lq's.6 Å A SflJDY OF $TE SYNTTIESIS AND REACIIOI\E OF PHT¡IAI¡AZINES A THESIS PXESE}{IED T'OR TTTE DEGREE Otr' DOCTOR OF FÍTILOSOFÍÍY Ín the UM\TER.SIIY OF ADELATDE by PETER G. PA.R.SONS B.So.(nons.) Depertnent of Organlc Chenistry Jr¡I'y, 1966. COI'IffiNtFi Page SUI/üI¡]ARY $TATEI/ENT ACKNOI'IIEDGE]ÆOITB II\TJSODUGTION 1 cHAsrm, 1. [he S.vnthesis of Phthalazineå 1.1 S¡mthesis from phthaJ-dehydes 1Lr 1"2 S,¡mthesis frorn phthalic acids 15 1"3 S¡mthesis froro phthalonitríIes 2A CHAPIER 2O Reactions of Pht4alazine with HaJ-osens. 2.1 Add.ition oompounds 35 1\ ', tilc. 2.2 Rea.ctions rvith cl¡lor.j'ne a¡d. chlorinating )+7 €ì- agents cHaslER ,. Snbstitution and Add.ition Reactions of Phthal azíne 3'1 [heoretical' principles 71 3'2 HXÐ caLcul-ations for phthalazine 75 )o) Electrophilic sr¡bstitution 80 3"4 Nucleophilic substÍtution 85 3"5 Ad.dition reactions 90 CII.¿¡HEER. 4" N*Substi.tu- ted. Phthal színe Derivatives 4"1 Phthailazine-Z-oxíde 9t 4"2 Phthalazi¡.ir¡m salts 96 Page EXBRI]V[ù]\TAI General- 1A2 Chapter 1 105 " Chapter 2o 129 Chapter J. 151 Chapter 4. 160 REEEREI\ffi, 16'9 S,UI,ÍI,lARY Application of existi-ng netJrods of phtha-lazine s¡rnttresis to the preparation of d.erivatives substituted. in the homocyclic ring v,'as or:Iy successful for the s¡rnthesis of 6-bromophthalazine. In attempts to d.evise a nelv s¡mthetic rrcute, d.esrrlphurisation of phthal æ-1 ]r d.j.tÏrione was for¡nd. to give a lory yield. of phthal azi-neo  more efficj-ent s¡nrtbesis was achieved. by Ìgrd.rogenation of 1r11--d.ichlorophthalazine over pallad.iunron-carbon at 1 atmosphere. A nely heteroc¡'cl1ic system, benzo[g]lhtJralaziner ffid a nu¡rber of 1-substituted. phtkrale,zJ-nes were prepared by this rethod. 1,2r5rl¡-[etrahyd.ro d.erivatives were obtained. r,hen tire hyd.z.ogenatj.on lvas carried. oub at 100 atmospheres" Dehydrezination of mono- and. &itgrd.razÍ^nophtkralazines vith rer:curic oxide ha,s prolåd.ed. a¡rother s¡rnthetic route to phthalazine d.erivativeso Orcid.ati.on of 1-hyd.razíno- and. 1 rJ¡-d.ihgrd-razinophthalazi¡ie rrittr quinones and. with broudne resulted. in cleavage of the azine ri-ng to form phthalonitrile; tlee r¡se of other oxíd.ants gave halogeno- and. hyd.ro4l¡gh thal az ine s . lhe oxid¿t5-on of pheny3Ìryd.razine ¡rj.th N-.brornosuccinj¡nid.e has been rejnvestigated. but, contrary to a previous report, no hyd.razo- benzene was d.etectedo Evid.ence was ol¡tai¡led. for tTre j:ritial fo¡rnation of benzened.iazonj-um brorrid.e '¡,hj.ch gave rj.se to the obsenred. prod.r.rcts, bromobenzene, pherSrl azid.e and. aniline. -Phth¡al-azine forned. stable 1:1 and. 1:2 ad.d.ition compor:nd.s lvith hailogens" The i-¡rfrared. a¡¡d. nuclear nagnetic resonaJ¡ce spectra of tLre ad.ducts ind.icated. that one of the nitrogen atoms vuas bound., presunably tkrrougþ its lo¡re pa:irr to the halogen molecuJ-e. The unusu.rlly higþ stability of the add.ucts r'¡as at-bributed. to resonance-stabilj.sed. back- coord.ination of the lralogen to the phtl:al-azine ring" Phthalazine wa,s found to react rapiC.ly'rrith ch.lorj¡re in aqueous solutíon to fozm nitrogen and. a mlxtr:re of $rthal.a1d.eÌgrd.e, o-d.ichlorometlgrlbenzaldeþd.e and. N-chlorophthalazone, tl¡e rati.o of prod.ucts d.eperd.ing on ths rate of add.ition of chlori:re, 'che concentra- tion of ckrlorj.d.e j-on a¡rià the $I of the med.ium; the sarne prod.ucts wero obt¿ci¡ed. using lgrpocir-lorous aoido The reaction of ch-lorine vrith sr:b- stituted. phthalaaines and. some related. azines also r"esulted. ín orid.a- tion and. ring-fissiono \'lechanisn:s have been proposed. to account for the formation of these pnod-uctso The nitration and. bronrination of phtkralazine ín )Q;lo sul.phllric acid. gave 5-st¡bstituted. d.erivatives; this orientation was pred.icted. bJ' reactivity in*j.ces calcr:-lated r¡sing the HlLcke1 roolecular orbital nethodo The rate of nitration was found. tc be 5.6 x 1O-5I. role-l at 61"90. .Am:ination and. hyd:ro:6r1ation occuged. ""o"-1 at the 1-position, as preùicted.. Phtlealazj¡e reacted. with keten and. v¡ith naleic ardeyd.rid.e, forning ad.d.ucts of r¡nlaao'¡¡n structureo treatment of phthal azine-2-o-að.e w:ith alkaline potassium ferricyanid.e resulted. j¡l the formation of nitrogen and. phthalald.ehydeo Gonversion of the 2-oxi-d.e to Z-acetylphthalazone wa.s effected. by heating r¡¡ith acetic arùryd.rid.e. Chlorination and. nítration of phtfta]-azíne-Z- oxid.e lÍas accoÍrplishe¿L by th,e use of chlorj¡re water and. potassiun nitrate in 9gl; sulphuric aoid. respoctively. N-S.rrbstituteiL phtbalazinir¡m salts were found. to undergo nucJ,eo¡iluilic attack at ttre l-posítion by l¡ydrorid.e, alkorid.e and. cyarxlde ions; the products, horrever, resísted. fi.