c id and th e m eth y l e s t e r o f s a l i c y l i c a c id do n o t condense w ith c h l o r c a f f e i n e i n th e p re s e n c e o f one e q u iv a le n t w eight o f a l k a l i . H y d ro x y c a ffe in e ca n n o t b e co n densed w ith p h e n o l. The p h e n o l and thym ol compounds o f c a f f e in e a re v e ry s t a b l e in h o t c o n c e n tra te d h y d r o c h lo r ic a c id . By s a t u r a t i n g th e e th e r o r x y len e s o l u t i o n w ith h y d r o c h lo r ic a c id gas, an d su b se q u e n t h e a ti n g i n a c lo s e d tu b e a t l60® , th e s e compounds a r e n o t a f f e c t e d . By h e a ti n g w ith c o n c e n tr a te d aqueous h y d r o c h lo r ic a c id i n a c lo s e d tu b e a t l 60 ®, th e p h e n y lo x y c a f f e in e i s b ro k e n down to p h e n o l and h y d r o x y c a f fe in e . The same d e c o m p o sitio n i s b ro u g h t a b o u t v e ry q u ic k ly w ith a l c o h o l ic sodium h y d ro x id e and a ls o to a l e s s d e g re e by h e a ti n g w ith w a te r. C, OTHER OXYCAFFEIHE COMPOUNDS. 1. 3 -Meth o x y - 8 - C h lo r c a f f e in e ( C g H n ^ O s C l ) ^ i s p r e p a re d by m e re ly h e a tin g 3» 8 - d i c h l o r c a f f e i n e w ith m eth y l a lc o h o l f o r a b o u t t h i r t y m in u te s . A f t e r c o o lin g i n i c e , a t h i c k brown m ass o f c r y s t a l s s e p a r a te o u t. T h is i s c l a r i f i e d w ith an im al c h a rc o a l in m e th y l a lc o h o l , f i l t e r e d , and r e c r y s t a l l i z e d t h e second tim e . About a 20$ y i e l d was o b ta in e d by Ea JT ischer. I t form s l u s t r o u s n e e d le s from m eth y l a lc o h o l, w hich m e lt a t 1 2 9 -1 3 0 °. (130-131° c o r r . ) , b u t s t a r t to s i n t e r a t 12 5 ®. 2 . 7 * S -D ie th o x y c a ffe in e (C 12H18N4 O4 ) & s o l u t i o n of 2 5 . g. o f 7> 8 - d i c h l o r ­ c a f f e i n e i n 280 c c . o f a b s o lu te e th y l a lc o h o l i s added to I 50 c c . sodium a lc o h o la te s o l u t i o n c o n ta in in g 6 . 5 g. o r t h r e e m oles o f m e t a l l i c sodium . By h e a ti n g a s h o r t tim e th e sodium c h lo r i d e s e p a r a te s o u t, b u t th e d i g e s t io n i s c o n tin u e d f o r one h o u r, and th e n th e s a l t f i l t e r e d o f f w h ile h o t. A f t e r th e f i l t r a t e becomes c o o l, f i n e , c o lo r l e s s n e e d le s o f th e 7 . 8 - d ie t h o x y c a f f e i n e s e p a r a te o u t, w hich a r e f i l t e r e d by s u c tio n and w ashed w ith a l i t t l e w a te r to remove t r a c e s o f sodium c h lo r i d e . E. F is c h e r o b ta in e d from 22 to 23 g, o f t h i s d ie th o x y c a f f e in e t h a t m e lte d a t 123-125®. By n e u t r a l i z i n g and evap­ o r a t i n g th e f i l t r a t e u n d e r s t r o n g l y re d u c e d p r e s s u r e , and r e c r y s t a l l i z i n g th e r e s id u e o u t o f h o t w a te r , he o b ta in e d ab o u t one gram m ore. He s e c u re d a t o t a l y i e l d o f 90$ o f t h e t h e o r e t i c a l . The p ro d u c t i s r e c r y s t a l l i z e d o u t o f e t h e r and th e n o u t o f w a te r, and m e lts a t 124-125® ( c o r r . 125 - 12 6 ®), how ever, i t s t a r t s to s i n t e r a t 122 - 12 3 ®. I t i s s o lu b le to th e e x te n t o f 1 g. in "JO cc. h o t e t h e r and 1 g, i n 10 c c . o f a b s o lu te a lc o h o l , 9° c c » o f b o i l i n g w a te r, and in 1250 c c , o f w a te r a t 2 3 ®, I t i s v e ry r e a d i l y s o lu b le i n c o ld benzene and g l a c i a l a c e t a te a c id . In h o t , d i l u t e sodium h y d ro ( 1 ) : A. Baumann. A rch. Pharm. I n s t . U niv. B e r lin 1 0 , 127-147; C, I I . , 2 0 3 7 , 1913* ( 2 ) ; S. F i s c h e r & F . Ach. B e r. 3 9. 423, 1 9 0 6 . E. F i s c h e r . U ntersuchungun i n d e r P u rin g ru p p e , p p. 594-96. In x id e i t 1 b d i f f i c u l t l y s o l u b l e , how ever, i t i s r a t h e r e a s i l y s o lu b le i n h o t , d i l u t e h y d r o c h lo r ic a c id , 3. T e tra m e th o sy c a f f e i n e (C i 3H i 8N40 6 ) ^ . To a s o l u t i o n c o n ta in in g f , 8 g, t e t r a c h l o r c a f f e i n e i n 80 c c . h o t d ry m eth y l a lc o h o l , a s o l u t i o n c o n ta in in g 2 .7 g. m e t a l l i c sodium ( 5 m o les) i n 80 c c . o f m eth y l a lc o h o l i s added. The m ix tu re i s h e a te d a q u a r t e r o f an h o u r on a steam b a t h , th e n f i l t e r e d h o t to rem ove th e sodium c h lo r i d e . I t i s th e n n e u t r a l i z e d w ith a c e t i c a c id and e v a p o ra te d to d ry n e s s u n d e r s t r o n g l y re d u c e d p r e s s u r e . The n e a r l y w h ite c r y s t a l l i n e mans i s r e c r y s t a l l i z e d o u t o f 3^ c c » h o t w a te r. The y i e l d i s a b o u t 5 g . A f t e r a seco n d c r y s t a l l i z a t i o n from w a te r th e m e ltin g p o i n t re m a in s c o n s ta n t a t 118-120° ( 119 - 121 ° c o r r . ) . F o r a n a l y s i s i t i s b e s t to c r y s t a l l i z e o u t o f m eth y l a lc o h o l and th e n o u t o f e t h e r , p e rh a p s s e v e r a l tim e s , t o remove t h e w a te r o f c r y s t a l l i z a t i o n . Then d ry a t 8 0°. T h is compound i s v e ry r e a d i l y s o lu b le i n g l a c i a l a c e t i c a c id , somewhat more d i f f i c u l t l y s o lu b l e i n h o t a lc o h o l , (m eth y l a lc o h o l, 1 g . i n ab o u t 5 c c . ) i s a ls o d i f f i c u l t l y s o lu b le i n c h lo ro fo rm and b e n z e n e . I t i s d i f f i c u l t l y s o lu b le i n e t h e r and s t i l l m ore so i n c o ld w a te r. I n h o t w a te r 1 g , d is s o lv e s i n ab o u t 13 p a r t s . ( l ) ; . E . F is c h e r & F. Ach. B er, 39, U2 3 , 1906, E. F i s c h e r . U ntersuchungun i n d e r P u rin g ru p p e , p , 597. E X P E R I ME N T A L I, H a lo g e n a tio n o f C a ffe in e . II- P r e p a r a tio n o f th e 8 - E th e r s o f C a f fe in e . III, P y r o ly s is & M o le c u lar R earrangem ent o f th e 8 - E t h e r - c a f f e i n e D e r iv a tiv e s , IV. P r e p a r a tio n o f 8 -M ethyl and 8 - E th y l c a f f e i n e . U2 I . HALOGENATION OF CAFFEINE. A. PREPARATION OF S-CHLORCAFFEIEE. CaHglUOaCl. 1. P ro c e d u re . OH3 -N - c=o 1 o=c 1 CH3-N - c=o \ 1 1 c - N—CH3 It 'c -H CHs-N - C - N * C a ffe in e ( a t b . p . o f CHCI3 ) + C la ---------- --- -----------* c - n -ch 3 It Sc -C l + HC1 CH3 -N - c - N* 8 - C h lo rc a ff e in e 0=C t Two m ethods w ere u se d f o r th e p r e p a r a ti o n o f S - c h lo r c a f f e i n e . The f i r s t method c o n s is t e d i n p a s s in g d ry c h lo r in e gas in to a b o i l i n g c h lo ro fo rm s o l u t i o n o f c a f f e in e ( l p a r t o f an h ydrous c a f f e in e ( d r ie d a t 1 2 0 °C .) to 8 p a r t s o f d ry c h lo ro fo rm ) a c c o rd in g to th e m ethod o f E. F i s c h e r ( l ) d e s c rib e d on page 3 1 . f o r th e second m ethod, a m o d if ic a ­ t i o n o f th e m ethod o f Y eisuke , ^ ^ f o r th e p r e p a r a tio n o f 8 - c h l o r t h e o p h y l l i n e , was em ployed, d e s c r ib e d on p a g e T h is c o n s is te d in c h l o r i n a t in g anhydrous c a f f e in e i n a m ix tu re c o n ta in in g 3 p a r t s by w eig h t o f c a r b o n te tr a c h lo r id e and 7 p a r t s o f n itr o b e n z e n e to 1 p a r t o f anhydrous c a f f e i n e i and a sm a ll amount o f io d in e a s a c a t a l y s t ; and k e p t a t th e b o i l ­ in g p o in t o f th e m ix tu re (a p p ro x . 103°)* In b o th m ethods in v o lv e d , th e s o lv e n ts w ere p r e v i o u s ly d r i e d o v e r c a lc iu m c h lo r id e ; and d u rin g th e c h l o r i n a t i o n an e l e c t r i c s t i r r o r was u s e d to in s u r e a more com plete r e a c ti o n . In a l l c a s e s , c h l o r i n a t i o n was sto p p e d im m e d ia te ly a f t e r co m p lete d isa p p e a ra n c e o f c a f f e in e h y d r o c h lo r id e , and th e s o lu t i o n b e ­ came c l e a r . C h lo r in a tio n beyond t h i s p o in t was found to r e s u l t i n a d e c re a s e d y i e l d and th e f o rm a tio n o f a sm a ll amount o f 7» 8 - d ic h l o r c a f f e in e . A f t e r rem oval o f th e s o lv e n t by d i s t i l l a t i o n ( i n th e second method by steam d i s t i l l a t i o n ) th e c ru d e p ro d u c t was c r y s t a l l i z e d from a l a r g e volume o f h o t w a te r in p r e f e r e n c e to d i s s o l v in g in concd. h y d r o c h lo r ic a c id and th e n p r e c i p i t a t i n g th e compound by d i l u t i o n . The l a t t e r m ethod o f p u r i f i c a t i o n d id n o t r e s u l t i n a s com plete re c o v e ry n o r a s p u re a p ro d u c t a s d id th e f i r s t . A sm a ll amount o f d i l u t e s u lf u r o u s a c id was added to th e w a te r u s e d f o r r e c r y s t ­ a l l i z a t i o n i n o r d e r to a v o id any p o s s i b i l i t y o f d eco m p o sitio n due to th e p re s e n c e o f a n y e x c e s s f r e e c h lo r i n e . The p u r i f i e d 8 - c h lo r c a f f e in e was a i r - d r i e d and th e n d r ie d a t 103-110® f o r ab o u t f i v e h o u r s . The aqueous f i l t r a t e was e v a p o ra te d down to a sm a ll volume to p r e c i p i t a t e more o f th e p ro d u c t when c o o le d th u s i n c r e a s i n g th e y i e l d to a sm a ll e x te n t . ( 1 ) ; E. F is c h e r and R e e se . Ann, 221, 3 3 6 , I 8 S3 . ( 2 ) ; Y eisu k e Y o sk ito m i. J . Pharm. Soc. Ja p an , No. 5 8 * U6 O-9 , 192 I+. *3 2. E x p e rim e n ta l D a ta . M a te r ia ls u s e d i n grams A nhydrous c a f f e in e C hlo ro fo rm N itro b e n z e n e C a r h o n te tr a c h lo r id e I o d in e T r i a l s F i s c h e r ’s Method._______ M o d ified Y o s k ito m i's M ethod. 1 s t _____ 2nd 3 rd __________4 th 5 th ___________ 225 300 300 1 50 200 1600 2UOO 2U00 IO 5O 1^00 U50 600 1 ,5 2 .0 Y ie ld , t h e o r e t i c a l a c tu a l p e r c e n ta g e M e ltin g p o i n t , d e te rm in e d " " .c o r r e c t 265 3 5 3 .3 205 7 7 , 3/0 3 0 0 .g 3O3 . I 8 5 . 1 ! $ 8 5 . 7$ 2 3 5 .4 1 3 9 .2 1 9 6 .4 78 . 8$ 83. 5$ 3 5 3 .3 1 7 6 .6 1 8 8 ,0 -1 9 0 .0 ° 1 8 7 .0 -1 8 8 .0 ° 1S6W0 -1 8 7 .0 « 1 8 8 .0 ° A n a ly s is N itro g e n C h lo rin e C a lc u la te d 2 4 . 51 # 1 5 .5 3 $ D eterm ined 2 4 . 05 # 1 5 .4 $ C o n s id e rin g th e s i m p l i c i t y o f th e m ethod, th e p u r i t y o f th e p r o d u c t, and th e h ig h y i e l d s o b ta in e d , F i s c h e r 's m ethod p ro v ed to he th e b e t t e r m ethod f o r t h e p r e p a r a ti o n o f S - c h l o r c a f f e i n e . Y oskitom i fou n d i t p o s s i b l e to p r e p a r e 7» 8 - d i c h l o r c a f f e i n e by u s in g a m ix tu re o f n itr o b e n z e n e and c a r b o n t e t r a c h l o r i d e b o i l i n g a t 93 °• w hereas th e r e s u l t s shown above p ro v e t h a t o n ly th e 8 - c h l o r c a f f e i n e was form ed when a m ix tu re o f th e s e two s o lv e n t s was u s e d w hich b o ile d a t IO 3 0 . T h is b r in g s o u t th e f a c t t h a t th e d e g re e o f c h l o r i n a t i o n o f c a f f e in e i s c o n t r o l l e d by v e ry narrow ra n g e s o f te m p e ra tu re , a s w e ll a s by th e s o l v e n t s , c a t a l y s t s , and c h l o r i n a t i n g a g e n ts u s e d . B. PREPARATION OF 8-BROMCAJFEHIE. CaHgN4 0 2B r. 1. P ro c e d u re . CH3-N - C=0 1 0=c C - N-CE3 h V .H CH3-N - ,C - N C a f fe in e 1 GHa-H - C=0 1 03 * 1 + B r2 ------------------> 1 1 0=C C - N-CE3 ' " ^C-Br CH3-N - C - N 8 -B ro m c a ffe in e + IB r The m ethod o f Y eisuke Y o s k ito m i( l) , d e s c r ib e d on page 3 2 , was u s e d f o r th e p r e p a r ­ a t i o n o f 8 -b ro m c a f f e in e . T his c o n s is te d b r i e f l y , in a d d in g s l i g h t l y m ore th a n one e q u iv a le n t o f d ry brom ine c o n ta in e d in an e q u a l volume o f n itr o b e n z e n e a t th e r a t e o f f o u r te e n d ro p s p e r m in u te to a b o i l i n g s o l u t i o n ( 103 ° ) c o n ta in in g t h r e e p a r t s o f c a rb o n t e t r a c h l o r i d e and seven p a r t s o f n itr o b e n z e n e to one p a r t o f anhydrous c a f f e i n e . The f l a s k was f i t t e d w ith an e l e c t r i c s t i r r e r and a r e f l u x c o n d e n se r. ( l ) j Y eisu k e Y o sk ito m i, J . Pharm. Soc. J a p a n , No. 5s » 4 6 0 -9 , 1924; C.A. 1 8, 3174, 1924. 1* 3 A f t e r th e b r o m in a tio n , w hich to o k a t l e a s t two h o u r s , th e s o lv e n ts and e x c ess ■bromine w ere rem oved from th e p ro d u c t by steam d i s t i l l a t i o n . The c ru d e g -b ro m c a ffe in e w hich s e p a r a te d o u t o f th e aqueous s o lu t i o n was p u r i f i e d by e i t h e r d i s s o l v in g i n a s m a ll amount o f concd, h y d r o c h lo r ic a c id o r 7 Ofi s u l f u r i c a c id and th e n p r e c i p i t a t i n g by a d d in g a l a r g e volum e o f w a te r , o r by m ere ly r e c r y s t a l l i z i n g from a l a r g e volum e o f b o i l i n g w a te r. The l a t t e r m ethod was p r e f e r r e d , a s i t gave b e t t e r y i e l d s and a p u r e r p r o d u c t. The aqueous f i l t r a t e was e v a p o ra te d down to a sm a ll volume to s e c u re a mg-Hnwim y i e l d . The r e c r y s t a l l i z e d 8 - b ro m c a f f e in e was a i r - d r i e d th e n h e a te d a t 105 - 1 10 ® f o r about f i v e h o u r s . 2. E x p e rim e n ta l D a ta ; T r i a l s M a te r ia ls u s e d i n grams A nhydrous c a f f e i n e Dry c a r b o n t e t r a c h l o r i d e " n itr o b e n z e n e Brom ine 1 st 5O.O 1 5 0 .0 350*0 ^7*0 2nd 2 0 0 .0 6 0 0 .0 l^KJO.O 1 8 8 .0 70.3 50.0 281.3 178.7, Yield, theoretical " , actual ” , p e rc e n ta g e 71 *1$ M e ltin g p o i n t , d e te rm in e d " " , c o rre c t ^3*5^ 2O3 .O - 2 O5 .O® 2 0 h .5-206,0® 206, 0° 8 -B ro m c a ffe in e was u s e d in te r c h a n g e a b ly w ith 8- c h l o r c a f f e i n e f o r th e p r e p a r a t i o n o f some o f th e 8 - e t h e r s o f c a f f e i n e , g -a m in o c a ffe in e and 8 - t h i o c a f f e i n e . T h is compound was a ls o s u c c e s s f u l l y p re p a re d by u s in g e q u a l p a r t s o f n itr o b e n z e n e an d c a r b o n t e t r a c h l o r i d e w hich b o i l s a t 93 °* I t was th o u g h t t h a t p e rh a p s t h i s te m p e ra tu re w ould b e f a v o r a b le f o r th e fo rm a tio n o f 7* 8 - d i c h l o r c a f f e i n e , a s i n Y o s k ito m i's m ethod f o r th e p r e p a r a t i o n o f 7 , 8 - d i c h l o r c a f f e i n e . E v id e n tly , th e s u b s t i t u t i o n o f th e seco n d brom ine i n th e c a f f e i n e m o le c u le i s more d i f f i c u l t th a n when th e second c h lo r i n e i s s u b s titu te d . D. PREPARATION OF 8 - IODOCAFFEINE. 1. C8H9 N4 0 3 I . P ro c e d u re . CH3 -N - C=0 1 0=C C - N-CHs • " JJ-H CH3 -N - C - N CH3-N - C=0 « 1 > 0=C C - N-CH3 c lo s e d tu b e 1 B ^C -I CH3 -N - C - N^ ( 1 50 ° ) 1 + I2 + HI The m ethod o f Y o s k ito m i^ ) d e s c r ib e d on page 3^» was u se d f o r th e p r e p a r a ti o n o f t h i s compound. However, s e v e r a l s te p s in th e p ro ce d u re were m o d ifie d . A f t e r c o o lin g , p r e s s u r e was removed in th e tu b e by b r e a k in g th e c a p i l l a r y s e a l . The tu b e was opened, a n d th e c o n te n ts w ashed o u t w ith s e v e r a l p o r ti o n s o f h o t c h lo ro fo rm , u s in g a g l a s s ro d to lo o s e n th e s o l i d m ass. The c h lo ro fo rm was f i l t e r e d w h ile h o t, and th e f i l t e r p a p e r w ashed w ith a s m a ll q u a n ti ty o f c h lo ro fo rm . The f i l t r a t e was shaken w ith a s l i g h t e x c ess ( l ) ; Y eisuke Y o sk ito m i, J . Pharm. Soc. J a p a n , No. 5 8 , H 60-9, 192^» C.A. 1 8, 317^, 192h. *5 o f 0 , 1011, sodium t h i o s u l f a t e s o l u t i o n to rem ove th e e x c e s s f r e e i o d in e , r e s u l t i n g i n a c o n s id e r a b le c l e a r i n g up o f th e s o l u t i o n . The sodium t h i o s u l f a t e s o l u t i o n was f i n a l l y sh a k en o u t w ith 10 c c . o f c h lo ro fo rm w hich was added to th e m ain p o r t i o n o f c h lo ro fo rm e x t r a c t . The c h lo ro fo rm was d i s t i l l e d o f f and th e r e s id u e removed and d r ie d i n an oven a t 100-105° f o r a t l e a s t o n e - h a lf h o u r to remove a l l c h lo ro fo rm . The i o d o c a f f e in e th u s o b ta in e d was a l i g h t y e llo w i n c o lo r , and was r e c r y s t a l l i z e d by d i s s o l v i n g i n h o t 95 $ e t h y l a lc o h o l and th e n c o o lin g a t a low te m p e ra tu re , A seco n d c ro p o f c r y s t a l s was ob­ t a i n e d by e v a p o r a tin g o f f about f o u r - f i f t h s o f th e a lc o h o l i n th e f i l t r a t e , and a g a in c o o lin g . The r e c r y s t a l l i z b d compound was d r ie d a t room te m p e ra tu re and f i n a l l y h e a te d i n an oven a t 105-110® f o r f o u r to f i v e h o u r s . I t was n e a r l y c o l o r l e s s , h a v in g b u t a v e ry s l i g h t y e llo w t i n g e , and was l i g h t and f l u f f y . 2 . E x p e rim e n ta l d a ta : T r i a l s M a te r ia ls u s e d in grams A nhydrous c a f f e i n e I o d in e 1st 2 0 .0 3 ^ .0 2nd 1 0 ,0 1 7 .0 Yield, theoretical " , actual " , percentage 32.8 11,6 35.3$ l6.4 S. 5 50. 0$ M e ltin g p o i n t , d e te rm in e d w , c o rre c t II. 2 1 6 .0 -2 1 8 .0 ° 2 1 5 .0 r2 1 7 .5 ° 2 1 6 , 0- 2 1 9 . 0 ° PREPARATION OP THE S-ETHERS OP CAPPEINE. A, G e n e ra l P ro c e d u re CH3 -N - 0=0 CH3-N - 0=0 » » U s u a lly a t th e b . p . ' 1 0=0 C — N—CH3 0=0 0 — N-CH3 + Na—0—B -----------------------------^ • » ^C-Cl o f th e A lco h o l (R-OH) ' " ^C-O-R+NaCl CH3-N - C - N u s e d a s th e S o lv e n t. CH3-N - C - N g - C h lo r c a f f e in e + sodium a lc o h o l a t e R -O x y c a ffe in e + sodium c h lo r i d e I n th e p r e p a r a ti o n o f S-m ethoxy and 8 - e th o x y c a f f e in e by E. P i s c h e r ( l ) th e sodium o r p o ta s s iu m a lc o h o l a t e was p r e p a r e d by sim p ly ad d in g a s l i g h t e x c e ss o f s o l i d sodium o r p o ta s s iu m h y d ro x id e to an e x c e s s o f th e a lc o h o l . The l a t t e r was u s e d i n s u f f i c i e n t q u a n t i t i e s t o s e r v e as a s o lv e n t f o r th e r e s u l t i n g p r o d u c t. I n r e p e a t i n g t h i s p ro c e d u re f a i r l y good y i e l d s were o b ta in e d i n th e p r e p a r a ti o n o f m ethoxy and e th o x y c a f f e in e . How­ e v e r , v e ry p o o r y i e l d s , o r i n some c a s e s no y i e l d s a t a l l , were o b ta in e d i n a tte m p ts to p r e p a r e th e h ig h e r a lk y l e t h e r s , a s w e ll a s some o f th e a r y l e th e r s o f c a f f e i n e . Very good r e s u l t s w ere s e c u re d i n th e p r e p a r a ti o n o f th e norm al a l k y l e th e r s from m ethoxy to n - h e p ty lo x y c a f f e in e i n c l u s iv e by a more e x a c t p ro c e d u re . In many c a se s th e y i e l d s w ere n e a r l y q u a n t i t a t i v e . W hile se co n d a ry p ro p y lo x y and b u ty lo x y c a f f e in e w ere a l s o s u c c e s s f u l l y p r e p a r e d , th e y i e l d was a b o u t o n e - h a lf to tw o - th ir d s t h a t o f th e norm al compounds, and c o n s id e r a b ly l e s s when t e r t i a r y b u ty lo x y c a f f e in e was p r e p a r e d i n th e same (1 )* E . F i s c h e r . B e r. 17, 1785* 188^ & U ntersu ch u n g u n , p p . 3 6 , 9 5 -9 6 , l6 2 . U6 m anner. The f o llo w in g g e n e r a l p ro c e d u re was a d o p te d : The a lc o h o l to "be u s e d was p u r i f i e d by r e d i s t i l l a t i o n o v e r c a lc iu m o x id e , and i f n e c e s s a r y , i t was d i s t i l l e d th e second tim e a f t e r ad d in g a few p ie c e s o f sodium . The f r a c t i o n h a v in g a c o n s ta n t " b o ilin g p o i n t , u s u a l l y w ith in one d e g re e , was u s e d . One m ole o f "bright m e t a l l i c sodium was r a p i d l y w eighed o u t to o n e -h u n d re d th o f a gram. T h is was added c a r e f u l l y i n s m a ll p ie c e s to from f o u r to sev en p a r t s by w eig h t o f th e a lc o h o l. B ecause o f th e in c r e a s e d s o l u b i l i t y o f th e h ig h e r e th e r s i n a lc o h o l, f o u r p a r t s o f t h e l a t t e r w ere fo u n d s u f f i c i e n t . A 5^0 to 1000 cc, round b o tto m lo n g neck f l a s k was found v e ry s u i t a b l e f o r t h i s work. A f t e r com plete d is a p p e a ra n c e o f th e sodium , one m ole o f p u re anhydrous ( d r i e d a t 120°) 8—c h lo r c a f f e i n e was added to th e a lc o h o l s o l u t i o n . The f l a s k was th e n c o n n e c te d w ith a r e f l u x c o n d e n se r, and th e m ix tu re g e n tl y b o ile d on a steam b a th o r o i l b a th f o r from o n e - h a lf to two h o u r s , d ep en d in g upon th e sp eed o f th e r e a c t i o n . The s o l u t i o n was im m ed ia te ly f i l t e r e d while, h o t to remove th e s a l t , and th e f i l t e r was w ashed w ith a s m a ll amount o f th e a b s . a lc o h o l. The m ethoxy, e th o x y , p ro p y lo x y (n & s e c . ) and is o -a m y lo x y c a ffe in e th u s p re p a re d s e p a r a te d o u t o f th e s o l u t i o n when c o o le d i n th e form o f r a t h e r sm a ll c o l o r l e s s n e e d le s o r c l u s t e r s o f n e e d le s . The h i g h e r e th e r s d id n o t c r y s t a l l i z e r e a d i l y i n th e c o o le d s o lu t i o n u n le s s th e a lc o h o l was some­ what c o n c e n tr a te d . I t was found b e s t to remove n e a r ly a l l th e a lc o h o l when n -h e x y lo x y and n - h e p ty lo x y c a f f e in e were p r e p a r e d by d i s t i l l i n g u n d e r red u ced p r e s s u r e . In a l l c a s e s a maximum y i e l d was o b ta in e d hy c o n c e n tr a tio n o f th e a lc o h o l ic f i l t r a t e a f t e r f i l t r a t ­ io n o f th e f i r s t cro p o f c r y s t a l s . T hus, a f t e r c o o lin g a second c ro p o f c r y s t a l s s e p ­ a r a t e d o u t; b u t u s u a l l y i t was l e s s p u re th a n th e f i r s t . The c ru d e p ro d u c t was r e c r y s t a l l i z e d one o r more tim e s o u t o f h o t 95f° a lc o h o l o r d i l u t e hO- 50 ^ a lc o h o l . The s o l u b i l i t y o f t h i s s e r i e s o f a l k y l e th e r s became g r e a t e r i n a lc o h o ls and l e s s i n w a te r a s th e a lk y l c h a in in c r e a s e d i n le n g th . To o b ta in a v e r y p u re anhydrous compound th e lo w e r members o f t h i s group w ere s u c c e s s f u l l y r e c r y s t a l l i z e d o u t o f c a rb o n t e t r a c h l o r i d e , w h ile th e h ig h e r members were r e c r y s t a l l i z e d o u t o f p e tro le u m e th e r . As e a ch compound p r e s e n te d a problem i n f in d in g th e b e s t means o f r e c r y s t a l l l z a t i o n , th e m ost s u i t a b l e s o lv e n ts a r e found l i s t e d i n th e e x p e rim e n ta l d a t a g iv e n f o r e a ch compound. The a r y l e th e r s o f c a f f e in e p r e p a r e d , namely ben zy lo x y and p h e n y le th o x y c a f f e in e , h a v in g a p h e n y l g ro u p on th e end o f th e a lk y l c h a in were p r e p a r e d i n a s i m i l a r m anner as g iv e n ab o v e. However, b e c a u se o f th e h ig h b o i l i n g p o in t o f th e a l c o h o l s , th e r e a c t i o n was made to ta k e p la c e c o n s id e r a b ly below th e b o i li n g p o in t o f th e a lc o h o l i n o r d e r to a v o id d e c o m p o s itio n . T o r th e p r e p a r a ti o n o f th e ph en y l e t h e r s , nam ely p h e n y lo x y c a ffe in e and x^hydroxyp h e n y lo x y c a f f e in e , two m ethods were u s e d . In th e f i r s t m ethod, w hich was a ls o s u c c e s s ­ f u l l y u se d i n th e p r e p a r a ti o n o f th e h ig h e r a lk y l e th e r s o f c a f f e i n e , th e r e a c t i o n was b ro u g h t a b o u t by a d d in g one m ole o f c h lo r c a f f e i n e to x y le n e c o n ta in in g one mole o f " b ir d s h o t" m e t a l l i c sodium and a s l i g h t e x c e ss o f p u re phenol a f t e r th e sodium had a l l d i s ­ a p p e a re d i n th e fo m a t io n o f sodium p h e n y la te . The m ix tu re was r e f lu x e d f o r a b o u t f i v e h o u rs . P a r t o f th e e th e r c r y s t a l l i z e d out o f th e c o ld x y le n e ; th e re m a in d e r was r e c o v e r ­ ed by rem oving th e x y le n e by vacuum o r steam d i s t i l l a t i o n , P h e n y lo x y c a ffe in e was p r e ­ p a re d i n t h i s m anner. The m o n o -e a ff e in e - e th e r o f h ydroquinone o r p -h y d ro x y p h e n y lo x y c a f f e i n e was p r e p a r e d by th e second m ethod. In t h i s p ro c e d u re one mole o f m e t a l l i c sodium was added to a b o u t seven volumes o f a b s o lu te e th y l a lc o h o l. An e x c e ss o r s l i g h t l y o v e r two m oles o f p u re hydro q u in o n e were th e n added and f i n a l l y one m ole o f anhydrous c h l o r c a f f e i n e . The m ix tu re was r e f lu x e d f o r f iv e h o u rs . The sodium a lc o h o l a t e f i r s t form ed s e rv e d th e same p u rp o se a s th e a l c o h o l ic p o ta s h u s e d in th e C la is o n r e a c ti o n . W hile th e p r o p e r t i e s o f p h e n y lo x y c a ffe in e and p -h y d ro x y p h e n y lo x y c a ffe in e a g re e d w ith th o s e fo u n d by B a u m a n n U ', th e m ethods o f p r e p a r a tio n w ere somewhat d i f f e r e n t . ( l ) » A . Baumann. C. I I , 2 0 3 6 , 1913* *+7 A ll o f th e a r y l e th e r s o f c a f f e in e w ere most s u c c e s s f u l l y r e c r y s t a l l i s e d o u t o f 95^ a lc o h o l o r d i l u t e a lc o h o l c o n ta in in g n o t l e s s th a n 5^$ a lc o h o l, •a, Tne e x p e rim e n ta l d a ta and p r o p e r t i e s f o r s ix t e e n o f th e S - e th e r c a f f e in e compounds a r e g iv e n on th e f o llo w in g p a g e s : 1. S-METHQXYCAJTE HIE. M a te r ia ls u s e d , in grams A nhydrous S - c h lo r c a f f e i n e A bs, M ethyl A lc o h o l (13. P. 65 . 