t- ÂogLNDE SOIvB S?ECTF.AL PROPEC.TIES A\D CIDXICAL REACTIONS 0-'T OLAZOI,ES A Tl:esis Presented fcr the Degrree of Doctor of PhiJosophY in the UfIT\TEFSIÎY OF ADELA]ÐE by ,ÞA-üt F " DOitAGiIüE, B.Sc. (iIons") Depa:'tnént of Orga:ric Ohemistry Decenber, 1968, MRssRc¡lusETTS lNsrtrurE oF TEcHNoLocy DEPARTMENT oF CHEMISTRY g¡. 56_025 CAMBRIDGE, MASSACHUSETTS O2I39 July 25, L969 The Registrat Unfversity of AdeLalde South AustraLfa 5001 Dear SLr: I arn pleased to gLve rny conaent for the Barr SmLth Llbrary to allow the borrowlng and photo-copyLng of ny Ph.D. thesla, ln accordance wlth the llbrar¡i rules. Sincerely yours, caa Paul Donaghue COI'TIEN'IS Page SUir'iir,lFJ \ai sr-riEiiú'N! t'aaj }CIO{O'i'LNETE}.IlS t avl PUBLICJTTIOì'IS (v,) T{!'R.OÐUClIO}I 1 rr-j LìTEìÐ .ì Spe Oxazol-es" VI1ru^ .u¡L ¡ c Mass ctra of ¿¿lol In'¿rod.uc'l;ion 10 .aa I èZ- Basic FragnentatÍon lVlodes of Oxazoles 20 1"3 Siceleta-l- Rearra::genent Proce sse s Involving B ron:ine lvfi grati-on )v Skel-eta-l- Rear.ralgenent Processes frwoivinA Phenyi or iliei;hyl- Group }Íi-grations )7 cH.AJmR 2. )iuclear lfaqnetic Resonance S TA of Oxazcles" AE Zø^¿ I Introð.uciion 2"2 theoreiioal C al-cul aiions 77 ¿-o,)õ7 t\i ucle a:' lf agnetic Resona::¡ce Specira &) -ci'Tqii) arY. j ,\ 7 O;<a-zol es* vfLa rlfr -/ 6 Cnen'j.cal Reacïions of 4^a )o t r1!uiugu9urvlr 74 109 )oa Res';iis a-trd. Ði scussi on Page EXER]IvtrllITAL Genera-l- 115 CIIAPMF. 1" General 117 Preparation of Aceloins and- Acel-oj-n E sters 111 Preparation of Oxazoles lt> Preparation of Isotopica-lly LabelJ-ed- Cornpowids i2)+ rì-J.\-Jircf z vif-'u .ry!! J c 130 â 27 -{rfä}DIX '?. t)) APPE\DI( 2" 1)t ¡ÐnFxtTl-i-y z 1)+5 :!LþltvüL )e ¿¡ t ?"I.F-'EREI[C,ES ¡+u sulilI-ARY o the electron-irnpact ind-uced- rtagneni,ations of oxazoies have been measliÏ€- stud-ied- i'rith the aid. of deuteriu¡n iabelling arld. high z'esoiution lhepositionofanal-lrytsubstiiuentcontajni:rgthreeorrnore riass carbon atoms carr be c.etermrned- from the mass spectr,:nr, a:id the group is present' spectrurn also shows characieristic peaks if a 5-me'Lhyl show ihai The spectra of oxazoles specificaJ-]y ìâ'oelieO' lvith C'eute;:-r¡n -'Ì'e a hyarcgen attachec. to ihe o-xa.zoLe ring is no'ú rândomised' rvith hyorogens on a meihyl or a phenyl subsiituent, and- ihat the lri{co" involve fragnientation observed- in the spectra of many oxazoies does noi a hyd.rogen attached- io the oxazoLe ring' (:ii-co A pathrvay has been posiulated. for -rJ:e initiai fragrnentati on , borc r,/i4rIo") of the oxazoLe rfug, rvhi-ch ir¡¡okes creavage of the 1-2 substitueni folio.,",æd by loss of co rvith concornitar:-i, n:-igration of the c-l is l-os'ü -tc c41o If the fragrnentation process is ì,i4ilo", ahydrogen atcn froni a substii;ueni concurrentiy l'¡ith the exp''lision of C0" the nass spectra of d.i-pheryi-oxazoles