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1948 The iM gration of Acyl Groups in Ortho- Aminophenols. Edgar Dumont Smith Louisiana State University and Agricultural & Mechanical College

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Recommended Citation Smith, Edgar Dumont, "The iM gration of Acyl Groups in Ortho-Aminophenols." (1948). LSU Historical Dissertations and Theses. 7912. https://digitalcommons.lsu.edu/gradschool_disstheses/7912

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A Dissertation

Submitted to tm Cra&uate Faculty of the Louisiana State University and A gricultural axid 2,leehaaaical C ollege in partial fulfillment of the requirements for the &©gres of Doctor of Philosophy

in

the Department of Chemistry

by adgar Dumont Smith B*D*, Tulan© U n iv ersity , 19D& &*&•» i’ulauo University, lb41 ^ a y * 1^46 UMI Number: DP69290

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UMI DP69290 Published by ProQuest LLC (2015). Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code

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ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106 - 1346 £he autiior wishes to eat pr ass M s gratitude to

p* • L* LeRosen, who suggested and guided tU s

Investigation, for Ms unfailing interest and many helpful suggestions*

i t t m m o f r n m w m

£* XHSaOBOCflOB •»«••»«•••••«•«•»« 1

IX* PJ5VIEW oy THE Uffi&ittUHS ««*•»*«•* * * . 4 m « TaaoaaricAL

A* M igrations during second a c yla tio n * * • • i&

3* Migration in acid»typ« solvents • • • • • *16

C* M igration during hydrolysis ********18

2, Stability of sulphonyl derivatives « * * • 20

E* iforstation of bensoxazoloaes •«••••» *&X

if* Heplaeement of acyl group *&2

IT * ^LPSaiMESTAL

A* Preparation of acyl derivatives * * • * * *£5

3* Analysis of isomerisation mixtures * * * * 31

0# Hydrolysis o f mixed ortho d lacy la * * * * *33

Dm Analysis of hydrolysis mixtures ***** *33

T* EI3GUS2UOH OP H33ULT3 ••*•*«•••«*•* 39 v i. someae* •••***•*•«•*•*•*•«•• 58

T i l * SELECTED 3I&UOailAP2nf **•#»«*•«*•• * 6 1

T i l l * VITA *•«•**.*••**•*•*•*•«• *71

ill L im OF S A B I®

X* Acyl Derivatives Studied »•••••••••« 26

XX* 'oialysia o t Ortho Mixed T iacyls •*#**+» * 4 8

III* Analysis of Alcohol Xsomerijsat ion products • • 60

I?* E ffe c t o f Heat on Pure Mixed Matey Is * • * * « 51

V* Analysis of Pyr id in# Isomer Isatiou Products * * 52

VI* Analysis o f Mixed Di&cyl flyd ro ly s is Products * 54

Iv u s *? o f n c a a a s

lm U ltr a V io le t Spectra o f ^onoac^rl B a riv & tii rm « * • 42

II* Ultra Violet Spectra of l;iaoyl JBerivativos « * • « 43

v o s t i u m

x considerable aiaount o f axperim ental data has been co llected

0 8 the general subject of acyl migrations in o-amioopfraaoIs since interest was f ir s t drawn to this problem by t m eminent .imarioan chemist* Julius stieglitas* in 189IU Tna groat majority of tala work has indicated that when two different acyl groups# derived fro® carboxyl Ic acids# are introduced into an o-aial no phenol the sum# @ixed diacyl derivative was generally obtained# regardless of tbs order of introduction* On hydrolysis the heavier acyl group has usually boon found on nitrogen# and in only a f m instances have fix tu re s o f the two possible monoaoyls been obtained* fas structure of the mixed diacyl derivatives has never boon proved# it generally being assumed that the group which was hydrolysed off by the actios ©f algali was the one attached to oxygen in the mixed d ia c y l*

'This work was undertaken because it was believed ta&t tae present availability of two powerful new tools of organic chemistry# chromatography and ultra violet spectrophotometry* might make it possible to isolate and identify the mixed diaoyl isomers if both were produced# to q u a n tita tiv e ly account fo r a l l o f tne products of t-ie reactions*

3y chromatographing the crude products of the acylatlons it was found that# In the specific instance Investigated here of

v i acetyl-b«s*oyl dmrivstlvss o t o—aminophono 19 two mixed d ia e y l derivatives war# present in both crude product# which, however, were predominantly &-acetyl~0~bensoyl md &»& ansoy l*»o-aoe tj 1 o-amino phenol dependlag on the aoylat ion sequence* Acetylation of G^henseylsminophenol gave 62 percent of the unrear ranged

M-benzoyi-O-acetyl form* while benzoyl&tion of o-acety larei nopneno 1 gave 91 percent of the usraarrshged isomer* Both of these pure mixed dtacyls were Isolated for the first time la this work,

and their physical properties and relative stabilities under the

influence of several factors was studied*

the s tru ctu re o f these two isomers was proved by the cosspar-

iscas of the ultra violet light abaorbtion of these compounds with

the absorption characteristics of the corresponding para derivatives wherein the orientation of the acyl groups is well known* This work constitutes the first good evidence for the structure of these mixed d ia c y ls .

I t has been demons! rated th at the ”161. r a t ions” which have been observed in acyl derivatives of o-eminophenol are, in reality,

Isomer 1 sat ions of the normal form of the d!;*oyls under the c a ta ly tic in fluence o f the solvent media employed* I t was shown, by means of a combination of chromatographic separations and u ltra violet spectrophotometry, that in alcohol and pyridine solutions equilibrium mixtures containing 85 percent ani 77 percent of tae more stable H-aeetyl-O-benaoyl form of the mixed diaoyls were pro­ duced, respectively* It was pointed out that taese isomer is at ions

v i i in alcohol are probably the axplan&tion of the conflicting data reported in the literature on these mixed diueyl derivatives,

Water and heat also served to isomer lse these dlacyla, while benzene, hexane, acetone, ethyl stuer, *md dioxnne were much lees effective, if not inert, In this respect,

finally it was shown in this study that hydrolysis of either of the two isomeric aoetyl-bensoyl derivatives of o-aminophenol in aqueous NaOR did not result in a single monoacylated product as has been report®! in the literature# Instead, it was found that th'88 hydrolyses produced a mixture of the raonoaoyls contain-, lag about 62 percent ©-benzoylaminophenQl and 3© percent o~a,cetyl~ asiinophenol regardless of the composition of the mixture of diacyls which was hydrolysed* The variations in composition of the hyd­ rolysis products, while slight, indicated that the greater toe proportion of the if-beHsoyX-o-acetyX mixed diacyl in the mixture hydrolyzed, the greater was the amount of ©-benzoyl ami no phenol produced*

Comprehensive theoretical explanations of the results discussed above have been proposed which are based on modern concepts of organic chemistry and involve the so-called "resonance” and "inductive** effects in the molecules concerned* A new principle has been devel­ oped for predicting which of two isomers should be the more stable#

This principle has been called "the principle of mlnicsuffl charge concentration" and states that the isomer having the greatest conc­ entration of positive charge at a point within its molecule, w ill

v i l i be the mov0 unstable form* St is anticipated that tliis principle w ill prove useful la the furthar development of the theories of organic reactions*

A surrey of the literature os these acyl lul^ratlcas has shows

the preseat theory to he consistent with the reported results, but due to the nosw^uastitatlve nature of the woric reported is the

literature, much of this work must he repeated &Xon$ the lines

laid hows is this research before the theory can be fully tasted*

1st XHfBODOCfXOM

The majority of reported work in this field ho® indicated that when two different acyl groups* derived fro® carboxylic acids* are introduced in to an o-assino phenol* g e n erally tm same mixed diacyl derivative is obtained regardless of the order of introduction of the two acyl groups* Ibis result has keen interpreted m meaning that a rearrangement has taken place during one o f the second acyl at ion processes* Os

hydrolysis of the mixed diacyl derivative usually only one mono- aeylatad product could be obtained* and most of taa workers in this field have assumed that the group widen was hydrolysed o ff of the mixed diacyl under the influence of alkali* was toe group attached to oxygen in the mixed diaoyl derivative* \

few workers* however* have postulated the possibility of a rearrangement occurring during the hydrolysis stop*

ifo satisfactory general explanation of the above exper­

im ental observations yet been proposed although attempts nave been made to explain t ne apparent migrations on the basis o f such varied faotors as the r e la t iv e acidity of the acyl

groups {39* 51}* the relative weight of tne acyl groups (34* 35}* and the sturlo effects present in the molecules involved (3S* 3?}*

The interpretations of organic re&otions now generally

1 z accepted are based largely

?aulitig* 'Vheeland 9 Bemick and others { 1@30-194d } nave been extremely useful in explaining and predicting the course of many previously unexplainable organic reactions* It was a

logical step* therefore* to attempt to use those concepts to

explain the phenomena Just discussed of migration of acyl groups la o—amino phene Is#

Starting from the experimental findings of Bell (SO) that when one of the entering acyl groups was on arylaulphoayl radical no migration occurred# it was reasoned that the migrations must be caused by tne unsaturated nature of the acyl groups#

From tads basic idea and a consideration o f the resonance and

inductive effects in the molecules concerned a comprehensive

theory of the reactions was developed to explain and predict the course o f t h e a c y l migrations#

The mrpo^e of this work# teen* was to formulate and p r e se n t these explanations# and to attem p t to reconcile any differences which might be found between theory and fact*

It was felt that tnis work might oo successful where so many previous Invest!rations have fallal primarily because the 5

present availability of two. powerful new tools of organic chemistry, oarom&togr&pby and ultra violet spectra* m ight

$-.&* i t possible to definitely identify tiio ctlxed dlaeyl isomers produced t m ti to quantitatively account for all of i&e products of tiu reactions* SLStfijar o r ski; l i oooom m o

In te re s t was f i r s t drawn to t nl& problem by atsieglitz (8) who had occasion to use the compound no phony I et hy 1 oar*

boaats firs t prepared ay Bonder (2) fey the redaction of tbs cor res tending n itr e a> mpound • S tie & lits was imp rested by the striding absence of basic proportion of this compound and hypothesised that after the redaction of the nitre ooowaud to an assise baae, a molecular rearrangement of the latter occurred.

Eansoa ill} , at Stieglifcs* suggestion, investigated the reaction <±ai found that this postulated rearrangement had indeed takan place and that when o^nitrophenylet jayl carbonate was reduced with tin and hydrochloric acid a urethane was obtained wuich wan soluble in bases arid evidently ua*J the e&rnetboxy radical attached to nitrogen* By suitably modifying conditions a basic substance was obtained la waieh tub -aarbetntcxy radical was apparently attached to oxygen* on st^uing, this latter compound rapidly c^ng ed over to the urethane* She same urethane was also obtained from ow&idnowhcno 1 and chlorooarbonio eth yl

& hm r in etnor solution* A siruilur rearrangement was observed wn&n e—nltrophonyl bonscata was reduced in acid solution*

To determine the constitution of tn© urethane Eanaom nude the dtiaoyl derivative using eensoyl Chloride In alkaline

4 solution as# found that the sass© diacyl derivative was produced when If-toensoyl-^-amincpkanol was treat©-* with o h lo tq car bon i e ethyl ©thor* Since saponification In tooth oases gave benzoic acid and hyci roxypneny 1 urethane. Hansom concluded that In the reaction o f oalorooarconic e th y l ether w ith E~benzoy X^o-araioo— phenol a rearrangement resulted so as to leave the lighter acyl group attached to nitrogen.