5- 66. 5 0) M e ta l li c Sodium R e flu x e d , h o u rs C9H12ll403. 2nd T r i a l 1 s t T ria l 200.0 1000.0 5 0 .0 3 5 0 .0 20.12 5 .0 3 1/2 1 R e c r y s t a l l i z e d from (1 ) W ater (UO-^O volum es) ( 2 ) 95 $ o r d i l , a lc o h o l ( 3 ) Carbon t e t r a c h l o r i d e ( f o r a n a ly s i s ) D rie d a t room tem p, th e n a t 110 ° f o r 4 -5 h o u rs . Y ie ld , t h e o r e t i c a l 11 t a c t u a l " , p e rc e n ta g e A n a ly s is N itro g e n 1 8 2 .1 g. 1 6 5 .2 g, 4 9 .0 g. 3 9 .1 g . 7 9 .8 $ 9 0 .7 $ C a lc u la te d 25-< D eterm ined 2 4 . 39 $ P ro p e rtie s C r y s ta l s t r u c t u r e - s m a ll, c o l o r l e s s , s h o r t n e e d le s o r c l u s t e r s o f n e e d le s . M e ltin g p o i n t , d e te rm in e d " 11 , c o r r e c t Sublim es S o l u b i l i t y , (A p p ro x .) W ater, g. i n 100 g. E th y l a lc o h o l C hloroform Carbon t e t r a c h l o r i d e P e tro le u m e th e r 1 7 2 .5 -1 7 4 .0 0 1 7 6 . 0- 1 7 7 . 0 ° 1 7 4 .0 ° to a c o n s id e r a b le e x te n t above i t s m e ltin g p o i n t . a t 25 ° 0 .2 9 s l i g h t l y s o lu b le n 11 n n p r a c t i c a l l y in s o l u b l e a t b . p . o f s o lv e n t 4 .6 o i l y d r o p le t s ) m o d e ra te ly s o lu b le 11 n ( f i r s t m e lts to n n v e ry d i f f i c u l t l y s o lu b le C o n v ersio n to h y d ro x y c a ffe in e (1 ) By h e a tin g i n d i l u t e HC1 - v e ry r e a d i l y c o n v e rte d . (2 ) By h e a ti n g i n c lo s e d tu b e - s l i g h t l y i n p re s e n c e o f a lc o h o l a t 170-200°. M o le c u la r R earrangem ent - q u a n t i t a t i v e l y changed to te tr a m e th y l u r i c a c id a t 170 - 200 ® i n an open o r c lo s e d tu b e . 48 g-ETHOXYCAJTZEIllE, M a te r ia ls used., i n grams A nhydrous C h lo r c a f f e in e Abs. e th y l a lc o h o l ( b . p . 7 8 .0 - 7 9 .0 ° ) M e ta l li c sodium B e flu x e d , h o u rs C10H14N4O3. 1 s t T ria l 2nd T r i a l 100.0 5 0 .0 3 0 0 .0 7 0 0 .0 1 0 .0 6 5 .0 3 1 1 B e c r y s t a l l i z e d from w a te r & a lc o h o l D rie d a t room temp, th e n a t 110 ° f o r 4 -5 h o u rs . Y i e ld , t h e o r e t i c a l " , a c tu a l " , p e rc e n ta g e A n a ly s is N itro g e n P ro p e rtie s C r y s ta l s t r u c t u r e - Sublim es - S o l u b i l i t y , (A p p ro x .) W ater, g . i n 100 g . E th y l a lc o h o l Carbon t e t r a c h l o r i d e P e tro le u m e t h e r 1 0 4 .2 g. 7 1 .0 g. 6 5 .1 # 3S.7 g. 74.3 # C a lc u la te d 23-53# D eterm ined 2 3 .1 8 # 5 2 .1 g. c o l o r l e s s , s h o r t n e e d le s o r r o d s . M e ltin g p o i n t , d e te rm in e d " " , c o rre c t CC14 ( f o r a n a l y s i s ) 1 3 7 . 5- 1 4 0 . 0 ° S p l i t ends (from w a te r ) . 1 3 8 . 0 - 1 4 0 . 5° l4 0 .0 ° slo w ly a t i t s m e ltin g p o i n t , r a p i d l y above 1 7 5 ° . a t 25° a t b . p . o f s o lv e n t 0 .2 9 3 . 5 ( f i r s t m e lts to s l i g h t l y s o lu b le v e ry s l i g h t l y s o lu b le n e a r ly in s o l u b l e o ily d ro p le ts ) r e a d i l y s o lu b le m o d e ra te ly s o lu b le d i f f i c u l t l y s o lu b le C o n v e rsio n to h y d ro x y c a ffe in e . (1 ) By h e a ti n g i n d i l u t e HC1 - r e a d i l y c o n v e rte d . (2 ) By h e a tin g i n a c lo s e d tu b e - p a r t i a l l y c o n v e rte d . M o le c u la r B e a rra n g e m e n t: P a r t l y r e a r r a n g e d to 1 , 3 , 7 - tr im e th y l 9 - e th y l u r i c a c id by h e a ti n g i n a c lo s e d tu b e a t 24 0 °. 1+9 3. g-N. PROPLYOXYCAPPEINE, C n H 16N40 3 . (llew Compound) M a te r ia ls u s e d , i n grams A nhydrous c h lo r c a f f e i n e Abs. p r o p y l a lc o h o l (* . P. 9 6 . 5- 97 . 5 0 ) M e ta l li c sodium H e flu x e d , h o u rs 1 s t T r ia l 5 0 .0 2 nd T r i a l 5 0 ,0 3 0 0 .0 3 0 0 .0 5.03 5 .0 3 1 1 E e c r y s t a l l i z e d from a b s . a lc o h o l D rie d a t room temp, th e n a t 110 ° f o r 4 -5 h o u rs . Y ie ld , t h e o r e t i c a l " , a c tu a l " , p e rc e n ta g e CCI4 ( f o r a n a ly s i s ) 5 5 .1 5 g. 5 ° .° g. 55.15 g. l^7.2 g. 9 0 .1 $ 90.6 D eterm ined 2 1 . o 0 ‘: A n a ly s is H itro g e n C a lc u la te d 2 2 . 22 $ P ro p e rtie s C r y s ta l s t r u c t u r e c o l o r l e s s n e e d le s o r r o d s . M e ltin g p o i n t , d e te rm in e d 1 2 9 .5 -1 3 0 .5 0 S ublim es slo w ly above I 5O0. S o l u b i l i t y , (A p p ro x .) W ater, g . i n 100 g . a t 25 ® 0 .0 4 5 E th y l a lc o h o l Carbon t e t r a c h l o r i d e P e tro le u m e th e r j, s l i g h t l y s o lu b le d i f f i c u l t l y s o lu b le p r a c tic a lly in s o lu b le a t b . p . o f s o lv e n t 0 .S 1 ( f i r s t m e lts to o i l y d r o p le t s ) v e ry s o lu b le s l i g h t l y s o lu b le v e ry d i f f i c u l t l y s o lu b le C o n v ersio n to h y d ro x y c a ffe in e . (1 ) By h e a ti n g i n d i l u t e HC1 - v e ry r e a d i l y c o n v e rte d . (2 ) By h e a ti n g i n a c lo s e d tu b e - above 25 O®, p a r t i a l l y c o n v e rte d w ith d e c o m p o sitio n . M o le c u la r R ea rra n g e m e n t: When h e a te d a t 260-270® i n an open tu b e . - ab o u t 35 $. 50 4. 3-SEC ONDARY-PROFYLOXYCAFPEINE. M a te r ia ls u s e d , i n grams A nhydrous c h l o r c a f f e i n e Abs. s e c o n d a ry -p ro p y l a lc o h o l (b . p . S I . 1 - 8 2 .0 ° ) M e ta l li c sodium R e flu x e d , h o u rs ClxHi6 N 40 3 (New Compound) 5 0 .0 3 0 0 .0 5 .0 3 1 R e c r y s t a l l i z e d from h o t w a te r o r d i l . a lc o h o l D rie d a t room temp, th e n a t 110 ° f o r U- 5 h o u rs , Y ie ld , t h e o r e t i c a l " , a c tu a l " , p e rc e n ta g e 5 7 .7 g. g. 3 9 .9 $ 2 2 .0 A n a ly s is N itro g e n C a lc u la te d 2 2 . 22 ^ P ro p e rtie s C r y s ta l s t r u c t u r e c o l o r l e s s n e e d le s o r ro d s D eterm in ed 2 1 . 77 $ M e ltin g p o i n t , d e te rm in e d 1 5 3 .5 -1 5 ^ .7 ° Sublim es slo w ly above i t s m e ltin g p o in t - S o l u b i l i t y , (A p p ro x .) W ater, g , i n 100 g. E th y l a lc o h o l Carbon t e t r a c h l o r i d e P e tro le u m e t h e r a t 25 ° 0 .0 7 5 0 ,6 5 ( f i r s t m e lts to s l i g h t l y s o lu b le d i f f i c u l t l y s o lu b le n e a r ly in s o l u b l e o ily d ro p le ts ) r e a d i l y s o lu b le s l i g h t l y s o lu b le v e ry d i f f i c u l t l y s o lu b le a t b . p . o f s o lv e n t C o n v ersio n to h y d ro x y c a f fe in e . (1 ) By h e a tin g i n d i l u t e HC1 - v e ry r e a d i l y c o n v e rte d . (2 ) By h e a tin g i n a c lo s e d tu b e - c o m p le te ly a t 2^5-255a . M olecular Rearrangement: Does not rearrange b e fo re decom position tak es la c e 51 5. S— IT. BUTYLOXYCAI’ZEIIJE. M a te r ia ls u s e d , i n grams Anhydrous c h l o r c a f f e i n e Abs. n - b u t y l a lc o h o l (b . p . 116 - 11 7 °) M e ta l li c sodium CisHialT^Oa. (New Compound) 1 st T ria l 3 0 .0 2 0 0 .0 2nd T r i a l 5 0 .0 3 0 0 .0 3 .0 2 5 .O 3 1 1 R e flu x e d , h o u rs R e c r y s t a l l i z e d from h o t d i l u t e e th y l a lc o h o l (UO-50 ^) D rie d a t room temp, th en in d e s s i c a t o r o v e r H2SO4 o r P2O5, Y ie ld , t h e o r e t i c a l " , a c tu a l 11 , p e rc e n ta g e A n a ly s is llitr o g e n 5S.2 g. ^ 3 .6 g. 7K 9 $ C a lc u la te d 21 065 D eterm ined 20 535 . ; P ro p e rtie s C r y s ta l s t r u c t u r e M e ltin g P o i n t , d e te rm in e d Sublimes 3 ^ .9 g. 3 1 .0 g . 89 .1 - S o l u b i l i t y , (A p p ro x .) ',7ater, g . i n 100 g . S th y l a lc o h o l Carbon t e t r a c h l o r i d e P e tro le u m e th e r . ; v e ry f i n e , s le n d e r , c o l o r l e s s n e e d le s w hich to sm a ll p r is m a tic c r y s t a l s . S 3.6 -9 0 * 0 ° 8 8 .0 -9 0 .0 ° ( o i l y l i q u i d , no decornpn.) v e ry slo w ly a t 90 ° and v e ry r a p i d l y above 200 ° . a t 25° O.O37 m o d e ra te ly s o lu b le q u i te s o lu b le v e ry d i f f i c u l t l y s o lu b le a t b . p . o f s o lv e n t O . 3 S (M e lts f i r s t to o i l y liq u id .) v e ry s o lu b le v e ry s o lu b le d i f f i c u l t l y s o lu b le C onversion to h y d r o x y c a ffe in e . (1 ) By h e a tin g in d i l u t e HC1 - r e a d i l y changed. (2 ) By h e a ti n g in a c lo s e d tu b e - r e a d i l y changed ( 25 0 °) M o le c u la r R e a r ra n g e m e n t : change None 52 6. 8-SEC0NDARY-BUTYL0XYCAPPEINE, C ^ H is^ O a , (flew Compound). M a te r ia ls u s e d , i n grams Anhydrous c h lo r c a f f e i n e Abs. S e c -b u ty l a lc o h o l (b . p . 9 9 -1 0 1 °) M e ta llic sodium 3 0 .0 1 2 5 .0 R e flu x e d , h o u rs 3 - 1 /2 3.02 R e c r y s t a l l i z e d from d i l u t e a lc o h o l o r w a te r ( f o r a n a l y s i s - d ry CCI4 ) D rie d a t room temp, and f i n a l l y a t 110 ° f o r 4 h o u rs . Y i e ld , t h e o r e t i c a l " , a c tu a l n , p e rc e n ta g e 3 ^ .9 g. 1 9 .5 g. 55.9 £ A n a ly s is N itro g e n C a lc u la te d 21 . 065S P ro p e rtie s C r y s ta l s t r u c t u r e lo n g , h a i r - l i k e n e e d le s . D eterm ined 20.3ty6 M e ltin g p o i n t , d e te rm in e d 122 . 5- 1 2 3 .S 0 ( o i l y l i q u i d , no d e c o m p o sitio n ) Sublim es slo w ly above i t s m e ltin g p o i n t . S o l u b i l i t y , (A pprox.) ;7 a te r, g. i n 100 g. E th y l a lc o h o l Carbon t e t r a c h l o r i d e P e tro le u m e th e r a t 25 ° 0 .0 3 m o d e ra te ly s o lu b le q u i te s o lu b le d i f f i c u l t l y s o lu b le a t b . p . o f s o lv e n t 0 .4 6 v e ry s o lu b le v e ry s o lu b le s l i g h t l y s o lu b le C o n v ersio n to h y d r o s y c a f fe in e . (1 ) By h e a tin g i n d i l u t e HC1 - v e ry r e a d i l y (2 ) By h e a tin g i n a c lo s e d tu b e - v e ry r e a d i l y ( 25O0 - s e v e r a l h o u rs ) M olecular Rearrangement: None 53 7. 8-TERTIARY-BUTYLQXYCAFPEINE, CxsHi8N403 , (iTew Compound). M a te r ia ls u s e d , i n grains A nhydrous c h lo r c a f f e i n e Abs. t e r t i a r y h u ty l a lc o h o l ( b . p . 8 1 .5 -g 2 .0 » ) M e ta l li c sodium 3 0 .0 1 2 5 .0 3.02 R e flu x e d , h o u rs 6 R e c r y s t a l l i z e d from d i l u t e a lc o h o l o r l a r g e volume w a te r D rie d a i r d r i e d , th e n a t 1 1 0 ° f o r H h o u r s , Y i e ld , t h e o r e t i c a l 11 , a c t u a l " , p e r c e n ta g e A n a ly s is N itro g e n P ro p e rtie s C r y s ta l s t r u c t u r e 3 ^ .9 g. K* 1 2 .3 g . 56 C a lc u la te d 21.0656 D eterm ined 2 1 . U 56 s le n d e r , c o l o r l e s s n e e d le s M e ltin g p o i n t , d e te rm in e d 1 5 S .0 - l6 l.6 9 S ublim es v e ry slo w ly above i t s m e ltin g p o i n t , a p p r e c ia b ly above 2 0 0 ° . S o l u b i l i t y , (A pprox.) ^Vater E th y l a lc o h o l Carbon t e t r a c h l o r i d e C hloroform P e tro le u m e t h e r a t 259 d i f f i c u l t l y s o lu b le m o d e ra te ly s o lu b le s o lu b le It d i f f i c u l t l y s o lu b le a t b . p . o f s o lv e n t s l i g h t l y s o lu b le v e ry s o lu b le v e ry s o lu b le n 11 s l i g h t l y s o lu b le C o n v ersio n to h y d ro x y c a ffe in e . (1 ) By h e a tin g i n d i l u t e HC1 - v e ry r e a d i l y ( 2 ) By h e a ti n g i n a c lo s e d tu b e - v e ry r e a d i l y The s u b s t i t u t i o n o f m ethyl groups f o r 2 hydrogens i n c a s e o f th e t e r t i a r y a lc o h o l seems to le s s e n th e s t r e n g th o f th e bond betw een th e oxygen and a lk y l carb o n atom . T his r e s u l t s i n th e r a p i d c o n v e rs io n to h y d ro x y c a ffe in e by r e p la c in g th e a lk y l group by a hydrogen atom , even w h ile th e e t h e r was b e in g p r e p a re d i n th e a lc o h o l s o lu tio n . M olecular Rearrangements None 5U 8. 8-N . AMYLOXYCAFFEINE, CigBaoD^Os, (New Compound). M a te r ia ls u s e d , i n grams Anhydrous c h l o r c a f f e i n e A bs, n -am yl a lc o h o l ( b , p . 135-138° ) M e ta l li c sodium R e flu x e d , h o u rs 2 0 .0 6 5 .O 2.02 1 R e c r y s t a l l i z e d from h o t e th y l a lc o h o l, th e n w a te r, ( f o r a n a ly s i s - warm p e tro le u m e t h e r ) , D rie d a i r d r ie d th e n i n a vacuum d e s s i c a t o r o v er P s Ob f o r s e v e r a l d ays. Y ie ld , t h e o r e t i c a l " , a c tu a l " , p e rc e n ta g e A n a ly s is N itro g e n P ro p e rtie s C r y s ta l s t r u c t u r e 2^*5 g . 2 i;3 g. 8 6 .9 $ C a lc u la te d 2 0 . 00 $ D eterm ined 1 9 . ^ 9$ c o l o r l e s s , s le n d e r m is c ro s c o p ic n e e d le s change s lo w ly to p r is m s , h av in g a w a x -lik e c o n s is te n c y when p u lv e r iz e d , M e ltin g p o i n t , d e te rm in e d 7 1 .8 - 7 2 . 6 ® S ublim es slo w ly above i t s m e ltin g p o i n t , q u i t e r a p i d l y above 130°. D is tills a t 21 1 -2130 a t 2 -3 mm, p r e s s u r e . S o l u b i l i t y , (A p p ro x ,) W ater, g . i n 100 g . a t 250 E th y l a lc o h o l Carbon t e t r a c h l o r i d e C hloroform P e tro le u m e t h e r 0 .0 1 9 v e ry s o lu b le m o d e ra te ly s o lu b le m o d e ra te ly s o lu b le d i f f i c u l t l y s o lu b le a t b . p . o f s o lv e n t 0 .093 ( F i r s t m e lts to an o ily liq u id ) v e ry s o lu b le q u ite s o lu b le v e ry s o lu b le v e ry s l i g h t l y s o lu b le C o n v e rsio n to h y d ro x y c a ffe in e . (1 ) By h e a ti n g i n d i l u t e HC1 - q u i t e r e a d i ly (2 ) By h e a ti n g i n a c lo s e d tu b e - q u i t e r e a d i l y (above 250 ° f o r s e v e r a l h o u r s ) . M o le c u la r R e a rran g em en t: None 55 9. S-ISO-AMYLOXYCAFFEIKE, CisHsolUOs. M a te r ia ls u s e d , i n grams A nhydrous c h lo r c a f f e i n e Abs. n - is o - a m y l a lc o h o l (b . p . 123-129®) M e ta l li c sodium 5 0 .0 3 0 0 .0 5 .0 3 R e flu x e d , h o u rs 1 R e c r y s t a l l i z e d from h o t d i l u t e e th y l a lc o h o l D rie d a i r d r i e d , th e n a t 110 ° f o r 4 -5 h o u r s . Y i e ld , t h e o r e t i c a l " , a c tu a l n , p e rc e n ta g e 6 1 .3 g . 5 ^ . 0 g . 9 1 .3 $ A n a ly s is N itro g e n C a lc u la te d 2 0 .0 0 # P ro p e rtie s C r y s ta l s t r u c t u r e s m a ll, c o l o r l e s s , n e e d le -s h a p e d c r y s t a l s . M e ltin g p o i n t , d e te rm in e d '* i» , c o r r e c t D eterm ined 1 9 . 52 # 1 2 5 . 0- 1 2 7 . 0 ° 129.5° Sublim es slo w ly above i t s m e ltin g p o i n t , r a p i d l y above 25 O0 . S o l u b i l i t y , (A pprox.) W a te r, g . i n 100 g . a t 25 ® E th y l a lc o h o l Carbon t e t r a c h l o r i d e C hloroform P e tro le u m e th e r a t b . p . o f s o lv e n ts 0 .0 0 7 0 ,1 0 0 ( P i r s t m e lts to an s l i g h t l y s o lu b le v e ry s o lu b le 11 11 p r a c t i c a l l y in s o lu b le O ily l i q u i d ) , f a i r l y s o lu b le e x tre m e ly s o lu b le ti 11 v e ry d i f f i c u l t l y s o lu b le C o n v ersio n to h y d ro x y c a ffe in e . (1 ) By h e a tin g i n d i l u t e Hcl - r e a d i l y (2 ) By h e a ti n g i n a c lo s e d tu b e - a t 250® w ith d e c o m p o sitio n . M o le c u la r R earran g em en t: None 10, 8—n-EEXYLOXYCAFFEINE, O14H22N4O3 , (New Compound). M a te r ia ls u s e d , i n grams Anhydrous c h l o r c a f f e i n e Abs, n - h e x y l a lc o h o l ( b . p . 151-155®) M e ta l li c sodium Dry to lu e n e 1 st T ria l 20.0 60.0 2 .0 2 2nd T r ia l 20.0 1 3 . ^ ( 1 - 1 / 2 e q u iv .) 2 .0 2 200 c c . Re f lu x e d , h o u rs S o lv e n t removed by vacuum d i s t i l l a t i o n R e c r y s t a l l i z a t i o n from d i l u t e a lc o h o l ( f i r s t d i s s o lv in g in 95 $* th e n d ilu tin g ), D rie d in a i r a t room tem p, , th en in vacuum d e s s i c a t o r P2 O5 f o r s e v e r a l days ( f o r a n a ly s i s - warm, d ry p e tro le u m e t h e r ) . Y ie ld , t h e o r e t i c a l " , a c tu a l " , p e rc e n ta g e 2 5 .7 g. 19 .1 g. 7 ^ .3 # steam d i s t i l l a t i o x . 2 5 .7 g. IS . 5 g. 7 2 .0 # D eterm ined I S . 38# A n a ly s is N itro g e n C a lc u la te d 19.0 5 # P ro p e rtie s C r y s ta l s t r u c t u r e lo n g , c o l o r l e s s , h a i r - l i k e n e e d le s M e ltin g p o i n t , d e te rm in e d 5 2 .5 - 53.6® Sublim es v e ry s l i g h t l y a t i t s m e ltin g p o i r - r a p i d l y a t 175 - 200®. S o l u b i l i t y , (A pprox.) W ater, g , i n 100 g . a t 25® E th y l a lc o h o l Carbon t e t r a c h l o r i d e C hloroform P e tro le u m e th e r 0.01 q u ite s o lu b le v e ry s o lu b le v e ry s o lu b le s l i g h t l y s o lu b le a t b„ p . o f s o lv e n t 0 ,037 ( F i r s t m e lts to o ily liq u id ) v e ry s o lu b le v e ry s o lu b le v e ry s o lu b le m o d e ra te ly s o lu b le C o n v ersio n to h y d ro x y c a ffe in e . (1 ) By h e a tin g in d i l u t e HC1 - r e a d i l y (2 ) By h e a tin g i n a c lo s e d tu b e - r e a d i l y changed, slo w e r th a n w ith th e she* c h a in e th e r s o f c a f f e in e . M olecular Rearrangement: None 57 8-n-KSPTYXOXYCAPOTEINE, C15H24N4O3, (New Compound). M a te r ia ls used., in grains A nhydrous c h lo r c a f f e i n e A bs. n - h e p t y l a lc o h o l ( b . p . 1 7 1 -1 7 5 .5 ° ) M e t a l l i c sodium Be f lu x e d , h o u rs 1 st T ria l 2nd T r i a l 2 0 ,0 1 0 ,0 1 0 0 ,0 5 0 ,0 2 ,0 2 1 ,0 1 2 2 S o lv e n t rem oved by vacuum d i s t i l l a t i o n H e c r y s t a l l i z a t i o n from d ry , warm p e tro le u m e th e r D rie d in a i r a t room te m p ., th e n i n vacuum d e s s i c a t o r o v e r P 3 0b f o r s e v e r a l d a y s. Y i e ld , t h e o r e t i c a l " , a c tu a l w , p e r c e n ta g e 2 7 .0 g. 2 3 .2 g. 8 5 .9 $ 1 3 .5 6 . 7 .5 g. 5 5 .5 $ A n a ly s is N itro g e n C a lc u la te d 1 8 ,1 8 $ D eterm ined 1 8 ,0 1 $ P ro p e rtie s C ry s ta l s tr u c tu r e lo n g , h a i r - l i k e n e e d le s o f wary c o n s is te n c y . M e ltin g p o i n t , d e te rm in e d 6l , 2 - 6 3 . 6 ® S u b lim es v e ry s l i g h t l y a t i t s m e ltin g p o i n t , f a i r l y r a p i d l y above 2 00 ° . S o l u b i l i t y , (A p p ro x .) W ater, g . i n 100 g , a t 25 ® E t h y l a lc o h o l Carbon t e t r a c h l o r i d e C h lo ro fo n n P e tro le u m e th e r v e ry s o lu b le m o d e ra te ly s o lu b le " n i t b . p . o f s o lv e n t 0 .0 2 ( F i r s t m e lts to an o ily liq u id ) v e ry s o lu b le 11 n n 11 s l i g h t l y s o lu b le f a i r l y s o lu b le 0 .0 0 5 C o n v e rsio n to h y d r o x y c a f fe in e . ( 1 ) By h e a ti n g i n d i l u t e HC1 - slo w ly (2 ) By h e a tin g i n a c lo s e d tu b e - slo w ly ( 25 O®) M o le c u la r R e a rra n g e m e n t: None 58 12. 3-ALL'YLOXYCAFFEI HE, C11H14N4O3 , (New Compound). M a te r ia ls u s e d , i n grams Anhydrous c h l o r c a f f e i n e Abs. a l l y l a lc o h o l (b . p . 9 6 .0 - 9 7 .0 ° ) M e ta llic sodium Dry to lu e n e 1 s t T ria l 3 0 .0 2nd T r ia l 2 0 .0 200.0 15.0 3.02 2 .0 2 200 Re f lu x e d , h o u rs ( i n o i l b a th ) S o lv e n t rem oved by d i s t i l l i n g a t atmo­ s p h e re p r e s s u r e steam d i s t i l l a t i o n R e c r y s t a l l i z a t i o n from d i l u t e a lc o h o l (HO-5O0 ) D rie d in a i r , th en a t 110 ° f o r *J- 5 h o u r s . Y ie ld , t h e o r e t i c a l " , a c tu a l " , p e rc e n ta g e A n a ly s is N itro g e n Carbon Hydrogen P ro p e rtie s C r y s ta l s t r u c t u r e 3 2 . 5 g. 2 1 . 8 6 g . 27. ^ g. 6 . 6 g . 53.5 $ C a lc u la t ed 2 2 .HO# 52 . 20 $ 5 .6 1# 3 0 .1 9 $ D eterm ined , $ 22 02 5 2.6 9 $ 5 .6 6 $ lo n g , c o l o r l e s s n e e d le s . - 1 2 2 . 0° M e ltin g p o i n t , d e te rm in e d 12 U. 0 - 1 2 6 . 0 ° Sublim es m o d e ra te ly a t o r above i t s m e ltin g p o i n t . S o l u b i l i t y , (A p p ro x .) W ater, g . i n 100 g. a t 250 0 .^ 7 E th y l a lc o h o l Carbon t e t r a c h l o r i d e C hloroform P e tro le u m e th e r s l i g h t l y s o lu b le n 11 m o d e ra te ly s o lu b le d i f f i c u l t l y s o lu b le 1 2 6 .0 a t b . p . o f s o lv e n t 1 .0 2 ( F i r s t m e lts to an o ily liq u id ) q u ite s o lu b le 11 11 v e ry s o lu b le v e ry s l i g h t l y s o lu b le C onversion to h y d r o x y c a f fe in e . (1 ) By h e a ti n g i n d i l u t e HC1 - r e a d i l y changed (2 ) By h e a ti n g i n a c lo s e d tu b e - p a r t i a l l y changed when h e a te d above 170 ® M o le c u la r R earran g em en t: Over 50 $ re a rra n g e d when h e a te d a t 170-125° f o r f o u r h o u rs to 1 , 3 , 7 - t r i m e t h y l 9 - a l l y l u r i c a c id . 59 13. 8-PHENYLOXYCAFFEINE, Cl4 H i4N403 . Materials used, in grams Anhydrous chlorcaffeine Phenol Metallic sodium (bird shot) 20.0 l6,5 (over 2 equiv,) 2.02 Dry isyiene ( h .p . I 3 6 .g - .I 3 S .6 ° ) 1 0 0.0 Refluxed, hours (oil hath) Solvent removed hy steam d i s t i l l a t i o n Recrystallized from water, then 95# Dried at room temp., then at 110® for 4-5 hours. Y i e ld , t h e o r e t i c a l " , a c tu a l 11 , p e rc e n ta g e 2 5 .0 6 . * 18.0 g. A n a ly s is N itro g e n C a lc u la te d P ro p e rtie s C r y s ta l s t r u c t u r e 72.0 ethyl alcohol # D eterm ined 2 0 . 03 # 1 9 .5 2 $ l u s t r o u s , c o l o r l e s s , n e e d le s , M e ltin g p o i n t , d e te rm in e d " n , c o rre c t l^ O .H -l^ .O ® S ublim es n o t n o tic e a b ly S o l u b i l i t y , (A p p ro x .) W ater, g . i n 100 g. E th y l a lc o h o l D ilu te a lk a li a t 25® IU 3 .O® 0.02 •’l i g h t ! y s o lu b le a t b„ p . o f s o lv e n t 0 .2 1 m o d e ra te ly s o lu b le does n o t r e a d i l y d i s s o l v e C o n v e rsio n to h y d r o x y c a f fe in e . (1 ) By h e a tin g in d i l u t e HC1 - i s n o t c o n v e rte d (2 ) By h e a ti n g i n a c lo s e d tu b e - unchanged when h e a te d a t 270-280° f o r s e v e r a l h o u rs. M o le c u la r R e a rra n g e m e n t: None 6o ik . 