¡rther d.egrad.ationo ô STATEi\MNT lhis tbesis oontai¡¡s no material which has been accepted. for the awa¡rd. of an¡r other clegree or d.iploma fu ar¡y Uni.versit'y, ar¡d. to the best of, 4y lo,owled.ge and' belief contains no material previously publishecl or written by another perËon, exoopt wlrere ôrre ¡¡eference is nad'e l¡¡ the text. ACKNOI¡TI;EDGEMET{Ï$ I a¡n cleepl.y indebted. to Dro H.J. Rodd.a for his guiclance and. eneouragement cluring supenrision of this 'Tfork. I wlsh to t}¡ank Mr. Ej.D. R.oney for tho rnolecular orbital calou1atlons. this resea¡oh was caried. out durj¡rg the tenu¡e of a Commorursalth Postgraduate Awarrd,, Tvìßich I gratef\rlþ aolmonrledge. Introd.uction Advances in method.s of synthesis and in physico-chernical techniques d.urirrg recent years have Ied. to a vast e:çansi.on in tlre field. of heterocyclic chernistryo In particular, those ring systems occurring in naturral products and. in biologically active materia-l-s have been extensively investigated.. Nj-trogen heterocycles are wid.ely d.istributeil in Nature and. a:¡e commorrly d.erived. from five or six- membered. aromatÍc ringso Îhe latter class is structuraÌIy based. on pyridi:re (t), w:rich shorvs a d.egree of aronaticity comparable with benzeneo Horvever, the pyridine molecule is unsyrrmetrical with :respect to bond. lengths and. charge d.istribution because nitrogen is more electronegative than carbon. fhe chem'ical reactivity of pynièine ther"efore d.iffers from benaene; electrophi.lic attack, for e¡am¡rler is much less favourable because of the electrpn wj.thd,raw:ing effect of the nitrogen atom, white nucleophilic attack is facilitateit.l llhe presence of trvo nitnogen atoms in a six-membered. aromatic nucleus worrld. be e:çecteil to result in even greater èifferences arìd. this has been for¡nd for the three i.someric d.iazi¡es (Zr 3 and ¿r). Pyrid.azine (Z) does not r:ndergo electrophilic substj-tution2 rvhereas nucleophilic èisplacement of substituents occurs read.ily "3 '4'5 A fi¡rther consequence of localisation of electrons on nitrogen is a reduction in the arornatic character of the èiazine ring. lhis effect seems from valence bond, be negligible in pyr5rniðine (¡) pyr=rzíne Ul.t calcuLations to "r,A 14)6 of appreciable magnitude in pyrid.azíne (Z) where the hetero atoms are -2- ad.jacento 7 The Kelcrrle structure (ea) nav:.ng a single bond. betrveen ã o V,N (1) (2a ) (2b) 5 l* 6 3 I ) N2 I N 1 (3) (t+) (5) tL¡e nit¡rogen atoms was consj.dered.T to nalce a greater contrlbution to the resonance trybrid. than the fo¡u (ZU). The C=N bond.s in pyridazine would. thenefore have increased. d.or¡ble bond. character arrd. would. be more susceptible to add.ition. Ihis pred.iction r¡vas f\¡Ifj.lled. by a recent o report" that pyrid.azine rrndergoes aitd.ition across the t=N bond. with tv¡o molecr:les of ¡r¡aleic ant¡yd.rid.e. Fht!¡alazine (5), whickr is the diazino stud.ied. i.n the present work, i.s fornally d.erived. by fusion of a benzene ri.ng to tf,e 4 bond. of pyrídazine and. woul-d. be expected. to parallel pyrid.azine in chero-ical behavior:r. the benzo rir€r however, offer"s rcore favourable sites for electrcphi,lic substitution and nay raodif! the properties of the heterp- cÍc1ic nucleu.s. Since the 1 12 bond. ín naphthalene has the greatest bond. o¡der, the d.or¡lc1e bond. ct¡aracter of the C=N bond.s j.n phthal-azine should. be erùranced. compared. with pyrid.azi-ne. -3- The phthalazine rJ.ng system has not been for¡nd. i¡r Nature and. has accordi¡rgly received. relativeþ ILttIe attention; most of tJ:e recent investigat'ions have been concerned. wj"th the preparation anil properbies of biologically aotive derivativ"""9'10'11 Reviews of phthalàzi;r7e chenistry reveal co¡rsid.erable interest in the d.erivatives of phthala- zones and. phthalaz-1r4-d.iones "12t13'14 Investigation of tkre deory- genated. phtLralazine ring, on thæ other hand, has been hamlpered. by the J.ack of suitable method.s for its s¡mthesis.