I f one of the mine hydrogen atoms w^s f ir s t replaced toy a hydrocarbon r a d ic a l, no raammgemeut occurred and isomeric substances were formed when the acyl radicals wore introduced in reverse order. Isomeric diaeyls wore also obtained wnen the amine and. phenolic groups wore is^ta or para to each other*

Hansom and Colson (£7) further investigated these rearrange* meats to determine i f a carboxyl ©ate- group would become attached to nitrogen in place of a lighter group already there, and also if, in the case that two carboxyl ester groups were Introduced, the lighter one *o a Id go to n itrogen , They hoped that by intro** due lag rad 1 aula o f nearly the same weight they would produce a rearrangement which would to© slow enough to afford a better ohano© o f studying the macoanism o f the migrations* This work showed that when two carooxyl radicals wore introduced into the molecule of an o-ansinapnenol, tue lighter one beaaui© attached to nitrogen, the position not being influenced toy the order In wuioh the groups were introduced* In order to accomplish this a molecular rearrangement occurred in one case* This was also found to to© 6

true when both of the radical® ware e^boayls* In case on® ra d ic a l was oar Co ay 1 and the other oar aoxyl, the latter became attached to nitrogen regardless of tins r e la tiv e waists of the entering groups# fhee# conclusions war# a ll based on the assumption lm tt on hydrolysis* the acyl group attached to oxygen was the one removed* Tneir hope th at Introduction o f ra d ic a ls o f n e a rly the seme weight, bon soy 1 and hexyl, would result In the formation of Isomeric safest nces was not realised, the velocity of the rearrangements apparently feeini almost instantaneous is ©very ease*

f fee displacement from nitrogen of a lighter fey a heavier acyl radical was noted »y Paal and Otten (3j, Mctot (4), tod

Preusdler {IS}, while the opposite behavior was observed fey

Cohen (5), and fey Hellor and Jacobsohn (30)* tinhorn and Pfyl

{ID) found that the reduction of the CU&oyl derivatives of the o-n itro phono Is which they studied gave regularly, presumably through the rearrangement of the normal reduction product, a mixture o f the gwxoyl amino phenol and t •>© corresponding achydro- base* Jtuwers (9) allowed aniline to react with 8«ac<$tyloxyv

5,5-dibroftCbensyl bromide and found that act only was the bromine atom of the silo cuuin replaced fey the aniline residue, but that the acetyl bad wandered frOim oxygen to nitrogen although the latter was attached to a side oaaixu In subsequent work with several co-workers Auwers found that th is rearrangement took place when various substituted anilines and primary aliphatic

vnines were used, and also when benzoyl arid other heavy acyl radicals were employed (12, 13, 14, 17)* Further work fey 7

Auwers Bendy {15) indicated that the O^aoetyl derivatives o f the phenyibydr&zo «©a of aromatic o~iiydrcxy aid©hydes war© st^dl® under ordinary conditions, but ta&t sevura). rodents caused tm acyl to wander to the nitrogen atom o f the side

Chain* Ttm reagents most effective in causing these migrations ware ethyl, methyl and amyl alcohols, acetic acid, ethyl acetate and chloroform* keagent® found to bo lass off active war® benzene, tcluona, ligroia, caroontetranioride and carbon disulfide.

S im ila rly , when an attempt was asde to prepare too fre e Base o f the Q-benzo&t© of the end form of 0©ta~&minepropicpn©no»e* the beasoyi radical wandered from ©atygen to nitrogen# while the end form rearranged to the koto for® (26}* fnis difference in a ttra c tio n detween oxygen and nitrogen was not always s© pronounced fo r i t was found &y Ldfiler and Hamlet (26) that when only one acetyl radical was introduced into the molecule ©f &v~Eiaethyl«»a~ e th y la l p ip e rid in e , i t attahaod to oxygen and did not wander to n itr o g e n *

Auwers sujd hisenlohr i£i>) studied the behavior ©f acetyl** benzoyl d eriv a tiv es o f 2*amiuQ~4-»meti iy 1 p x©«ol, and found that waen tne waeetyl derivative of this phenol was subjected to the

3cnotten»Baumann reaction tm same diacyl derivative was obtained as that form©i oy the reduction o f &*nitro*4-*m0thyl~pheaylb©osB©afce, and it was taerefore regarded as the O-bejjso./l->X**»acetyl oompouM*

When tx^is d e r iv a tiv e was hydrolyzed by aqueous a lk a li, or by cold concentrated sulfuric aclc, it gave only w-uenzoylate, which was interpreted to mesa ' that the heavier of th e acyl radicals iiud migrated from nitrogen to oxygen during the .'iydrolysis* U'ha isom eric di&eyl derivative# oncoyIasi »©~4~ffle t hy 1 phony X* acetate was prepared by rev or sing the order of acyl at ion arid was found to saponify normally to the iUbensoyl aooeaoyl*

In a oontinuation of this research with other combinations of acyl radicals on this ease# ixtirers end l-isonlohr made the tacit assumption that is all the diacylatod derivatives prepared the radical last introduced was bound to oxygen# without is each case# comparing the derivative with Its suppos#& iaomsr made by introducing the radicals in the reverse order# Vhe rearrange* meats they observed were attributed to the influence of alkali# and they arrived at the conclusion that "only when there is a considerable difference in the weights of the two radicals# as for example# between benzoyl and acetyl# was there a complete displacement during saponification of the lighter by the heavier group* When the difference is less pronounced part ■'Of the mixed ester is saponified normally and one obtains a mixture of two different aeylamino derivatives in varying proportions* or only the normal saponification product"* In no case was such a rearrangement observed with meta and para amino phene Is#

3h*e problem o f providing an o vera ll mechanism to explain the results which have 4U3^ been described was undertaken by

Salford (2b) in 1919 and continued by him with a succession of students and oo~ workers until his death in 194a# haiford took late account toe possibility of migrations occurring both during acylation and during hydrolysis and In every instance he attempted 9

to obtain the tm p o ssib le mixed di&oyl d eriv a tiv es by the introduction of the two differ eat acyl radicals in Inverse order* The two derivatives, whether Isomeric or id e n tic a l, were saponified separately and the products c a re fu lly examined and compared*

Tm work o f Awrer* and h i sen lob? was repeated by Baiford sumi Couture (34) on the acetyl arid ben soy 1 derivatives of

2-s^ino-4-m©thy l-phene 1 and they obtained somewhat d iffe r e n t results* Two different mixed diacyl derivatives were secured from tne case waleh had melting points that differed but slightly from those reported by tourers and hisenlohr* Sach of these, however, upon hydrolysis with dilute alkali gave a mixture of the two monoaoyl derivatives wnich indicated that a partial rearrangement had occurred during the saponification of each*

Salford reported that this was toe only case in which isomeric acetyl-*bossoyl derivatives had been prepared from an o-amino- phenol in the aora than twenty such compounds tested by him and his students* All other o-aminophenols testad resulted in a single mixod diaoyl derivative* This was likewise tuo only instance in which as found a N -acetyl compound among th e a&pon*

1float ion products of an &oetyl~be»zoyl derivative*

In l €j&6 the h n g liah chemists. Bell and Kenyon (40) found that hydrolyaia of o*bdS3syliuinefliDlnopaenol gave 2-hydroxy acet&nilide Instead o f th e desired product, o«amlnop&onyl-- acetate* Bell (4b* SO, 51) followoi up tills work alone in the xo

hope that thie type of ra&etion might throw light on the raeoh- aaissa of the Migration of acyl ,s*fo«p* i» o-sminu phono Is * Bo observed toot when on# of too esteriag groups wm an a r y ls u l- phony 1 radical no migration occurred# and suggested that this

Indicated th# possibility that the migration was hound up with the "uosaturated nature of tn# acyl groups'1* In att®mpting to extend his theoretical explanation of the migrations# Boll repeated the preparation of &&vw a l ooaspouMs duri og th e ocurs© of which Halford and students had claimed to obtain complete r©arrasgofsewt• He discovered# contrary to tho findings of these tarli«r workers* that h« was ©foie to obtain two distinctly difiV

©rent d lacy I ted s'bov© their molting point* sod that a rearrangement of on# or of both isomers could foe caused oy hasting*

Perhaps because B e ll’ s only evidence fo r his claims lay in the mixed melting point determination* which he was able to obtain, his finding* have been almost completely ignored is in# literature to the present time* Incited, Bell himself has reported so fu rth er wor& to strengthen his observations* 7he la te r work is this field (sine® X9&2) has a ll been publiesed by Halford m& eo~»wor&ers who hays substantiated B ell’s findings with regard to the stability of the aryXaulphonyl derivatives, but did sot 11

rooheck the results on Welch Halford arA Hell wr® in conflict.

Heeeat work by Halford arid Aleasaaodor {60) and by Groanse aM

Halford (S3) showed, however* timt it was possible to prepare c e rta in sta b le monoaeyl d eriv a tiv es o f o-gjfnino ph&noIs w herein the acyl ra d ical was attached tc the o^ygan atom* was found to bo the case wit a ti.e rnetJ^lphenylcarbamyl radical* and w ith tlic etnylpbonylcerbamyl radical respectively* finally

Halford and Biiolton (62) snowed that tJ» ^repulsion effects** proposed by Latimer (48) as an explanation o f organic m igrations in general* was not satisfactory in these instances* tv a o a m x o x u

Previous work in this field Ms indicated that the migrations might occur either during the introduction o f the second acyl

group* or during the hyd rolysis o f th e mix vi d Iacyl derivative*

:^ost trie rs Li-ive nog-1 sc tod the p o ssib ility of migrations

oscurring nt both o f ines© steps* although Kelson and Davis (43)

speculated on th© possibility of bath of the migrations occurring,

and they noted th a t i f migration had oceorrsd in ©n© d irectio n

during aeylafcios, a reversed m igration had occurred on hydro ly s is *

$0 ezperimestal proof has yet be©** offered to prove at which

step migration occurs, however, and no satisfactory explanation

of the migrations nas yet h&m. brought forward,

£rom a consideration o f the experimental data collected In

this work it now appears that the simplest# and probably toe best,

explanation of the phenomena which have been observed in acyl at ed

o-^ainophenols Is that true migrations do not occur at all* Instead,

the effects which have been observed have bean due to the formation

o f eq uilib rium m ixtures o f the two isomerlo mixod d iacyls caused

by tiie catalytic influence of the solvents employed. The present

theory of these isomerissations Is as follows*

A. i-lLrratlons -Mtlxux Seopnd .oblation;- ?.»ae roarransaaonta

are believed to be caused by the c a ta ly tic e ffe c t o f the solvent

medium used for these acyl at ions—-in this work, pyridine,—on

tne normal or uzir ©arranged mixad di aoy I compound formed by the

IS 13

react ion* T h i s c a ta ly tic activity of pyridinei» hypothesised to proceed through too formation of an intermediate add it loti compound o f the mixed diaeyl am pyridine* followedthe by elim in a tio n o f a complex s a l t o f %'m acyl g r o u pattached to oxygen* Tiiesse reactions lead to t h e formation of t h e phaool&to

Ion of tho residual monoacyl which probably exists in the oho late fo re saowB la the follow ing e^a&fclonss

(i)