8-PARA-EYDR0XYFHEN0L0XYCAPPEINE, Ci4H 14N404 . M a te r ia ls u s e d , i n grams Anhydrous c h lo r c a f f e i n e Ahs. e th y l a lc o h o l (b . p . 7 S . 0 - 7 9 . 0 0 ) M e ta l li c sodium H ydroquinone 2 0 .0 1 5 0 .0 2.02 10.0 He f lu x e d , h o u rs H e c r y s t a l l i z e d from 95 # o r d i l u t e a lc o h o l D rie d a t room te m p ., th e n a t 110 ® f o r s e v e r a l h o u rs Y ie ld , t h e o r e t i c a l " , a c tu a l 11 , p e rc e n ta g e A n a ly s is IT itro g en P ro p e rtie s C r y s ta l s t r u c t u r e 26.93 g. 6.5 g. 2 ^ .2 $ C a lc u la te d I S . 5^# D eterm ined I S . 02$ m ic ro sc o p ic s h o rt n e e d le s o r e lo n g a te d p rism s in c l u s t e r o r r o s e t t e fo rm s. M e ltin g p o i n t , d e te rm in e d 11 " , c o rre c t 207. 0- 209. 0® 2 06 . 0 - 2 0 7 . 0 ® S ublim es n o n e, when h e a te d a t o r above i t s m e ltin g p o in t S o l u b i l i t y , (A pprox.) W ater, g . i n 100 g. E th y l a lc o h o l Carbon t e t r a c h l o r i d e C hloroform P e tro le u m e th e r D i l u te a l k a l i at 25® 0 .0 1 5 s l i g h t l y s o lu b le d i f f i c u l t l y s o lu b le n ti p r a c t i c a l l y in s o lu b le v e ry s o lu b le a t b . p . o f s o lv e n t O.2 3 f a i r l y s o lu b le v e ry s l i g h t l y s o lu b le ri i) ii v e ry d i f f i c u l t l y s o lu b le C o n v ersio n to h y d r o a y c a f fe in e , (1 ) By h e a ti n g i n d i l u t e HC1 - n o t changed (2 ) By h e a ti n g i n a c lo s e d tu b e - n o t changed (270-280® f o r s e v e r a l h o u rs) M o le c u la r R e a rra n g e m e n t: None 6i 15. S-BEHZYLOXYCAZFEIHE, C15HX6H4O3 , (Hew Compound)• M a te r ia ls u s e d , i n grams A nhydrous c h lo r c a f f e i n e Dry b e n z y l a lc o h o l ( b . p . 202 - 2 0 9 0 ) M e ta l li c sodium H e a te d , h o u rs ( i n an o i l b a th ) 3 0 .0 200.0 3 .0 3 4 ( a t 150- 160° ) S o lv e n t rem oved by steam d i s t i l l a t i o n R e c r y s t a l l i z e d from h o t a lc o h o l Y ie ld , t h e o r e t i c a l " , a c tu a l " , p e rc e n ta g e A n a ly s is K itro g e n Carbon Hydrogen P ro p e rtie s C r y s ta l 3 9 .3 g. 3 1 .5 g. 8 0 .1 # C a lc u la te d 18. 06# 6 0 . 00 # 5 .3 7 # s tru c tu re D eterm ined 1 7 .9 6 # 59.8 9 # 5.3 5 # c l u s t e r s o f c o l o r l e s s , h a i r - l i k e m ic ro sc o p ic n e e d le s M e ltin g p o i n t , d e te rm in e d 1 7 2 .0 - 1 7 3.5° S ublim es n o n e , when h e a te d a s h ig h a s 255 ° . S o l u b i l i t y , (A pprox.) W a te r, g . i n 100 g. E th y l a lc o h o l C hloroform Carbon t e t r a c h l o r i d e P e tro le u m e th e r a t 25® 0 .0 2 s l i g h t l y s o lu b le p r a c t i c a l l y in s o lu b le ti it rt 11 a t b . p . o f s o lv e n t 0 .0 4 6 m o d e ra te ly s o lu b le v e ry d i f f i c u l t l y s o lu b le m 11 n n ti ti C o n v e rsio n to h y d ro x y c a ffe in e , ► ( l ) By h e a tin g in d i l u t e HC1 - s lo w ly b u t c o m p le te ly c o n v e rte d (2) By heating in a closed tube - very little hydroxycaffeine formed. Molecular Rearrangement: When heated above 200®, it rearranged to trimethyl 9**benzyl-uric acid (m. p. 187.0-189.29® ) 62 16. 8 -PHENYLETHOXYCAFFEINE, M a te r ia ls u s e d , i n grams A nhydrous c h l o r c a f f e i n e Abs. p h e n y le th y l a lc o h o l ( b . p . 213 - 2 1 3 . 7 ®) M e ta l li c sodium H e a te d , h o u rs ( i n o i l b a th ) C ie H je ^ O s , (New Compound), 20,0 1 2 5 .0 2.02 b ( a t 160 - 17 QO) S o lv e n t rem oved by d i s t i l l a t i o n u n d e r re d u c e d p r e s s u r e R e c r y s t a l l i z e d from e th y l a lc o h o l D rie d a t room temp. , th e n h e a te d a t 110° fo r U-5 hours Y i e ld , t h e o r e t i c a l fi , a c t u a l 11 , p e rc e n ta g e 2 7 .5 g. 2 3 .6 g. 8 5 .8 l» A n a ly s is N itro g e n C a lc u la te d 1 7 .8 3 # P ro p e rtie s C r y s ta l s t r u c t u r e c l u s t e r s o f s h o r t , w edge-shaped c o l o r l e s s n eedles* nete "m in e d 1?. ’>S;» M e ltin g p o i n t , d e te rm in e d 1 U2 .0 - S ublim es doe 8 n o t sublim e when h e a te d up to 2^0° • S o l u b i l i t y , (A pprox.) W ater E th y l a lc o h o l C hloroform Carbon t e t r a c h l o r i d e P e tro le u m e t h e r a t 25 ® V ery d i f f i c u l t l y s o lu b le s l i g h t l y s o lu b le p r a c t i c a l l y in s o lu b le ti a t b,, p„ o f s o lv e n t dliY . c u l t i y s o l u b l e m o d :r u te ly s o lu b le it C o n v ersio n to h y d ro x y c a ffe in e . (1 ) By h e a ti n g i n d i l u t e HC1 - s lo w ly but c o m p le te ly changed (2 ) By h e a ti n g i n a c lo s e d tu b e - p a r t i a l l y c o n v e rte d w ith d e c o m p o sitio n at 260 =2 7 0 ° , Molecular Rearrangement; None 63 A ttem p ts w ere made to p r e p a r e d ip h e n y lm e th o x y c a ffe in e and trip h e n y lm e th o x y c a ff e in e from d ip h e n y l carl) i n o l and t r i p h e n y lc a r h i n o l r e s p e c t i v e l y . The same p ro c e d u re was em ploy­ ed i n b o th c a s e s a s was u s e d f o r th e p r e p a r a ti o n o f p h e n y lo x y c a ff e in e . No s u c c e s s f u l r e ­ s u l t s w ere o b ta in e d i n e i t h e r c a se . In a tte m p tin g to p r e p a r e d ip h e n y lm e th o x y c a ffe in e , m ost o f th e p ro d u c t re c o v e re d a f t e r d i g e s t i n g th e m ix tu re in th e x y len e s o lu t i o n was a h y d ro -c a rb o n m e ltin g a t 210 - 2 1 3 ° . It- d id n o t g iv e th e q u a n t i t a t i v e t e s t f o r n i tr o g e n . I t was v e ry i n s o l u b l e in w a te r, a l c o h o l , s tr o n g a c i d s , o r a l k a l i . I t was th o u g h t to b e te tr a p h e n y le th a n e , w hich m e lts a t 2 0 9 0 . The m ore s o lu b l e p o r ti o n rem a in in g i n th e f i l t r a t e , a f t e r c o n c e n tr a tio n down to a s m a ll v o lu m e, p ro v e d to b e im pure c h lo r c a f f e i n e and m e lte d a t ISO to 1S6,0®, T r ip h e n y l - c a r b i n o l w ith th e c h lo r c a f f e i n e in a x y le n e s o lu t i o n c o n ta in in g one e q u i­ v a l e n t o f sodium was t r i e d , a s w ith th e p r e v io u s m ethods. One o f th e f i r s t p r o d u c ts t h a t s e p a r a te d o u t was unchanged c h l o r c a f f e i n e , w hich, a f t e r b e in g r e c r y s t a l l i z e d , m e lte d a t 1 S 9 .5 ” 1 9 1 .5 ° • A f t e r e v a p o r a tin g down th e f i l t r a t e s , a compound was re c o v e re d , m e ltin g a t 1 6 4 .0 to 1 6 7 .0 ° . I t was q u i te i n s o l u b l e i n w a te r. I t d id n o t c o n ta in n itr o g e n . U n d o u b ted ly many o f th e s e e th e r s may be s u c c e s s f u lly p re p a re d by h e a tin g i n C l a i s e n ’s a l c o h o l i c p o ta s s iu m h y d ro x id e , o r by u s in g aqueous p o ta ssiu m o r sodium h y d ro x id e s o l u t i o n a s was done by Baumann f o r th e p r e p a r a tio n o f many o f th e a r y l e th e r s o f c a f f e i n e . The r e a c t i o n in v o lv in g th e p r e p a r a tio n o f s e c o n d a ry a lk y l e th e r s o f c a f f e in e was much s lo w e r and gave lo w er y i e l d s th a n d id th e p rim a ry a lk y l e t h e r s ; w h ile o n ly a v e ry s m a ll amount o f th e t e r t i a r y - b u t y l o x y c a f f e i n e was p r e p a r e d a f t e r s e v e r a l h o u rs o f d i g e s t i n g and no t e r tia r y - a m y lo x y c a f f e in e was form ed. I I I . PYROLYSIS AND MOLECULAR REARRANGEMENT OF THE ETHEH-CAFFEINE DERIVATIVES. The m o lecu la r rearrangement o f methoxy and e th o x y c a ffe in e in to th e corresponding u r ic a c id d e r iv a t i v e s , as d is c u ss e d in the h i s t o r i c a l p art o f t h is t h e s i s , was r e p e a te d . V arying c o n d itio n s were used f o r the purpose o f ob serv in g com parative y i e l d s and p u r ity c l th e r e s u lt in g compounds. A. MOLECULAR REARRANGEMENT OF 8-METHOXICAFFEINE INTO TETRAMETHYL-URIC ACID, ^ CH3-N - C=0 t » 0 =c C - N-CH3 1 " ^C-O-CHa Ch 3-N - C M e th o x y c a ffe in e 1 7 0 - 200 ° v CHa-N - C=0 » 1 0=C C - N-CHa * ' " y 0=0 CH3—N - C - N-CHa T e tr a m e th y l- u r ic a c id H eating in a c lo s e d tube w ith a b so lu te methyl a lco h o l? In th e f i r s t a ttem p t, th e m eth o x y c a ffe in e was h ea ted i n a c lo s e d tube w ith about ten volumes o f m ethyl a lc o h o l f o r tw elve hours at 1 7 0 -2 0 0 °. A m ixture o f h yd roxycaffein e and te tr a m e th y l-u r ic a cid was o b ta in e d . The m ixture browned at 225° and m elted at 3 2 5 - 3 6 O0. This method was rep ea ted , but u s in g about th ree p a r ts o f th e a lc o h o l to one o f the e th e r and h e a tin g a t 1 2 0 - 2 0 0 ° f o r f i v e h ou rs. A ^ 3 y i e l d was ob tain ed o f a m ixture o f prism s and n e e d le s . The prism s m elted a t 2 1 7 - 2 1 2 ° and were th e rearranged te tr a m e th y l-u r ic a c id , w h ile the n e e d le s m elted a t 3 1 8 - 3 2 0 ° and were undoubtedly impure h y d ro x y ca ffein e, ( l ) j W islicem us & K o rb e r, B e r. 35» 1991t 19®2» H. B i l t z & Stru b e, Ann. Hi 3» 199-2 0 0 , 1916-1917. S e v e ra l t r i a l s w ere made in h e a tin g m e th o x y c a ffe in e a lo n e in a c lo s e d tube- a s w e ll a s i n an open v e s s e l a t v a ry in g te m p e ra tu re s . In a l l c a s e s th e p ro d u c t was r e c r y s t a l l i z ed from h o t a lc o h o l . E x p e rim e n ta l D a ta : Grams M e th o x y c a ffe in e u se d T em p eratu re h e a te d H ours h e a te d C lo se d o r open tu b e ( p a r a f f i n b a th ) Y i e ld , i n grams " , p e rc e n ta g e M e ltin g p o i n t , ( c o r r . 2 2 8 .0 ° ) A n a ly s is $ N itro g e n 1s t 2 170 - 200 ® 12 T r i a 1 s 3rd 4 4 2nd 5t h 2 360 ° 21*0 - 250 ° 170 - 2 1 0 ° 5 4 7 c lo s e d 3 .0 3 .8 9 5 .0 $ 225 - 226 ° 10 225 - 2 3 0 ° c lo s e d open w ith CH3 OH 0 .7 3 5 .0 $ 4 th 7 5 .0 $ open 1 - 1 /2 open 8 .6 0 .5 S6>0$ 2 5 . 0$ 220 - 2 2 2 . 5 ° 225 - 227 ° 2 1 7 -2 2 0 ,4 ° 223 - 22 4 . 5 ° C a lc u la te d D eterm ined 2 4 .4 2 $ 2 5 .O $ (a n h y d .) I t was found t h a t i f an e x c ess o f m ethyl a lc o h o l was u s e d i n a c lo s e d tu b e w ith m e th o x y c a f f e in e , a m ix tu re o f t e t r a m e th y l - u r i c a c id and h y d ro x y c a ffe in e was i n v a r i a b l y o b ta in e d . H e a tin g i n a two p ie c e tu b e f i t t e d to g e th e r w ith a ground g l a s s j o i n t c o n ta i n ­ e d i n a l a r g e t e s t tu b e and th e l a t t e r p la c e d in a p a r a f f i n b a th p ro v ed to be a v e ry good m ethod. The optimum te m p e ra tu re was found to be 180-210° f o r from f o u r to f i v e h o u r s . Ho d i f f e r e n c e was o b se rv e d i n th e y i e l d s o r p u r i t y o f th e te tr a m e th y l u r i c a c id o b ta in e d when t h e re a rra n g e m e n t was p e rfo rm e d i n a c lo s e d tu b e o r i n an open tu b e h a v in g a v e ry sm a ll o p e n in g a t th e to p . I n th e l a s t t r i a l made, any p o s s ib l e t r a c e s o f unchanged m e th o x y c a ffe in e o r hydroxy* c a f f e i n e w ere removed by th e f o llo w in g p ro c e d u re ; The c ru d e p ro d u ct was d ig e s te d on a ste a m b a th w ith 10$ h y d r o c h lo r ic a c id . W ater was added f i n a l l y and th e m ix tu re e v a p o ra t­ ed t o d ry n e s s . The r e s id u e was d is s o lv e d i n a sm all q u a n tity o f h o t w a te r , c a r e f u l l y n e u t r a l i z e d w ith 0 .2 N. b ariu m h y d ro x id e s o lu t i o n to form an i n s o lu b le s a l t w ith h y d ro x y ­ c a f f e i n e , and a g a in e v a p o ra te d to d ry n e s s . The r e s id u e was th e n e x t r a c t e d w ith two to f i v e sm a ll p o r ti o n s o f h o t c h lo ro fo rm . A f te r d i s t i l l i n g o f f th e s o lv e n t , th e t e tr a m e th y lu r i c a c id rem ain ed in a v e ry p u re form . U n le ss th e h e a tin g was n o t lo n g enough, o r a t h ig h enough te m p e ra tu re f o r com plete re a rra n g e m e n t, th e above p ro c e d u re was fou n d u n ­ n e c e ssa ry . P ro p e rtie s ; T e tra m e th y l u r i c a c id m e lte d a t 2 2 5 -2 2 7 °, a f t e r r e c r y s t a l l i z i n g tw ic e from h o t a l ­ c o h o l, w ith o u t d e c o m p o sitio n . I t sublim ed r e a d i l y i f h e a te d a t 200° o r above. I t was fo u n d to be more s o lu b le i n w a te r th a n th e iso m e r. A p p ro x im ately 4 .3 9 g . d is s o lv e d i n 100 g. o f w a te r a t 25° and 3 6 . 2g. a t 100°. I t was s l i g h t l y s o lu b le i n c o ld e th y l a lc o h o l and f a i r l y s o lu b l e in h o t a lc o h o l. A n a ly sis showed t h a t i t c o n ta in e d w a te r o f c r y s t a l ­ 65 l i z a t i o n w h ich was v e ry d i f f i c u l t to remove even i f h e a te d a t 120 - 1300 f o r s e v e r a l h o u r s . I t was s l i g h t l y s o lu b le i n c h lo ro fo rm and v e ry d i f f i c u l t l y s o lu b le in c a rb o n t e t r a ­ c h lo rid e . I t form ed v e ry s le n d e r n e e d le s o u t o f w a te r o r a lc o h o l, and i f allo w e d to r e ­ m ain i n th e s o lv e n t f o r two o r t h r e e days th e s e changed to m o n o c lin ic s i x - s i d e d p ris m s o r p la te le ts . I t was found to be e a s i l y decomposed by a l k a l i , b u t v e ry s t a b l e to w ard s a c id s , and w ith s to o d h e a ti n g i n 10 to 20$ h y d r o c h lo r ic a c id f o r s e v e r a l h o u rs w ith o u t change o r a p p r e c ia b l e d e c o m p o s itio n . T e tra m e th y l - u r i c a c id gave th e m urexide r e a c t i o n v a ry r e a d ily . I t was v e r y b i t t e r i n t a s t e . B. M o le c u la r R earran g em en t o f 8-E thoxy c a f f c in e to 1 , 3» 7-T rim e th y 1 -9 -E th y l- -Uri c A c id . ^ ^ M ethod: OHg-ir - C=0 CHa-N - 0=0 1 ! (240-250°) 1 1 0=0 0 - N-CHa -----_ ---------- > 0=0 C - N-GHS 1 ” ^C-0” C2Ho 1 » ^0=0 CHS-N - 0 - N CHS-N - C - N-C2H6 E thoxy c a f f e in e T rim e th y l - 9 - e t h y l - u r i c a c id . The m ethods o f p r e p a r a ti o n w ere th e same a s f o r th e p r e p a r a tio n o f t e t r a m e th y l - u r i c a c i d e x c e p t t h a t a h ig h e r te m p e ra tu re was u s e d , (ab o u t 2 4 0 -2 5 0 °). However, in t h i s c a s e , a m ix tu re o f 1 , 3 « 7 - tr i m e t h y l - 9 - e t h y l - u r i c a c id and h y d ro x y c a ffe in e was o b ta in e d . Dry e th o x y c a f f e in e was h e a te d in th e p re s e n c e o f ab o u t th e same amount o f a b s o lu te e t h y l a lc o h o l i n a c lo s e d tu b e a t 240-250° f o r te n to tw e lv e h o u rs. The m ix tu re was washed o u t o f th e tu b e w ith sm a ll p o r tio n s o f d i l u t e a lc o h o l. To c r y s t a l l i z e , th e a lc o h o l ic m ix tu re was b ro u g h t to b o i l i n g u n t i l a l l was i n s o l u t i o n , th e n f i l t e r e d h o t and c o o le d . The h y d ro x y c a ffe in e c r y s t a l l i z e d o u t in lo n g s le n d e r n e e d le s , an d th e u r i c a c id compound i n p ris m s. To remove th e h y d ro x y c a ffe in e , th e m ix tu re was n e u t r a l i z e d w ith bariu m h y d ro x id e a n d t h e r e s id u e e x tr a c t e d w ith c h lo ro fo rm a s d e s c r ib e d on page 64 f o r th e p u r i f i c a t i o n o f t e t r a m e t h y l - u r i c a c id . The p ro d u c t was th e n c r y s t a l l i z e d o u t o f h o t 95$ e th y l a lc o h o l . The c r y s t a l s w ere washed and d r ie d i n th e visual manne r , f i n a l l y h e a tin g i n an oven a t 1 0 5 - 1 1 0 ° f o r f o u r to f i v e h o u rs. The m o le c u la r re a rra n g e m e n ts o f n itr o g e n s u b s t i t u t e d im lno e t h e r s ^ ) h a s lo n g b e e n o b s e rv e d by W heeler and Jo h n so n , W islicem us, K orber and G oldschm idt and o t h e r s . I t in v o lv e s th e tr a n s f o r m a tio n o f th e g ro u p in g /« -G x* -N to th e '? -C N g ro u p in g . NR R earrangem ent o f s e v e r a l n itr o g e n s u b s t i t u t e d im lno e th e r s was found to o c c u r most e a s i l y u n d e r th e c a t a l y t i c in f lu e n c e o f a lk y l io d id e , b u t a ls o a p p e a re d to ta k e p la c e by s im p ly h e a ti n g . ( 1 ) ‘ H B i l t z & M arg arete B e rg iu s . W. W i s l i c e m u s & H. K o rb er. Ann. 4 l 4 , 51+” ^ 7 » 1917, a ls o J . Chem. Soc. 1121, 589-90, 1 9 1 7 . B er. 35, 1991, 1902; G. A. 12, 145, 1918. ( 2 ) : L a u d e r. J o u r. Chem. Soc. 8 3 , 4o6, 19°3* W islicem us & Goldschm idt. B ar. 33, 1 ^ 7 , 1900, 66 W ith t h i s i n m ind, th e a tte m p t was made to a c c e l e r a t e th e re a rra n g e m e n t o f e th o x y c a f f e i n e , by h e a ti n g i n th e p r e s e n c e o f e t h y l - i o d i d e . Two gram s o f e th o x y c a f f e in e were h e a te d w ith 0 .3 4 c c . (one m ole) o f e t h y l - io d i d e i n a c lo s e d tu b e a t I 5 Q -I 6 O® f o r e ig h t h o u r s . A f te r rem oving th e io d in e and p u r if y in g th e p r o d u c t, 1 ,8 g , o f e th o x y c a f f e in e were re c o v e re d unchanged (m, p , 139—1^0«5®)* T h is was r e p e a te d , u s in g 1 , 0 g . o f e th o x y c a ff e in e and 0 ,1 7 g. e t h y l - io d i d e and h e a tin g to 2l+0-250« f o r f i v e h o u r s . I n t h i s t r i a l , 0 .2 1 g . o f 1 , 3 , 7 - tr im e th y l 9 - e t h y l - u r i c a c id was form ed (m .p , 1 9 8 -2 0 1 °) o r a 21$ y i e l d . T h is y i e l d was low er th a n t h a t o b ta in e d by h e a ti n g e th o x y c a f f e in e a lo n e a t th e same te m p e ra tu re . Hence i t was c o n c lu d e d t h a t , a s f a r a s e th o x y c a f f e in e was c o n c e rn e d , th e e th y l io d id e had no o b s e rv a b le c a t a l y t i c i n f l u ­ ence i n a id i n g t h e re a rra n g e m e n t. E x p e rim e n ta l d a ta : 1s t M a te ria ls - u s e d , i n gram s. E th o x y c a f fe in e A b so lu te e th y l a lc o h o l T em perature h e a te d Hours h e a te d Open o r c lo s e d tu b e Y ie ld , i n gram s. ” , p e rc e n ta g e M e ltin g p o i n t , ( c o r r . 203 .0 -2 0 4 .0 ® ) A n a ly s is $ N itro g e n 4 5 T r i a :L s 3 rd 2 nd 5 - 2400 - 250 ® 250 - 260 ® 1 0 -1 2 c lo s e d 5 240-245® 4 th 5t h 5 - 5 - 250 - 26 0 ® 245 - 255 ® 8 2 2 8 c lo s e d open c lo s e d open 0 .5 1 .0 0 .5 2 .2 2 .5 6 1 2 . 5$ 2 0 . 0$ 1 0 . 0$ l|4 .0 $ 51 . 2$ 197-199° 194-197® 195 - 200 ® C a lc u la te d 2 3 . 53$ (a n h y d .) 1 9 9 . 6 - 2 0 2 . 8 ® 194-196, D eterm ined 22.7.7$ 21 .8 8 $ (1 , Ha 0) Very h ig h y i e l d s can n o t be ex p ected b e c au se o f th e p a r t i a l c o n v e rs io n to h y d ro x y c a f f e i n e , and a l s o b e c au se o f th e m oderate s o l u b i l i t y o f th e compound i n a l l o f th e s o lv e n t s u s e d . However, upon r e c r y s t a l l i z a t i o n , th e p u r i t y o f t h i s compound was h ig h , s e p a r a t i n g out i n b e a u t i f u l c o l o r l e s s , p r is m a t ic p l a t e l e t s . The optimum c o n d itio n s w hich r e s u l t e d in th e maximum y i e l d were o b ta in e d by h e a ti n g a t 245-260® i n an open o r c lo s e d tu b e f o r a t l e a s t s i x h o u r s . I t was fo u n d e s s e n t i a l to u s e b a riu m h y d ro x id e to remove th e h y d ro x y c a ffe in e , and to c r y s t a l l i z e t h e e x tr a c t e d u r i c a c id tw ic e o u t o f a lc o h o l. P ro p e rtie s : ■2)t 7 _ T rim e n ty l 9 »ethyT “u r i c a c id was found to b e a s t a b l e , w h ite , c r y s t a l l i n e compound, m e ltin g a t 197-199® w ith o u t d e c o m p o sitio n . I t sublim ed r e a d i l y i f h e a te d a b c ie i t s m e ltin g p o i n t . 67 I t c r y s t a l l i z e d o u t i n m o n o c lin ic , a lm o st r e c t a n g u l a r l e a f l e t s . 3* 7 -T rim e th y l 9 - e t h y l - u r i c a c id was q u ite s o lu b le in h o t w a te r, a lc o h o l, and c i o ro fo rm . I t was s l i g h t l y s o lu b le i n c o ld w a te r and a lc o h o l . I t was v e ry s l i g h t l y s o l u b l e i n h o t c a r b o n t e t r a c h l o r i d e . A n a ly s is showed t h a t i t must c o n ta in one m o le c u le o f w a te r o f c r y s t a l l i z a t i o n when c r y s t a l l i z e d o u t o f w a te r o r 95$ a lc o h o l. This was v e ry d i f f i c u l t to rem ove even a f t e r p ro lo n g e d h e a ti n g a t ab o u t 1 2 0 °. C, PYROLYSIS AND MOLECULAR REARRANGEMENT OF 8-N. PROFYLGXTCAFFEINE TO 1 , 3 , 7-TRIMETHYL9-N-PROFYL-URIC ACID.* M ethods: CH3-N - 0=0 • 1 CH3-N - C=0 2 5 O -2 7 O 0 • » 0=C C - N-CHa -------------------- > 0=0 C - N-CH3 ' " ^C-O-CsHv « " ^C=0 CH3-N - 0 - N CH3-N - C - N-C3H7 n - P r o p y l 0 x y -c a f f e in e T r im e th y l- 9 - n - p r o p y l- u r ic a c id . The e a r l i e r a tte m p ts to s e c u re th e m o le c u la r re a rra n g e m e n t o f 8 - n - p r o p y lo x y c a f f e in e by h e a ti n g a lo n e o r i n th e p re s e n c e o f n -p ro p y l a lc o h o l i n a c lo s e d tu b e w ere u n s u c c e s s ­ f u l . The h e a ti n g was done a t te m p e ra tu re s ra n g in g from 235 to 290° f o r two to tw e lv e h o u r s . When h e a te d above 2 50 ® c o n s id e r a b le h y d ro x y c a ffe in e was form ed w ith v a ry in g am ounts o f o t h e r d e c o m p o sitio n p r o d u c ts . T h is e t h e r showed s t a b i l i t y tow ards o rg a n ic b a s e s su c h a s d i m e th y l - a n i l ln e . When b o i l e d i n t h i s s o lv e n t f o r t e n h o u rs t h e r e was p r a c t i c a l l y no d e c o m p o sitio n . I t was a l s o c a p a b le o f b e in g b o i le d i n a c o n c e n tra te d sodium h y d ro x id e s o l u t i o n f o r t h i r t y m in u te s w ith o n ly s l i g h t d e c o m p o sitio n . When n -p ro p y lo x y c ^ ffe in e was b o i le d i n a c e t i c a n h y d rid e o r g l a c i a l a c e t i c a c id f o r two h o u r s , no change o r d e c o m p o sitio n was o b se rv e d . A ls o , when t h i s e t h e r was h e a te d w ith p u re n -p ro p y l e t h e r i n a c lo s e d tu b e a t 250 to 2 7 O0 f o r tw e lv e h o u r s , no change o r a p p r e c ia b le d e c o m p o sitio n r e s u l t e d . However, when th e two e th e r s w ere h e a te d t o g e th e r a t 3 OO t o 3 ° 5° f o r e ig h t h o u r s , a 3 7 . 5$ y i e l d o f 8 - e t h y l c a f f e i n e was p ro d u ce d . T h is r e a c t i o n w i l l be ta k e n up i n more d e t a i l u n d e r th e c o n v e rs io n o f th e c a f f e i n e - e t h e r s to th e S - a l k y l c a f f e i n e d e r i v a t i v e s . I t was th o u g h t t h a t p e rh a p s by h e a tin g n -p ro p y lo x y c a ffe in e a lo n e i n an open tu b e c o n ta in e d i n a p a r a f f i n b a th , more s u c c e s s f u l r e s u l t s c o u ld b e a t t a i n e d tow ards m olecu­ l a r re a rra n g e m e n t. U nder t h i s c o n d itio n h ig h te m p e ra tu re s w ere re a c h e d w ith o u t th e e x c e s s iv e p r e s s u r e e x i s t i n g a s i n a c lo s e d tu b e . A lso th e l i b e r a t e d g a s r e s u l t i n g from t h e slow d e c o m p o sitio n o f th e compound was allo w e d to e sca p e th ro u g h a c a p i l l a r y tu b e a t t h e to p w ith o u t a p p r e c ia b ly a f f e c t i n g th e undecomposed p o r t i o n . T h is p ro c e d u re p ro v e d s u c c e s s f u l i n b r in g in g ab o u t p a r t i a l re a rra n g e m e n t w ith o u t v e ry much d e c o m p o sitio n . In th e f i r s t t r i a l , 5 g . o f anhydrous n - p ro p y lo x y c a ffe in e were h e a te d in an open tu b e c o n ta in e d i n a p a r a f f i n b a th p la c e d on a h o t p l a t e , a t a te m p e ra tu re o f 2^5 to 2 5 5 ® f o r e i g h t h o u rs . A f t e r c o o lin g * th e c o n te n ts o f th e tu b e were washed o u t w ith s e v e r a l s m a ll p o r ti o n s o f h o t w a te r. Enough concd. h y d r o c h lo r ic a c id was added to make th e s o lu ­ t i o n a b o u t 10$ a c i d , and th e n b o i le d f o r a t l e a s t an h o u r. T hus, any o f th e unchanged e t h e r was changed i n to h y d ro x y c a ffe in e . The l a t t e r was removed by c a r e f u l l y n e u t r a l i z ­ in g w ith s a t u r a t e d b arium h y d ro x id e s o l u t i o n , e v a p o ra tin g to d ry n e s s and e x t r a c t i n g th e r e s i d u e w ith c h lo ro fo rm ; The r e s id u e was c r y s t a l l i z e d o u t o f h o t w a te r i n w hich i t was • Hot yet conclusively proven. 