shov¡ a peak a*, g/s 16J (C"-A^rh.r")r'uheformationof'¡'hichdernandsaphenyirnigration"This t) ) peù,: g/e 161 is promi:rent in the si' trra of 2'5- ¡1-:'ð' ['l-d'ipÌren-¡iorazoJ-es' but ninor in the spec'iJru;n oÎ 2rçlt-,ñerryloxazoLe" Deuterj--un l-abeii:-ng studies enableC. tne d.etection of -;;-c a-l--ueílate i'earra::genen't pa1;l-va'Vs cí' ihe for"raticn iTi'¿ne spec-ür'ijin of 2rt¡{2-tnpirenSt--i:xazoLe" 'A' coniparisol: (ii) of tlre peak at úS 165 in 'uhe spectra of stj-lbene arrJ- ! r10-d.i-ttyd'ro- 'i,lee pJ:enan'uhrene, r'ri-tJe its forrnation j¡l spectra of d'iphenyloxazoLes' shows 'uhat a coünnon mechanis^tr d-oes not opera-r,e in the heterocyclic arrd' ca-:"bocycJ-ic sYstems . lhenuc]-earmagneiicresonancespectraweredeterrninedfora n¡nber or oxazoLes, and some correiations establ-ished. beil'reen the cherriea]- posi-uion of shift a:r.d. splì.tting patte:r: of a methyl resonance, and the substi.uution of the methyl groupc solveåt shift stucjies aÌso proved- art oxazole" of some vafue in d-eternri:ring the substituiion patiern of the magnitud-e of the solvent shift for the meiJ:yl resonance of neihyÌ oxazoles v¡as fourrd- to be strongly d-ependent on -r-J:e composi-tion of of solute. ihe solvent, but independent of the concentration ,Examina- tion of a nurrber of d-iffereni -types of polar soluiès showeC' that in al-1 -r'he cases the magnitud.e of the sol-vent s."rift lvas i:rdeper'd'en-t' of concen- tration of solute" Some preliminary suggestions have been adva-nced' io accor¡rt for ihis observ-ation. a.'leyd-rid-e to allyl _A. stui.y of the Diels-A]der ad.d-iiion of rna-leic oxazoi-es i¡rC.icateO- that the ad.åition proceeds viz xt end"o-tramsitj-on state, vrith an angle of aporoxijlla'üe] y 60o b"too"en ihe pl-a-ne of the oxazole and. dienophile" the inertness of aryl oxazoles to cycì-o- ad-d-ltion is ascribed. to a]"I electron:c rather ihan a steric effec-b" ( r-r-r-) ST.{TE}ENT. This thesis contains no material- which has been acceptec. for the award. of ariy other d.egree or d-iploma ín eny uruiversity, a¡rd. to the best of my knovùed.ge and- belief contai¡l5 no materiaf previouslJ¡ published. or written by arroiher person, except v¡here d.ue reference is mad-e in the -t ext. ( al'J I wish to tha¡rk most sincerely Dr" H"J. Rocrda for his gu-idance arrrl encouragenent d.uring supenrision of this v¡ork" I aro ind.ebted to Dr. J"li. Bowie for helpfu-l- suggestions a]1cl" sii¡ruiatj¡rg C,iscussion on ma-ss spectral problems, to Dr. T'lrÍ' Spotst"'ood j:r for hrs suggestions as to the interpretaiion of solvent shj-fis the IIoII}¡Io spectra, arrd. to Mr. BÐ.. Roney for assistarrce v;ith computationa.l problems i.:e the tlreoretical ca-1cirl-atíons" I am grateful- to L{r. R.L. Pa-ltrid.ge for record-irrg the n.m"Ï'" spectra, and. io Mr" D.ts. cobb for àetermining some of the mass spectrae This research rtras carried out d.uring ihe tenr:re of a Con¡nonv¡eal-th ?ostgrad.uate A'rca'd., wluich I gratef',:lly aôlcnov'ùedge' (") PUBLTCAÎIONS. Part of the work d,escrlbed. in this thesis has been publishei' in ihe folloiving Papers: "Îhe lVlass spectra of some A1)qÊ and. Aryl Oxazo1-esr[ Bor¡,,ie, Jü., Ðonaghue, P"!'