T iM t pyridine c o m p le xformed oy t/d® se rie s t f reactions is unstable and m.+y recombine with txie phene, lat o ion show© above in one of the follow ing two ways* I t may reattach at the phenolic "roup to give baoh the original mixed dl&oyl by a simple ref^rsal of the p&tha cnowsi in liquations ( 1) and { 2 } § or It may cause roarrciiyarMiiit io occur ay attaching the unshared electros puir of t m altvogm a-teaa* Shese im&i&roi% of nitrogen arc now very sm m ytlo l® to capture by a& electro- pU ilis attack slsae t m ohclatios aaovm in ^m atioa (&) betwees oxygen and t m positive o&rboa/X oareas atoa ox1 tad m j l ^mup attached to aitro g ea would nav# tuo effect of raduoisg the a t tr a c t iaa o f th is positive o cat or for tiu nitrogsa ’acsia&red pair XaaviBg them relatively free for other interact ioa» *&» forraation of the unstable intermediate Croats ey suoh in te r­ action is shown in h^uatioa 13) eelow:

fhis inter -ad i ate may yisld a rearranged mixed diacyl derivative by splitting off pyridine and breaking the oosd bo tween nitrogen sad its original acyl as illustrated in the following reactions 15

The utilisation of pyridine in the manner discussed on the ur©- ceding pages, and etibseqaent isomer isation w ill be moat likely wises there exists & strongly charged positive center to attract the unshared electron' pair of the pyridine nitrogen atom*

Ordinarily, in the mixed dtiacyl derivatives, this strong positive oenter is furnished by the carbonyl carbon atom of the acyl group attached to oxygon since the +5? effect o f the nitrogen atom is relatively strong, and hence tends to reduce the positive charge of its carbonyl carbon atom relative to the carbonyl carbon attached to oxygen* From a consider at ion of the resonance and inductive effects involved in the molecules concerned, it w ill ds recognised ti&t in the specific Instance for which quantitative data has been obtained in this research, the H-benaoyMMtcetyl form of the mixed tiiaoyl w ill furnish a greater positive charge on the carbonyl carbon atom attached to oxygen than will its

Isomeride. therefore, it follows that the SUft on m y 1-0 ~ac ©t y 1 form should isom erizo more rapidly then tne opposite Isomer#

That tiis equilibrium mixture attained between th e two forms in pyridine solution should have a higher percentage of the IT* acetyl-0-bensoyl isomer also follows from a consideration of the factors causing too above interaction between pyridine and the mixed diacyl derivatives* She necessary condition for such inter­ action is that a strong positive center bo supplied by the diaoyl derivative to which t/*e nitrogen atom of pyridine anti «&&rs its electrons* *e was Just stated* tnc :u«banzoyl-0-&c©tyi form of the mixed. deriv&tive is the o no which w ill furnish the greatest

"point charge'1 for such. & reaction and accordingly w ill do the more unstable for® ox the dieicyl m m though the summation o f the

chargee o f the two carbonyl carbon atoms in the opposite isomer may he just as great. It is deliaved that tale discussion constitutes the statement of a n m end ge.-ioral conocat which may prove v-ary useful in the formulation o f the theory of organic

react ions, and which we have termed the "principle of minimum

charge concentration”*

5hese rearrangements in pyridine constitute what iteaHBett

(59| ha* named "general base catalysis” and it Is anticipated that sim ilar restrrcugeoMmte w ill occur in other b asic ca ta ly sts*

B* Migration in Acid-gyqe Solvents i-» fixese migrations are also

believed to bo caused by mi interact ion between the solvent and

the unrearranued form o f the mixed d ia o y ls, but comes about in a

somewhat d iffe re n t manner than that postulated for pyridine* In

acidic solvents such as ale hoi or water, tne intermediate complex

i s presumed to be formed through hydrogen bonding o f th e solvent

with tne oxygen at^ms of the acyl groups* $ais may be represented

in the follow ing manner* 1?

ffci® hydrogen bonding loads to mi increased pssitiwe ©asu?g® on the carbonyl oar boa atoms o f the acyl groups wMe&# is tu rn , load® to an increased tendency to the ©notation indi cat ad is S^uatloa (5) by the dotted arrows* '10© unstable transition comply formed in th is way ©ay than re v e rt to m unasc©ited s ta te by e ith e r of two oat ha | by & staple reversal of $m reactions shown la Station (5) # or by m aintaining tbs ch elate bonds shown by the dotted arrears# and breaking instead tbs bonds linking nitrogen and oxygen to their original acyl groups* Tho latter course of the reaction would lead to a rearranged form o f the original di&cyl m Ind* icated la &quaticn id) «

roaotlons illustrated by aquations (5) and (6) are# of course* reversible oaas so that an equilibria© mixture of the tv/o forms of tiie mixed ii;ioyla would again bo obtained as was postulated

X>r*vlously for basic sclTsnts* ff do composition ©f the equilibrium fix tu r e would not n ecessarily* however# be the sa©* 3,3 that found to obtain in basic solvent© since the mooiioniaaaa and saavlromients 18

of the two types of isomer1satloss are not the same* While, tne sane general factors cause isomerla&tion in the acid c&t&lysseA form of the reset loss as caused isemerisatloa la basis catalysts* the interchange of aoyl groups i n acid type eolveat depends oa the increased posit ive charge placed on the carbonyl oar bos atoms o f both acyl groups brought about by hydro gen hood lag w ith the solvent* it would oe expected* therefore* that the equilibrium mixture found i n the acid type solvents would he la the rase direction as that in basic so If eats, hut a slightly different

ra tio o f products would he a n ticip ated *

the direction of equilibrium can also u@ predicts by a

consideration of the principle of minimum charge concent ration

stated In pari A of this theoretical section* £hl* principle

leads to fcne conclusion that the better Neutralised for® of the of the silked diueyl after hydrogen bond!h<& h m occurred w ill be

the isore stable* and consequently the one present in larger quantities at equilibrium* i’his setae form* of course* w ill be the one th at w i l l isomer iso more »lowly la hydrogen bonding solvents*

applying the acoTe principles to the specific case of acetyl**

aeazoyl migrations in examinephonoI* it w ill be seen that the 2U

seet/lpO-*b@nso/l isomer is the bettor neutralised system and

therefore* oy tne minimum charge principle* should ho the isomer

predominantly found in the equilibrium mixture format In acidic

solvents suoh as alconol cr vator®

0. migration -,arli».: IMxolyaUi- It schds probubl* that tusaa 19

apparent migrations ar© In reality ouly another ta mi f ©station of the isomerl nations o t th e mix ad d ia c y l d e riv a tiv e s utsdar th e influence of w^ter as a ©at&ly&t is tbs matme t just described.*

*he present theory is that 'isomerl*&tIon occurs vary rapidly is aqueous so lu tio n to y ie ld as equilibrium m ixture o f the two isomeric mixed diacyl derivativest wnioh ta® hydrolyses normally at the oxygen connection* Since hydro ly s is in sodium hydroxide solution is a sue leo phi lie attack »;/ hydroxyl less os the most positive center of the di&cyl©f it follow® that the acyl group attached to oxygen w ill he the one normally attacked* It further follows that tiie mixed d ia e y l Isomer which is more unstable according to the minimm char re principle w ill he the one welch Is more readily attached by tna hydroxyl ions*

Applying these predictions to the ac & t;/X~o

>*-bansoyl mono&cyl in the hydro lysis products* Since* however, tois isomeric form of the diacyl is the one present in smaller quantity in the equilibrium mixture* t d© predominance of the lUoeneoylate w ill be reduced* and might ccnceivably be negated e n tir e ly fix-.-©ndin.-; on the relative rates of .ny4rolysis and i soaer 1 sat i o n *

Since the same factor which oauses t 1 0 ?]Ubensoyl«£wao»tyl 20

isomer to hybroXy*e rapidly* i*s* the strong positive c«wg« on its easygen ourbonyI carbon atom* also o&as;: is this Isomer to la# relatively unstable in m\ueoue so lot ion and consequently present to a smaller degree than its ieotmsr in to© equilibrium mixture, it follows that in a ll such iybro lya^s of mixed a i acyl deriv- at iron of e-mino phenol a mixture of pro-duo t a moat he obtained*

Xt sootss possible*, however, th a t a tru e m ig ra tio n d u rin g hydrolysis might occur if, in a misted di-acyl derivative of o~ asinophonol, the two acyl groups on ployed di f fared widely enough in taeir a b ility to confer outerge o n their respective carbonyl carbon atoms* In such a case it is conceivable tnat attack of' bydrcxyl ions migat take place, at least partially, at the nitrogen connect ion instead of, as normally, at the oxygen link* age* M fi could lead to Chelation Between the naahared nitrogen e le c tro n s and th e ca rb o n yl caraon atom o f th e acyl group attached to o x y g e n and subsequent migration*

It is worth noting here also that certain mixed di&cyls of p-amino phenol might iaydrclyse partially at t ae nitrogen conn­ ection leading to a mixture of hydrolysis products* A true migration could not occur, however, since the necessary chelation is impossible in the para aoapounds*

£. S ta b ility o£ SaioO M url . 2)W iX*lLU*t- 3*11 (SO) was tiie first to shew eotperlmeatally that migrations lid not occur in o-amino-* phenol derivativaa waen on* of the acyia employed was derived from a ealphonle acid, and this .vork was confirmed by Halford -and Shelton (62)« Yhe ostue of t i s lae& o f migration was correctly interpreted by B e ll a® celng due to the absence o f un&aier&t ion in these sulphonyl radical®* if the correct electronic formulae for the two types o f derivative* be w ritten &a alsown be>lowp it becomes obvious that in the sulphonyl type of derivative (X )f

there can be practically no valence bond resousuaoo and aence no electron accept lag center to cause cueist Ion and consequent csigratl on.

fora^tjpa of dongcxagolonea:~ ffhe work of Salford and inrnm

(56) on the formation of benzox&aolones by treatment of certain monoaoyls ^ith base is readily explained on tjce basis of the resonance theory* If the "P" group of a carboxyl radical is aromatic so that ft resonanca stabilised Ion may be formed by splitting of the carboxyl group in tne manner illustrated below* a stable bemsoxasolone au*y be formed in waslo solution* fuis zz

type o f reaction w ill ©©cur* of a? arsa, if * second aoylatlost la attempted either In pyriilB® solutions,, or by the usual

3cho1ten.-Batwiaim tenot,tdsu

r’* Sg|),to,o.an!q » i p .-. ,^yA.fiamJa^aa^ saifori and X.eBossu (U ) h'.va reported th* sapiAOesicsit of baasoyl group by acetyl luring a second aoylatlou In pyridine solution in w.,iah a largo ««ess of acetic an^drido was us fid# If only a short time of reaction wua alloivad they Isolate! only the diacetyl and the ©onoacsiyl derivatives of the particular m-amlaophenol with waleh they ware working# If a longer tine was allowed for the roast Ion to proceed further* they were able to isolat e only the trlasetyl and monoaootyl derlv^tivea*

Im above inter change of acyl groups is explained on the basis of the present theory as follow * : \o first step of the reactions is obviously tho to ra tio n of the b-o hnsoy l*»0~£toety 1

iocmar afnich then quickly rearranges to form too equilibrium mixture which# as ijs.9 been stated# consists predominantly of the

better neutralised X-*&cetyl—Q—oensoyl Isomer* Besides these two

isomers* one u*s also in %'m pyridine solution a large excess of

acetic ^hydride* some of which is presumably combined with the

pyridine in the fora of the very reactive .acetyl salt of pyridine shows in Equation {2) of this section* A schematic representation of the succeeding steps le/*&J.n£: to the elimination of the benzoyl group is given In Figure 1* It w ill bo swm ffcosa an exam ination of this figure that it is not necessary to Introduce any new 23 G£ M iTL &M&LA