62 q u i t e s o lu b l e . Upon c o o lin g , c l u s t e r s o f c o l o r l e s s , lo n g p l a t e l e t s o r b lu n t n e e d le s s e p a r a te d o u t o f th e s o l u t i o n . The p ro d u c t was r e c r y s t a l l i z e d a g a in o u t o f h o t w a te r, an d a f t e r becom ing a i r d ry th e c r y s t a l s were d r ie d a t IO 5 to 110° f o r s e v e r a l h o u rs . T h is compound assum ed to be th e t r i m e t h y l- 9 - n - p r o p y l- u r i c a c id m e lte d a t I 3 6 .O to 138.1+®. A 7 . 2 $ y i e l d was o b ta in e d . T h is e x p e rim e n t was l a t e r r e p e a te d u s in g a s l i g h t l y h ig h e r te m p e ra tu re ( 25 O-27 O0 ) f o r t e n h o u r s . . I t was o b s e rv e d i n t h i s t r i a l t h a t a f t e r th e e th e r had been h e a te d f o r a b o u t two h o u rs a t 25 O to 2 6 0 ° , th e m e lte d compound changed e n t i r e l y to a s o l i d c r y s t a l ­ l i n e m ass. H ence, i t was d e c id e d t h a t th e u s u a l d e c o m p o sitio n o f th e e t h e r to hydroxy­ c a f f e i n e h ad ta k e n p l a c e . D u rin g t h i s p e r io d o f h e a ti n g , how ever, v a p o rs coming from th e s o l i d mass co n densed on th e s id e s o f th e u p p e r p o r tio n o f th e tu b e a s an o i l y l i q u i d and r a n down to th e b o tto m o f th e tu b e . Hence i t was d e c id e d to c o n tin u e th e h e a tin g f o r s e v e r a l more h o u rs a t a te m p e ra tu re o f 260 t o 2J0°, A f t e r ab o u t f i v e h o u r s ,t h e s o l i d m a t e r i a l i n th e tu b e changed n e a r l y c o m p le te ly to an o i l y l i q u i d . The h e a tin g was c o n tin u e d a t th e same te m p e ra tu re f o r t h r e e h o u rs , o r u n t i l i t was o b se rv e d t h a t th e r e a c t i o n was c o m p le te d and f u r t h e r h e a tin g o n ly caused d e c o m p o sitio n . A f te r a t o t a l o f te n h o u rs h e a tin g , th e tu b e was c o o le d and th e c o n te n ts rem oved w ith h o t w a te r a s b e f o r e . B ecause o f some d e c o m p o s itio n , th e aqueous s o lu t i o n was c l a r i f i e d w ith an im al c h a r c o a l. To th e s l i g h t l y y e llo w f i l t e r e d s o lu t i o n 5 c c , o f concd. h y d r o c h lo r ic a c id was ad d ed , an d i t was b o i l e d g e n tly f o r a t l e a s t o n e - h a lf an h o u r o r u n t i l th e volume o f l i q u i d had b e e n re d u c e d to about 25 c c . The s o lu t i o n was n e u t r a l i z e d w ith concd, sodium h y d ro x id e an d th e n sh ak en o u t w ith s i x , 25 c c . p o r ti o n s o f c h lo ro fo rm . A f te r d i s t i l l i n g o f f th e s o lv e n t th e r e s i d u e was c r y s t a l l i z e d o u t o f h o t e th y l a lc o h o l, i n w hich i t was q u ite s o lu b l e . Upon c o o lin g , th e compound form ed c o l o r l e s s s h o r t n e e d le s o r c l u s t e r s o f n e e d le s . A f t e r th e t h i r d r e c r y s t a l l i z a t i o n o u t o f h o t a lc o h o l , th e p ro d u c t was f i r s t a i r d r i e d , and th e n d r ie d i n an oven a t 105 to 110° f o r tw en ty h o u rs . A 35*51° y i e l d was o b ta in e d . The m e ltin g p o i n t was 13S.8 to lU 0 .6 ° , w hich a g re e d w ith t h a t o b ta in e d in th e firs t tria l. P r o p e r t i e s an d A n a ly s is . A n a ly s is : H itr o g e n (by m ic r o -K je ld a h l) 1 s t T ria l 2nd T r i a l C a lc u la te d Anhydrous 1 H3 O 2 2 . 22 $ 2 0 .7 ^ $ D eterm ined. 2 1 .0 0 $ 2 0 . 7^ E v id e n tly t h i s compound c o n ta in e d one m o lecu le o f w a te r o f c r y s t a l l i z a t i o n . F u r th e r p r o o f o f th e s t r u c t u r e sh o u ld be made by ru n n in g c arb o n and hydrogen d e te rm in ­ a t i o n s , and p e rh a p s by th e d e te r m in a tio n o f th e m o le c u la r w e ig h t. A v e ry c o n c lu s iv e p r o o f f o r t h e c o n f ig u r a tio n c o u ld be made by th e p r e p a r a ti o n and i d e n t i f i c a t i o n o f th e d e c o m p o sitio n p r o d u c ts by o x id a tio n w ith c h lo r in e w a te r o r d e c o m p o sitio n w ith s tr o n g a l k a l i . P ro d u c ts a n a la g o u s to th o se from t e t r a m e th y l - u r i c a c id and t r i m e t b y l - 9 - e t h y l u r i c a c i d by o x id a tio n o r o t h e r d eco m p o sitio n methods sh o u ld be o b ta in e d . These r e a c t i o n s a r e d e s c r ib e d i n d e t a i l i n th e h i s t o r i c a l and d e s c r i p t i v e p a r t o f t h i s t h e s i s . The p r o p e r t i e s o f th e tr im e th y l- 9 - n - p r o p y l- u r i c a c id p re p a re d i n th e two t r i a l s m en tio n e d w ere fou n d to be a s f o llo w s : I t was v e ry s o lu b le i n h o t w a te r a s w e ll as h o t a lc o h o l , and m o d e ra te ly s o lu b le i n th e s e s o lv e n ts when c o ld . I t was q u i t e s o lu b le in c h lo ro fo rm . I t c r y s t a l l i z e d i n th e form o f lo n g p rism s o r b lu n t n e e d le s , and u s u a l l y o c c u rr e d a s * c l u s te r s o r r o s e t t e s . The m e ltin g p o in t was from I 3 8 .8 to l4 0 .6 ® .w h ich i s a b o u t te n d e g re e s h ig h e r th a n th e o r i g i n a l compound b e fo r e re a rra n g e m e n t. I t su b lim ed v e r y s l i g h t l y when h e a te d above i t s m e ltin g p o i n t. A f te r c o o lin g , th e m e lte d compound 69 c o n ta in e d i n a m e ltin g p o in t c a p i l l a r y tu b e , s o l i d i f i e d to a c l e a r tr a n s p a r e n t s o l i d . j.n is compound p r o v e d .to lie v e ry " b it te r i n t a s t e . I t gave a pronounced m urexide r e a c t i o n . As can be o b s e rv e d i n th e m ethods o f p r e p a r a ti o n em ployed, t h i s compound was v e ry s t a b l e tow ard b o i l i n g (a p p ro x , 10$) h y d r o c h lo r ic a c id . However i t p ro v e d to b e e a s i l y decompos­ ed when h e a te d a s h o r t tim e on th e steam b a th w ith d i l u t e sodium h y d ro x id e . T hese p r o p e r t i e s fo llo w c l o s e l y th o s e g iv e n f o r th e p re c e d in g t e t r a a l k y l u r i c a c i d s . However f u r t h e r p r o o f s h o u ld be g iv e n b e f o r e i t may be c o n c lu s iv e ly s t a t e d t h a t th e compound i s t r i m e t h y l- 9 —n—p r o p y l - u r i c a c id . A lso th e m echanism o f t h i s r e a c t i o n , w hich r e s u l t e d i n th e in te r m e d ia te f o rm a tio n o f a s o l i d s u b s ta n c e ( a p p a r e n tly h y d r o x y c a f f e in e ) , a n d an o i l y l i q u i d , s h o u ld b e m ore th o ro u g h ly i n v e s t i g a t e d . Time d id n o t p e rm it more th o ro u g h work a lo n g t h i s l i n e . E x p e rim e n ta l d a t a : Gms. n - p r o p y lo x y -c . used. *4 R e s u ltin g Compound R ecovered. Grams Temp, Hours Name y ie ld M. P . h e a te d h e a te d ( i n c lo s e d tu b e ) n -p ro p y lo x y c a f f e in e 2 . 5 128 - 13 0 ° 5 c c . a b s . 235-2*40° *4 C3 H7 OH H eated w ith 10 c c . a b s . 2*40-250° C3H70H 12 H y d ro x y c a ffe in e n - p ro p y lo x y c a ffe in e 10 c c . a b s . 250 - 260 ° C3 H7 OH 2 5 5 c c . p ro p y l H y d ro x y c a ffe in e +Decomp. p ro d u c t l.*42 0 .2 0 .5 337-3*40° 87 - 90 ° 330-333° 1 .1 128 - 1 3 0 . 5 ° 260 - 270 ° 10 Hydro x y c a f f e in e Decomp, p ro d u c t 0.*4 330-332° 280- 290 ° 10 H y d ro x y c a ffe in e 0 .7 337-339° 250 - 260 ° 2 H y d ro x y c a ffe in e p r o p y lo x y c a ff e in e o.*4 2 .7 330 - 3 *40° 126 - 129 ° n -p ro p y lo x y c a f f e in e 1 ,3 127 - 130 ° 260- 270 ° 12 300 - 305 ° 8 e th y lc a ife in e 0 .7 5 1 8 5 -1 8 7 .5 ° 2*45-255° (open tu b e ) 8 + T rim ethyl 9 -p ro ­ p y l - u r i c a c id H y d ro x y c a ffe in e 0 .3 6 1 3 6 . O-1 3 8 .u ° 0 .1 3*40-3*42° 2 .1 3 1 3 8 . 8 - 1 *40. 6 ° e th e r 2 c c . p ro p y l e th e r 250-270 (open tu b e ) 10 4 -tT rim ethyl 9 -p ro p y l^ u r ic a c id ♦ v i i t r a t e from hydroxycaffeine was n e u t r a l i z e d w ith barium h y d ro x id e e v a p o ra te d to d ry n e s s and e x tr a c t e d w ith c h lo ro fo rm . ++ C l a r i f i e d w ith anim al c h a rc o a l. 70 D. MOLECULAR REARRANGEMENT OP 3-A1LYL0XYCATTSIITE TO 1 , 3 , 7-TRIMETHYL-9-ALLYL-URIC ACID. (A new compound) Method CH3-N ' 0=0 ' OHa-N - C=0 » 0 - N-CHa H2 H H2 ■ ^C-C-C - 0 = 0 C - n' - - I.7Q-- 200° ,.> CH3-N - 0=0 i t 0=0 0 - N-CHa i « ^0=0 OHa-N - C - N H a H - C H2 =f i B ein g an u n s a tu r a te d e th e r* , a ll y lo x y c a f f e i n e was s u s p e c te d o f "being r e a d i l y t r a n s ­ form ed i n t o th e c o rre s p o n d in g a l l y ! —u r i c a c i d hy h e a t. The r e s u l t s o f t h r e e t r i a l s showed t h a t t h i s s u p p o s itio n was c o r r e c t . In th e f i r s t a tte m p t, 2 g . o f tw ic e r e c r y s t a l l i z e d anhydrous a l l y l o ^ c a f f e i n e were h e a te d a lo n e i n a c lo s e d tu b e a t 200-204° f o r te n h o u rs. A f te r c o o lin g th e t u b e ,a r e d d is h brown c l e a r s o l i d mass was form ed. I t was fo u n d to be q u i te s o lu b le i n h o t a lc o h o l from w hich i t was c r y s t a l l i z e d tw ic e . A lo w e r te m p e ra tu re was t r i e d i n th e second t r i a l . The e t h e r ( 1 .3 g . ) was h e a te d i n an open tu b e h a v in g a s m a ll op en in g a t th e to p . T his was h e a te d in s id e a la rg e rte s t tu b e c o n ta in e d i n a p a r a f f i n b a th k e p t a t 1 70-180° f o r f o u r h o u rs . The same am berc o lo r e d m ass was form ed. The c ru d e p ro d u c t was removed from th e tu b e by d i s s o l v in g in h o t a lc o h o l ; th e l a t t e r was th e n removed by e v a p o ra tin g to d r y n e s s . About 15 c c . o f 10$ h y d r o c h lo r ic a c id w ere added to th e r e s id u e and th e m ix tu re d ig e s te d on th e steam b a th f o r a b o u t f o r t y - f i v e m in u te s . W ater was added and th e p ro d u c t e v a p o ra te d down to d ry n e s s , so t h a t p r a c t i c a l l y a l l o f th e h y d r o c h lo r ic a c id h ad e v a p o ra te d o f f . The r e s id u e was ta k e n up i n h o t w a te r, th e n n e u t r a l i z e d w ith barium h y d ro x id e , and e v a p o ra te d to d r y n e s s . The r e s id u e was e x tr a c t e d w ith h o t c h lo ro fo rm , and a f t e r rem oval o f th e l a t t e r , t h e p ro d u c t was c r y s t a l l i z e d tw ic e from 6 to 8 cc. o f h o t a lc o h o l. A v e ry p u re p ro d u c t was o b ta in e d . In th e t h i r d t r i a l a much h ig h e r te m p e ra tu re was u s e d . Two g . o f a l l y l o s y c a f f e i n e w ere h e a te d i n a c lo s e d tu b e a t 240-250° f o r f i v e h o u rs . The r e s u l t i n g p ro d u c t was c r y s t a l l i z e d from h o t a lc o h o l. I n t h i s c a se a m ix tu re o f h y d ro x y ca f f e in e and t r i m e t h y l 9 - a l l y l - u r i c a c id was o b ta in e d , w ith a sm a ll amount o f d e c o m p o sitio n . T h is i n d i c a t e d , t h a t 240-250° was a much to o h ig h te m p e ra tu re to employ. E x p e rim e n ta l d a ta ! Grams A l l y lo s y c a f f e i n e u s e d T em perature H ours h e a te I Open o r c lo s e d tu b e Y ie ld , t h e o r e t i c a l 11 , a c t u a l 11 , p e rc e n ta g e M e ltin g p o i n t 1st 2 .0 200-204° 10 c lo s e d 2 .0 0 .7 3 5 .0 $ l4 5 -i4 s ° T r i a l s 2nd 1 .3 170 - 1 85 ° 4 open 1 .3 0 .7 53.3$ 143 * 0 - 144 . 5 ° 3 rd 2 .0 240-250° 5 c lo s e d 2 ,0 1 ,0 5 0.0$ 1 3 9 . o- i 4 i 71 A n a ly s is : N itro g e n Carbon H ydrogen C a lc u la te d 22.1*0$ 52 . 80 # 5.6*+# D eterm ined 22,1+2# 52.9955 5.7355 I f l a r g e r q u a n t i t i e s o f a ll y lo x y c a f f e i n e had "been u s e d , no doubt l a r g e y i e l d s w ould h av e b e e n o b ta in e d . The g r e a t e s t l o s s o c c u rre d i n c r y s t a l l i z i n g th e t r i m e t h y l a l l y l - u r i c a c i d b e c a u se i t was m o d e ra te ly s o lu b le i h c o ld a lc o h o l. U n le ss th e f i l t r a t e was c o n c e n tr a te d down to a sy ru p y c o n s is te n c y , o n ly a b o u t a 50 # y i e l d c o u ld be o b ta in e d when w orking w ith a s m a ll q u a n ti ty . F u lly a s good r e s u l t s were o b ta in e d by h e a ti n g in an open tu b e a s when a c lo s e d tu b e was u s e d . By h a v in g a v e ry sm a ll o p e n in g a t th e t o p , a v e r y s m a ll p o r t i o n o f th e v a p o riz e d m a t e r i a l e sca p e d . D ecom position a t te m p e ra tu re s up to 20 0 ® was v e ry s l i g h t , b u t was n o t ic e a b l e a t 250 ®. P ro p e rtie s : 3» 7 - T r i m e t h y l- 9 - a l l y 1 -u r i c a c id m e lte d a t 11+3.0 to lH 4 , 5° , a f t e r r e c r y s t a l l i z in g from a l c o h o l , w ith o u t d e c o m p o sitio n . I t sublim ed m o d e ra te ly a t t h i s te m p e ra tu re , b u t n o t a s much a s t e t r a m e t h y l - u r i c a c id . I t was v e ry s t a b l e tow ard d i l u t e a c id s b u t v e ry s u s c e p t ib l e to d e c o m p o sitio n by a lk a li, 1 , 3* 7 - T r i m e t h y l - 9 - a l l y l - u r i c a c id was q u i te s o lu b l e i n h o t e t h y l a lc o h o l from w hich i t c r y s t a l l i z e d upon c o o lin g a s c o l o r l e s s e lo n g a te d p l a t e l e t s . I t o f te n form ed c l u s t e r s o r r o s e t t e s o f w edge-shaped p ris m s . T his compound was q u i te s o lu b le in h o t w a te r an d m o d e ra te ly s o lu b le i n c o ld w a te r. I t was a ls o v e ry b i t t e r i n t a s t e . I t gave a p ro n o u n ce d rauread.de r e a c t i o n . E, PYROLYSIS OP OTHER ALKYL-ETHERS OP CAFFEINE. I t was en d eav o red to b r in g ab o u t th e m o le c u la r rea rra n g e m e n t o f s e c -p ro p y lo x y c a f f e i n e i n a m anner s i m i l a r to t h a t w hich b ro u g h t ab o u t th e p a r t i a l c o n v e rs io n o f th e n - p ro p y lo x y c a f f e in e to th e t r i m e t b y l- 9 - p r o p y l - u r ic a c id . The a tte m p t was d is c o n tin u e d , b e c a u s e o f th e extrem e e a s e w ith w hich t h i s se co n d a ry d e r i v a t i v e was c o n v e rte d i n to h y droxy c a f f e in e . S e v e ra l u n s u c c e s s f u l a tte m p ts were u n d e rta k e n to b r i n g ab o u t th e mol­ e c u l a r re a rra n g e m e n t o f n - b u ty lo x y c a f f e in e . F o llo w in g th e p ro c e d u re fou n d s u c c e s s f u l f o r t h e re a rra n g e m e n t o f n - p r o p y lo x y c a f f e in e , n - b u ty lo x y c a f f e in e was h e a te d i n an open tu b e a t 260-290® f o r a t l e a s t tw e n ty h o u rs . A f t e r two to t h r e e h o u rs , th e e t h e r was t r a n s ­ form ed to a s o l i d c r y s t a l l i n e mass and rem ained i n t h a t c o n d itio n w ith g ra d u a l d a rk e n in g a n d d e c o m p o sitio n u n t i l th e end o f th e e x p e rim e n t. L ess th a n h a l f o f th e r e s u l t i n g p r o d u c t was re c o v e re d a s h y d r o x y c a f fe in e . At th e same tim e , anhydrous h y d ro x y c a ffe in e was h e a te d a t th e same te m p e ra tu re and d u r a tio n o f tim e. At f re q u e n t i n t e r v a l s , 1 c c . p o r t i o n s o f n - b u ty l a lc o h o l w ere added. No r e a c ti o n o c c u rre d , and v e ry l i t t l e decom posi­ t i o n r e s u l t e d . The h y d ro x y c a ffe in e was re c o v e re d unchanged. S e v e ra l -u n su c c e ssfu l a tte m p ts were a l s o made to s e c u re th e m o le c u la r re a rra n g e m e n t o f n-am yloxy and n —hex y lo x y c a f f e in e . The r e s u l t s o f th e p y r o l y s i s o f th e s e a l k y l - e t h e r s o f c a f f e in e a r e g iv e n in th e fo llo w in g t a b l e : 72 dram s e t h e r u s e d H eated w ith 5 g. sec-Propyloxycaffeine — 5 g . • n-Butyloxycaffeine 5 g . n -B u ty lo x y - 5 cc. abs. Temp. h e a te d Hours h e a te d 250-260® 2 H y d ro x y c a ffe in e 25 O- 2650 2 n -B u ty lo x y c a ffe in e J m8 250 - 265 ® H y d ro x y c a ffe in e decomp. p ro d u c ts 8 caffeine butyl ale. 5 g . n -B u ty lo x y c a ffe in e R e s u ltin g Compound R ecovered Confound Y ie ld M. P. 270-290® (open tu b e ) 20 H y d ro x y c a ffe in e decomp. p ro d u c ts 2 g . n -B u ty lo x y c a f f e in e 3*+2® 2 g , n-A m yloxyc a ffe in e 270-280® 2 g . Iso-A rayloxy- 10 c c . I N . c a f f e i n e Na Amyl a te 200-210® 8 2 g. Iso-A m yloxyc a ffe in e 280-290® 12 2 .g . n -H e x y lo x y c a ffe in e 270-280® 2 g. n -B u ty lo x y - 0 . 6 l c c . c a f f e in e C3H5I 1 /4 H y d ro x y c a ffe in e decomp. p ro d u c ts 4 .0 3*0 340-342® 89-91° 330-340® 2 .0 325 - 3 2 8 , 0 ° 0 .5 335-339° 5 Decomposed Iso-Am yl o x y - c a f f. 1 .5 1 2 5 .5 -1 2 6 .5 ° H y d ro x y c a ffe in e 1 ,0 325 - 32 8 ® 5 Decomp. p r o d u c ts r e s id u e p o r ti o n c ry s ta lliz e d O.O 5 137-140° 1 5 0-l60« 8 B u ty l oxy c a f f e in e 2 .0 2 g. n-Butyloxy- 0.6l cc. caffeine C2H6I 230-240® 6 Decomposed 1 g. n-Amyloxy- 0.29 cc. caffeine CsHbI 240-250° 5 H y d ro x y c a ffe in e & 0 .1 o th e r decomp, p r o . 1 g. n-Hexyloxy- 0.34 cc. 2 UO-25 O® 1 Decomp. p ro d u c ts R esidue c a ffe in e — CgEgl 8 8 . 8- 8 9,6® 325 - 332 ° 0 .2 249-255® I t was o b s e rv e d t h a t th e h ig h e r e t h e r - c a f f e i n e d e r i v a t i v e s when h e a te d up to 2 5 O® a lo n e f o r n o t o v e r two h o u rs were n o t a p p re c ia b ly changed. However when t h e y were h e a te d a t te m p e ra tu re s above 25 O® o r f o r o v e r two h o u rs t h e i r c o n v e rs io n to h y d r o x y c a ffe in e and v a r io u s d e c o m p o sitio n p ro d u c ts was f a i r l y r a p i d . E th y l- io d id e had no c a t a l y t i c e f f e c t i n a id in g m o le c u la r rea rra n g e m e n t o f th e h ig h e r e t h e r s , o r i n form ing t r i m e t h y l - 9 - e t h y l - u r i c a c i d . 73 HEABBANGEMEHT OS' « . B M TO 1 , 3 , 7“TRIMETHYL-9-BENZYL-URI0 M ethod: CHa-N — C=0 i i o=c . CHs-H - 0=0 1 c - n -ch 3 « C—0—CH3—C6Hg 200 ® ch3- n - c - n B en zy lo x y c a f f e in e 1 0=C C - N-CHa » " Nc»o CHa-N - C - N-CHjs-OeHe T r im e th y l- 9 - b e n z y l- u r ic a c id . I n a l l th e t r i a l s , e x c e p t th e f i f t h , th e anhydrous b e n z y lo x y c a ffe in e was h e a te d i n a c lo s e d tu b e a t te m p e ra tu re s ra n g in g from 200 ® to 205 ® f o r two to t e n h o u rs to d e te rm in e th e optimum c o n d itio n s f o r e n t i r e re a rra n g e m e n t. The c o n te n ts o f th e tu b e w ere washed o u t w ith h o t a b s o lu t e e th y l a lc o h o l , c o n c e n tr a te d down somewhat, and s e t away f o r a day o r m ore to c r y s t a l l i z e . A f t e r rem oving th e c r y s t a l s , th e f i l t r a t e was e v a p o ra te d down to 3 o r 4 c c . o f d i l u t e d w ith w a te r (p ro d u c t was found to be d i f f i c u l t l y s o lu b le i n w a te r) i n o r d e r to o b t a i n a maximum y i e l d . B oth crops o b ta in e d w ere c r y s t a l l i z e d th e second tim e o u t o f h o t a lc o h o l , and th e f i l t r a t e c o n c e n tra te d down and d i l u t e d w ith w a te r a s b e ­ f o r e . The m e ltin g p o in t rem ained c o n s ta n t a f t e r th e seco n d c r y s t a l l i z a t i o n , and th e c r y s t a l l i n e fo rm s w ere m o stly s i x - s i d e d , r a t h e r t h i c k , l u s t r o u s , c o l o r l e s s p l a t e l e t s . I t m e lte d a t 1 S0 . 0 - 1 S2 . 0 ®. I n th e f i f t h t r i a l , a f t e r w ashing o u t th e tu b e w ith a lc o h o l and e v a p o ra tin g o f f th e l a t t e r , th e p r o d u c t was d ig e s te d i n 10 $ h y d r o c h lo r ic a c id fo r* o n e h o u r o r m ore, f o r th e p u rp o s e o f c o n v e r tin g any o f th e unchanged e th e r i n t o h y d ro x y c a ffe in e . The h y d r o c h lo r ic a c i d was n e a r l y e v a p o ra te d o f f and th e h y d ro x y c a ffe in e rem oved from th e r e s id u e by th e b a riu m h y d ro aa d e m ethod, p r e v io u s ly d e s c r ib e d . The r e s id u e was d is s o lv e d in a lc o h o l and c l a r i f i e d w ith anim al c h a r c o a l, f i l t e r e d , and allo w e d to c r y s t a l l i z e . By c o n c e n tr a tin g an d d i l u t i n g th e f i l t r a t e w ith w a te r , an a lm o st t o t a l re c o v e ry was made. The p ro d u c t was v e r y p u re and showed e lo n g a te d , m o stly r e c t a n g u l a r , t h i n l u s t r o u s p l a t e l e t s , m e ltin g a t 137 to 189,2® , E x p e rim e n ta l d a ta : Grams B en zyloxycaffein e used Temperature heated H ours heated 1st 2nd 5 2 250 - 260 ° 2 ^ th 5t h 5 5 5 200 - 205 ® 23 O- 2 HO® 250 - 2 6 5 ® 2 U5—255 ® 10 6 3 8 c lo s e d c lo s e d s i x - s id e d p la te le ts re c t. & h ex . p i t . hex. p la te le ts 1 .7 3 5 .0 ^ 1.0 50 . 0 $ 1.0 20 . 0$ Open or c lo sed tube c lo s e d C r y s ta llin e form o f product Y i e ld , a c t u a l " , p e rc e n ta g e T r i a l s 3r d c lo s e d open n eed les & elong. th in p la te le ts p la te le ts 1 .^ 2 3 .0 $ 1 .5 3 0 . 0$ 7^ le t 178-181° M e ltin g p o i n t T r i a l s 2nd 3rd 4 th 1 8 0 .2 - lS l.g o 1 7 9 .8 -1 8 2 ° 166 - I 9 O0 5t h 292-2940 ii , a f t e r d i g e s t in g i n HC1 A n a ly s is : N itro g e n Carbon Hydrogen 1 8 5 -1 8 7 .5 ° C a lc u la te d 187-189*2° D eterm ined 18.0654 17.9154 60.0054 5 9 . 37 $ 5*3754 5 .4 6 $ 1 7 .8 8 # 1 8 .0 2 $ D is c u s s io n : I t i s e v id e n t t h a t h e a tin g a t 200 to 205° f o r t e n h o u rs (u n d o u b te d ly a much s h o r t e r p e r i o d w ould h av e been s u f f i c i e n t ) was s u f f i c i e n t to b r in g about mfl-Hmnm re a rra n g e m e n t a n d gave th e maximum y i e l d . The i n c r e a s e i n th e m e ltin g p o in t from 180-182° to 187-189° by d i g e s t i n g i n 10 to 20$ h y d r o c h lo r ic a c id i s h a rd to e a p la in . The c r y s t a l s t r u c t u r e a l s o changed from t h ic k h e x a g o n al p l a t e l e t s to v e ry t h i n e lo n g a te d r e c t a n g u l a r p l a t e l e t s . The p r o d u c t b e f o r e t r e a t i n g w ith h y d r o c h lo r ic a c id may have been an e q u ilib r iu m m ix tu re o f t h e b e n z y l e t h e r and th e re a r ra n g e d b e n z y l- u r ic a c id . However, no h y d ro x y c a ffe in e was rem oved a f t e r th e a c id d i g e s t io n . P e rc e n ta g e o f n itr o g e n rem ained p r a c t i c a l l y th e same i n a l l c a s e s . The compound o b ta in e d in th e f i f t h t r i a l was c o n s id e re d to be th e m ost p u r e t r im s thy]-, 9 - b e n z y l- u r ic a c id . P ro p e rtie s : The m e ltin g p o i n t was 1 8 7 .0 to 1 8 9 ,2 ° , w ith no d e c o m p o sitio n a t t h i s te m p e ra tu re . T his compound d id n o t n o t ic e a b l y su b lim e when h e a te d a s h ig h a s 25 5 ° . The v a p o rs g iv e n o f f co n densed and ra n b a c k a s an o i l y l i q u i d . As d is c u s s e d ab o v e, i t was found v e r y s t a b l e to w a rd s a c i d s , q u i t e s o lu b le i n h o t a lc o h o l and m o d e ra te ly s o lu b le i n c o ld a l c o ­ h o l . I t was found s l i g h t l y s o lu b le i n h o t w a te r and v e ry d i f f i c u l t l y s o lu b le i n c o ld w a te r . T his compound c o n ta in e d no w a te r o f c r y s t a l l i z a t i o n a s d id th e a lk y l u r i c a c i d s . I t was v e ry b i t t e r in t a s t e . 