. ¡ Rodd.a, l{"J., Cooks¡ R"G. ¡ 13. and. l'f i-l-Iiârns ¡ D.H. ¡ J illass ., 1968, 1, nThe crr|{, skeletal-reaffaflgement Fragment in the }lass Spectra of HeterocycU-c Systems Containing Diphenyl Substituents. A Deuterium Labelling Siud'yrtl Scnvie¡ J.H., Donaghue, P.F. , Rodda, 71.J .2 artd' Sjmons, B 'K; ' Teiralredron, 1968t 4, 3965. Î(TRODUCTION Inrecentyearstheadventofthehighspeedcomputerhaslecrto of a renerved. interest in i;he theoretical d.eriva-r,ion of the properties organic mol-ecufes. I\fuch of this 'lvork has been concerned' with hetero- as a resuft, there has been an increased c1¡rcLio aromatic =y"t"*"r1-L "rtd interest i:r the properties, particularly spectra-l properties, of these cornpourrds o tr ^In suggested. the generic na¡r,e axazol-e for cornpounð's . 188J Hantzsch' containíng the nucteus (1). IIe al-so proposed a l-et'cering system (1a) to ind.ica-te the position of substitution but, in all but the oId-est refer- ences, this has been supersed.ed by a nrr"nerical system (t¡). 7 N 4 N ) \ a p 0 0 0 I (r ( 1b (r ) ") ) Although on-1y one naturaliy-occurring ccrnpounC. has been formd- io f-7 contain tl¡e oxezole nucleusr" / oxazol-es can be prepared' fron g-a:ni¡o oq acidsro u.td- frora proteinsrT and' a:ee thus chemicdr-Iy relateå to a iarge 10 m¡nber of natr:ra] Iy-occr.rring compound.s" It has been suggesteð'" that oxazoLe r:nj-ts may forrn part of proteù mol-ecuf-es, but this suggestion has not been subste¡rtiated.' The first krown preparation of an o>iazole 1l'as Ay Zlniil in 16t'p. Iïe obtairred-, fron the reaction of benz)-f. with al-cohol-ic a.rrronia, a- con- 2 poìirl¿ which he ca-l-led- zzobenzlL., a:rô which Lu.ureni1 L^t"" na¡ned- benzji-a*n. In'1881 J"pp1J p"opo="d. the structure 2t4t5-tttphrcrryLoxazofe (Z) for azobenzr]-¡ a'd- this assj-gnmenì; was confirmed in ,937''4 Jappus pro- posa-l represented- the first post-*lation of ib'e oxazole ring systen a-s a structr:ral entityr aJd. six years later an indeper.deni series of obser- vations 1ed. Ila¡tz="h15 to an id.eniica-l- formu]-aii on of t]ne oxazole nucleus. cgH5 N R C O cH í'rrlH co d RCON HcHR'CO2R" Ro-.fi, allq¡I, a:¡r1 R" a.liVl, zry! csH5 coH = U s / _\ (z) l)) (u) Dr_:ring iàe j:ritiaJ- developrent of axazoLe chemistry. ¡ e large ¡/ nuinber of s¡rntheij-c routes io the rj-ng system ï¡as evolved.'o the rnosi general of these a:'e the Robi:rson4+abriel s¡mthesis, the Davidson cyclj-sation, the Harrtzsch s¡"nthesls, ancl t]re Fischer conclensaticn.