CH

FAST

\*

XV

Fa s t

CH

0

C- £ H

H L JOL

1 24

concept a to the present theory of % /i§ T t-£££J tm i o in order to explain the results observed hy d&iford ami LCBosen* $he isolation of the isono&eetyl derivative from a fixture eoaiais**

ing such a large excess o f aoetyl&tlug agent seems fairly reasonable in tno 1 ight of t-*i» representation* Since* in the oiidU lt for® of tne raoaohoeijyl derivative tne unshared pair o f electrons of tao nitrogen atom are considerably "used up" in neutrallain* tne excess of positive cuarga on the acetyl carbonyl

Caro on atom* tne interaction of t pyri&inlu» a-.il t with this one late form is very m ch slower than the Interaction of this salt with tne corresponding znonofeeasoyl cBmpound* !?he slowness of this reaction is apparently the csr.plaf.mtion of the isolation of tni* mono acetyl derivative which at first appeared so unlikely*

Si van rsore time* of course* tiie acetyls.! ion react ion proceeds s t i l l further and the triao^tyl derivative is the result# A* c h a ra c te rla&frion o f j^ lv ^ U .v e a ,{-» a tabulation of the compounds prepared and studied is the course of this work, a&d some of their physical properties. Is given in fable X. afcoept as noted la the footnotes to this table, all of these compounds were prepared by aoyl&ti©as is p y rid in e solution# About a 10 pereest axdeas of the aoydating agent# either bm m io or acetic anhydride, was used* The pyr it in a solution of the reactants was heated os a steam bath for about thirty minutes, and the reaction mixture cooled to room temperature* Finally, t is cooled solution was poured into ice water with vigorous stirring, whereupon the crude product separated in nearly quantitative yield* Sxoept in the cases wherein migration was found to occur, this procedure gave almost pure products which were easily purified further by reerys tu lli z&t ion from ale olio 1#

The mixed diacyl derivatives {i#e* those wherein the two acyl groups were dissim ilar) were prepared in the same manner except that, of course, it was necessary to first prepare the desired mono** acyl am then again ucylat o using the ascend acyl at ing agent*

It was found Impractical to purify the mixed diacyl derivatives of the ortho series obtained in this way by the usual recrystall- isition procedures since, in alcohol, the two isomers rearranged t© form as equilibrium mixture, while the solubility of the two comp­ ounds la the other solvents tried proved to be too similar* In 26

AflgUB«EtffAtl¥4MI StUdlOi

Melting ?oint Ultra tioXet Compound in dG (oorr.) A3s* Maxima Pound lite r a tu r e x 10-® p-^i»Opia9aylb0i32oat9a XS3-5 153& 22.5 p-Amiaoph«nyl&o©t&ta 70-2 75* 241 9*2 P-AQat/lamloopheiaol 166 1M<3 250 1@*S p-Pi&eetylamlnophenol ISO 15*k 247 13*3 P-Bensoylasiino phenol £14-6 22?|J 2051 £23 15*0 2X5% 2£7» 205 X1.0 p-Bibenzoylaminopheno 1 233-5 235® 228 24*2 271 19*5 K-Beaxoyl^-O-Acatyl- 172-4 171P 220 1S.0 ^-Amino phenol 268 18*0 £-Ac etyl-0-.o enaoyl- 167-9 157% X?lP 237 &G.Q p-Affi inepheno 1 o-Aoatylaainophonoi 203-4 201—4(1 242 10*5 207-8° 264 5*0 233d 6,9 263d 3*0 o-Siacetylasain© phenol® 124-5 124-5* 238 6*0 £40d 1 2 .0 o-Ben acylaraino phenol 170-1 166® 205 S .4 296 6 .6 2£2d 17*6 0*0 o-3 ibeagoylarsino pheao 1 183-5 16£-S* 230 26.0 £29^ 30.0 2S$d 12.3 H-Bensoyl-O-Ac etyl- 136-40 134-8tt 230 23,9^ o-Amino phenol 123-7* 220d 20.3 263d 12.5 N— A cot y 1-0-3 eaaoy 1. 139-41 134-8“ 230 23,98- o - Araino phenol 132-5* 232d 50.0

(a) rrepared by reduction of corresponding nltro compound w ith SnOlg. (5) prepared by method o f Galatia except that tar fomat ion and resultant necessity of vacuum d istill­ ation was eliminated by the addition of a tm crystals of aydro^alnone aod sodium bisulfite before neutralising the acid hydrolysis mixture with sodium bicarbonate, {&) This high melting CD to,pound was prepared, during an attempt to acetylats bensylidane o-aminophenol. It gave the same spectra as, and ¥tided the melting point of, the 204° oonrooand. (d) 3#f «*® t0 * * ^sortition maxima found in has an e solution. All other a os orb t Ion data snowa were ta&en in absolute a lco h o l, (e) The usual acyl at ion method jjare a mixture of mono— and dlaeetyl 'leftiratives wnlch 27

proved very d ifficu lt to separate* thX@ compound was therefore prepared by heating the usual mixture of reactants for hours under reflux* ai>u then evaporating the pyridine solution until crystals separated* (f) Molar extinction eosffioleai* (g) Alcohol eq u ilib riu m m ixture* (&} Hdlmev, II. f Aim*, 210* 378 (1882). (1) bal&ti®, L., Be*., 850 {1926) • (j) humiere, A* et al*, Bull* Boe# OMm,, ( 5 ) , 33* 785 (19051* (it} Belletain, *Kan&buch der organs 1 sc hen Ohemle” , IV , x i i i , 464 (1930)* (1 ) Brnitli, &.W., Ber*, 34, 4043 (1891)* (m) Hever&in, *'* ansi leletra* h*, Her*, 3^, 138 (1906)* f«) Single, J.B* and Williams, L+b\ , An* Ohem* J«, 37* 51 (190?)* (o) Bexistsin, ibid*, x iii, 470 (1930)* (p) Beverdl n$ f * , B e r*, 3 £ , 3793 (1906). U) Beilsteia, ibid., x iii, 3?0 (1930). it) Bamberger, A., Bar*, g£, 2050 (1904), (s) Beilstein, ibid*, x iii, 375 (1930). (t) Bel 1st ©is, ibid*, x iii, 373 (1930)* (u) Saifbrd, 1m 0», 0. Am* Oho©* See*, li* 2068 (1919). (v> Bell, J* Ohem* So®*, 2966 (1931) &s

these instances, therefore, tae crude mixtures ware dissolved in

benzene and s©par at el into the two pur a Isomers by chromatographing on a prewaahed ac lumn of 1?1 silicic acid am .©Hite* Although

it is reallsad that adtorbants differ widely in their strength ami

capacity f •: r such separations, the following procedure is given

hers to serve as a general guide* d quantity of the diaoyl mixture

containing not more than 0*1 gram of either di&oyl (i*e* 0*2 grams

of a 50-50 mixture could be used) was dissolved in about 30 ml* of

benzene* A # 4 chromatographic tube (t*d* 44 mm** length 200 mm®}

was packed under fu ll water pomp vatomsm with I t l s ilic ic acid and

C e llit e , and the column washed w ith os® volume o f acetone, one

volume o f e th e r* and one volume o f basses® (one volume means the

quantity of liquid required to completely wet the dry adsorbent in

the tu be)* The d iao yl so lutio n was tn©» pour ad os the column and

developed with a half volume of a solution of approximately 1*5

percent acetone in benaena* F in a lly the column was washed w ith one

volume of ligroin (boiling range aoout 65-7? degrees centigrade) to

remove the benzene and acetone fro the column and to complete the

development* The column was extruded from the ohromatograpnio tub©

and streaked w ith a 1 percent so lution o f p-m at hoxybens ened i azo nium

fluoroborate* followed by a 3 percent solution of KOH in raefeteyl

alcohol* This combination gave a bright orange band on the adsorb­

ent which clearly delineated %m areas in which the two isomers were

adsorbed, but the bands could be made to stand out s till setter, and

the test made more sensitive by further streaking the column with a

6 22* solution of m i which caused the orange co lor to change to a 29

deep rod* £he streaked portions o f th@ column wore out away# and

the column divided in to the two sections containing the d iffe re n t

Isomers* fhese two sections were eluted separately with acetone#

and the pure isomers obtained by evaporation of the resulting

solutions, fhe ultra violet spectra of the two isomers thus obtained

shewed that the N-acatyl-0 - densoy 1 compound was the one mere strongly

adsorbed and consequently retained in the top portion of the

column.

r£ho ultra violet absorption curves of the compounds listed in

fable I were obtained by weighing accurately a quantity of each

acyl derivative such that the resulting solution in 10 &U of

absolute alcohol was 0.01 mu lor. She abserbtion curve was then

determined on a Seetaan Ultra Violet Spectrophotometer by starting with the G*Q1 M# solution and diluting it as becafii® necessary by

pipettir^ a 1 ml. aliquot and diluting It to 10 ml* So attempt was made to calibrate the 10 ml* volumetric flasks# or the 1 ml*

pipettes used in this work since# at first# the curves were desired

for qualitative identification of the acyls r&tn&r than $>r quant­

itative determinations. In evaluating t&a quantitative data reported

in this study this fact should be kept in raind*

fhe hexane used in taking the ultra violet asscrbtion spectra

of tuc ortho series of acyl derivatives was specially purified by

chromatography using a column of silica gel as the adsorbent# Tm

hexane was divided into cuts as It came through the column and only

tnose fractions retained which could oo balanced on the Beo&m&nn

instrument at 220 millimicron®* attempts to weigh out solutions of 3 0

© f ioaown ©©Boost rat loss for these spectroscopic determinations, as

&3d been done w ith th e alcohol so lo t to ss, proved im p ractical due to the extreme insolubility of a ll of these compounds is ~msane* The procedure fin ally ado pad was to maite up an approximately saturate solution of the acyl derivatives is hexane and filte r off the uadisaolved material* The spectra of the resulting solutions were determined and the concent rat ions found by evaporating a 10 ml* aliquot to dryness under vacuum, dissolving the residue in 10 ml# of absolute alcohol and comparing the Int ensity of its absorrbt ion maximum with that ©f the 0*01 11* alehohoi solutions previously sent icned*

The shape of these ultra violet absorbtlon curves in hexane was

essentially identical with that found in aloo,*ol solution for all derivatives of the ortho series but the mixed dlacyIs# The intensities of absorbtlon at the various peaks were different, however, an w ill

be sejn from an inspection ©f the data gives in Table 1# These

absorbtlon curves in hexane are not snows in taa figures except for the mixed d ia c y l d e riv a tiv e s where s ig n ific a n t differences in shape ware observed#

An attempt was made to determine the spectra of tae tw mixed

diacyl derivatives of the ortho series using water as the solvent*

Those experiments snowed tuat the compounds wore sufficiently soluble

in water for this par pose, out that rearrangement also occur ed in

this solvent* The rate of this isomeriaation seamed to bo somewhat

slower than th at caused by alcohol since I t was found th at the two 31

mixed diacyl solutions could still b© distinguished by % heir spectra

after about IS minutes standing,

B* i& a l^ a of the Xsomerlsat ion.,Mixtures a- The method used to analyze the mixtures of Isomeric mixed di&oyl deriva,itvas obtained