0 . PYROLYSIS OP 8-PHMY1QXYCAFFEIRE, g-PARAHYDROXYPHS-TYLOXYCAFFEINB AND g-FHENYLETHOXYCAFFEINE. Two grams o f 8 -p h e n y lo sy c a f f e in e w ere h e a te d i n a c lo s e d tu b e a t 270 to 280° f o r f i v e h o u rs . S l i g h t d e c o m p o sitio n r e s u l t e d . However 1 .4 g . o f th e unchanged e t h e r were re c o v e re d by c l a r i f y i n g and c r y s t a l l i z i n g th e p ro d u c t from h o t d i l u t e a lc o h o l, ( m e ltin g p o i n t 1 3 9 . 0 - l 4 l . 6 ° ) . U n d o u b ted ly , h e a tin g a t a s t i l l h ig h e r te m p e ra tu re would r e s u l t i n c o n s id e r a b ly more d e c o m p o sitio n . Two grams o f 8 -p a ra h y d ro x y p h e n y lo x y c a ffe in e w e re h e a te d i n a c lo s e d tu b e a t 270 to 280° f o r f i v e h o u r s . A d a rk c o lo re d m ass rem ained i n th e tu b e , and by th e o d o r, c o n s id ­ e r a b l e d e c o m p o sitio n had ta k e n p la c e . The c o n te n ts was d is s o lv e d i n h o t d i l u t e a lc o h o l , c l a r i f i e d w ith an im al c h a r c o a l, and a llo w e d to c r y s t a l l i z e by c o n c e n tr a tin g th e s o l u t i o n t o a s m a ll volum e. The r e s u l t i n g p ro d u c t t h a t s e p a r a te d o u t was r e c r y s t a l l i z e d a g a in . A y i e l d o f O.3 5 g . o f th e unchanged 8 -h y d ro x y p h e n y lo x y c a ffe in e was re c o v e re d , m e ltin g a t 75 - 2 0 5 . 5 0 . The r e s t o f th e m a t e r i a l l e f t i n th e d i l u t e a lc o h o l ic f i l t r a t e c o n s is te d o f a gummy d i s c o l o r e d m ass. 2 0 3 .0 Two g . o f p h e n y le th o x y c a f fe in e w ere h e a te d i n a c lo s e d tu b e a t 200 to 210° f o r f o u r to f i v e h o u r s . The r e s u l t i n g p ro d u c t was v e ry s l i g h t l y d i s c o l o r e d and a f t e r c r y s t a l l i z i n g o u t o f h o t a lc o h o l , 1 .8 g . o f th e unchanged p h e n y le th o x y c a f fe in e was r e ­ c o v e re d w hich m e lte d a t lU 2 .2 to lh h .8 ® . To d e te rm in e w h e th e r a h ig h e r te m p e ra tu re would have any e f f e c t , 5 g . o f th e e t h e r w ere h e a te d a t 260 t o 270° f o r two and o n e - h a lf h o u rs in a c lo s e d tu b e . The c o n te n ts o f th e tu b e h a d become c o n s id e r a b ly d is c o lo r e d . Upon w ashing th e m a t e r i a l ou t o f th e tu b e w ith 300 c c . a lc o h o l i t was found t h a t ab o u t 1 g . o f gummy m a t e r i a l rem ained in s o l u b l e i n th e h o t a l c o h o l . Upon d r y in g t h i s r e s id u e i t was found to m e lt p a r t i a l l y a t 50-60° and h a d a s tr o n g a ro m a tic o d o r s i m i l a r to th e p h e n y le th y l a lc o h o l . The p ro d u c t w hich c r y s t a l l i z e d o u t o f t h e a lc o h o l c o n s is te d o f 2 .6 g . o f h y d r o x y c a f fe in e , m e ltin g a t 335 to 3 ^ 0 ° . The re m a in d e r o f th e m a t e r i a l l e f t a f t e r e v a p o ra tio n o f th e f i l t r a t e was a gummy m ass h a v in g an a ro m a tic o d o r. I t was e x p e c te d t h a t t h i s e t h e r would show a t l e a s t p a r t i a l rea rra n g e m e n t by h e a t ­ i n g , b e in g th e n e x t hom ologue above b e n z y lo x y c a ffe in e . However, th e r e s u l t s o b ta in e d by h e a t i n g a t te m p e ra tu re s ra n g in g from 200 to 27 O® showed no t r a c e s o f a r e a r ra n g e d p r o d u c t. 17. THE CONVERSION OF THE 8-ALKTL-ETHERS OF CAFFEINE AND HYDROXYCAFFEINE TO 8-METHYL AND S-ETHYLCAFFEINE BY KEATING IN THE PRESENCE OF ALIPHATIC ACID ANHYDRIDES AND ETHERS. A. S-METHYLCAFFEINE.U) M ethods: CHa-N - C=Q 1 0=0 1 C - N-CH3 « ^C-O-R CH3-N - C - N^ 1 260-270® + 0=(COCH3 ) 2 ---------------- > 14-5 h r s . CH3 -N » 0=C » CHa-N - C=0 t C - N-CH3 +R-C00CH3+C0B » ^C-CHa C - The anhydrous a l k y l e th e r compound was h e a te d i n a c lo s e d tu b e w ith an e x c ess o f r e d i s t i l l e d (1 3 7 -1 3 8 °) a c e t i c a n h y d rid e a t a te m p e ra tu re o f 260 - 270 ° f o r a b o u t f o u r to f i v e h o u r s . A f te r c o o lin g , th e somewhat d is c o lo r e d c o n te n ts o f th e tu b e were washed o u t w ith h o t a lc o h o l and e v a p o ra te d to d ry n e s s on th e steam b a th . The r e s id u e was th e n d is s o l v e d i n ab o u t 100 c c , o f h o t w a te r and c l a r i f i e d by ad d in g an im al c h a r c o a l, and b o i l i n g a few m in u te s . I t was th e n f i l t e r e d and th e f i l t r a t e c o n c e n tra te d down to IO - 1 5 cc A f t e r c o o lin g a t a low te m p e ra tu re , th e m e th y lc a ffe in e c r y s t a l l i z e d u s u a l l y a s c l u s t e r s o f v e ry sm a ll n e e d le s o r p l a t e l e t s . The p ro d u c t was r e c r y s t a l l i z e d o u t o f 95 ^ e t h y l a lc o h o l , fo rm in g l u s t r o u s , w h ite , t h i n p l a t e l e t s . The f i l t r a t e s rem a in in g a f t e r e a c h r e c r y s t a l l i z a t i o n were e v a p o ra te d down to about o n e - f i f t h th e o r i g i n a l volum e, and th u s a seco n d c ro p o f c r y s t a l s was o b ta in e d . The r e c r y s t a l l i z e d m e th y lc a f fe in e was d r ie d ( l ) : ( T h i s compound h as n e v e r b e fo r e been p re p a re d from c a f f e i n e . ) Bohringer & Sohne. D .R .P. 1 2 8 ,2 1 2 . C. I . , 5^9# 19®^. Von E r n s t VTasser, S y n th ese d e r O rganischen A r n z e in d t te l , F e rd in a n d E nkein S t u t t g a r t , pp. 20k~20^, 76 a t room te m p e r a tu r e and f i n a l l y i n an oven a t 110 ° f o r f o u r to f i v e h o u r s . I n th e e a r l i e r p a r t o f t h i s w ork, th e same g e n e ra l p ro c e d u re was t r i e d w ith h y d r o x y c a f fe in e a s was u s e d f o r th e p r e p a r a ti o n o f 8 -m e th y lx a n th ln e from u r i c &6 i d . ( l ) In th e f i r s t t r i a l , 5 §» o f h y d r o x y c a ffe in e were h e a te d i n a c lo s e d tu b e i n t h e p re s e n c e o f 2 .4 g , o f a c e t i c a n h y d rid e a t 180-190® f o r f o u r to f i v e h o u rs . In a n o th e r t r i a l , 2 . 5 g . o f h y d r o x y c a f fe in e w ere h e a te d a t th e same te m p e ra tu re w ith 4 c c . o f a c e t i c a n h y d rid e . I n "both c a s e s , p r a c t i c a l l y a l l th e h y d ro x y c a ffe in e was re c o v e re d unchanged. I n th e t h i r d t r i a l , 2 , 5 g . o f h y d r o x y c a f fe in e , 5 c c i a c e t i c an h y d rid e and 20 c c . o f p y r id in e were h e a te d i n a c lo s e d tu b e a t 190-200® f o r f i v e h o u rs . Most o f th e h y d ro x y c a ffe in e was r e ­ c o v e re d u n ch an g ed , T our g . o f h y d r o x y c a f fe in e , 10 c c . o f a c e t i c a n h y d rid e and 100 c c . o f d i- m e th y la n i l i n e and 1 g , o f m e t a l l i c sodium w ere h e a te d u n d e r a r e f l u x c o n d e n se r a t th e b o i l i n g p o i n t o f d i-m e th y l* .a n ilin e (193*5°) f o r e ig h t h o u rs . About 50$ o f th e h y d ro x y c a ffe in e was re c o v e re d unchanged (m. p . 335°) • A f t e r e v a p o ra tin g down th e aqueous f i l t r a t e , a f t e r rem oval o f th e h y d r o x y c a f fe in e , and l e t t i n g s ta n d f o r s e v e r a l days a t a low te m p e r a tu r e , a few p l a t e - l i k e c r y s t a l s form ed. These had a m e ltin g p o in t o f 95-97°t w hich c o rre s p o n d s c l o s e l y to t h a t o f c a f f e d in a . The compound d id n o t g iv e th e m urexide t e s t . I n l a t e r e x p e rim e n ts , 8- e t h y l c a f f e i n e was s u c c e s s f u l l y p re p a re d by h e a ti n g hydroxy­ c a f f e i n e w ith p r o p r io n ic a n h y d rid e , h e a tin g i t s l i g h t l y above th e m e ltin g p o in t o f h y d r o x y c a f fe in e (3 4 5 °) f o r a s h o r t tim e . T h e re fo re i t i s l o g i c a l to assum e t h a t m e th y l­ c a f f e i n e c o u ld be s u c c e s s f u l l y p re p a re d i f th e h y d ro x y c a ffe in e and a c e t i c a n h y d rid e w ere h e a te d a t a much h ig h e r te m p e ra tu re th a n was u s e d above. T his was n o t a tte m p te d l a t e r b e c a u s e o f th e s u c c e s s a t t a i n e d by u s in g th e a lk y l e th e r s d i r e c t l y w ith o u t f i r s t c o n v e rt­ i n g them to h y d r o x y c a f fe in e . E x p e rim e n ta l d a ta : M a te r ia l u s e d Methoxy- E th e r C a ffe in e u se d . E thoxy- n -P ro p y lo x y - n -B u ty lo x y - Iao-Amyloxy- Grams o f e t h e r - c a f f e i n e 2 .0 2 .0 5 .0 2 .0 2 .0 A c e tic a n h y d rid e 5*® c c » 5 .0 cc. 5*0 c c # 5 .0 c c . 5 .0 cc Y ie ld , t h e o r e t i c a l " , a c tu a l " , p e r c e n ta g e 1 .8 5 M e ltin g p o i n t ( c o r r . 2 0 7.0-208.5® ) A n a ly s is : M itro g en 0 .2 0 1 0 . 8$ 1 .7 4 0 .8 0 4 5 .9 $ 205*5“ 2°8.0® 2 0 6 .5 209. 0° C a lc u la te d 26 . 92 $ 4 .1 2 5 2 .2 0 l.4 s 53.33^ 1 .5 6 0 .7 0 4 4 .9 $ 67 . # 207 *0 209 . 0 ®' 2 0 8 .0 209.5® 206. Ou 209. 0® 1 .0 0 D eterm ined 2 6 . 83 $ P ro p e rtie s : 8 -M ethyl c a f f e in e s i n t e r e d a t 205 ® and m e lte d a t 207 to 209 ® w ith o u t d e c o m p o s itio n . I t su b lim ed r e a d i l y a t t h i s te m p e ra tu re and form ed f i n e w h ite n e e d le s . I t was found to b e m o d e ra te ly s o lu b le in w a te r. A s a t u r a t e d aqueous s o lu t i o n c o n ta in e d 0 .7 4 g. p e r 100 g. ( l ) : Von E r n s t W asser, S y n th e se d e r O rganischen A rm z e im itte l F e rd in a n d E nkein S t u t t g a r t , p . 204-205. Bohringer & Sohne. D .R .P. 1 2 8 ,2 1 2 , C, I . , 5^9* 1902. 77 a t 25 and 3 2 .5 g . a t IOC®. Thus i t was found to he a b o u t o n e - t h i r d a s s o lu b le as c a f e in e i n w a te r a t t.5 0 . I t was found q u i te s o lu b le in h o t a lc o h o l , a c e to n e , b e n z e n e , and c h lo ro fo rm , and s l i g h t l y s o lu b le in th e s e s o lv e n ts a t room te m p e ra tu re . lh e c r y s t a l s t r u c t u r e o f m e th y lc a f fe in e was f i r s t fo u n d to b e v e ry s m a ll c l u s t e r s o f s l e n d e r c o l o r l e s s n e e d le s when c r y s t a l l i z e d from w a te r. However, upon r e c r y s t a l l l z i n g a se co n d tim e , e lo n g a te d , l u s t r o u s p l a t e l e t s in v a r i a b l y form ed, th e same a s were form ed when i t was c r y s t a l l i z e d o u t o f h o t a lc o h o l. I t d id n o t c o n ta in w a te r o f c r y s t a l l i z a t i o n . T h is compound p ro v e d to be: v e ry s t a b l e tow ards a c id s b u t l i k e c a f f e in e was r e a d i l y decom posed by a l k a l i . H aving no r e a d i l y r e p la c e a b le hydrogen atom i t was found l e s s r e a c t i v e th a n c a f f e i n e . M e th y l- c a f f e in e was s l i g h t l y more b i t t e r i n t a s t e th a n c a f f e in e . B. s - ethylcaji'eihe / 1^ M eth o d s: CH3 -N - C=0 ' ' 290-310® 0=C C - N-CHa $ ---------- > 1 ” /C-0-H + O-C-C3 H5 5 h o u rs CHa-N - C - N' C-C2H5 0 CH3-N - C=0 1 0=C 1 C — N-CHa + RO—C—C3H5 + CO2 ' " ^0-C3He CH3-1j - C - N 1 . P r e p a r e d from a lk y 1 - e t h e r c a f f e in e (e x c e p t m e th o x y c a ffe in e ). A b s o lu te p r o p r i o n ic a n h y d rid e was p re p a re d by d i s t i l l i n g o v er c a lc iu m o x id e . The p o r t i o n d i s t i l l i n g o v er a t 1 6 2 ,0 to 1 6 5 .5 ° was u s e d . I t was found n e c e s s a ry to h e a t th e m ix tu re o f p r o p r i o n ic a n h y d rid e and e t h e r - c a f f e i n e a t a somewhat h ig h e r t e c p e r a t u r e to c a r r y on t h i s r e a c t i o n th a n was n e c e s s a ry i n th e p r e p a r a ti o n o f S - m e th y lc a ff e in e . T h is o f c o u rs e r e s u l t e d i n a lo w er y i e l d b e c au se o f s l i ^ a t d eco m p o sitio n and t h e fo rm a tio n o f h y d r o x y c a f f e in e . The an h y d ro u s e t h e r - c a f f e in e was h e a te d in a c lo s e d tu b e w ith from one to two volum es o f p r o p r io n ic a n h y d rid e a t te m p e ra tu re s ra n g in g from 265 - 32 0 ° f o r about f iv e h o u rs. A f t e r w ashing th e c o n te n ts o f th e tu b e out w ith sm a ll p o r ti o n s o f h o t a lc o h o l, t h e m ix tu re was e v a p o ra te d to d ry n e ss on th e steam b a th , th e n d is s o lv e d i n w a te r .and c l a r i f i e d w ith an im al c h a rc o a l. B ecause o f th e f a c t t h a t t h e r e was alw ays more o r l e s s h y d r o x y c a f fe in e p r e s e n t , th e r e s id u e was d is s o lv e d i n ab o u t $0 c c . o f h o t w a te r and th e n n e u t r a l i z e d w ith b arium h y d ro x id e s o lu t i o n . I t was a g a in e v a p o ra te d to d ry n ess and th e r e s i d u e e x tr a c t e d w ith f i v e to s i x 25 - 3 O c c . p o r tio n s o f h o t c h lo ro fo rm . A f te r rem oving t h i s s o l v e n t , th e p ro d u c t was c r y s t a l l i z e d tw ic e o u t o f h o t a lc o h o l. The c r y s t a l s o f e t h y l c a f f e i n e form ed a s c l u s t e r s o r b u n d les o f sm all w h ite n e e d le s , when c o o le d a t a low te m p e ra tu re and th e s o lu t i o n was n o t to o d i l u t e . The p ro d u c t was s u c tio n f i l t e r e d and w ashed w ith a sm a ll amount o f c o ld a lc o h o l. The f i l t r a t e was c o n c e n tra te d and a second c ro p o f c r y s t a l s o b ta in e d . ( l ) : ( T h i s compound has been s y n th e s iz e d from u r i c a c id , bu t no r e c o r d was found o f i t s e v e r h a v in g been made from c a f f e in e ,) . B o h rin g e r & Sohne. D .R .P. 128,212, 0. I . , 5^9» 1902. B e lls t e in IV p . 933* is E x p e rim e n ta l d a ta : E th e r- C a ff e in e Used Materials used Ethoxycaffeine Grams o f e t h e r - c a f f e i n e 5 n-Froprionic Anhydride H e a te d 10 at cc, 2 5 cc, 295- 305® 5 Yield, theoretical M , actual " , percentage U.6 0»33 7.17$ M e ltin g p o i n t Iso-Amyloxy 2 Hours heated (C o rr. Iso-propyloxy 5 cc» 3IO-32O® 3IO-32O0 5 5 1,7^ 0.3® 17.0**$ 185.0-187.2® 185*0-188.5® 1«58 13*9/° 1 8 2 .0 -1 8 5 .5 ° 186,0-187.5°) Analysis Nitrogen Calculated 25,22$ Determined 25. 09$ The y i e l d s o f e t h y l c a f f e i n e c o u ld have u n d o u b ted ly b een in c r e a s e d by u s in g l a r g e r q u a n t i t i e s o f th e e t h e r . c a f f e i n e ; and by h e a tin g a t a te m p e ra tu re o f 290 to 300 ® f o r o n e - h a l f to one h o u r. But i n any c a se some decom position i s bound to o c c u r when h e a te d a t so h ig h a te m p e ra tu re . 2. E th y lc a f f e in e p r e p a r e d from h y d ro x y c a ffe in e . Two g . o f anhydrous h y d ro x y c a ffe in e were h e a te d i n a c lo s e d tu b e w ith 5 c c » ° f p r o p r i o n ic a n h y d rid e . When th e te m p e ra tu re reach ed 360 ® th e fu rn a c e was im m edlateljjr s h u t o f f . ^he c o n te n ts o f th e tu b e w ere c o n s id e ra b ly b la c k e n e d and rem ain ed i n s o l u t i o n when c o o le d ' I t was washed o u t w ith h o t a lc o h o l and e v a p o ra te d to d ry n e s s . The r e s id u e was d is s o lv e d i n a b o u t 100 c c . o f h o t w a te r and c l a r i f i e d by a d d in g an im al c h a rc o a l and b o i l i n g f o r t e n to f i f t e e n m in u te s . The m ix tu re was th e n f i l t e r e d h o t and th e c l e a r f i l ­ t r a t e e v a p o ra te d down to ab o u t 10 c c . A f a i r l y good y i e l d o f y e llo w is h w h ite c l u s t e r s o f s m a ll n e e d le s s e p a r a te d o u t a f t e r c o o lin g a t a low ten q o e ra tu re . These w ere f i l t e r e d , w ashed and d r i e d i n th e u s u a l m anner, f i n a l l y h e a tin g i n an oven a t 1 10 * f o r ab o u t f i v e h o u r s . The f i l t r a t e was c o n c e n tra te d down and a second sm a ll c r o p o f c r y s t a l s was o b ta in e d .^ ^ ^ ^ e th y lc a ffe in e ( 19. 0$ y ie ld ) was obtained which m elted at 1 8 7 *8 S e v e n -te n th s o f a g . o f a brown r e s id u e rem ained c o n s is t in g o f v a r io u s decom posi­ t i o n p r o d u c t s ^ ^ ^ ^ t r i a l | 2 g , o f anhydrous h y d ro x y c a ffe in e w e re h e a te d i n a c lo s e d tu b w ith 7 cc o f p roprionic Inhydride up to 3*«# . then the heat was immediately shut o f f . The c o n te n ts o f th e tu b e were t r e a t e d as i n th e f i r s t t r i a l e x c ep t t h a t th e s e p a r a tio n o f u n c h a n g e d h y d r o x y c a f f e i n e was a f f e c t e d by th e barium h y d ro x id e m ethod. Only 0 . 0 3 go o f v e rv J L e e th y l c a f f e i n e was re c o v e re d w hich m e lte d a t 186 to 187.6® . T his te m p e ra tu re ^ o f h e a ti n g . e r e n o t s u f f i c i e n t t o c o n v e rt e l l th e h y d r o ry o a f fe in e t o e t h y l c a f fe in e . 79 T his experim ent was rep ea ted th e t h ir d time "by h e a tin g 2 g, o f anhydrous h y d r o ^ c a f f e m e in a c lo s e d tube w ith 2 c c , o f p r o p r io n ic anhydride. The tube was f i l l e d w ith n itr o g e n gas and h ea ted a t 355 to }S0° f o r about f o r t y m in u tes. A fte r c la r i f y i n g and n e u t r a l i z i n g w ith barium hydroxide s o lu t io n , as in th e second t r i a l , a y i e l d o f 0 , 1 3 £• ( 6 ,2 5 0 y i e l d ) o f e t h y lc a f f e in e was o b ta in ed , m eltin g at 18^ .5 to 1 8 6 ,5 ° . Hence, a llo w in g tn e r e a c t io n to ta k e p la c e in the p resen ce o f an in e r t gas d id not r e s u lt in an in c r e a se d y i e l d , or reduce d ecom p osition . I t may be concluded th a t a tem perature o f about 350° (5° above th e m eltin g p o in t o f h y d r o x y c a ffe in e ) m ain tain ed fo r not over t h ir t y m in u tes, or 3 5 5 ° f o r f i f t e e n to tw enty m in u te s, was found to be th e optimum fo r o b ta in in g a maTrlrrmm y ie ld o f e t h y lc a f f e in e from h y d r o x y c a ffe in e . U sin g v e r y s l i g h t l y more than one e q u iv a le n t o f th e a c id anhydride and e v a cu a tin g th e tube b e fo r e s e a lin g might le s s e n decom position to some e x te n t. Time did not perm it th e ca r ry in g out o f th e se v a r ia t io n s in th e procedure. The mechanism o f t h i s r e a c tio n , when h yd ro x y ca ffein e was u se d , was very s im ila r to th a t in v o lv in g th e u se o f e t h e r - c a ff e in e compounds excep t th a t an a c id was s p l i t o f f in s t e a d o f an e s t e r . The y i e l d s ob tain ed by the two methods were approxim ately th e same. 3 , E t h y lc a ff e in e prepared from h - and iso p r o p y lo x y c a ffe in e and p r o p y l-e th e r . In th e f i r s t t r i a l , 2 g. o f n -p r o p y lo x y ca ffein e w e r e heated w ith 5 c c . o f n-propyl*e th e r ( r e d i s t i l l e d over sodium) in a c lo s e d tube a t 260-270° fo r tw elve hours. A fte r p u r i f i c a t i o n and c r y s t a l l i z a t i o n , 1 , 3 g. o f n -p r o p y lo x y ca ffein e was recovered unchanged (m. p . 127 - 1 3 0 ° ) . In the second t r i a l , 2 g . o f n -p r o p y lo x y c a ffe in e and 2 c c , o f p r o p y l-e th e r were h e a te d in a c lo s e d tube a t 3OO-3 O50 f o r e ig h t hours. The c o n ten ts o f th e tube were c o n s id e r a b ly d is c o lo r e d due to decom p osition. A fte r evap oration o f the p r o p y l-e th e r , th e r e sid u e was d is s o lv e d in water and c l a r i f i e d w ith anim al ch a rco a l. I t was f i l t e r e d and th e s o lu t io n evaporated down to about 10 c c . Upon c o o lin g , th ere was ob tain ed ,in the fonn o f c lu s t e r s o f very sm all n e e d le s ,0 .7 5 £• o f S - e t h y lc a f f e in e , m e ltin g a t 1S5-1S7«5° a f t e r r e c r y s t a l l i z i n g out o f a lc o h o l. A n a ly sis showed 2 5 . 5 ^ n itr o g e n (c a lc u la te d 2 5 . 22 $ ) . Two g. o f secondary p r o p y lo x y c a ffe in e were heated in a c lo se d tube w ith 2 cc. p r o p y l-e th e r a t 295-302° fo r e ig h t h ou rs. The c o n ten ts o f the tube were tr e a te d in the same manner as was th e n -p r o p y lo x y c a ffe in e . A fter r e c r y s t a ll iz i n g out o f hot a lc o h o l, 1 ,0 5 g. o f g - e t h y lc a f f e in e were ob tain ed . The m eltin g p o in t was I 8 3 . 5 -1 S 5 .5°» A n a ly sis gave 2^ .89$ n itr o g e n ( c a lc u la te d 2 5 . 2 2 $ ) . D iscu ssio n : The mechanism o f t h i s r e a c tio n can be exp lain ed on th e b a s is o f an in term ed ia te form ation o f p r o p r io n ic ald eh yd e. The p y r o ly s is o f an a lip h a t ic e th er to an aldehyde and th e hydrocarbon a t h ig h tem perature i s q u ite g e n e r a l.'1 ' Hence a t 3 0 0 ° , th e fo llo w ­ in g r e a c tio n s took p la c e to some e x te n ts 300° H C3H7-0-C3H7 ^ C2H5— A=o+c sHs H ence: II 300° C a ffein e - 0-C3H7+0=C-0 3 H5 ——--------^ C affein e - CgHg+C3 H7 C00H ( l ) . Hturd, P y r o l y s i s o f Carbon Compounds, Monograph S e r i e s , pp. 198-199 H inschelwood & Askey, P ro c . Roy. Soc. (London( 115A, 2 1 5 , 1$2J, zo In ord er to prove th e above e x p la n a tio n fo r the form ation o f e t h y l- c a f f e in e from th e p r o p y l-e th e r and th e e th e r compound o f c a f f e in e , the l a t t e r should be heated, w ith p r o p r io n ic aldehyde to s e e i f th e same r e s u lt would be o b ta in ed . I f t h i s proved tru e i t m ight o f f e r a way o f p rep arin g th e h igh er a lk y l—c a ff e in e compounds. P ro p e rtie s : 8 - E th y l c a f f e in e was found to m e lt a t 1 8 6 .0 -1 8 7 .6 ° (1 8 6 -1 8 7 .5 c o r r , ) , a f t e r b e in g r e c r y s t a l l i z e d tw ic e from h o t a lc o h o l. I t d id n o t decompose a t t h i s te m p e ra tu re , b u t su b lim e d to a c o n s id e r a b le e x t e n t , fo rm in g f i n e , in te rw o v e n , w h ite n e e d le s . I t d id n o t c o n ta i n w a te r o f c r y s t a l l i z a t i o n , l i k e m e th y lc a f f e in e , i t was found to be q u i te s t a b l e to w a rd s a c i d s , b u t was e a s i l y decomposed by a l k a l i . A s a tu r a te d aqueous s o lu t i o n was fo u n d to c o n ta in a p p ro x im a te ly O.6 3 g, p e r 100 g. o f w a te r a t 25 ° , and 2 g . a t 100 ° , b e ­ in g ab o u t o n e - f i f t e e n t h a s s o lu b le in h o t w a te r as m e th y lc a f fe in e . I t was found to be f a i r l y s o lu b l e i n h o t a lc o h o l, and m o d e ra te ly s o lu b le i n c o ld a lc o h o l. I t c ry s ta lliz e d o u t o f w a te r o r a lc o h o l i n th e form o f c l u s t e r s o r b u n d le s o f v e ry s m a ll n e e d le s . C. ATTEMPTS TO PREPARE 8-n-PROFYL AND g-n-BUTYLCATFEIIIE. S e v e r a l u n s u c c e s sfu l attem pts were made to prepare 8 -n -p r o p y lc a ffe in e by h e a tin g n -b u ty r ic anhydride w ith th e e th e r - c a ff e in e compounds and a ls o w ith h y d r o x y c a ffe in e . The same method or procedure was u sed as fo r th e prep aration o f e t h y lc a f f e in e . The e th er compounds were h eated a t tem peratures ranging from 260 to 352°. The p roducts recovered were e it h e r th e -unchanged e th e r - c a ff e in e a t the lower tem peratures, or h y d r o x y c a ffe in e and v a r io u s decom p osition products at tem peratures above J>00°. ’.Then h y d ro x y ca ffein e was h e a ted w ith b u ty r ic anhydride a t jb S 0 fo r a few m inu tes, about h a l f o f th e hydroxy­ c a f f e in e was recovered unchanged. The remainder had decomposed. n -V a le r ic anhydride was heated w ith h yd roxycaffein e up to j k S 9 f o r a few m in u tes. 70^9 o f th e h y d ro x y ca ffein e was recovered. I t was concluded th a t in order to make p o s s ib le the r e a c tio n f o r th e p rep a ra tio n ‘o f 8 -p rop yl and 8 -b u ty l c a ff e in e by t h is method, the tem perature would have to be s t i l l h ig h e r than was n e c e ssa r y in preparin g e t h y lc a f f e in e . T his would r e s u lt in p r a c t i c a ll y com p lete decom p osition o f th e compounds under the c o n d itio n s employed. 81 A, HALOGENATION OF CAFFEINE. S—C n l o r c a f f e i n e , w a s fou n d , t o b e m o st s u c c e s s f u l l y p r e p a r e d b y E . F i s c h e r ' s m e th o d . T h i s c o n s i s t s m e r e l y i n p a s s i n g d r y c h l o r i n e g a s t h r u a d r y c h lo r o f o r m s o l u t i o n c o n t a i n — i n g a n h y d r o u s c a f f e i n e u n t i l a l l o f t h e c a f f e i n e —h y d r o c h lo r id e ." h a s d i s a p p e a r e d , a n d t h e s o l u t i o n a g a in b ecom es p e r f e c t l y c l e a r . I t w as fo u n d e s s e n t i a l t o s t o p a t t h i s p o i n t i n o r d e r t o p r e v e n t t h e f o r m a t i o n o f a s m a l l am ount o f 7» 8—d i c h l o r c a f f e i n e . A m o re p u r e p r o d u c t an d a b e t t e r y i e l d w as o b ta in e d b y r e c r y s t a l l i z i n g c h l o r c a f f e i n e o u t o f a l a r g e v o lu m e o f h o t w a t e r r a t h e r t h a n d i s s o l v i n g i n c o n c d . h y d r o c h l o r i c a c i d a n d t h e n d i l u t i n g t o a l a r g e v o lu m e . A s h i g h a s 8 5 . 7 # y i e l d w as o b t a i n e d , m e l t i n g a t 1 8 8 . 0 t o 190® ( c o r r . 1 8 8 . 0 ° ) . 8- C h l o r c a f f e i n e w as u s e d n e a r l y e n t i r e l y f o r t h e p r e p a r a t i o n o f t h e 8- m o n o - e t h e r s o f c a f f e i n e . 8—B r o m c a f f e i n e w a s m o st s u c c e s s f u l l y p r e p a r e d b y t h e m e th o d s o f Y e is u k e T o s k i t o m i , b y e m p lo y in g a m i x t u r e o f n i t r o b e n z e n e a n d c a r b o n t e t r a c h l o r i d e a s s o l v e n t s a n d a d d in g a s m a l l am ount o f i o d i n e a s a c a t a l y s t . I t w as a l s o fo u n d p o s s i b l e t o p r e p sir e 8- c h l o r c a f f e i n e b y t h e sam e g e n e r a l p r o c e d u r e a s w as u s e d f o r t h e p r e p a r a t i o n o f 8- b r o m c a f f e i n e . D u r in g t h e c h l o r i n a t i o n o r b r o m in a t io n , t h r e e p a r t s o f c a r b o n t e t r a c h l o r i d e a n d s e v e n p a r t s o f n i t r o b e n z e n e w e r e u s e d , a n d k e p t a t t h e b o i l i n g p o i n t o f a p p r o x im a t e ly 103° . 8- I o d o c a f f e i n e w a s p r e p a r e d a l s o b y Y o s k it o m i 's m e th o d . T h is c o n s i s t e d i n h e a t i n g a n h y d r o u s c a f f e i n e w i t h s o l i d i o d i n e i n a c l o s e d tu b e a t 1 $ 0 ® f o r e i g h t t o t e n h o u r s . B . THE 8-MONO-ETHERS OF CAFFEINE. I n t h e p r e p a r a t i o n o f t w e l v e a l k y l e t h e r s o f c a f f e i n e t h e m o st e f f i c i e n t m e th o d w a s fo u n d t o a d d 1 m o le o f a n h y d r o u s 8- c h l o r c a f f e i n e t o 1 m o le o f m e t a l l i c so d iu m c o n ­ t a in e d i n enough o f th e a b s o lu t e a lc o h o l t o a f f e c t s o l u t io n o f th e p r o d u c t w h ile h o t . O n ly m e th o x y a n d e t h o x y c a f f e i n e w e r e p r e p a r e d w i t h s a t i s f a c t o r y y i e l d s b y u s i n g E . F i s c h e r ' s m e th o d , w h ic h c o n s i s t e d i n u s i n g a s l i g h t e x c e s s o f s o l i d p o t a s s i u m o r s o d iu m h y d r o x id e i n a n a l c o h o l i c s o l u t i o n . The n o rm al a lk y l e t h e r s w ere o b ta in e d i n n e a r ly q u a n t it a t iv e y i e l d s , and t h e r e - \ a c t i o n w a s u s u a l l y c o m p le t e d w i t h i n o n e - h a l f a n h o u r . The s e c o n d a r y c a f f e i n e e t h e r s \ w e r e f o n n e d r a t h e r s l o w l y , a n d g a v e fro m 4 0 # t o 50# y i e l d s . O n ly a b o u t a 1 2 # y i e l d w a s o b t a i n e d o f t e r t i a r y b u t y l o x y c a f f e i n e a f t e r t h e - r e a e t d o n w a s a ll o w e d t o t a k e p l a c e f o r / s e v e r a l h o u rs. A f t e r r e m o v in g t h e so d iu m c h l o r i d e a n d c o o l i n g t h e a l c o h o l i c s o l u t i o n i t w as f o u n d t h a t t h e e t h e r s h a v i n g no m o re t h a n t h r e e c a r b o n a to m s i n t h e a l k y l c h a i n c r y s t a l l i z e d o u t w e l l . H o w e v e r , b e c a u s e o f t h e i n c r e a s i n g S o l u b i l i t y o f t h e h i g h e r m em bers o f t h e s e r i e s i n a l c o h o l s i t w as fo u n d n e c e s s a r y t o d i s t i l l o f f m o st o f t h e a l c o h o l ( u s u a l l y u n d e r r e d u c e d p r e s s u r e ) , o r d i l u t e w i t h w a t e r . W ith s e v e r a l o f t h e s e com pou nds a UO t o 5 0 # h o t a lc o h o l s o l u t io n a ffo r d e d a v e r y good s o lv e n t f o r c r y s t a l l i z a t i o n . A n a ly s is show ed t h a t n e a r ly a l l o f t h e s e e t h e r s c o n ta in e d w a te r o f c r y s t a l l i z a t i o n , e s p e c i a l l y w hen c r y s t a l l i z e d o u t o f w a t e r o r d i l u t e a l c o h o l . B e c a u s e o f t h i s f a c t , c a r b o n t e t r a ­ c h l o r i d e w as u s e d t o r e c r y s t a l l i z e t h e e t h e r s h a v in g no m o re th a n t h r e e c a r b o n a to m s i n t h e s t r a i g h t c h a in i n t h e a lk y l g r o u p . F o r t h e h i g h e r m em bers p e t r o le u m e t h e r p r o v e d t o be a good s o lv e n t fo r c r y s t a lliz a t io n . The two a r y l e th e r s , 8 -b e n z y l o x y c a f f e i n e an d p h e n y l e t h o x y c a f f e i n e , w e r e m ade by t h e same g e n e r a l procedure as were th e a lk y l e t h e r s . H o w ever t h e r e a c t i o n w as c a r r i e d o u t a t tem p eratu res below 170° in s te a d o f at th e b o ilin g p o i n t , F h e n y l o x y c a f f e i n e was p r e p a r e d by f i r s t form ing 1 mole o f sodium p h en y la te in a x y l e n e s o l u t i o n b e f o r e a d d in g t h e h a l o - 82 c a f f e i n e , and. a llo w in g the r e a c tio n to take p la ce at the "boiling p o in t o f the s o lv e n t . As a m a tter o f f a c t , a few o f th e h ig h e r a lk y l eth er s o f c a ff e in e and the a r y l e th er s were a ls o prepared "by f i r s t p rep arin g the sodium a lc o h o la te in a to lu e n e or x y len e s o lu ­ t io n . However "better r e s u lt s were ob tain ed in most c a se s "by u sin g an e x c ess o f the a lc o h o l as th e s o lv e n t . I t was found im p o ssib le to s a t i s f a c t o r i l y prepare the parah y d ro x y p h en y lo x y ca ffein e by th e above m ethods. This compound was prepared w ith m oderate­ l y good y i e l d s by f i r s t adding 2 m oles o f hydroquinone to an e th y l a lc o h o l s o lu tio n con­ ta in in g 1 m ole o f so d iu m eth y la te. A fte r adding 1 mole o f c h lo r c a f f e in e , the r e a c tio n was made to take p la c e a t the b o ilin g p o in t o f th e s o lv e n t . Undoubtedly as good, i f n o t b e t t e r , r e s u l t s would have been a tta in e d by employing t h i s procedure f o r th e p rep a ra tio n of o th e r phenyl e th e r s o f c a f f e in e . A ll o f the arom atic e th e r s o f c a f f e in e were r e c r y s t ­ a l l i z e d from 95^ or d i lu t e a lc o h o l. In stu d y in g and comparing th e p h y s ic a l p r o p e r tie s o f the c a f f e in e eth er s i t was ob served th a t a l l o f th e a lk y l eth er s f i r s t c r y s t a l li z e d out o f s o lv e n ts as n e e d le s . Upon lo n g s ta n d in g , th e normal eth er s above p r o p y lo x y c a ffe in e slo w ly changed from lo n g , s le n d e r , waxy n e e d le s to p rism s. The m eltin g p o in t was found to become g r a d u a lly low er as th e normal h lk y l chain in c re a se d in le n g th . A ll o f th e se compounds m elted w ithout d eco m p o sitio n , and th o se m e ltin g below 9 0 ° were capable o f b ein g d i s t i l l e d under 3 "to 5 mm. p r e s s u r e .w ith o u t a p p recia b le decom p osition. When h eated above t h e ir m eltin g p o in t s , th e a lk y l e th e r s sublim ed r e a d ily , f o llo w in g the low erin g o f the m e ltin g p o in t i t was a ls o observed th a t w ith th e in c r e a se in m olecu lar w eight o f the s tr a ig h t chain compounds, th e s o l u b i l i t y in w ater decrease& ;and in c r e a se d in a lc o h o l, hydrocarbon and chlorh yd rocarb on s. The arom atic e th er s o f c a ff e in e d iff e r e d from th e a lk y l e th e r s in forming lu s tr o u s n e e d le s or elo n g a ted p l a t e l e t s . They m elted w ith ou t decom p osition, but did not n o t ic e a b ly sublim e even i f heated a t tem peratures cau sin g s l i g h t decom p osition. The arom atic e th e r s were a ls o d i f f i c u l t l y s o lu b le in w ater, and p r a c t i c a ll y in s o lu b le in ch lorh yd rocarb on s. A ll o f the c a ff e in e e th e r s gave th e murexide r e a c tio n . However the phenyl d e r iv ­ a t i v e s gave a b r ic k red c o lo r in s te a d o f th e u su a l b r ig h t red or s c a r l e t . The s t a b i l i t y o f th e e t h e r - c a f f e in e d e r iv a t iv e s towards a l k a l i s proved to be much g r e a te r than c a f f e in e or most o f th e u r ic a cid d . Hot d i lu t e h y d ro ch lo ric apid r e a d ily converted a l l o f th e a lk y l e th e r s to h y d r o x y c a ffe in e . The same r e s u lt was ob tain ed to more or l e s s degree when theph compounds were heated a lo n e at tem peratures from 2 5 O to On the o th e r hand, i t was found th a t th e phenyl eth er s were very s ta b le towards b o ilin g 10fi h y d r o c h lo r ic a c id or when h eated a lo n e a t tem peratures below decom p osition. In g e n e r a l, th e branched chain a lk y l e th er s o f c a ff e in e p o sse sse d p r o p e r tie s v e r y s im ila r to the s tr a ig h t chain compounds. However, the branched eth er s w ere/W s-tt r e a d ily c o n v e r te d to h y d ro x y ca ffein e by h e a tin g in d i lu t e h y d ro ch lo ric a c id or h e a tin g alo n e a t 1 a h ig h tem perature. E v id e n tly , the s u b s t it u t io n of a lk y l groups fo r hydrogen ou -th e carbon atom a tta c h e d to the e th e r e a l oxygen le s s e n s the oxygen-carbon bond. /T h is per­ m its an ea sy replacem ent o f the e n tir e a lk y l group by hydrogen, r e s u lt in g iri the form­ a t io n o f h y d r o x y c a ffe in e . In c a r ry in g on t o x i c i t y experim ents w ith se v e r a l c a ff e in e d e r iv a t iv e s , i t was ob served th a t as regards the a lk y l e th e r s , m etlioxycaffein e was but s l i g h t l y l e s s t o x ic than c a f f e in e . As the m olecular w eight o f the eth ers in c r e a se d the t o x i c i t y became g r a d u a lly l e s s . A lly lo x y c a f fe in e and n -b u ty lo x y c a ffe in e were e x c e p tio n s , in b ein g more t o x ic than c a f f e in e . The condensed d a t a on th e p r e p a r a t i o n o f s ix te e n 2 -m o n o -c a ffe in e -e th e r s i s giv en in T a b le I . Some ox the p h y s i c a l c o n s t a n t s of th e s e compounds a r e g iv e n in Table I I . TABLE I , PBEPAEATIOU OS’ S-ETHEB-CAIFEIKE COMPOUNDS Uame o f Compound H ethoxyc a ffe in e E th o x y c a ffe in e n - P r o p y lo x y c a f f e in e I s o - p r o p y lo x y c a f f e in e n - B u ty lo x y c a f f e in e Sec. b u ty lo x y c a f f e in e T e rt .b u t y l o x y c a f f e in e n-Amylo x y c a ff e in e Iso -a m y lo x y c a ff e in e n -H e x y lo x y c a ff e in e n - H e p ty lo x y c a ff e in e A lly lo x y c a ff e in e B en zy lo x y c a ff e in e P h e n y lo x y c a ff e in e P h e n y le th o x y c a ffe in e p-H ydroxyp h e n y lo x y c a f f e in e Grams , o f M atei• i a l s Used Abs. C l. b . p. C a ff. A lcohol o f a l e . Ha ( c c .) 200 1000 M ethyl 100 700 E th y l 50 300 6 5 .5®66 . 5 ® 2 0 .1 2 78 . o«79 . 0 ® 1 0 .0 6 9 6 . 5°- 20 n -P ro p y l 300 I s o ­ p ro p y l 200 n b u ty l 125 s e c b u ty l 125 t e r t b u ty l 65 n Amyl 300 I s o amyl 60 Hexyl 20 100 17 1 . o s- H eptyl 175. 5° 9 6 . o«97.0® 2 02 . 0 ®2 0 9 .® 50 30 30 30 20 50 30 200 a lly l 30 20 20 20 200 B enzyl 1 6 .5 g. p henol 2 ( e q u i v ,) 100 g. x y len e 125 P h e n y le th y l a l„ 10 g. hydro™ quinone 15 O cc. e th y l He f l u x Hours T heor. y ie ld grains A ctual y ie ld grains Y ield grains 3 /4 182.1 1 6 5 .2 9 0 .7 1 1 04.2 7 1 .0 6g .l 9 7 .5 ° 5.03 1 55.1 4 7 .2 9 0 .1 79.5° 5.03 1 57.7 2 2 .0 3 9 .9 3 .0 2 1 34.9 3 1 .0 8 9 .1 3 4 .9 1 9 .5 55.9 116 . 0 0- 117.0® 99.0®10 1 . 0 ® Slo 5°82.0® 135.0®13 s . 0 ® 128.0®1 2 9 . 0® 1 5 0 . 0 ®155.0® 3 .0 2 3- 1 / 2 3 .0 2 6 3 4 .9 4 .2 1 2 .3 2 .0 2 l 2 4 .5 2 1 ,3 86.9 5.03 1 6 1 .3 5 6 .0 9 1 .3 2 .0 2 l 2 5 .7 1 9 .1 7 4 .3 2 .0 2 2 2 7 .0 2 3 .2 85.9 3 .0 2 1 32. s 2 7 .4 8 3 .5 3 .0 2 4 3 9 .3 3 1 .5 8 0 .1 2 .0 2 6 25a 1 S E0 7 1 .s 2 .0 2 4 2 7 .5 2 3 .6 S 5 .s 2 1 3 . 0 ®» 213.7® 2 .0 2 5 2 6 .9 6 ,5 24.1 TABLE I I . PHYSICAL CONSTANTS OF THE 8-ETEER-CAFFEI1JE COMPOUNDS. Ikuiie and A u .jir ic a l i-'ormula Mol Wt. H eth o x y caffein e C9K12N4O3 E thoxy c a f f e i n e O 10 H 14N 4 O3 + n-P ro p y lo x y caffein e C h H 16R40 3 + S e c .P r o p y lo x y c a f f . C h H is N 403 + n -B u ty lo ry ca ffe in e Ol2H i8N403 + S e c .B u t y l o x y c a f f . 0 12H18N4 O3 +T e r t - B u t y l o x y c a f f , 0 l 2Hi8h403 +n-A m yloxycaff e i n e 0 isH 2 oH403 Is o - A m y lo x y c a f fe in e ^ 13H 30N4Q3 + n -H e x y lo x y c a ff e in e GX4H23 N403 + n - H e p ty l o x y c a f f . 2 lsH 2^ 4 0 3 + A 1 iy lo x y c a f f e in e C h H 14H403 P h en y lo x y caffein e S 14 H14N4 O3 P-IIy dro xyphenyl 0 xy C14 H14N4 O4 +Benzyloxy c a f f e i n e O15 H1SH4 O3 + P h e n y le th o x y c a f f . 216^18^403 + Hew compounds, 224 238 252 M e ltin g P o in t 172.5-17^,0® 1 7 4 .0 ° (c o rr,) 137.5-lUO.O® l4 o .O ° (c o rr,) 129.5-130.50 S o lu b ilit y in water at 25® : 100° C r y s ta lliz e d C rystal from Structure H2 0, CH5 OH 0,29 4 .5 9 0 .3 0 0 .0 4 3.56 O .gl C.CI4 h 20 C2 Hb0H,CC14 h 2 o ,c 2 h5oh 252 1 5 6 .5-1 5 8 .5 ® 0 ,0 7 O.6 5 C.C14 26 b 8 8 , 6 - 9 0 .0 ° 0 , 0k 0 ,3 2 260 1 2 2 .5-1 23 .8 ° 0 .0 3 0 .4 6 C2 HsOH,Dil. a lc o h o l H2 0,C 2 HB0H 26 b 1 5 3 .0 -161 .6 ° 280 7 1 . 8 - 7 2 .6 ° 280 C.314 h 2 o ,c 2 h5oh 0 .0 2 0,09 1 2 5 .0 -12 7 .0 ° 0 .0 0 7 0.100 29 U 1 2 9 .5 ° ( c o r r .) 52 .5 - 53.6° 0 .0 1 1 0 .0 4 308 bl.2 - 6 3 .6 ° O.OO5 0.02 25 O 1 2 4 .0 -1 2 6 .0 ° 286 1 4 1 .0 -1 4 3 .4 ° 0 .0 2 2 l4 3 .0 ° (c o rr.) 0 .0 1 5 2 0 7 .0 -209 .0 ° 302 0o^7 Blunt n e e d le s C lu ster s " Blunt " S p lit ends Blunt ” M iscroscop ic n e e d le s Slender " R ect. prism s Slender n e e d le s C lu sters " Slender " D il. C2 Hb0H P e t. e th er D i l . C2 H&0H H a irlik e Slender H a ir lik e C lu sters H a ir lik e 0.21 D il. C2 H5 0H P e t. e th e r D il. CsHsOH P e t. eth er C2 Hs 0H. D il. a lc o h o l C2 H5 0H 0.2 3 C2 H5 OH Blunt ° .° 2 C2 HB0H or d i l.a l c o h o l C2 Hs0H M icroscopic " Slender " Wedge-shaped n e e d le s 1 .02 R eedies Lustrous n e e d le s j 300 1 7 2 .0 - 1 7 3 .5 ° 314 1 4 2 .0 - 1 4 4 .4 ° 0 .0 0 5 C, THE MOLECULAR REARRANGEMENT OR THE 8-MONOETHERS OR CAPEEIIIE BY HEAT. £ r , i i '' _ In r e p e a t i n g th e work o f K se fiB r-a n d B l i t z on th e m o le c u la r rea rra n g e m e n t o f m ethoxy and e th o x y c a f f e i n e to t e t r a m e t h y l - u r i c a c id and t r i m e t h y l - 9 - e t h y l - u r i c a c id r e s p e c t i v e l y , i t was fo u n d t h a t th e re a y r ^ g ^ e m e p tI jo o k - p la c e ,.fu lly a s w e l l, i f n o t t e t t e r , when th e e t h e r s were h e a te d i n an open tu b q A y ath er th a n i n a c lo s e d tu b e , T e tra m e th y l^ u rAc was o b ta in e d i n y i e l d s a s h ig h a s 95/3r' w h ile t r i m e t h y l- 9 - e t h y l —u r i c a c id form ed i n a b o u t 50/3 y i e l d s ^ / P e rh a p s s l i g h t l y more o f th e r e a r ra n g e d compound would have been form — . e(^ ^ a te m p e ra tu re a s ' h ig h a s 27 O to 280° had been u s e d , p r o v id in g ton-m uch decom posif t i o n -h ad n o t ta k e n p l a c e . /» The t r i m e t h y l- 3 —e th y l—1u r i c a c id was c o n v e n ie n tly s e p a r a te d from h y d r o x y c a f fe in e by fo rm in g th e in s o l u b l e barium s a l t o f th e l a t t e r . A ll a tte m p ts to c a u se th e m o le c u la r rea rra n g e m e n t o f n - p ro p y lo x y c a ffe in e to t r i m e t h y l- 9 - n - p r o p y l- u r ic a c id by h e a tin g i n a c lo s e d tu b e w,ere u n s u c c e s s f u l. However, by h e a ti n g t h i s e t h e r i n an open tu b e a t 25 O to 27 O® f o r ten? h o u rs -(-seven to e ig h t h o u rs w e r e - s u f f i c i e n t ) a 35 /® y i e l d o f trim e th y l-g -n -p rg jp y lr-u ric a^id^w as p rp d u p ed . /ia e ltin g a t . to lH 0.6® . ■ The p r o p e r t i e s o f t h i s c o i^ o u n d ^ ii^ & 'c a te 'h ^ e u b 'te d ly " th a t i t i s th e ^ u a b o v e named s u b s ta n c e . However, f u r t h e r p r o o f o f i t s c o n f ig u r a tio n w ould be d e s i r a b l e , ' a s w e ll a s th e e x p la n a tio n o f th e fo rm a tio n o f in te r m e d ia te p ro d u c ts d u rin g th e p y r o ly ­ s is . I t was o b se rv e d t h a t a s o l i d s u b s ta n c e thought to be h y d ro x y c a ffe in e and an o i l y l i q u i d t h a t r e a d i l y v a p o riz e d were form ed a f t e r th e h e a tin g had been c o n tin u e d f o r two to t h r e e h o u r s . (B ecause o f t h i s f a c t , th e r e a c ti o n may n o t be a m o le c u la r rea rra n g e m e n t i n th e t r u e s e n se o f th e term . A lly lo x y c a f f e in e j h a v in g an u n s a tu r a te d a lk y l group, was r e a d i l y made to r e a r r a n g e to th e iso m e ri^ t r i m e t h y l - 9 - a l l y l ’'u r i c a c i d . Over y i e l d was o b ta in e d by h e a tin g th e e t h e r i n an open o r c lo s e d tu b e a t 170 to 185° f o r f o u r . t q f i y e h o u rs . A sm all amount o f h y d r o x y c a f fe in e was p r o d u e e d a l ong w ith th e re a rra n g e d p ^ o tu c t,,<">"vComplet e a n a ly s i s and p r o p e r t i e s showed t h i s compound to be th e trim e th y 1- a l l y 1- u r i c a c i d . . -/•/ B e n z y lo x y c a ffe in e was made to r e a r ra n g e n e a r ly a s e a s i l y a^ m e th o x y c a ffe in e , form ­ in g th e tr im e th y 1 - 9 - b e n z y l- u r ic a c id . The h e a tin g was done i h ja n open &nd c lo s e d tu b e a t a te m p e ra tu re o f 200 to 205 ° f o r te n h o u r s , o r a t a s l i g h t l y h ig h e r te m p e ra tu re f o r a s h o r t e r p e r i o d . No h y d ro x y c a ffe in e was p ro d u c e d ,,a lo n g w ith th e r e a r r a n g e d p r o d u c t. However, n o t much o v e r a 50 ^ y i e l d was o b ta in e d in any o f th e t r i a l s . _ '■''li,The fj.ve r e a r r a n g e d compounds m entioned above were more s o lu b le i n w a te r and a l c o - h o l th a n '" t h e i r isom ers.^ th e e t h e r - c a f f e i n e compounds. They a ls o p o s s e s s e d a much more b i t t e r t a s t e . The c r y s t a l s t r u c t u r e o f t h i s group showed more o f a ten d en cy tow ards p ris m s o r e lo n g a te d p l a t e l e t s th a n n e e d le s . A ll o f th e s e u r i c a c id s m e lte d a t h ig h e r te m p e ra tu re s th a n th e O th e rs . T h e y ^ u b lim e d when h e a te d above t h e i r m e ltin g p o i n ts , e x c e p t t r i m e t h y l- 9 - b e n z y l - u r ic a c id . In c o n tr a s t to th e o r i g i n a l e th e r conpounds th e y w ere v e ry s t a b l e tow ard h o t d i l u t e h y d r o c h lo r ic a c id , b u t were v e ry e a s i l y decomposed by d i l u t e a l k a l i . A ll gave a pronounced m urexide r e a c ti o n . The e x p e rim e n ta l d a ta on th e p r e p a r a ti o n and some o f th e p h y s ic a l c o n s ta n ts o f th e f i v e r e a r ra n g e d u r i c a c id s i s g iv e n in th e fo llo w in g t a b l e : PREPARATION OP THE ALKYL AND ARYL-URIC ACIDS BY THE PYROLYTIC MOLECULAR REARRANGEMENT OP THE g-ETHERS OF CAFFEINE. o - E t h e r - c a f f e in e u sed M ethoxycaf f e i n e No. g. 2 C o n d itio n s o f H e a tin g temp. °C Hours 170 - 200 ® ii ti 4 4 ii 10 2 225 - 230 ° 170 - 210 ° 360 ° 4 240-250° it E th o x y c a ff e i n e n ii ii n n -P ro p y 1o xyc a f f e i n e ti A lly lo x y c a f f e in e it ii B e n z y lo x y c a ffe in e ii ii ii ii 24-0-250° 250 - 260 ° 250 - 260 ° 12 4 5 7 1 .5 10 R e a rra n g e d P ro d u ct Open o r C losed tu b e . c lo s e d (w ith c h 3oh) c lo s e d open 11 11 c lo s e d (w ith c 2h*oh) c lo s e d it 5 245 - 255 ° 245 - 255 ° 2 8 2 8 8 5 250 - 270 ° 10 n 2 200-204° 10 c lo s e d 2 1 .3 240-250° 170 - 185 ° 5 4 2 200 - 205 ° 10 5 5 5 5 230 - 240 ° 250 - 260 ° 250 - 265 ° 6 2 8 245-255° 8 5 5 5 5 240-245° open *n 11 11 open c lo s e d 11 n 11 open Name # Y ie ld T e tra m e th y lU ric A cid 11 11 11 11 35-00 11 11 11 11 95.°/» 75-0# 86 . 0 # 25 . 0 # T rim e th y l-9 e th y l- U r ic A cid 1 2 .5 # 11 11 11 n 11 11 11 11 T r im e th y l-9 -n P r o p y l- u r ic a c id 11 11 T rira e th y l-9 A l l y l - u r i c a c id . .» " 11 11 20 . 0 # .4 4 .0 # 10 . 0 # 51 . 2 # 7 .2 # 3 5 .5 # 3 5 .0 # 50 . 0 # 53. s# 50 . 0 # T rim e th y l-9 b e n z y l-u riC a c id , > it 11 2 0 . 0# 11 n 3 5 .0 # 11 " (im pure) 2 8 .0 # 11 it 30 . 0 # £7 PHYSICAL CONSTANTS OF FIVE ALKYL AND ABYL-URIC ACIDS. Name and E m p ir ic a l F orm ula T e tra m e th y l U ric CgHi2N403 S o lu b ility Sub- in w a te r Mol. .7t, M e ltin g P o in t lim e s a t 100° 224 2 2 5 .0 -2 2 7 .0 o 223° ( c o r r . ) Yes Q uite C r y s ta l l i z e d form C r y s ta l S tr u c tu r e C2 H5 OH o r H20 S le n d e r n e e d le s Hex. m o n o c lin ic p rism s T rim e th y l 9 - E t h y l - 23 S CioHi4N403 U ric 1 9 9 .6 -2 0 2 .3 ° " 2 0 3 -2 0 4 °( c o r r . ) M o derately C2 H5 OH B e e t; p rism s • T rim e th y l 9 - n 252 p r o p y l C n H l s N403 1 3 S .S - l4 0 .6 ° « Q u ite H20 N eed les & e lo n g a te d p rism s • T r im e th y l 9 - A lly 1- 25 O C11 H14N4 O3 l 4 3 .0 - l 4 4 .5 ° " S lig h tly C2H5 OH E lo n g a te d p rism s *T rim eth y 1 9 -B en zy l C is H is ^ O a 1 8 0 .2 -1 8 1 .3 ° No 302 Very C2 Hb6 h d iffic u ltly Hex. p rism s p la te le ts 0 .1, , The en d eav o r was made to b r in g ab o u t th e m o le c u la r rea rra n g e m e n t o f n -b u ty lo x y c a f f e i n e , n - and iso -a m y lo x y c a ffe in e and n -h e x y lo x y c a ffe in e to th e c o rre s p o n d in g u r i c a c id s w ith o u t s u c c e s s . T em peratures above 25 O0 f o r two h o u rs o r lo n g e r w ere s u f f i c i e n t to c a u se c o n v e rs io n to h y d ro x y c a ffe in e . F u r th e r h e a tin g o r a h ig h e r te m p e ra tu re th a n 2 5 0 ° c a u se d c o n s id e r a b le d e c o m p o sitio n . E th y l io d id e d id n o t have any c a t a l y t i c e f f e c t i n a id i n g th e m o le c u la r rea rra n g e m e n t o f e th o x y c a ff e in e , n o r d id i t b r in g ab o u t t h i s phenomenon w ith any o f th e h ig h e r e th e r s , o f c a f f e in e . P h o n y le th o x y c a ffe in e d id n o t f o l l o w 'i t s low er horaologae i n show ing th e l e a s t te n d ­ ency t o r e a r r a n g e when h e a te d to a s h ig h a s 270 ° . However i t behaved a s an a lk y l e t h e r i n b e in g p r a c t i c a l l y e n t i r e l y c o n v e rte d to s t a b l e h y d ro x y c a ffe in e . The p h en y l e th e r s o f c a f f e i n e were v e ry s t a b l e tow ards h e a t, and r e s i s t e d any change when h e a te d to a s h ig h as 27 O to 230° f o r f i v e h o u rs . No h y d ro x y c a ffe in e was p ro d u ce d . An o u ts ta n d in g f a c t was b ro u g h t to l i g h t in c o n n e c tio n w ith th e p y r o l y t i c r e a r ra n g e ment o f th e e t h e r s o f c a f f e in e . In n e a r ly e v e ry case b e t t e r r e s u l t s were o b ta in e d when th e h e a tin g was done i n an open tu b e . In f a c t , s u c c e s s f u l r e s u l t s w ere s e c u re d w ith n - p ro p y lo x y c a f f e in e o n ly when an open tu b e was u s e d . T h is was u n d o u b te d ly due to th e faclf t h a t d ec o m p o sitio n p r o d u c ts a s m ethyl-am ine and ammonia were form ed. These sub­ s ta n c e s r e a d i l y d e s tr o y e d t h e 't e t r a a l k y l - u r i c a c id .w h ic h i s v e ry e a s i l y decomposed by a lk a lis . In a tu b e h a v in g a v e ry sm all o p en in g a t th e to p th e s e g a s e s w ere allo w e d to e s c a p e to a g r e a t e x te n t . D ecom position was a ls o u n d o u b ted ly d e c re a s e d by th e e lim in a ­ t i o n o f e x c e s s iv e p r e s s u r e . s$ D. THE COITTEESIOH OF THE 8-AiEYL-2lHERb OF CAFFEINE AND HYDROXYCAFFE IHE TO TWO g-ALKYLCAFFEI1IB DERIVATIVES. For some r e a s o n , th e o r d in a r y m ethods o f m e th y la tio n w ith m ethyl io d id e o r m ethyl s Til f a t e a r e in c a p a b le o f r e p l a c i n g th e hydrogen atom i n p o s i t i o n (S) o f c a f f e in e . C o n se q u e n tly 8 —m e th y l and 8—e t h y l c a f f e i n e have n e v e r been made b e fo r e from c a f f e in e . On th e o t h e r h a n d , u r i c a c id i s r e a d i l y m e th y la te d to S -m e th y lx a n th in e by a c e t i c a n h y d rid e , and th e l a t t e r r e a d i l y m e th y la te d to 8 - m e th y lc a ff e in e w ith m ethyl i o d id e , a s was o b se rv e d in th e h i s t o r i c a l an d d e s c r i p t i v e p o r t i o n o f t h i s t h e s i s . The s u c c e s s a t t a i n e d i n th e p r e p a r a t i o n o f 8 -m e th y l a n d e t h y l c a f f e i n e by f i r s t r e p la c in g th e hydrogen in p o s i t i o n (g ) w itn an o x y g e n -a lk y l group o r a h y d ro x y l g ro u p , throw s some l i g h t on t h i s problem . 