1b this work was essentially the same as that* discuses under part

A above, 3&r the separation o f the two pore i&omera from the mixtures resulting on ioylaticn in pyridine solutions* for the purpose of analysis, however, it was only necessary to use about one milligram o f th e m ixture and chromatograph from Seasons solution on a # 1

earoa&t ©graphic tube (i«d* 9 mm*, length SO mm,}* oince appreciable

quantities of material would be lost by streaking and cutting away the streaked portion of %m column as b e fo re, the columns in tnese

quantitative determinations were out "blind" after sufficient

preliminary runs were mad© to establish the position lim its of the

two bands* The powdered columns were thee dried under vacuum to be

sure that no solvent remained wMnfe might absorb in the ultra violet,

and the dried powdered adsorbent transferred back into & clean # 1

olircnaatographlo tube* About 3-6 volumes of absolute alcohol were

poured continuously over t.uls packed adsorbent colunn to o© sure th at

elution was complete, and the resulting filtra te transferred to a

30 ml* volumetric flask and diluted to volume* The resulting solutions were then quantitatively analyse! by means of a comparison of tn©

intensity of their absorbtion of ultra violet light at £30 millimicrons with tnat found at this wave length for tub 0*01 molar solutions

previously prepared by dirsot weighing, Numerous runs had esthbllsned the reproduceabi 1 i ty of the alcohol oqullibrium mixture which mti

Its absorbtlon maximum at this wavelength* ^ro® the roclarity values

thus found for the 50 mi* of diacyl solutions tno number of grams of

sack purs isosaar In t m mixture bslng analyzed could easily be

calculated*

in some of the earlier quantitative determinations by this mat hod*

the dried and powdered adsoraent after removal of the solvent under vacuum was transferred to a fritted funnel and the diaoyls eluted by

pouring over the adsorbent about 40 ml* of absolute a lc o h o l* Shia method was abandoned* however* since I t was found th a t elation was

not always complete by this method* probably due to mecimnloal

difficulties*

In the analysis of the di acyl mixtures produced by acyl at ion In

pyridine* heating* or reoryst&lllsition from alcohol* a 0*01 grates

sample of the dried material was weighed carefully and dissolved In

exactly 10 ml* of benzene* One m illilite r aliquots of the resulting

benzene solutions were then taken for analysis as described above*

IsomerizatIons in alcohol were carried out by dissolving a

© *0 l g r a m sample o f the mixed d ia c y l* or d ia c y l m ixture* in about

5 ml* of absolute alcohol and allowing to stand for varying lengths

of time in an open beaker* Che beaker was then placed, in a vacuum

desslcator and the alcohol solution evaporated to dryness* in some

runs an infra red lamp was used to maintain the temperature inside

the dessicator at about 3 5 -4 0 ° G* but th is uppeered to have no affect

o n the analysis of the resulting residue* indicating' that the comp­

osition of the alcohol equilibrium mixture is not appreciably affected fcy variations in temperature fro© about 20° 0* to about 40° G. ?he

residue fro® these eeepovaticme was dissolved in 10 ml* o f bonaeas and 1 ml* aliquots of this ia&on for analysis*

The isomerlsatloss in pyridine were carried out in a similar manner * sad here a ls o , small v a ria tio n s in t'm temperature at which

evaporation was oar tied out seemed to have no effect on the comp* o s ition of the resulting residue*

S* Hydrolysis of the biased ortho^JIiaoyiss- hydrolysis of the mixed diaeyls was ca rried out in aqueous solutions using an eauksss o f

BaOH o f from 10-100 percent* i'ao pur a mixed diacyl© both went in to

solution in this ©odium rather slowly* but there was a noticeably

greater solubility on the part of the N-bsnsoyl-O-acetyl isom;*r•

After solution of the two iaostors was made complete by stirring and warming to »oout 50° 0** the two solutions* wnlch were green in

color* *are allowed to cool* Tae monoac/luted products of the hyd­

rolysis war© precipitated by addition of dilute 1101 dropwiee until

the solution was slightly acid to Hydrlon paper* Tao solutions went

through an interesting color change at this point* the green alk­

aline solution showing a yellow to orange color on acidifying* $his

color change was found to b© sharp and re lia b le enough to use as an

indication of complete neutralisation of the alkali present* Pre­

cipitation of tn© hydrolysis products seemed to be complete slightly

before neutrality was obtained*

Th0 precipitates obtained in this way from both pure mixed

diacyls was filtered off and dried# £h© products were light tan In 34

ooXor and melted at about 150° £• over a rang© of only 4U5 degrees* the tan oolor oculd bo removed by r©peated alcohol re c ry s ta llis a tio n © bat r ©turned upon dissolving the whit© crystalline product again in

HaDH and precipitating as before with acid# Tne characteris 11 o indicator behavior was also regained in this way* and it seems obvious that theaps is some colored substance produced by the solution of one or both of the menoaoyls in ifaOH end subsequent preolpitatio n with acid* 3y evaporation cf the clear filtra te from th© separation of the firs t crop of hydrolysis products* a mixture cf salt and a reddish colored material could be obtained is sufficient quantities to give a strong fluorescence to a bensea© extract of the material* Ho farther work was done with this material* however*

la the quantitative ru n s reported in this work* the © o lid hpd*» rolysie product which precipitated on neutralisation of the b a s ic so lu tio n was filte r e d off* dried and weighed* A portion of the rsat© r ia l was then taken f o r analysis by means o f a combination of chromatograpijy and spectrophotometry as outlined in part D of this section* Those analyses snowed th a t th is firs t crop m ate ria l was* f o r a l l p r a c tic a l purposes* made up entirely of the two possible senoacyls*

the filtra te from the separation of this first orop material was evaporated to dryness under vacuum and the resulting Mixture of so lid m aterials weighed and analyzed fo r its monoaoyl content# This second crop product was found to eon ta in from 50 percent to only 4 oeroent atonoacyls* t m higher figure being found in th@ runs where only a very small amount of mixed diuoyl was taken for hydrolysis and 35

d ilu tio n was eouaequeaily high* M s second crop stater i&X

consistently contained a large predominance of the monoaaertyX d e riv a tiv e * howevor9 apparently In d ic a tin g taut toe li~b@nsoyl~ o-aainophencl is the more insoluble of tm two monoaeyis in aqueous

eclut ion*

- * &*aly*l* of Hydrolysis Mixtures:-. The analysis method used for

th e firs t crop material described above was praetie&lly id e n tic a l w it h th a t described in part B of this section for the analysis of

the diacyl mixtures* It was found that using the same system of

adsorbents and developing agents* approximately the g&me ratio of

rates of movement down the adsorbent which was obtained between the

K^&eetyl and H-beaaoyl mixed diaeyis* also was obtained with the

corresponding monoacyls* She o~acetylamlaaopheaol arcs relatively

strongly adsorbed w hile the o~benaoyld®lneph@nol moved f a ir ly ra p id ly

down the adsorbent column* The same streak recent* p~met coxy*,

benseneliazoniuaa fluoroborate* was also applicable to mono-*

acyls end so the analytical separation was performed exactly as was

o u tlin ed fo r toe mixed diacyl d e riv a tiv e s * In tu o se runs, however*

the complete ultra violet spectra (between BBQ and 310 millimiorons \ was taken and showed that this first crop consisted of practically

100 percent monoaoyls* the absorbtlon curves being identical with

tiiose determined earlier for tbs pure raouoacylaisd products* The

aosorbtion peak a t 204 millimicrons was used for quantitative

estimation of the monoacetyl compound and the absorbtlon peak at

296 millimicrons was used for the monobensoy1 material* liar H e r f i <0 a <** a o s i 1 , 4 o 3 m © sJSA ** § © © © 2 i 1 ©£* to t * 1 «r3 0 04 *14 w © © (HI * *4 g i* © © « «© © © g Ik 'H ft J0 & c *4 to P Sg S* -S % 4 * g © o ■#4 0 0 4 * 54 P m * » § >» © 4» **4 It 4 * © 4* P Jf O Sk *4 <1 © 0 © 5 g a ** 3 *r4 Ik ® m p 1 *p4 f l 4 0 m © P* ® 04 44 a 3» © o © § 9 % ftr 0 « Si s i St O g © > 2 rt © © I o« I? 0 0 © a P « •r* 0 « Ps 04 m p 9 0 5 -4 53 4 * a 43 6 s « 4* ft 4k 0 a o <*■» 0 0 45 0 fk 1 G 4 V! i as #*4 s © 4* * 9 p H «4 wk a i rk 0 p 44 «J g to p a S3 B © <4 4* P <4 0 © © 9 © 4» 0 tS :? H m 44 i o Q +r$ a Ik 1 0 6 s ©B *4 o P 9 s 0 to © *0 ?* 8 44 4* if* M 1 © g <3 -rf 3 © 8 3* o 0 to +4 1 43 W 0 s * I § 0 o a O *H to «rl o O $ S «4 I 4* 8 *» f* © **4 4* 0 & t © © -4 I ! I 1 © 3 to 0 8 IS a © i 14 S a *» 0 3 i a © a 0 P 9 1 0 o 49 §• B 8 © t to %4 I % "0 4* » 5? % S o •P m js +* A m 8 a 3 * *9 £4

3 a»H a&eorotien at t&a ftigk waT©lmgt&» enaplo^ad for o § <3 o § *4 <-4 s' i 8 © © £ & I | a© !3i; m « | O •HSf ► a t © > *3t f i • 0 g I ! f S to u I I S 5 P 9 g 0 •*4 *» 1 4» 0 X 3 jo i 3 1 m4 4» Ik N «? f« ! I I O 04 JS3 Or S m & © 9 © i Q S I » s Ik m i <4 <0 8 of abomt SO paroorit ©oaoaoyls,4 * than a lmpurit'taa war© 0 tta&Xoot&i duo * 04 x O 9 £7

as bat Da 9lilt 1 oii o f tno *?

In order to dot ermine t&s amount of o-bensaylaminophenol present in the second ordp m ixture* a fresh 1 ml# aliq u o t o f the benzene extract was placed on a f I chromatographic tube packed w it n Ca&Gg* Using pure banse&e as a developing agent* the hen sole and acetic acids were irreversibly adsorbed and remained at the top o f the Column* w h ile the mosoaoetyl and monooensoyl compounds had about the same r e la tiv e movements on th is column previously observed on s il ic io a c id rO e llite columns# ibdut four volumes o f bsnseos were usad to devoAop tha chromatogram# th erefo re * a fte r the

1 ml* aliquot had been placed on the QaCOg column# SMs quantity o f developing age® was sufficient to completely slut© the o~be»soyl* amlnophenol from the column* but le ft the acetyl cofih:*ouzii s till adsurbed near the bottom o f the column* She bunsens solution in the filtra te was t^en evaporated to dryness# tab residue taken up in dO ml* of absolute alcohol# und t « absorbtlon intensity of tue r e s u lt in s o lu t io n determined u-n tae Uee&nami at £bt> m illim icrons#

This absorbtlon# it was felt* was fairly representative of the amount of the mono ben soy 1 derivative present in the second crop product m

altijoo&a a® a&^ainatioo of tia® ooisplata altr& violet cunra t&as obtained revsalad praseooo of gome imparity absorbing rat Her strongly arouod £60 mllltmicroos* sxscusaxos- 0/ ixmiigs

la order to prove some oi the consequences of the nm theories o f th e mee nanisms causing the m igrations o f acyl groups la o«* amino phene Is i t was* f i r s t o f a l l * necessary to be able to prove the orientation of the acyl group® la the mixed dl&cyls of the ortho series# io t example* Baiford wm was easily the most prolific worker in this field* believed that ia the mixed aoetyl«beaaoyl d e riv a tiv e s o f ©«-^®inephenol the ben soy I -iroup wsa the on® attached to nitrogen# He based tnis belief on the fact that oii hydrolysis of the single mixed diacyl which he was able to isolate* he obtained only the fsoQoaoyi hiving tee oensoyl group attached to nitrogen*

^eoordisg to tiie taeories presented in this dissertation* however* the reverse o rie n t *tion should be th e more stable for® o f til© mixed d ia c y l and eonse pieat ly the one pres m t in larger q u a n titie s in the mixtures o f diaoyls which it was predicted -would result on ae yla tio a

ia pyridine* Obviously* some method had to be devised to prove which orient at ion was actually the correct one in order to disprove

Halford's assumption*

there are numerous instances in the «sore recent literature where sim ilar problems of deciding between two or mere possible structures aas oeen settled by a consideration of the ultra violet

spectra o f toe compound in question in comparison with toe spectra of similar type compounds (65)# It was a logical step* therefore*

39 40

to attempt to apply this method acre*

For this purpose a ll ot the sight possible aostyl-bensoyi derivatives of p-amino phono 1 awe prepared and their ultra 7.1©lot absorbtlon spectra determined between 220 and 310 millimicrons.