8 —M e th y lc a f fe in e was o b ta in e d i n y i e l d s from ^5 to n e a r ly JO$ by h e a tin g th e S—a l k y l - a f f e i n e e th e r s ( e x c e p t m e th o x y c a ffe in e ) in th e p re s e n c e o f a s l i g h t e x c e ss o f a c e t i c a n a y d rid e i n a c lo s e d tu b e a t 260 to 3J0° f o r fo u r to f i v e h o u rs. A ttem p ts to p r e p a r e b .iis compound from h y d ro x y c a ffe in e by th e same method were u n s u c c e s s fu l b ecau se n o t h ig h enough te m p e ra tu re was em ployed. g - X tn y lc a f f e in e was s i m i l a r l y p re p a re d by h e a tin g th e S - a lk y l c a f f e i n e e th e r s above m e tn o x y c a ffe in e w ith a s l i g h t e x c ess o f n - p r o p r io n ic a n h y d rid e in a c lo s e d tu b e a t 290 to 310° f o r f i v e h o u r s . The h ig h e s t y i e l d o b ta in e d was 17$. A 19$ y i e l d was o b ta in e d by u s in g h y d r o x y c a f fe in e and h e a tin g a t 36 O0 f o r about te n m in u te s , TThen n - and i s o - p r o p y l o x y c a f f e in e w ere h e a te d w ith an e x c e ss o f n -p ro p y l e th e r a t 3OO0 f o r ab o u t e ig h t h o u rs a j y / bO^ y i e l d o f S - e t h y l c a f f e i n e was form ed. In a l l c a s e s a sm a ll amount o f h y d ro x y c a ffe in e was p r e s e n t a t th e end o f th e r e a c ti o n . The m echanism o f th e r e a c t i o n when an a c id an h y d rid e was u sed can be e x p la in e d on th e b a s i s o f s p l i t t i n g o f f an e s t e r and carb o n d io x id e , le a v in g th e a lk y l group to a t t a c h d i r e c t l y to t h e c a rb o n i n th e e ig h th p o s i t i o n . When n -p ro p y l e th e r was u s e d ,t h e r e r e ­ s u l t e d "undoubtedly th e p a r t i a l c o n v e rsio n o f t h i s compound to p r o p r io n ic a ld e h y d e a t th e > h ig h te m p e ra tu re em ployed. The ald e h y d e r e a c te d w ith th e c a f f e i n e - e t h e r , r e s u l t i n g i n th e f o rm a tio n o f e t h y l c a f f e i n e and p r o p r io n ic a c id . A p r o o f o f t h i s e x p la n a tio n would o f c o u rs e c o n s i s t i n th e u s e o f p r o p r io n ic ald eh y d e i n s t e a d o f p ro p y l e t h e r and p ro d u ce th e same r e s u l t s . I f th e a ld e h y d e gave s u c c e s s f u l r e s u l t s , i t m ight o f f e r a s t i l l b e t t e r way to p r e p a r e e t h y l c a f f e i n e , a s w e ll a s s u g g e st a way to p r e p a r e th e h ig h e r S - a lk y l c a f f e in e compounds. g - M e th y lc a ff e in e p ro v ed to be s l i g h t l y l e s s s o lu b le i n w a te r and a lc o h o l th an c a f f e i n e , w h ile S - e t h y l c a f f e i n e was s t i l l l e s s s o lu b le i n th e s e s o l v e n t s , Methoxy­ c a f f e i n e c r y s t a l l i z e d in th e form o f b e a u t i f u l l u s t r o u s t h i n p l a t e l e t s , and th e e th y l d e r i v a t i v e s form ed c l u s t e r s o f sm a ll n e e d le s . B oth compounds were found to be s t a b l e t o ­ w ards a c i d s , b u t were r a t h e r e a s i l y decomposed by a l k a l i . In g e n e r a l, th e s e d e r i v a t i v e s a r e l e s s r e a c t i v e th a n c a f f e i n e , a s t h e r e no lo n g e r rem ain s a r e a d i l y r e p la c e a b le h y d ro ­ gen atom . The two a l k y l - c a f f e i n e d e r i v a ti v e s gave th e m urexide r e a c t i o n . They were a ls o fo u n d to su b lim e n e a r l y a s r e a d i l y as c a f f e i n e . In th e e n d eav o r to p r e p a r e S -n -p ro p y l and S - n - b u ty lc a f f e in e , i t was found t h a t th e r e a c t i o n d id n o t ta k e p la c e a t te m p e ra tu re s below which th e compounds u s e d were de­ com posed, u n d e r th e c o n d itio n s employed. I t i s su g g e ste d t h a t s u c c e s s m ight be a t t a i n e d i n th e p r e p a r a ti o n o f th e s e two compounds by a llo w in g th e r e a c ti o n to ta k e p la c e in an open v e s s e l w ith a v e ry sm a ll op en in g a t th e to p . Under th e s e c o n d itio n s a v e ry h ig h te m p e ra tu re c o u ld be m a in ta in e d w ith l e s s d eco m p o sitio n b e c au se o f th e g ra d u a l esca p e o f t h e v a p o rs o f ammonia and m ethylam ine. T h is would n e c e s s i t a t e th e f r e q u e n t a d d itio n o f sm a ll am ounts "of th e a c id a n h y d rid e , e th e r o r ald e h y d e u s e d , o r f i t th e to p of th e tu b e w ith a s p e c i a l r e f l u x in g d e v ic e . 85 Condensed tables showing the preparation and some of the physical constants of and 8 -ethylcaffeine are given below: 8 -methyl PREPARATION OF 6 -METHYL 8 -osycaffeine g. Acid anhydride or ether Methoxycaffeine Ethoxycaffexne n-Propyloxycaffeine n*But y10 xycaffeine Iso-amyloxycaffeine 2 Acetic anhyd. 11 11 it ti 2 11 2 ti 2 5 Ethoxycaffeine Is0 -propyl0 xycaff, Iso-amyloaycaffeine Hydroxycaffeine n-Propyloxycaff. Sec-propyloxycaff. AND 8-ETHYLCAFFEINE Conditions of heating (closed tube) Temp, Hours 2 60 -2 70 ° 11 11 11 11 11 11 11 « n n II 8 -Ethylcaffeine 1 1 11 11 5 295-305° 5 310 -3 2 0 ° 11 11 2 2 2 11 N-propyl ether n it n ji 36 O0 5 c} , Yield Name 8-M ethyl c a f f e in e 11 ii 11 it rt 1 11 ii 5 2 N-proprionic anhyd. n it 1 1 it 2 8 - A lk y l-caffeine 11 11 n n it min. 11 11 11 11 3 00 -3 0 5 ° 8 295-302° 8 h 11 1 0 .8 45.9 53.3 4 4 .9 67.5 7.2 1 7 .0 13.9 1 9 .0 37.5 52.5 PHYSICAL CONSTANTS OF 8 -METHYL AND 8 -ETHYLCAFFEIKE Mol Wt. Melting Point Approx, S oln. i n 100 g. HgO 25° : 100° 8 - M e th y lc a ff e in e CeHi2N40 e 208 207 -2 0 9 .0 ° 0.74 32.45 C2Hb0H or Ha0 Elongated, lus­ trous platelets 8 - E th y l c a f f e in e 222 O. 6 3 2.64 CaHgOH or H20 Slender needles sometimes rose t t e s o f needle?? Name and Empirical Form ula C lo H l4 ? 4 0 2 207- 208 . 5° (corr.) 186-187.6° 186-187.5° (corr.) Crystallized from Crystal Structure 90 COUCLUSIONS 1* A ll o f the a lk y l and some o f the a ry l eth ers o f c a f f e in e can "be most s u c c e s s ­ f u l l y prepared by adding 1 mole of h a lo c a ffe in e to an excess o f the a b so lu te a lc o h o l c o n ta in in g 1 mole o f sodium a lc o h o la te . Undoubtedly the b e st method f o r p rep arin g the p .ie n y l-e th e r s o f c a ff e in e c o n s is t s in adding th e phenol and h a lo c a f f e in e in equim olecu lar amounts to an e th y l a lc o h o l s o lu tio n co n ta in in g 1 mole o f sodium or potassiu m e th y la t e . 2. B e sid e s th e p r e v io u s ly prepared te tr a m e th y l-u r ic a c id and tr im e th y l-9 -e th y lu r ic a c id th e io llo w in g s u b s t it u t e d u r ic a c id s may be prepared by the pyro­ l y t i c m olecu la r rearrangement o f t h e ir iso m ers, th e c a ff e in e e th e r s : tr im e t h y l- 9 -n -p r o p y l-u r ic a c id , t r im e th y l- 9 - a l l y l - u r i c a c id , and tr im e th y l9 - b e n z y l- u r ic a c id , 3- The u se o f an open tube in s te a d o f a c lo s e d tube during the p y r o ly s is and re­ arrangement o f the c a f f e in e e th er s cau ses the l e a s t decom p osition , and gener­ a l l y g iv e s as h igh and o fte n h ig h er y i e l d s . I t appears to be im p o ssib le to b rin g about the p y r o ly tic m olecular rearrange­ ment o f the S -e th e r s o f c a f f e in e having more than th ree carbons in the s tr a ig h t a lk y l c h a in , or th e a r y l e th e r s h ig h er than b e n z y lo x y c a ffe in e . The phenyl e th e r s do not rearrange when heated a t a h igh tem perature, 5. 8 -M ethyl and 8 - e th y lc a f fe in e can be prepared in d i r e c t ly from c a f f e in e . This i s brought about by f i r s t s u b s t it u t in g an o x y g en -a lk y l group or a hydroxyl group in p la c e of-.th e hydrogen in the e ig h th p o s it io n o f the p u rin e n u cleu s. These d e r iv a t iv e s are then heated w ith an a c id anhydride or a lk y l eth er at a tem perature above 260°, This r e s u lt s in the s p l i t t i n g o f f o f an e s te r or an a c id and carb on -d ioxid e (w ith an h yd rid e). 6. n -P r o n y lc a ffe in e cannot be prepared by the same methods s u c c e s s f u lly employed fo r the p rep aration o f m ethyl and e t h y lc a f f e in e , because the e x c e s s iv e heat reo u ired to b rin g about the r e a c tio n causes decom position o f the purine m olecu le. 7. I t i s p r e d ic te d th at a lk y l aldehydes can be used in p la c e o f a c id anhydrides or eth ers f o r th e p rep aration o f the g - a lk y lc a ff e in e d e r iv a t iv e s . ADDENDA I. The P rep aration and P r o p e r tie s of H yd roxycaffein e, and 8 -C h lo r th e o p h y llin e . 8 -j\m in o c a ffe in e, 8 -T h io c a ffe in e , II. T o x ic ity Experiments w ith C affeine and some o f i t s D e r iv a tiv e s . III. Moth P ro o fin g Experiments w ith C affein e and some o f i t s D e r iv a tiv e s . 91 A. PREPARATION OP HYDROXYCAPF2 I 1JE OR 1 , 3 , 7-TRIMETHYL-URIC ACID. Met ho d: CH3-N - C=0 1 CH3-H - C=0 1 0=c C - N-CH3 " C-O-R ( a l k y l ) CH3-N - C - N 8 - A ik y l- E th e r - C a f f e in e 1 1 10ft HC1 Heat . 1 0=C C - II + R-OH ' 11 NC-OH CH3-H - C - N* H y d ro x y c a ffe in e One p a r t "by w e ig h t o f th e 8 - al ky l - e t h e r o f c a f f e i n e , such ae e th o x y c a f f e i n e , was added to a b o u t 5 p a r t s o f 10 # h y d r o c h lo r ic a c id i n a f l a s k and h e a te d on th e steam h a th f o r tw e n ty to t h i r t y m in u te s . The e th e r g r a d u a lly went i n to s o lu t i o n d u r in g t h i s tim e , and a f t e r th e r e a c t i o n was a b o u t com p leted , th e h y d ro x y c a ffe in e began to s e p a r a te out o f t e n w h ile th e s o l u t i o n was s t i l l h o t. A f t e r c o o lin g , lo n g s le n d e r n e e d le c l u s t e r s o f h y d r o x y c a f fe in e were f i l t e r e d o f f , and th e f i l t r a t e alm o st n e u t r a l i z e d and c o n c e n tra te d down to a b o u t o n e - f i f t h th e o r i g i n a l volum e. Thus, a second cro p o f c r y s t a l s was ob­ ta i n e d , The e n t i r e p ro d u c t was r e c r y s t a l l i z e d a g a in out o f h o t w a te r o r a lc o h o l. It was a i r d r i e d , th e n h e a te d a t 110-120° f o r ab o u t te n h o u rs . An a lm o st q u a n t i t a t i v e y i e l d was o b ta in e d by c o n c e n tr a tin g th e m other l i q u o r to a sm all volume each tim e . E x p e rim e n ta l d a ta : M a te r ia ls u s e d i n grams 1st S -E th o x y c a f fe in e 10# H y d ro c h lo ric a c id 30 150 oc. Y i e ld , t h e o r e t i c a l " , a c tu a l " , p e rc e n ta g e 2 6 ,4 M e ltin g p o in t ( c o r r . 3 ^ 5° ) A n a ly s is N itro g e n T r i a l s 2nd 1 1 .5 60 cc. 8 .7 1 0 .1 8 6 . 1# 2 1 .2 S0 . 3# 340-3^3° 332 - 335 ° C a lc u la te d 2 6 . 66 $ (a n h y d .) 2 5 . 00 # (1 Ha0 ) 3r d 5 .0 20 c c . M 3 .5 7 9 .3 # 325-335 D eterm ined 2 5 . 76 # The p r o p e r t i e s o f h y d ro x y c a ffe in e a r e g iv e n i n d e t a i l in th e h i s t o r i c a l and d e s c rip tiv e p a rt o f th is th e s is . 92 B. PE3PABATI0N OP S-AllINOCAFFEINI, f 1) Method: CH3-N - C=0 ' 1 ( 130 -llK)®) 0=C C " N-CH3 ^ NH3 ( a lc o h o lic ) — ' " / C-Br CH3-N - c - it* CH3 -N - C=0 t t C - N-CH3 -> o=c 1 " C-NHa V CHa-17 - C - IT + HBr One p a rt o f dry brom or c h lo r c a ffe in e was put in to a c lo se d tube w ith 100 p a r ts o f a concd. s o lu t io n o f a lc o h o lic ammonia. I t was heated in a furnace k ep t a t I 3 O—l^JO0 f o r s i x to e ig h t h o u rs. A fte r c o o lin g and opening the tu b e, the product was washed out w ith c o ld d i s t i l l e d w ater and d r ie d . The crude am inocaffeine was r e c r y s t a ll iz e d by d is s o lv in g in h ot concd. a c e t i c a c id or concd. h yd roch loric a c id , the l a t t e r b e in g p r e fe r r e d . Upon d i lu t i n g w ith 3 O to HO volumes o f co ld water th e product c r y s t a lliz e d out as r a th er sm a ll b lu n t n e e d le s . B ein g very in s o lu b le in co ld water i t was th o r o ly washed and then s u c tio n f i l t e r e d . I t was d r ied a t room tem perature, and f i n a l l y a t 110-120° fo r fo u r to f i v e h o u r s. A m inocaffeine may be a ls o formed in sm all amount by h e a tin g b rom caffein e f o r a lo n g tim e in th e p resen ce o f an e x c ess o f potassium cyanide in a d i lu t e a lc o h o lic s o lu ­ t io n . E xperim ental data: T r i a l s Materials used in grams Bromcaffeine Concd. alcoholic NH3 Yield, theoretical fl , actual n , percentage Melting point, determined (Corr. 36 °°) 2nd 1 st 5.0 7.5 7 5 .0 cc. 5 0 .0 cc. 3 rd 2 0 ,0 (Cl-caff eine) 1 5 0 .0 cc. 5 .7 3 .8 18. Z *.7 1 6 .7 s z M 3.7 97.3i 357 - 360 ° 358 - 360 ° 355 - 360 ° 91.2JS Properties. Aminocaffeine is very difficultly soluble in hot or cold water and alcohol. How­ ever it readily dissolves-in concd. acids. It forms colorless, microscopic needles when*pure, but first crystallizes as light brownish yellow,blunt,rod-shaped needles. It melts at over 36 O0 to a light brown colored liquid and sublimes upon further heating without decomposition. Notwithstanding the fact that it contains an amino group, it is ( l ) : E. F is c h e r , Untersuchungen in der Puringruppe pp. 3U~5. 93 C, PREPARATION OF 8-THIOCAFFEINE. f 1 ) Method: CH3-N - 0=0 ' 1 0=0 C - N-CH3 1 " C-Cl CH3-IT - C - IT* CH3-N - C=0 » « + KSH -----------------> 0=0 C - N-CHs * " nc - s h CH3 -N - C - IT* 90 - 100 ® + KOI The 1 N. p o ta s s iu m hydrogen s u l f i d e was f i r s t made hy p a s s in g d ry hydrogen s u l f i d e g a s th ro u g h a 1 K, p o ta s s iu m h y d ro x id e s o lu tio n u n t i l s a t u r a t e d . One p a r t o f c h lo r c a f f e i n e was added to 15 p a r t s o f th e 1 N. s o lu t i o n o f p o ta s s iu m hydrogen s u l f i d e . T h is was h e a te d s e v e r a l h o u rs on a steam h a th , o r u n t i l i t went i n to s o l u t i o n . The s o lu t i o n was a c i d i f i e d w hich c au sed th e t h io c a f f e in e to p r e c i p i t a t e out in v e ry f i n e n e e d le s h a p e d c r y s t a l s . A n e a r ly q u a n t i t a t i v e y i e l d was o b ta in e d . I t was s u c tio n e d f i l t e r e d , a f t e r c o o lin g i n i c e . The p ro d u c t was r e c r y s t a l l i z e d by d i s s o lv in g i n h o t e th y l a lc o h o l a n d th e n c o o le d . The f i l t r a t e was e v a p o ra te d down to o b ta in a second c ro p . A f te r b e in g f i l t e r e d i t was d r ie d f i r s t a t room te m p e ra tu re and f i n a l l y i n an oven a t 110 - 1 1 5 ® f o r s e v e ra l h o u rs. E x p e rim e n ta l d a ta : T r i a l s M a te r ia ls u s e d in grams 8 - C h l o r c a f f e in e 1 N. KSH s o l u t i o n Y i e ld , t h e o r e t i c a l ” , a c tu a l " , p e rc e n ta g e M e ltin g p o in t ( c o r r . 3 1 6 . 0 ° w ith decom pn.) 1st 2 0 .0 ^ 5 0 .0 c c . 2nd 1 0 .0 2 0 0 ,0 c c . 9 . 9^ 1 9 .8 1 9 .5 9 8 .5 # 9 .7 9 7 .7 # 308-312® (w ith 308-310® (w ith decom pn.) decompn.) P ro p e rtie s . T h io c a f f e in e form s c o l o r l e s s n e e d le s when c r y s t a l l i z e d out o f a lc o h o l o r by a c id ­ i f y i n g an a l k a l i n e s o lu t i o n . I t s m e ltin g p o in t i s 316 .O® ( c o r r . ) . T h is compound i s n e a r l y i n s o l u b l e i n w a te r, b u t r e a d i l y goes in to s o lu t i o n i n a m o d e ra te ly d i l u t e a l k a l i n e s o lu tio n . I t p o s s e s s e s a f a i r l y b i t t e r t a s t e , though s l i g h t l y l e s s th a n t h a t o f c a f f e in e its e lf, T h io c a f f e in e g iv e s th e rm irexide r e a c ti o n . ( l ) : E. F i s c h e r . U ntersuchungen i n d e r P u rin g ru p p e . E. F i s c h e r . B e r. 32 * D. r . P. 1 0 0 ,875; c . I . 957, 1899. ( S p l. Bd. I l l , S. 70^) p . 60. 9l+ D. PHEPABATIOII OF S-CHLORTKEOPHYLLIITE Metaods CH3-N - 0=0 ' ' ( 9 3 ° ) (-HC1) cfla-N - C=0 « • j3 s -N - 0=0 (-HCH0 & -H O I) ! ! 0=C C - K-CH3 + 2C12 -----------------_ > 0=C C - H-CH2 C1 ------— -------» 0=0 C - IT-S " C-H ( I 2 c a ta ly s t) ' « NC-C1 H eat (HOH ' “ \*CH3-H - C - H CH3 -H - C - N* CH3-IT - C - N ' C a f fe in e 7> S - D ic h lo r c a f f e in e 8- C h l o r t h e o p h y l l i r 1 1 8 - C n lo r th e o p h y llin e was p r e p a re d by th e method o f Y eisuke Y oskitom i by f i r s t form ­ in g 7 , S - d ic h l o r c a f f e in e a s d e s c r ib e d on page 3^ • t h i s p ro c e d u re , 1 p a r t o f anhyd­ ro u s c a f f e in e was c h lo r i n a t e d i n a m ix tu re o f 5 p a r t s o f n itro b e n z e n e and 5 p a r t s o f c a r b o n t e t r a c h l o r i d e in th e p r e s e n c e o f a sm a ll amount o f io d in e a s a c a t a l y s t ; and was k e p t a t th e b o i l i n g p o in t o f ab o u t 93" th e s o lu tio n became e n t i r e l y c l e a r . The rem oval o f th e s o lv e n ts and th e h y d r o ly s is o f th e 7> S - d ic h l o r c a f f e in e to S - c h lo r th e o p h y l l i n e was a c c o m p lish e d i n one o p e r a tio n . This c o n s is te d in steam d i s t i l l i n g th e m ix­ t u r e u n t i l c o m p lete rem oval o f th e s o lv e n ts was a cco m p lish ed . The p r e c i p i t a t e d r e s id u e o f th e p ro d u c t was p u r i f i e d by d i s s o lv in g in th e l e a s t p o s s ib l e q u a n tity o f h o t concd. h y d r o c h lo r ic a c id and th e n d i l u t i n g w ith a l a r g e volume o f w a te r. T h is caused th e 8 - c h l o r t h e o p h y l l i n e to c r y s t a l l i z e in th e form o f m ic ro sc o p ic alm o st c o l o r l e s s n e e d le s . I t was a ls o r e c r y s t a l l i z e d by n e u t r a l i z i n g a V,o sodium h y d ro x id e s o lu t i o n o f th e 8 - c h l o r th e o p h y liin e w ith hydro c h l o r i c a c id , w ith v e ry good r e s u l t s . The compound was f i l t e r e d o f f , a i r d r i e d , th e n h e a te d a t 110 ° f o r s e v e r a l h o u rs. E x p e rim e n ta l d a ta : T r i a l s M a te r ia ls u s e d i n grams A nhydrous c a f f e in e Dry n itr o b e n z e n e D ry c a r b o n t e t r a c h l o r i d e I o d in e Y ie ld , t h e o r e t i c a l " , a c tu a l 11 , p e rc e n ta g e M e ltin g p o in t (c o rr. 300. 0 ° w ith decom pn.) 1s t 7 5 .0 375.0 375.0 1 .0 82.9 te .9 51 . 7£ 2nd 1 0 0 .0 5 0 0 .0 5 0 0 .0 2 .0 1 1 0 .4 5 4 .5 49.3f> 2 9 4 .0 -2 9 6 .0 ° (w ith d e c o m p o sitio n ) ( d is c o lo r s a t 2 8 0 .0 °) P ro p e rtie s I t i s f a r i l y s o lu b le i n h o t a lc o h o l, b u t v e ry d i f f i c u l t l y s o lu b le in a c e to n e and c h lo ro fo rm , p r a c t i c a l l y in s o lu b le in c o ld w a te r, and o n ly s l i g h t l y s o lu b le i n h o t w a te r (150 to 1 ) . However, i t i s s o lu b le i n c o n c e n tra te d h y d r o c h lo r ic a c id . T his compound p o s s e s s e s r a t h e r s tr o n g a c id p r o p e r t i e s , h a v in g an a c id r e a c t i o n , and d i s s o l v e s r e a d i l y i n d i l u t e a l k a l i s and ammonia. I t i s decomposed, how ever, by an e x te n d ­ e d h e a tin g w ith an e x c e ss ox a l k a l i , and i s r a p i d l y decomposed by w anning w ith s tr o n g n i t r i c a c id . I t g iv e s th e m arexide r e a c t i o n . 8- C h lc r th e o p h y liin e form s a sodium s a l t i n a c o n c e n tr a te d aqueous s o lu t i o n o f sodium h y d ro x id e , which come down a s f in e w h ite n e e d le s,. 95 x-iu s i l v e r s a l t fo rm s f i n e c o l o r l e s s n e e d le s , which, became c o lo re d upon ex o o su re to l i g h t , 8 - G iilo r th e o p h y llin e h as p r a c t i c a l l y no t a s t e due p a r t i a l l y to i t s i n s o l u b i l i t y , c r y s t a l s t r u c t u r e , when r e c r y s t a l l i z e d out o f c o n c e n tra te d h y d r o c h lo r ic a c id by d i l u t i o n o r by n e u t r a l i z i n g a d i l u t e a l k a l i n e s o lu t i o n o f th e compound, i s in th e form o f v e ry f i n e n e e d le sh ap e c r y s t a l s . I I , TOXICITY OF CAFFEINE AND SOME OF ITS DERIVATIVES AS DETERMINED BY THEIR EFFECT UPON GROWTH OF RATS WHEN MIXED WITH THE STOCK RATION. G e n e ra l P ro c e d u re , I n n e a r l y a l l c a s e s young r a t s w ere s e l e c t e d , w eighing from 50 to 80 g . e a ch . Two a n im a ls w ere u s e d i n each p e n . The compound to b e f e d to th e r a t s i n each t e s t was a c c u r a te ly w eighed ou t and th e n g ro u n d i n a m o rta r w ith a sm a ll q u a n tity o f th e s to c k r a t i o n b e fo r e b e in g th o r o ly m ixed w ith th e w hole q u a n t i t y o f s to c k r a t i o n . Thus th e compound was in s u r e d o f b e in g v e ry t h o r o l y in c o r p o r a t e d w ith th e f e e d . The s ta n d a r d s to c k r a t i o n was made up a s f o llo w s ; Corn m eal Powdered whole m ilk O il m eal Ground a l f a l f a S a lt 60^ "}0cjo 6$ 3$ 1# by w eight " " " n " ” " " T h is r a t i o n and f r e s h w a te r were k e p t b e fo r e th e r a t s a t a l l tim e s . A ll a n im a ls w ere w eighed i n d iv i d u a l l y once each week. The u s u a l l e n g th o f tim e i n k e e p in g t h e r a t s on th e s e t e s t s was te n w eeks. O b s e rv a tio n s and D is c u s s io n o f R e s u lts . * The e a s i e s t and m ost c o m p a r a b l e m ethod o f s tu d y in g th e t o x i c i t y o f c a f f e in e and s e v e r a l o f i t s d e r i v a t i v e s was to o b se rv e th e grow th c u rv e s and th e c h a r t s showing th e w eekly r a t e o f g ro w th . The l a t t e r in fo rm a tio n may be a ls o o b ta in e d i n th e t a b l e g iv in g th e a v e ra g e grow th o f r a t s p e r week. The e f f e c t o f each compound upon th e b e h a v io r and g e n e ra l a p p e a ra n c e o f th e a n im a ls , and th e c o n d itio n o f th e i n t e r n a l o rg an s when an au to p sy was made w i l l be d is c u s s e d . 