Since tl*e e*tno ami para .lerlvati rm o f the umin©phenol* have a similar conjugated system cf double bonds bstwoen their phenolic and amino groups, it was fe lt that tli© spectra. of tm mt respond lag o os^unds of taa tw series should show certain resemblances uni oh sight serve to sat on up taes© compounds. In the para series ulX sight of the possible acyl derivatives mentioned are well known go®rounds, and it ins been well establish d in tno liter ature that migrations do not occur In the para derivetivas. ‘Ihere i® also, o f course, no question as to the structure of the t m ortno mono- acyls, or of the two ortho diacyls wherein the acyl groups are the sj*sq. If the hoped for sim ilarity could be observed for these four cofD Ounds, therefore, it was fe lt that one could then i*ely on the method to prove orientation in the mixed Jiaeyl, or d lacy la, of the ortho series wherein migrations have been reported, and whose structure are consequently in doubt.

That the anticipated sim ilarities in the ultra violet absorbtlon curves of the two aeries of compounds were indeed found In alcohol s o lu tio n is w ell wrought out in Figures 2 and 3., In Figure 2 the sim ilarity that exists between the ultra violet spectra of the acetyl and benzoyl monoacyl d e riv a tiv e s o f ortho and para aminophenol is shown. For reasons as yet not c le a rly understood, th is s im ila rity 4,1

i s not as pronounced m tisat found astw&en tho other corresponding ortho and para derivatives studied* but even tors there is as difficulty la matching the -^toorotloa caries of t ' m orth© d e riv e ativas with their isomers in th e para series*

le ft baud portion o f the upper half o f Figure 2 shows the absorption curves fo r the ft—aee&yl and O-feensogrl mono acyl derivatives of the para series* but m is indicated In this

Figure* the corresponding cfctho compounds could not be prepared*

Attempts to prepare ttoae derivatives by &oyX&tic& of o~to»syl- i&eneamlso phenol and subsequent gentle hydrolysis were unsuccess­ fu l* the dibeuscyl and msmoaceiyl derivatives being obtained instead*

It is of Interest to note that Bell and Kenyon (37) also attempted these preparations in approximately the same tossi&er and reported that only the two mono-H-acyla resulted*

fhe lower half of Figure 3 snows the striking sim ilarity between the absorbtioa curves of the dlaoetyl ana dihensoyl derivatives of ortho and para smiuoptonol* Bespit® the fact that the o-dttonaKiylaminoptonol shows only on® distinct peak while the para iscser shows two* there would certainly be m doubt as to which of the curves of the ortho isomers matched those of the para series*

It seemed at this point* tton* that there would be no d i f f ­ iculty in deciding* by a simple comparison of the ultra violet spectra* which structure corresponded to tfca single ortho mixed dlacyl reported by Eaiford* Warni this was don© it was found that* MOLECULAR EXTINCTION COEFFICIENT x 1 0 "3 5 2 220 -

30 PAHA 0 —0 0 0 —0 0 SCAlSS 60 0 BO 70 -EfO /AT H-BErfXOH O FIGURE 2 & 4 C S T Y H N A L Cgf O H O L 0 - B iN * 0 V L I N A L C O H O L N-AUTYL IN ALCOHOL IN N-AUTYL ta Vi e Seta f 0ool Derivatives M0noaojl of Spectra let io V ltra J 0 0 1 20 0 0 50 40 30 220 10 300 90 ALCOHOL WAVELENGTH MILLIMICRONS IN

JO— JO (E

O L HT PA£PAA£ COULO HOT O R T H O 5 C R I C S 0 —0 0 0 —0 0 N - B i N r o Y L t N N -A C E T Y LIN A L C O H O L 90

alcohol 300

10 0 — 0 ALCOHOL EQUILIBRIUM MIXTURE O—O n -acetyl - o-senzoyl in alcohol 0 - 0 N-ACITYL-O-BENLOYL lNH£X**£ N'BiNlOYL-O-ACETYL f/Y ALC ONOL 0 - 0 N-0£NlOYL~OACLTYL IN HEXANE

10 lo 70

0 — 0 0/ACETYL IN ALCOHOL 0 — 0 OfACETYL IN ALCOHOL 0 — 0 Dt BENZOYL IN ALCOHOL 0 — 0 OfBBNtOYL iff A LC OHOL

o20

10

WAVELENGTH IN MILLIMICRONS FIGURE 3 U ltra Violet Spectra of Diacyl Derivatives 44

as Iniic&t©d by the solid curves in the uppar M lf o f Vigors 2 , the spectra of the two *al%ei diaoyls of the orthos series | prop-* ared by acylatlng In reverses order )w ere Identical, and t m t th is spectrum matched up w e ll w ith the para series absorption curve o f the K -acetyl-O —bmssoyl compound,

Th%& result was in line with the structure of the mixed di&oyl predicted by the present theory to be present la the'larger quant­ i t i e s , as opposed to the stru ctu re proposed by Halford* I t also sensed to lend support to H alford*a ol& ia th at two re was only one mixed d i^ c y l produced In the ortho series no matt or in which order the acyl at Ions wore performeda point on which Halford* s results had be on challenged by Bell {511 on the basis of mixed melting point© which he obtained with the two diacyls propared by acylations in different orders.

In this work preparation of the ortho mixed diacyls by In tr o ­ ducing the -jJOQty and b m z o y l groups In re v e rs a l o rd e rs had le d to two products which physically seemed idant leal, They were both light tan in color, the diacyl obtained by bensoyl&tton o f o- acetylaaI nophono 1 having only a slig h tly higner melting point In its crude form ta.® the Jiaoyl prepared, by aoylatlng in the opposite sequence, -fter one reerystallls tion o f each from alcohol the s im ila rity was even more marfced, the supposed acety 1—o—cansoy 1 derivative melting at 133*.6° 0*, whereas the ® ~ bmzoy 1-0-acetyl com' ound melted at 132-6° 5, Bell had reported 132-5° 3, for the fo rm e r arid 125-7° 0 , for tuo la tte r, while Halford had found l<34**©0

:* for ooth materials. 45

4 mixed salt in ; point determination on the two .i iaoyls above

results ia & very definite depression of salting point to 112-*

115° 0* , a^d lo ft a. melt which remained even after several days standing at room temperature* 4 similar osa&vior 2kwi been

observed by 8ell and lad him to conclude that there were actually

isomer® produced by ths two ucylationc, and that Itaiford’d report

of a single diacyl being formed wa® incorrect#

la spite of the strong support seemingly given ,:;aiford’s results

ay tas single ultra violet spectre® found in aloonol solution* the

depression of melting point ssealed so peculiar that it was fe lt that

tassa two materials chiuia b© studied further« liecry&talli*&tit.tt

o f the materials from oenssne gave further evidence that the two

substances war-, not identical# Besides n noticeable differ once is

the ease of solubility of the two products* and a g en*rai difference

physical agpeoranoe on being wet w ith -bensene ( the K-bcnssoyl-G-.

acetyl material becane pasty* while the other material remained

cryst a llin e in appearance}* i t was found t m the £**ae«tyl«J5-bea®oyl

compound wave a first crop of crystal® m elting at Id7-8° 0 * whereas

the f i r s t crop from tne oensene so lu tio n o f the &*»ben®0yl~O«aeetyl

d e riv a tiv e melted a t 1 1 5 ^ ° C* She second crops had m olting points of 155*6° 0* and 117«*8° G# respectively* The firs t crop® from both of taese benzene recrystal libations were then r©crystalUsed again

from alcohol* It was found that the melting point of the 137*8° material was depressed to 133*4° G#* while that of the llu*i$° material was raised to 13&-3GU c* This time a mixed molting point run on 46

the alcohol recryat&ilisad materials showed an elevation of melting point of the low at molting compound to 129-22° 0*, indioat log th&t now the two products were id ant leal*

***• above results indicated so strongly that toe d iaoyIs were differtttt# tnough possibly Intorocn vsrt i b I e , that it was decided, to attempt to separate the two forma enr omatogr ap h ic a lly * As has aeon indicated in the Experimental section of this dissertation. It was found that, on a prsw&shad column of i;l slllcio aoid and C ellita, a separation of beta the 13£-6° compound and tm 133*60 product in to two components could be e ffe c te d * By running a s u ffic ie n tly larg e chromatogram enough o f each component was obtained to determine melting points and ultra violet spectra* It was found th&t both hands from the chroma to pram were white crystalline solids, the top band melting at 139*41° 0* and the bottom band melting at 136-40°

0* fhe absorption soeotra in absolute alcohol, however, was again found to be identical* A mixed me It lag point showed the same depression to 112-15° 0 ., wad reorystallisatlon of the two high melting products from alcohol served to again depress the molting points o f the two dlaoyls to about 133° Q* ^eeryst a lii set ion from acetone or benzene, however, gave back the original high m elting m a te r ia l*

All of the above work point od to the fact that there must be, after a ll, two different dlacyls though apparently neither o f th e materials produced by the acylations in pyridine were pure* It was decide! that, perhaps* large araounts o f alcohol served to completely

Isomer is© the two pure materials to form an equilibrium mixture of 4?

the two, and that this vr&» the s x p ln a a tion of the identical abs­ orption syeotrum found for both materials* 2o tost this idea the

next s te p was to te s t the &*A&urhtis>a spectra o f the two pure mat­

e r ia ls from the ebroimto&r&si in some inert solvent wulcli would not

cause ta is isomeric change* formal..hexaue was th e s o lv e n t chosen

for this purpose, and i t w in ue scon from the dotted line curves

In the upper r ig a t hundl c a lf o f f ig u r e 3 taut this procedure supplied

the final proof taut lu c r e were indeed two isomeric mixed Ulac/X

derivatives of o-amino phenol# f h is tim e th e abeorbticm o f th e

two m aterials was distinctly different, and, matching those curves

to those of the two mixed diaoyl# of la® p a rase r ie s gave unmlsta&e-

able evidence of toe Identity of then two compounds* By mean# of

tais matching o f curves i t was found that the diacyl which ##& the

more stron gly adsorbed on tn* s i l i c i c soidaCeliite adsorbent was

the B-aoetyl-i-bensoyl form, and the less strongly adsorbed material

was, of course, the ^—bensoy 1-0—acetyl isoiser*

inis rearrangement of twe isomers into an equilibrium fixture

andi t trie influence of alcohol .v.s wholly unexpected and the poss­

i b i l i t y o f such behavior in o—amino phenol' deriv ative# has been

completely ignored by previous investigators, A similar benavior

was, however, observed by .iuwers and Bondy (15) in wording with the

0—acetyl d e riv a tiv e # o f the phenylbydrasonest o f c e rtain aromatic

o-h'/droxy aldehydes* Obviously, tnis type of nehavlor is the explan­

ation of ta® conflicting results reported by B&iford end by Bell,

Repeated alcohol recryst all if at ions in Baiford#a wor& must have 48

resulted in th® separation of the N~&caty1-O-benzoy 1 lsoet©; which, would m;v© been present in the larger amounts in the feloohoi

e q u ilib riu m m ixture than its 1 sera ©rid1?. Talc predomln&uee of the

R-aeatyl isrsior is clearly shown by the &h&r,e of the alcohol

equi 1 ibri\us mixture curve in figure 3 .

duviag established the fact that there were two acetyl**

beasoyl nixed diacyla of o-&mi no phenol9 Investigations mr& then

underts&en to quant itatIvsly analyse the crude dlaoyls prepared

by direct acylaticn in pyridine* and also by the alcohol r©cryst­

allization of these crude products* This was accomplished by a

combination of chromatography sad ultra violet speotne determinations

as outlined in the Bxperlmuiital section of this dissertation* The

results of these analyses are given in Table II*

Those results bring out the fact that morn isomerization

TA3LB XX-

A m lzftls....o..f QxXMJ&iMMlJlXmMM.

Bun Sample d escrip tio n HeaotIon PrO'luct Auslyz is a fie ld ( ■} » Sab U b ° A recovery 1 Crude i'3 98 38 6Z 91 2 t; n (1 37 m 94 3 Crude- ‘j’A 84 91 8 84 4 " ” from 30 ,i£ Ale# MAP 93 7 94 5 t» S* M »f - Q2 10 90

(a) Analyses based on amount of sample recovered by elution of the hands with aoetond* fb) ^-acetyl-O-bensoyl-©—amino- phenol. ( o) s-beaa soyl-G-ao*ty l-o-u;;iinophono 1 •

occurred in toe acetyl at ion of o-hensoylamlnophenol than oy toe

ben soy lot ion of o-acetylassinophenol* The averse© of two runs on

the aeetylated monooor.zoyl compound showed that 36 percent o f taa product pro par ad in this manner consist© of the rearranged isomer, wiwreas the benxoyiatIon of o*»acatylamlaopneno 1 yielded only 9 percent of the isomer issd material# { It w ill also oe a dan from this table taut the yields of di&oyl -were hat tor for tne acetyl .-t ion reaction* do particular significance is attached to t;.iis fa c t, however9 i t aia&pi# being considered te a t a c e tic anhy­ dride is a faster acyluting timn cenacle. asiaydride*)

fable II also brings out the fact that recryst&llisutlon from alcohol seems tc increase tee amount of N-aoetyl»0~bentfoyI isomer i n the r earyst a ll i sat ion product# fhia result can be ta;oen to mean one or both of two taingss tl) that the 3U-acetyl~0-benzoyl isomer is the form present in the larger quant 11ies in the equilibrium mixture, and/or {£ ) th u t the ;:*-ac*?ty l~0~b m aoy 1 term is the more insoluble of the two di&cyls i n alcohol* The ultra violet curves just discussed indicate thet the firs t point is certainly true, but to dbcid© the second point one needs to know the composition of the alcohol equilibrium mix. tor a, und the rate at which this e q u ilib riu m m ix tu re is harmed in a lc o h o l s o lu tio n *

Sable I I I g ive s a partial answer to those questions. It was felt that the actual determination of t he ra te of tn© isomer 1 sat Iona in alcohol should bo left to a later study, but the data summarised in l^ble III snows clearly tnat too composition of the alcohol equilibrium mixture lies far over on tne i^cetyl-$~benaoyl side as was predicts i, a priori, from a consideration of the principle of minimum charge concentration outlined la tn© ^neoretical -art 50

©£ th is wor&* I t w ill furthair be seen from th is ta b le tna& tne laoiaeriaations in alcohol were complete for a ll except the pare

JWDcssoy 1*0—acetyl Is ora or » in 1ms than the time which was required to evaporate of the approximately 5 ml* of alcohol in which 0*01

fABLS I I I

i^ U & A a MuJ&s&MX. Xqggg£laa^

-\XlJk Uample .^esorintion At and ixig r rodact Analyj

ftme M a* $53° ,i Heco' 1 ■ u re irA 0 hrs * 85 ' 15 10? £ 9 1 1$ TIA 0 83 17 e? r * s> Oi:> i i. a% 0 04 16 89 4 rt » b 0 85 16 95 5 Pure 13 D 57 4 5 « II 5 Z 71 2 9 8? n t i 7 s # 72 28 6 5

{a) Analyses based, on amount of sample recovered by elution o f the bands w ith acetone* { b) H«aae t yl*»c~b &nsoyl«o-*amlno- phenol* (c} K-henaoyl-0*-acotyl*-o^arainoph®nol« iresims of the materials was dissolved* No explanation can be given here for the peculiar behavior of the pure '8«bettsoyl«0~aeetyl isomer# but it may be significant that the .percent of sample recovered in toese runs was slightly lower than In the average of a ll other runs*

Xt w ill be noticed that the composition of the alcohol equil** iorium mixture# i«e* 85 percent H**ficetyl^O-banajoyl«owaf9ia6phenol a.pd only 15 percent of the opposite 'isomer# is approximately the analysis which one would estimate from a consideration of the ultra

▼iolet absorbtion curves of tue two pare isomers in hexane as compared w ith tne uasorotion curve o f tne s q u ill or lam m ixture found in alcohol (Figure 2)#

Sable IV shows the result of heating the two -pore Isomers 51

for varying lengths o f tim e a t two d i f f e r e n t temperatures near their eoascton m e ltin g point * T liil© t he results of tries© runsare in co n — elusive since e^uillurium was not reached in e it h e r of these runs, i t appears th&t* as expected, the N—a c el y 1 -h - b an compoundso y 1 isor^erisQj s u c h nor© slowly th a n i t s isomer ifce, Fto® composition

% m m i t

JidSLtL.sm. .Barft. a ix od Mmzy&

Pun Sample d escrip tion Tdsp* Standing Product An&lj %* n ta * W 1* Pur© SA 140 2 hr® . 69 31 f z * Pure liB 140 2 -59 41 3 . Pure 132 ?0 61 39 4* Pure f3 132 70 54 46

(a ) Analyses based on amount o f sample recovered by e lu tio n of bands with acetone* (b) &»&cety l-G-banzoy1-o-ataino- phenol* {©) N-ben*oyl-0-acetyl~o-ami»opheaol, o f the equilib rium m ixture toward which the two .isomers ware tending is estimated to be about 55-60 percent of ta® more stable I-acetyl-

O-oensoyl form* It is worth noting, hs a jjartial explanation of the slowness with wnioh equilibrium was approached in the 152° runs, that aoout 20 imurs were required, before the K-benacyl-O—aootyl form was completely molten at tils temperature, and that the rw&cetyi-O- benzoyl isomer was s till not completely melted after this time*

Vast is prcuably the most significant part of thiswork is s-a»ubari*e«i in 'faale V* Tni s t a b l e ©howsthe analyses of the products produced by dissolving sample© o f the compositIons Indicated in pyridine and then evaporating o ff th e pyridine a f t e r th e varying lengths of standing time shown* An inspection of t h i s ta b le w ill 52

roveu.1 that in pyridine solution both di&ayla isoiaeri«ed rapidly to fo m m equilibrium mixture of the two forms just as in alcohol, but that titis time the equilibrium mixture contained V? percent cl the H-acetyl—Q-beesoyl lorn rather titan tno 6b percent found

"ASHA v

Bun Sample rescription Standing Product Analysis6 Tima ,4 0 * ^d*3 ;J Recovery 1 P ure HA 6 n rs * 77 23 98 2 rt s? 0 66 14 106 3 91 i NA 3 77 23 95 4 38 ,! KA 3 76 36 94 5 P ure :/B 8 77 23 98 .p & ** i» 0 ax £»? 94

(a) Analyses baaed on amount of sample recovered by elution o f the bsuaJs w ith acetone, (b) H~acetyl-Q-b ensoy l«»Q-amino- phenol* (o) K-neacoyl~0-&eetyl-o-&mii3ophenol* in alcohol* Huns 2 and 6 bring out the fact, predicted theoretic-* ally , that the lUacetyl-O-beasoyl isomer rearranges much more slowly than does its isomeri&s* In the time required to evaporate off the

pyridine used to dissolve the two samples in those runs, SI percent of tae K-bensoyl-O-aoetyl derivative was isomer I sect and only 14.

percent of the opposite isomer* (The fact that tne percent c£ the rearrangement was slightly nigher than that found In the runs where sufficient time was allowed for equilibrium to he established is

attributed to an analysis error* The absolute recult mi& not con­ sidered significant ©iiough to cause a repetition of the run, how­

ev e r*)

Solvents wuich were found not to catalyse the isomerirations were benzene, hexane, e th e r, acetone and 1,4 diox&n©* h e c ry s t& ll- is & tio n * m&n from tiM© i* inadvisable* however* since enough i a o s c r i sa vi o a occurs ec heat lag la ta^sa mo Ivtfats * that t he m elting points os' be© two pur© isomers is appreciably lowered* Sifcis was fauna to os e&poc 1 aliy true for the more unstable K^bmsoyl form of the mixed diaayl derivatives,

-^n in tor ©st lug confirmation of the theoretlcai explanations igirm in this dissert at ion {page £2-24) for too replacement of an acyl group by an enter-Ing acyl, m i th© formation of %m complex pyridinlum H»altlf cf fix© acyl groups* was afforded by tm fo llow ing experiment* 4 small amount of pur© di&oetyl c-smieapheaol w

Just as was done In carrying out the preparation of the acyl deriv- s tiv e s * The solution w&© cooled -and poured into to© water * and the re s u ltin g m ixture evaporated to dryness under vacuum. Two d is tin c tly different crystal line type© could b& se,;p in the residue* long need les such as had been previously obtained in the preparation o f the d i­ acetyl compound* find oompaet platelets resembling those obtained in tun preparation o f th-e mono acetyl compound* ;£©oa&mlc&l separation and Tiixi&i melting points proved thnt to® residue did* indeed* consist of a mixture of tno mo no- and disoetyl derivatives of n—stnlKophenol*

This f©ot was also con firmed by t^&iog the ultra violet spectra of the two different crystalline forms-

Table VI brings oat toe also heretofore unsus pasted result a of a careful chroma t o.'-'t s phi c $ ©par&t 1 on o f the * rod acts of hydrolysis o f t r+9 various fix tu re s of the two mixed .di&cy Is In hqueous wnDx:m 54

wisss results were predicted by the present theory of the rearrange*, meats, however * ^roca t;*a basic assumptions that t ae isame?''i55ations in aqueous solution are Tory rapid to yield an e.|ui librium mixture

«ABLS ¥X

ftl.Miaad,.Plml„HaUga.to.ii.ig. Products

Hus Sample y ir s i Crop Second Crop To tals *& -.b * Tr. n _q hascription %r,a v-J 5 m fie ld tiu $33 .1 Y ie ld 0 III I fie ld 1 Pure &A 29 71 89 41 10 20 41 59 89 a 93 t ;:A 3? 8*3 m