96 A verage Growth o f E a ts P e r Week i n Grams. S to c k r a t i o n o n ly ( a ) " ” ■ 17 <•> " A verage 0,0105a C a ffe in e 0 .0 2 5 i ' OOP* . 0.100* . * - 18 3 U .l 1 8 .2 17 « - l61t 0 20 • ll(2 0.50)5 » 6 2 i - 00# 1 .5 0 * “ * -rfo .S it.o 0 ,1 0 ^ 0 , 205a 0 , 30 $ 0,505^ 0 ,1 0 $ 0 . 20 $ 5°^ C a f f e in e . M e rc u ric c h lo r id e II H « « B H HgCl2 a lo n e e q u iv . to t h a t i n 0 .3 0 $ C a ff. HgCl2 C a f f e in e . M e rc u ric c h lo r id e 8- C h lo r th e o p h y llin e -5 .3 -9 .9 - 1 1 .2 - l 6 .0 « 9 / 4. _ 3 *q " - 1 9 .0 0 ,1 0 $ 0 . 20 $ 0 . 50 $ 8 -B ro m c a ffe in e 0 .1 0 $ 0 . 20 $ 0 . 50 $ S - C h lo rc a f fe in e » » 0 , lOf® 0 . 20 $ 0 . 50 $ 8- I o d o c a f f e in e 0 ,5 0 $ 0 .5 0 $ 0 . 50 $ 0 .5 0 $ 0 . 50 $ 0 . 50 $ 0 . 505S 0 .5 0 $ 0 . 50 $ 6 0 ■ " » n g -M e th o x y c a ffe in e g -E th o x y c a ffe in e g - n -P r o p y lo x y c a f fe in e g - n -B u ty lo x y c a f fe in e S -Is o -a m y lo x y c a ffe in e g - A lly lo x y c a f f e in e 8 -Ami no c a f f i ne 8 -E ydroxy c a ff e in e g -T h i 0 c a f f e i n e g q l 4 .2 l5 3 i 5; 7 g.5 il+.g U.S 5 #g 10 . 5 1 2 .2 3^3 13^ l #g g ly^-g 1^3 97 The t h r e e c ag es u s e d as c o n t r o l s , o r t h a t were f e d on th e s to c k r a t i o n a lo n e , show­ e d an a v e ra g e w eekly g a in o f 1 8 .2 grains. T h is was u se d a s a s ta n d a r d o f com parison w ith th e o t h e r r e s u l t s , 1 . C a f f e in e . There was a g ra d u a l d e c re a s e in grow th i n th e r a t s f e d as l i t t l e a s O.Olfr and 0.025$, c a f f e i n e . However, t h e r e was no n o tic e a b le e f f e c t upon th e b e h a v io r o f tn e a n im a ls u n t i l a l e v e l o f ab out 0 .5 0 $ o r above was re a c h e d . At t h i s l e v e l th e r a t s g a in e d o n ly 6 .2 g. p e r week o r a d e c re a s e o f 1 2 .0 g. They a p p eared v e ry nerv o u s and irrita b le . The a n im a ls on th e 1.0$> and 1 .5 $ l e v e l s v e ry soon d ev elo p ed a p u f f in e s s a ro u n d th e m outh. The e a r s became p a l e , and th e h a i r a p p e are d rough. They were v e ry n e rv o u s and jumpy when h a n d le d . T h e ir eyes rem ained c lo s e d and th e y had a g e n e ra l dumpy a p p e a ra n c e . A utopsy showed s l i g h t l y a tr o p h ie d k id n e y s and s p le e n , and c o n g e ste d lu n g s . H ow ever, th e d i g e s t i v e t r a c t a p p e are d q u ite norm al. Im m ed iately b e fo r e d y in g , th e r a t s became p a r a ly z e d th e n w ent in to c o n v u ls io n s , f i n a l l y h em orrhaging e x c e s s iv e ly from th e lu n g s . T h is shows th e e f f e c t o f th e drug upon th e n erv o u s system and r e s p i r a t i o n . 2 . S -B ro m c a ffe in e . Uo a p p a re n t i l l e f f e c t s were o b se rv e d even w ith th e a n im a ls on th e 0. 5/0 l e v e l w hich showed a g a in o f 1 ^ ,2 g. p e r week. They were b u t v e ry l i t t l e more n e rv o u s th a n th e r a t s in th e c o n tr o l p e n s. 3 . 8- C h l o r c a f f e in e . T h is compound showed s l i g h t l y more to x ic e f f e c t th an d id brom c a f f e i n e , and c a u se d a g a in o f 8 .5 g. p e r week p e r a n im a l. The a n im a ls had a f a i r l y h e a l t h y a p p e a ra n c e b u t were q u i te n e rv o u s. 4. S - I o d o c a f f e in e p ro v e d to be th e m ost to x ic o f th e h a lo g e n d e r i v a ti v e s Of c a f f e i n e . The r a t s g a in e d b u t M-.S g. p e r week when fe d on th e 0 . 50 $ l e v e l , and one o f t h e s e a n im a ls d ie d i n l e s s th a n n in e w eeks. The, l i v e r was d a rk , b u t o th e rw is e n orm al. The r a t hem orrhaged q u i te a b i t from th e lu n g s th e day b e fo r e i t d ie d . 5. C a ffe in e - m e r c u ric c h lo r i d e . As would be e x p e c te d , t h i s a d d itio n compound o f c a f f e i n e p ro v ed to be q u i te t o x ic on r a t s . However, one r a t , a f t e r becom ing a p p a r e n tly t o l e r a n t to th e com p o u n d ,liv ed te n weeks w ith o u t g a in in g o r lo s in g w eig h t to any e x t e n t . In com paring th e e f f e c t o f f e e d in g 0 .3 $ c a f f e in e -m e rc u r ic c h lo r id e and m e rc u ric c h lo r id e a lo n e e q u iv a le n t to t h a t in th e 0 . 3$ c a ff e in e -m e rc u r ic c h lo r i d e , p r a c t i c a l l y no d i f f e r ­ ence was fo u n d , though p e rh a p s th e l a t t e r was s l i g h t l y more to x ic , ( - 9 .9 to - 1 1 .2 g. grow th p e r w e e k .) b. g - C h lo rth e o p h y llln e . The o n ly d if f e r e n c e betw een t h i s compound and 8- c h l o r c a f f e i n e i s th e a b sen c e o f a m ethyl group i n th e se v e n th p o s i t i o n . However, th e t o x i c i t y t e s t s p ro v ed t h a t c h lo r th e o p h y llin e was th e most to x ic o f any o f th e c a f f e in e h a li d e d e r i v a t i v e s th u s f a r s tu d ie d . The f a c t o r t h a t th e b i t t e r t a s t e m ight in f lu e n c e th e a n im a ls n o t to e a t a s u f f i c i e n t amount o f food would n o t e n t e r in h e re a s th e compound i s p r a c t i c a l l y t a s t e l e s s due to i t s g r e a t i n s o l u b i l i t y , e x c e p t in d i l u t e a l k a l i . The a n im a ls f e d on th e 0 .2 $ o r h ig h e r l e v e l s a l l d ie d . Upon a u to p sy , th e an im als on th e ^ 0 .5 cj l e v e l showed a d a rk c o n g e ste d l i v e r , and a v e ry sm all d a rk s p le e n . A ll o f th e r a is * examined had th e a v e ra g e amount o f food in th e d i g e s t iv e t r a c t . In a l l c a se s th e a n im a ls showed a g ra d u a l d e c re a s e in w eight u n t i l l i f e was no lo n g e r p o s s ib l e . 7 A lk y l- e th e r comuounds o f c a f f e i n e . In a l l o f th e s e compounds t e s t e d th e r e was fo u n d , w ith th e e x c e p tio n o f b u t y lo x y c a f f e in e , a d e c re a s in g t o x i c i t y a s th e le n g th of 'h e a lk y l c h a in in c r e a s e d . M eth o x y caffein e p o s s e s s e d ab o u t th e same t o x i c i t y (on th e Q l Jo l e v e l ) as c a f f e in e , w h ile iso -a m y lo x y c a ffe in e produced p r a c t i c a l l y th e same r e s u l t s 96 a s th e s to c k r a t i o n a lo n e . B u ty lo x y c a f fe in e p o s s e s s e d a p e c u li a r e f f e c t on th e r a t s . They w ere a p p a r e n tl y h e a lth y and were h o ld in g t h e i r own o r g a in in g w eight and th e n d ied v e r y su d d e n ly w ith inu.cn p a in and spasm s. A utopsy r e v e a le d n o th in g p a r t i c u l a r l y abnorm al a b o u t th e i n t e r n a l o rg a n s . As would "be e x p e c te d a l l y l o x y c a f f e i n e , h a v in g an u n s a tu r a te d a l k y l g ro u p , proved to he mucii more t o x ic th a n th e o th e r o ^ -c o m p o u n d s. The a v e ra g e w eekly g a in was h u t 1 ,6 g. The a n im a ls g r a d u a lly l o s t w eig h t and were q u ite d u ll and l i f e l e s s in a p p e a ra n c e . How­ e v e r , th e y d id n o t d ie even a f t e r b e in g on th e d i e t f o r o v e r seven w eeks, and g a in e d v e ry r a p i d l y when p u t on th e s to c k r a t i o n a lo n e a f t e r t h i s p e rio d , 8 . 8-Amino c a f f e i n e . T h is compound when fe d a t m ore t o x ic th a n c a f f e i n e . T h is i s in a cco rd an ce w ith i n c r e a s e d t o x i c i t y upon a d d in g th e amino group to th e r e v e a l a p a r t i c u l a r l y n e rv o u s c o n d itio n , b u t ap p e are d age g a in p e r week was 5*6 g r a n s . th e O.ffi l e v e l p ro v ed to be a l i t t l e o th e r compounds w hich show an m o le c u le . The an im a ls d id n o t u n t h r i f t y and l i s t l e s s . The a v e r ­ 9. 8 -H y d ro x y c a ffe in e . The r a t s fe d on th e O. f y l e v e l s w ith t h i s compound d id f u l l y a s w e ll a s th e c o n tr o l s . They d id n o t show th e nervous c o n d itio n a s d id th o s e on th e same l e v e l o f c a f f e in e . The a v e ra g e g a in p e r week was 17*8 gram s. T h is c l e a r l y b r in g s o u t th e f a c t t h a t th e s u b s t i t u t i o n o f an hy< ro x y l group f o r th e hydrogen in th e e ig h th p o s i t i o n on th e c a f f e in e m o lecu le g r e a t l y low ers th e t o x i c i t y o f th e compound. I t i s c la im e d how ever t h a t th e d i u r e t i c e f f e c t o f t h i s compound i s g r e a t e r th a n t h a t of c a f f e i n e , w h ile i t does n o t have th e e f f e c t on th e h e a rt and c e n tr a l n e rv o u s system to e a r l y a s g r e a t an e x te n t a s does c a f f e in e . 10. 'T h io c a ffe in e . The e f f e c t o f th e th io group on th e c a f f e in e m o lecu le d e c re a sec th e t o x i c i t y o f t h i s compound alm ost as much as d id th e h y d ro x y l group. The a v e ra g e w eekly g a in was I 5 .3 gram s. The an im als were in a t h r i f t y c o n d itio n a t a l l tim e s , and w ere n o t n e rv o u s a s were th o se on th e 0 . 5^9 c a f f e in e r a t i o n . However, one r a t seemed to g a in much f a s t e r th a n th e o th e r . Two c h a rts ,s h o w in g th e c o m p arativ e t o x i c i t y o f c a f f e in e on d i f f e r e n t l e v e l s and s e v e r a l c a f f e in e d e r i v a ti v e s on th e same l e v e l when f e d to r a t s , fo llo w . Suminary. 1 . C a ffe in e c a u se d a sm a ll d e c re a s e in th e r a t e o f grow th o f r a t s i n even a s low a l e v e l a s 0.01^9 i n th e s to c k r a t i o n . Those a n im a ls fe d in l e v e l s betw een 0. 5 to 1 .0 £ showed th e u s u a l symptoms and d ie d in a few weeks, 2 . The m o n ohalides o f c a f f e in e showed i n c r e a s in g t o x i c i t y in th e o r d e r named: b ro m c a ffe in e c h l o r c a f f e i n e and io d o c a f f e in e . C h lo r c a f fe in e was b u t s l i g h t l y l e s s t o x ic th a n c a f f e in e i t s e l f . 3 . The removal o f one m ethyl group, in the case o f c h lo r th e o p h y llin e , g r e a tly in c re a se d the t o x i c i t y o f the compound. T h ere oroved to be v e ry l i t t l e d if f e r e n c e in th e t o x i c i t y o f th e m e rc u ric c h lo r id e a d d i t i o n p r o d u c t o f c a f f e in e and t h e e q u iv a le n t amount o f m e rc u ric c h lo r id e fe d a l o n e . 5 B u ty lo x y c a f fe in e and a l l y l o x y c a f f e in e were th e only a lk y l e th e r compounds o f c a f f e in e w hich s h o w e d any a p p r e c ia b le t o x i c i t y . In g e n e ra l, th e t o x i c i t y d e c re a s e d a s th e le n g th o f the chain in c r e a se d . 6 The a d d itio n o f one amino group s l i g h t l y in crea sed th e t o x i c i t y . 7 ] The a d d it io n o f one h y d ro x y l group g r e a t l y d e c re a se d th e t o x i c i t y . s'. The a d d i t i o n o f one t h i o group g r e a t l y d e c re a s e d t h e t o x i c i t y . Growth of RatB on Stock Ration Plus Varyin Anounts: o f Jaffein eT O pH o o 20 o ■H 10 -o^ rH 0 ,te o f Growth o f E ats when Fed on Stodc Rat io n P lus 0 , 5 0 ^ o f C a ffein e , or i t I D e r iv a tiv e s . 10 20 30 1—1 'H 4-> 60 o O 20 CO CO CO o CO -l-> ■rl 10 o I— I CO CO CO o CO 0 10 20 99 III. M0THPR00IPI1TG TESTS WITH CAPPEIUE AETD SOLS OS’ ITS DERIVATIVES, COMPARED 7TITH LARVEX, AIID EQUATE. Method: Aqueous s o l u t i o n s were made up i n v a ry in g c o n c e n tra tio n s ( C h lo rth e o p h y llin e was d i s s o l v e d in l'o sodium h y d r o x id e ) . Two in c h sq u a re s o f b r i g h t g reen p u re woolen f la n n e l w ere im m ersed i n th e s o lu t i o n s f o r tw enty m in u te s , and th e n hung up to d r a in w ith o u t s q u e e z in g o u t th e s o l u t i o n . The sam ples were f i n a l l y d r ie d i n a d ry in g room a t 130 to 1 ^0 ° p . One s q u a re o f each d i f f e r e n t l y t r e a t e d sample was p la c e d in a sm a ll P e t r i d is h and a b o u t 15 m oths o f v a ry in g s iz e s were p la c e d on each sam ple ( th e c a s e - b e a r in g s p e c ie s was u sed ). The t r e a t e d sam ples ( a s w e ll as two u n tr e a te d sam ples f o r c o n tr o l s ) upon w hich th e m oths were a llo w e d to f e e d , w ere p la c e d in a l a r g e t i n can. A sm all b e a k e r c o n ta in in g a w a te r soaked sponge was p la c e d b e s id e th e P e t r i d ish e s to f u r n i s h a d e q u a te m o is tu re c o n d it io n s , A c h e e se c l o t h was t i e d o v er th e to p o f th e can and th e l a t t e r p la c e d in a d a rk p la c e a t room te m p e ra tu re . The sam ples were examined about ev ery two weeks. Due to th e f a c t t h a t th e moth la r v a e do n o t l i k e th e l i g h t , th e y e x te n d th e f o r e ­ p a r t o f t h e i r b o d ie s o u t o f th e c a se s and b e g in moving about a f t e r b e in g exposed to b r i g h t l i g h t f o r a s h o r t tim e . Thus i t was r e a d i l y o b se rv e d w h ether th e y were a l i v e o r n o t , by c lo s e o b s e r v a tio n u n d e r m agnifying le n s e s . By p u t t i n g th e la r v a e on b r ig h t g re e n w oolen f l a n n e l (a ry b r i g h t c o lo r d i f f e r e n t from t h a t w hich th e y have fo rm e rly been on can be u s e d ) grow th was seen by th e enlargem ent o f th e c a se s on th e ends and a ls o th e f i l l i n g i n o f l o n g i t u d i n a l s l i t s w ith d i f f e r e n t c o lo re d m a t e r i a l a s th e d ia m e te r was b e in g in c r e a s e d . 100 R e s u lts : No, M a te r ia l u s e d 1 C o n tro l No, 1 " No. 2 Cone. €p. Grains h e ld p e r g. o f c lo t h O ctober 26 No. a l i v e O b se rv a tio n s .November 12 No. a l i v e December 20 No. a l i v e 15 15 5 5 11 6 L a rv e x ii « 0 .0 5 0 .1 0 0 .2 0 0 .0 4 2 3 0 ,0 4 4 3 0 .0 4 9 2 2 3 4 0 0 1 0 0 0 C a ffe in e 0 .0 5 0 .1 0 0 .2 5 0 .5 0 1 .0 0 2 .0 0 0 .0 4 3 6 0 .0 4 3 3 0 .0 4 5 9 0 .0 6 0 5 0 .0 6 5 7 0 .0 9 2 2 7 15 2 12 5 3 3 2 1 2 1 0 3 3 0 0 .0 5 0 .1 0 0 .2 0 0 .0 2 7 5 0 .0 2 0 9 0 .0 2 6 6 4 4 4 12 2 4 4 2 0 0 .0 5 0 .1 0 0 .0 2 1 7 0 .0 2 3 4 10 6 7 2 1 0 0 .0 5 0 .1 0 0 .0 4 0 7 0 .0 2 5 8 0 .0 5 0 .1 0 0 .2 0 - 0 .0 7 6 5 -0 .0 4 0 1 0 .0 2 3 7 T e tra m e th y lu r i c a c id , n 0 .1 0 23 2b B u ty lo x y c a f fe in e 25 K onate ( f u l l s tr e n g th ) 3 4 5 6 7 ii it s it 9 ii 10 11 12 13 14 15 it C h lo r th e o p h y llin e n it C l-c a ffe in e ii 16 17 B r-c a ffe in e 13 19 S H -c a ffe in a ii ii 20 21 22 5 5 3 3 2 1 10 6 3 12 3 13 8 8 7 1 2 0 0 .0 1 3 2 15 4 3 0 .2 0 0 .0 1 7 6 6 6 0 0 .1 0 0 .2 0 0 .0 0 9 4 O.OI 67 13 8 3 6 O.2 1 3 9 6 2 1 101 C o n c lu s io n s : Only a b o u t one—t h i r d o f th e m oths rem ained a l i v e on th e c o n tr o l ( u n tr e a te d ) sam p les a f t e r m ore th a n two m onths. I t may be c o n c lu d e d , t h e r e f o r e , t h a t th e t e s t was n o t c o n d u c te d u n d e r i d e a l c o n d itio n s o f te m p e ra tu re , h u m id ity , and p e rh a p s o th e r f a c t o r s . However, f a i r l y r e l i a b l e r e s u l t s w ere o b ta in e d w hich b r in g out th e compar­ a t i v e m o th p ro o fin g v a lu e o f th e compounds u s e d . L arv ex p ro v e d to b e th e m ost e f f e c t i v e m oth p ro o fin g s u b s ta n c e , r e s u l t i n g i n th e d e a th o f n e a r l y a l l o f th e m oths w ith in one m ohth. K onate was n e x t in e f f e c t i v e n e s s , b u t was d e c id e d ly i n f e r i o r to L arvex. C a ffe in e was o n ly s l i g h t l y e f f e c t i v e a t th e end o f one month, and th e n when u s e d i n c o n c e n tra tio n s o f 0 .5 ^ o r above. T hree m oths w ere fo u n d a l i v e on th e sam ple t r e a t e d w ith 1 . ^ c a f f e in e s o lu t i o n a t th e end o f o v e r n in e w eeks. H ence, i t may be co n clu d ed t h a t w h ile c a f f e in e does p o s s e s s m o th p ro o fin g p r o ­ p e r t i e s i t i s much i n f e r i o r to L arvex from th e s ta n d p o in t o f c o s t and e f f e c t i v e n e s s . Hone o f th e s i x c a f f e i n e d e r i v a ti v e s showed o u sta n d in g d if f e r e n c e s i n m o th p ro o fin g a b i l i t y when com pared w ith c a f f e in e u sed in th e same c o n c e n tr a tio n s . T e tra m e th y l u r i c a c i d , w hich i s th e m ost b i t t e r o f th e s e compounds, gave no b e t t e r r e s u l t s th a n th e o t h e r s . The h a l o - c a f f e i n e d e r i v a ti v e s were p erh ap s v e ry s l i g h t l y b e t t e r m o th p ro o fin g s u b s ta n c e s th a n c a f f e in e ; w h ile b u ty lo x y c a ff e in e was s l i g h t l y l e s s e f f e c t i v e . T h ere seems to b e no c o r r e l a t i o n betw een th e t o x i c i t y o f c a f f e in e and i t s d e r i v a t i v e s when f e d to r a t s and th e m o th p ro o fin g p r o p e r t ie s o f th e s e compounds. In many c a s e s a good m o th p ro o fin g s u b s ta n c e does n o t n e c e s s a r i ly k i l l th e m oths when p u t o n to th e m a t e r i a l , b u t p r e v e n ts th e m oths from e a tin g th e f a b r i c , o r cau ses them to s ta r v e to d e a th . INDEX A c e c a ff e in e , 25 A lla n t o in , 4 1 ,3 .6 - t r im e t h y l ( c a f f o l i n ) , 25 A llo c a ffe in e , 12 A llo c a f f u r ic a c id , 12 A llo x a n , 4 8 -A m in o c a ffe in e , 92 Amalie a c id , 26 8 -n -A m y lo x y c a ffe in e , 54 8 -is o -A r a y lo x y c a ffe in e , 3 7 - 3 8 , 5 5 A p o c a ffe in e , 24 Arom atic d e r iv a t iv e s o f u r ic a c id , l4 -l6 B a r b itu r ic a c id , 5 B en zo ic a c id , 3-o :cy ca ffein e compounds o f paraoxy, 8 -B e n z y lo x y c a ffe in e , 6l 3 -B r o m c a ffe in e , 3 2 -3 3 , 43-44 B rom hydroxycaffein e, 9 8 - n -B u t y lo x y c a f fe in e , 51 8 -s e c - B u t y lo x y c a f f e in e , 52 S - t e r t . B u ty lo x y c a ffe in e , 53 C a ffe id in e , 26 C a ffe in e , 22-28 ch e m istr y , 24-27 d ecom p osition "by a l k a l i e s , 2 6 - 2 7 m othproofing t e s t s , 9 8 -1 0 1 o x id a tio n , 24-26 s a lts , 27 e th e r compounds (s e e E thers o f c a f f e in e ) , h alogen d e r iv a t iv e s , 3 0 - 3 6 . 42-45 o c c u r re n c e , 2 2 p h y s ic a l p r o p e r tie s , 24 p h y s io lo g ic a l p r o p e r tie s , 28 p r e p a r a tio n , 2 2 -2 3 to x ic ity t e s t s , 95- 9 ® C a f f o lid e , 1 , 7-dim et h y l- 3 - e t h y ll4 C a f f o lin , 25 C a ffu ric a c id , 25 8 - C h lo r c a f f e in e , 42-43 8 - C h lo r th e o p h y llin e , 9*+-95 C h o le s tro p h a n e ( d im e th y l- p a ra b a m ic a c i d ) , D ie th o x y h y d r o x y c a f f e in e , 40 3 6 - 4 l, *+5-62 26 9» 25 E ther compounds o f c a ff e in e (R -o x y c a ffe in e ), 2-a lly lo x y , 5s 8 -n -am yloxy, 5*+ 8 -iso -a m y lo x y , 37~3S » 55 3 6 - 4 l, 4 V.T1 D ih yd an toin , 1 ,7»9“ 'kI,i IIie*'*:iy-*-~3-e k47-*-“s P^ro-5»5“ > l 4 E th e r compounds o f c a f f e i n e ( c o n t 'd . ) 8 - n - b u ty lo x y , 51 8 - s e c . b u ty lo x y , 52 8 - t e r t . b u ty lo x y , 53 8- c a r v a r c r o l o x y , 39 8- o - c r e s o l o x y , 3S 8 - m - c r e s o lo x y , 38 8- p - c r e s o l o x y , 39 7 .8 - d ie t h o x y , 4 0 -4 l 8 - e t h o x y , 3 7 , 48 8 - e u g e n o lo x y , 39 8 - g u a i c o lo x y , 38 8 - n - h e p ty lo x y , 57 8 - n -h e x y lo x y , 56 8 -p -h y d ro x y p h e n y lo x y , 39 8 -m eth o x y , 3 6 , 47 8 - 0 - 0 x yphenyloxy, 39 8 -p h e n y lo x y , 3 8 , 39 8 ,p h e n y le th o x y , 62 8 -n -p r o p y lo x y , 49 3 - s e c . p ro p y lo x y , 50 le tr a m e th o x y c a f f e in e , 4l 8 - thy m o lo x y , 38 8- E t h y l c a f f e i n e , 77-80 Halogen d e r i v a t i v e s o f c a f f e i n e , 3 O- 3 6 , 42-45 8 - b r o m c a f f e in e , 32 - 3 3 , 43-44 S -c lilo rc a ffe in e , 3 I - 3 2 , 42-43 3 >8- d i c h l o r , 35 7 , 8- d i c h l o r , 3*^"35 3 - m e th y l- 8 - c h l o r , 40 te tra c h lo r, 3 5 -3 6 8- i o d o c a f f e i n e , 3 4 , 44-45 H e te ro x a n th in e , 18 H y d a n to in , 2 5 , 33 1 -m e th y l, 25 1 , 3 - d im e th y l- 5-m e th y la m id o , 25 h y d razo d im e th y l, 33 H yd ro q u in o n e, 8- d i c a f f e i n e e th e r o f , 40 H y d ro x y c a ffe in e , 7-9* 91 H y d ro c a ffu ric a c id , 25 H y d ro x y c a ffe in e g ly c o l, 24 5-Hydroxy-l-methyl-3-ethyl-hydantoylmethyl-amide, 8-p-Kydroxyphenyloxycaffeine, 39» 60 Hypocaffeine, 25 8-Iodocaffeine, l4 3*+» 44-45 Methylaminocaffeine, 33 S-Methylcaffeine, 2 9 , 75"77 Mothproofing tests with c a f f e in e and i t s d e r i v a t i v e s , Murexide reaction, 4, 26 98-101 P a ra x a n th in e, 21 8 ~ P h e n y le th o x y c a ffe in e , 62 P y r o c a te c h o l, 8 - d ic a f f e i n e e th er o f , 39 P y r o l y s i s o f th e h ig h e r a lk y l e th e r s o f c a f f e i n e , 71-72 P y r o ly s i s o f 8 -p h e n y lo sy and 8»parah y d ro sy p h en y lo x y c a f f e in e and 8 -p h e n y le th o x y c a ffe in e , 7 4 - 7 5 R e s o r c in o l, 8 - d i c a f f e i n e e th e r o f , 39 R e s o r c in o l, 8 -m o n o c a ffe in e e th e r o f , 39 S a r c o s in , 26 T e t r a a lk y lc a ff e in e d e r iv a t iv e s 8 - e th y l-c a ffe in e , 77-80 6 - m e t h y l- c a f f e i n e , 2 9 , 75-77 T e t r a m e t h y l- u r e i d in , 13 T e tr a m e th y l- u r ic a c i d , 1 0 -1 3 , 6 3 -6 5 T h eo b ro m in e, 21-22 T h e o p h y llin e , 1 9 -2 1 8 - T h io c a f f e in e , 93 T o x i c it y e x p e rim e n ts w ith c a f f e in e and i t s d e r i v a t i v e s , T r im e th y l-7 - b e n z y l- x a n t h i n e , 29 U ric a c id s , 3“ 5 a ro m a tic d e r i v a ti v e s o f , l4 -l6 7 - b e n z y l - 3 , 9 - d im e th y l , l6 7 - b e n z y l - l , 3 ,9 “ t r i m e t h y l , l6 9- p h e n y l , 1 4 -1 5 1 »3 >7 - 1 rim e t h y l - 9 - p h e n y l , I 5- I 6 7 - b e n z y l - 3 , 9 - d im e th y l - u r ic a c id , d i m e th y l - u r i c a c i d s , 6 -7 3 . 9 - d im e th y l, 6 7 . 9 - d im e th y l, 9 1 , 3 - d im e th y l, 6 3 . 7 - d im e th y l, 6 1 , 7 - d im e th y l, 6 1 . 9 - d im e th y l, 7 7 - m e th y l- 1 , 3 , 9- t r i m e t h y l - u r i c a c id , m o n o m e th y l-u ric a c i d s , 5-6 3 -m e th y l, 5 9 -m e th y l, 5 7 -m e th y l, 6 1 -m e th y l, 6 l6 l6 9 -p h e n y l- u ric a c id , 1 4 -1 5 te tr a m e th y l- u r ic a c id , 1 0 -1 3 . 6 3 -6 5 d e c o m p o sitio n , 11-13 ■ p re p a ra tio n , 10—11, 6 3 -6 5 p ro p e rtie s, 11 t r i m e t h y l —u r i c a c i d s , J—10 1 . 3 . 7 -tr im e th y l (h y d r o x y c a ffe in e ), 1 . 3 . 9 - t r im e t h y l, 9 1.7.9-trim ethyl, 10 3„7,9~trimethyl» 7 -9 , 91 95-98 U ric acids ( c o n t 'd . ) l , 3 »7 - t r i m e t h y l - 9- e t h y l - u r i c a c i d , p re p a ra tio n , . 1 3 , 6 5 -6 7 13 - 1 *+, 6 5 -6 7 p ro p e rtie s , 14l> 3 » 7 - t r i m e t h y l- 9 - p h e n y l - u r ic a c id , 1 5—16 1 ,3 » 7 - tr im e th y l- 4 - ,5 - d im e th y o x y - 9 - e th y l- u r ic a c id , 14- X a n th in e s , 1 6 - 3O x a n th in e , l6 -1 8 a ry l, 2 9 -3 0 d im e th y l x a n th in e s , 19-22 1 ,3 - d im e th y l ( T h e o p h y llin e ) , 19-21 1 .7 - d im e th y l ( P a r a x a n th in e ) , 21 3 .7 - d im e th y l (T h eo b ro m in e), 21-22 m onomethyl x a n th in e s , 18-19 1 - m e th y l, 18 3 - m e th y l, IS 7 -m e th y l ( h e t e r o x a n t h in e ) , 18 8 - m e th y l, 18-19 9 - m e th y l, lg te tra a lk y lx a n th in e s , 2 9 -3 0 1 , 3 . 7 , S - te tr a m e tb y l ( 8 - m e th y lc a f f e in e ) , 2 9 , 75“ 77 1 .3 .7 - t r i e t h y l - S - m e t h y l , 29 l » 3 « 7 - t r i m e t h y l - S - e t h y l T( s e e E t h y l c a f f e i n e ) , 77-80 1 . 3 . 8- t r i m e t h y l - 7 - b e n z y l , 29 tria lk y lx a n th in e s , 2 2 -2 9 1 . 3 .7 - tr im e th y lx a n th in e (se e C a f f e in e ) , 22-28 3 . 7 . 8- t r i m e t h y l , 28 1 . 3 . 8- t r i m e t h y l , 28 1 . 3 . 7- t r i e t h y l , 29 1 . 3 . 7- t r i b u t y l , 29 1 .3 .9 - t r im e t h y l- is o - ', JO