( a| M»aeetyl—G-aiainopheno 1* (b) &~batteoyl«"€}«*axaiaophenol* Cc 1 Yields are based on the assumption that the relative sunountb of the two gaosouqyls oas as indicated in the "Totals*1 00 Inna* containing pr©dominantly the iW*o e ty aefcsoy 1 isom er, ana that the th^easeyl-h-acetyl form o f the mixed aiaayl is the one roost rapidly isomerised* i t w i l l be s e a s th at the results tabulated in Table' 71 are in the crier predicted by theory with the single exception of the pars th-bsnsoyl-O-acetyl isomer*. .fine® hydrolysis is an. irrevers­ ible process, start m with the par© au*o©tyl-o-baasoyl material one woul; expect that in the time required for isomerisation to ass a pail id? lam m ixture some o-^acetylnsslaotph^no 1 ^oul-i h& produced by normal hydrolysis of tne N-eoetyWd-beoooyl diacyl at it© oxygen connection* Once some a-benac/I-A-acetyl mixed hi acyl iu*& been form- ad, however, it w ill aybrolyse much mere rapidly than its isomerids eeeause of the high oihtf.gd oonoentratioc on it© oxygen carbonyl carbon atom. This more rapid hydrolysis of t»<* £-benzoyl*G-&c©tyl form w ill cause u shift of the equilibrium to produce u till more o f

th i;* form, aud consequently les^ o f tu© &—scety l~u-ba»aoyi form ©f

the mixed iia c y l* Dherefore, one would expect a predominance o f the o-bensoylaminepa^iiol even in t m hydrolysis product* of the p u re

^-acetyX-0—beaseyl-o-imlnophenel* M s prediction is seen to be v e r I f led oy tne results of run # 1* If on© etxrts with a mixture

o f th e two isomeric di&oyls, It w ill be immedletel;/ apparent from

the fq?e#>ing c&seussios th a t the predominance o f tue h-oenseyl moaoacyl should increase m tm quantity of the li—aensoyl-G-acetyl

isom er in the mixture being hyarolysed Increases* 7o*se 2>r*a le tions are borne out by runs £, 3, and 4 in which it w ill be saem that there

is a steady increase % n th e amount o f th e o-b@n soy Xaml no phenol Ifs

the hydrolysis products* A iwsslble explanation of the inconsistent

results obtained is run t 5 ra-sgr simply bo that too s&r.»Xl a s&sipX© was user tc obtain good quantitative recoveries (o n ly Q«10 gram w-.s used in both runs 1 and 5 )* I t may a lso be th a t* as wasp r w lo t# *

ly found in the alcohol i somer I sat Iona , txxs pure ^-bensoyWi-acetyl

mixed d ia c y l Is a non-conformist« and ta u t additional work w ill be

recassary to leurn the nature of i t s individualistic behavior*

It will os also noted from Dhole VI that the second crop materials,

In the throe runs th-it wore analysed, consistently contained &. stabile?

i:>er cent age of tne -T-benKoyl mono acyl than of the f-acjtyl* SMs

aa^taa to j nil cate a .^roster solubility la aqueous solution of the

mono acety l derivative# and wqy be a partial tacplenation of tn© failure

o f previous wo ?mvst to isolate ta.s oui&pouncl* Dhe latest cpiastitisd o f iBonoaoylat©d products war© found in the second crop m ixture ia the runs where only & ©s^Xl amount of diucyl wa# hydrolysed and d ilu tio n was aonse^asait ly high* I t ©©©as lik e ly * therefor©* tfe&t

‘‘suiting ontrt of ta© neutralised hydrolysis © in tare would serve to alco si completely remove th© sscno&eyl® from so lution ©ad obviate the necessity of working up a second orop* 2his procedure would have the dieedvaatuge* though* of probably also precipitating appreciable quuatitle® of bansoic acid*

fh©3®,tiaan* war© to© results wnich led to the complete form- ul&tion of tit© new theories of aoyl migration which or© presented la tills dissertation* $h* fast that pyri&in© solution© were found to catalyse ths isomeric changes mad© i t no longer necessary to postulate a complicated a©ehania® for the rearrangament of the acyl group© during tn© actual acyl at ion step* ffh© simpler idea 1© now favored that firs t to© normal unrear ranged iaomer Is produced* laid that tnls material then laameris©* undor tn© o&t&lytle influence of

\?yr id in©* Giae© the xr-b easoyl^-aoetyl compound ©an b© shewn to isomerise »-•*© rapidly thnm its isomer* it s©ems reasonable t© expect

© parer product from tne acetylatlou of o-heasoyXsmiaophexiol than from the opposite acyl at ion ©eigueno©*

}<© difficulty snouli he experienced in showing* by the methods outlined here* taat use of th® aeyl&tion method a la o lead® to a mixture of tha two isomeric mixed dl&oyls In about the ©am© proportions as war© found in tnia study* In these reactions the catalytic effect of the media* mtov end iVeQH, would be expected 5?

to catalyse the tsomerlsations*

^reparation of the mixed 3iacyl derivatives in ether solution* using the acyl chlorides as the acylating agent* should also produce a mixture of isomers* In these instance® the small amount of hydrogen ion in the ethereal solution would probably be sufficient to promote the type of rearrangements discussed in this worh* This worse has brought out very forcibly tho great value which modern cinroraat ©graphic mot hods taay have in e :*r ry ing out studios o f ruactIon mechanisms Is organic chemistry wiser© a quantitative

recovery of all of the products of the reactions is important* By means of this new tool considerable light has bees shod on the general subject of acyl migrations in o-atainophenola* In the

specific instance investigated in this research* that of the mig­

ration of acetyl and bensoy1 groups in c-am in© phenol# It has boon

conclusively demonstrated that acylation in pyridine produced a m ixture o f the two isomer ie mixed d ia e y la * The crude products*

however* were predominantly ^-aoetyl-O-benssoyl and H-bensseyl-

o-acetyl o-arninophenol depending on the acylation sequence*

dcetylatioa of o-benzoylsmliaophenol gave 62 percent of the unr©ar­

ranged B«benzoy 1-G -acetyl form# w h ile bensoylaticm ©f o-ao@ iyl-

aaino phenol gave 91 percent of the unr©arranged isomer# Both of

these pare mixed diacyls were isolated in their pure £orsa for the

firs t time by means of chromatograph!c separations# and their

physical properties and relative st bilitiea was studied under the

influence of several factors*

The stru ctu re o f these two isomer® was proved by tee comparison

of the alt a violet light absorption of taese compounds with the

absorbtion cnaractaristios of the corresponding p d e riv a tiv e s

m 59

wherein the or lest at los of the acyl groups is well mown* This woris constitutes the firs t good evidence for the structure of thhso mixed d iscyls*

I t has bees doracunst rated that the 'hslgr&fcions*1 which have been observed is acyl derivatives of o~aminophenols are# Isa reality* isomer I sat Iona of the aortal form of th® mixed dl&oyl under the c a ta ly tic influence o f the soIvent media employed* I t was shown, by m->a»3 of a combination of ettronatogr&phie separations had u ltra violet spectrophotometry* that Is alcohol and pyridine solutions equilibrium mixture© containing 85 percent and ?? percent of the more stable K~aG@tyl«*0~b©n35©yl form of the mixed dl&cyls were produced« It was pointed out that these iscm ri sat ions is alcohol ore probably the explanation of the conflicting results reported by 2alforl and by Bell* Water and heat also served to bring about th>ae la o m * is s tie n s * w h ile ben a one* hox&ne* acetoao* ether and dioxase were mueh less effective* if sot inert* in tais respect»

Finally* it was shown in this study that hydrolysis of either of tae two isomeric aostyl-bensoyl derivatives of ©- ,*mino phenol In aqueous ItaOH did not result in a single mo no acyl at sd product as huJ been reported by both B aiford and B e ll* Instead* i t was found th at these hydrolyses produced a m ixture o f the mouoaoyls contains ing about 62 per gant o-bensoylaminophenol and $8 percent o-aoetyl* arni no phenol regardless of the oompoaitlon of the mixture of dlaoyls which was hydrolysed* She variations in composition of the hydrolysis 60

product ft* wM Is slight* indicated that the greater the proportion of K—b«n«©yl-G-aeetyl mixed dlaeyl in the mixture l^drolysM, the greater was the amount of o-besstoyiamiaophenol produced*

Comprehensive theoretical explanations of these results have been proposed which are based on modern concepts of organic chem­ istry and involve the so-called n resonance41 and 44inductive” effects in the molecules concerned* 4 nm principle his been developed for p re d ic tin g which o f two Isomers should be the taore stab le* fh is principle has been called **the principle of mlnimuia charge conc­ entration** and should prove useful is further development of the theories of organic reactions* A survey of the literature on these acyl migrations has shown the present theory to be consist ant with the reported results* but* due to the son-quantitative nature of the worfc reported in the literature* raueh of this wor'k must be

repeated along the Uses laid down is this research before the

theory can be f u lly test-Kl* Si3Laaf.£D BIBLIOGRAPHY

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J* Am* Ciitiflfl* 800** 4&* 2305 (1924) ©6

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J* Am* Ciieau Hoc*, 46it 430 (1924)

36* H alford* L*G*, T a ft, R *, ana Lanfcalma, H#P#

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37. Halford* 1* 0. and weolfolK, C*M.'

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38* Halford* k*C* and Colhort* J.C*

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lc y l and a ry ls ajfcph&rjyX d e r iv a tiv e s o f

or t ho~ara in© pheao la *

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3» j

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2nd* ©ci* § pp* aQS—8* VITA

2d*ar Bument Smith was born in vmr Orleans, Louisiana, on

May 1 6 , 1818* th e son o f Mr* end Mrs# Hugh F , Smith o f th at c ity *

SXarasnt&ry education was received in the grammar schools o f Mm

Orleans* and in hirers ids M ilitary Academy, Gainesville, Georgia*

He was graduated from the Marion M ilitary Institute Mghb school of Marios* Alabama, in May, 1835*

She following September, he entered ful&ae H&ivwrsity of nm Orleans, Louisiana, from which institution he received the

Bachelor of Science degree la June, 1858* He served m a Graduate

Assistant In Organic Chemistry at fulaae from 1958 to 1941, and was graduated in June, 1941, with the degree of Master of Science,

Upon graduation from ful&ne, he accepted appointment as a

Chemistry fellow at the Rice Institute of Houston, [email protected], and worked during the summer of 1941 as a caamlst in the Metallurgical laboratories of the Tennessee Coal, Iron and ftailrodd Comply of

Birmingham, Alabama, He entered Fdoe in September, 1941, but after only s ix weeks tn ere was forced by his £ ra ft Board to discontinue his education and again took in d u s tria l employment, th is time w ith th e Bow Chemical company lh Freeport, $@otaa* He worked fo r th is company fo r almost throe year®, moat o f which time he was employed as a chemist in the Organic Research Laboratories* He wm married in June, 1945, to M iss, Leona Held o f Houston, d'exas, and now has one son by th is m arriage, James Dumont, born in August, 1944* In

71 August o f 1944 Ho went on active duty with the United States

Havy* living accepted a Oomsisslon as assign* After training at various stations is Florida* he was assigned a© Bcmar Of flo o r to tiie uss G e e k rlll* us 398* on board which vessel ho serves until Ms discharge m Lieutenant (3*&*1 in May* 1946*

Upon leaving the flav&l Service he accepted employment as

a chemist with the BthyX Corporation of Baton Hong©* Louisiana*

ana worked there until September* 1946* At this time he accepted

appointment as a Part*?im@ Assistant in the Physics Department

of Louisiana State University la order to resume his interrupted

education* la January* 194®* he resigned this position in order

to accept a Havy Hese&reh Fellowship in Chromatography in the

Chemistry Department of the University* Ho is act? a candidate

for the degree of Doctor of philosophy in ahomistry* EXAMINATION AND THESIS REPORT

Candidate: ^ Edgar Dumont Smith

Major Field: ^ Chemistry

Title of Thesis. She M igration o f Acyl Croups in o-Aminophenols

Approved:

Major Professor and Chairman

± X Dean of the Graduate/Sclihol

EXAMINING COMMITTEE:

vv O • L. k~ - r ^ t O ^ r ^ r aa^—

Date of Examination:

4 - 7 -