rl zel-rf4 FREE RADICAL CYCLISATIONS A THESIS PRESENTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in the UNIVERSITY OF ADELAIDE by T0NY LAWRENCE, B.Sc. (Hons. ) Departnrent of Organic Chemistry 1980 +: CONTENTS SUMMARY I STATEMENT II ACKNOhILEDGEMENTS III INTRODUI]TÏ()N 1 Background chemìstry 2 Outljne of the research project 21 Rates of cyclisation 27 Energies of activation 30 HEX.s.EN-1-YL RADICAL 32 2-METHYLHEX-5-EN-1-YL and 3-METHYLHEX-5-EN-1-YL RADICALS 43 2,z-DII4ETHYLHEX- s-EN- L-YL and 3,3-DIMETHYLHEX-s-EN-1-YL RADICALS 60 2,2,s.IRIMETHYLIIEX- 5- EN - 1.YL RADI CAL 78 2,2-DIIIETHYLPtNT-4-EN-1-YL and 3,3-DIMETHYLPENT-4-EN-1-YL RADICALS 97 OCT.7.ENE.2-YL RADICAL 108 4-METHYLHEX.5.EN.l-YL RADI CAL 118 HEX-s-YN-l-YL, HEPT-6-YN-l-YL and OCT-7-YN-l-YL RADICALS 131 5,6-EP0XYIjEXIìN- 1-YL RADI CAL r52 AFTËRl^IARD 159 EXPERIMENTAL SECI ION 163 Methods of reduction r64 Methods of analysis 17I Syntheti c rnethods 176 RE FERENCES 244 I SUMMARY The fol'ìowing free radicals were generated in solutíon by the reaction of tri-n-butyltin hydrÍde with the correspond'ing bromocompounds: Hex-5-en-1-yl, 2-Methyl hex-S-en-1-yl, 3-Methy'l hex-5-en-1-yl' 4-Methyl hex-5-en-1-yl, 2,2-Dimethy'l hex-5-en-1-yl, 3-3-Dimethyl hex-5-en-1-yl, 2,?-,5-Trimethyì hex-5-en-1-y'1, 2,2-Dimethyl pent-4-en-1-y1, 3,3-Dimethyl pent-4-en-1-yl, 1-Methylhept-6-en-1-y1, Hex-S-yn-1-y1, Hept-6-yn-1-yl' Oct-7-yn-l-yl, and 5,6-Epoxyhexan-1-yl . Under careful'ly controlled corditions each brcmide was reduced with tri-n-butyltin hydride in benzene, and the relative yieìcls of cycìic and acJ¿clic hyd:"ocarbon products were deiernrined by gas'liquid cltroma- tograph'ic ana.lysis. The rates of intramolecular cyclisation of each radical relative to its rate of hydrogen atom abstraction from tri-n-butyltin hydride were determined over a range of temperatures and reagent concentrations. Energies of activation were calcujated. Structures of the cyclic transìtion states were studied by analysing the ci's and lttans isomer djstributions of 1,2-d'imethyl- and jons 1,3-dìnrethy'lcycl oal kanes o whi ch were formed by i ntramol ecul ar acldi t of mononrethylaì kenyì radicals. Where ìt appeared possible, atternpts urere made to re1ate these s'Ludies to earlier work in free radical cyclisation. The ex'isting explanat'ions for the selective exo-cyclisation of the hex-5-en-1-yì radjcal were evaluated in the light of present observations. Summary of the results: (1) To the extent that they do cyclise the above radicals undergo selective and irreversible øxo-cyc'lisation, with the sole except- ion of the 2,2,5-trimethylhex-5-en-1-yl radical whjch undergoes both ¿xo- and øndo-cyc'lisatjons at comparable rates. (2) Methy'lsubstitution at C2, or C3, or C4 increases the rate of intramolecular cyc'lìsation of the hex-5-en-1-yl radical in djrect relaticnsh'ip to the extent of the tnethyì induced gauche inter- act'ions. Lowered enthalpy of activatjon is observed with these rate enhancements without significant changes in the entropy of acti vati on . (3) Intramolecular cycl isat,íon of the 2,2,S-trimethy'l hex-5-en-1-y'l radical contradicts the hypothes'is that selective 1,5-cycl isation of the hex-5-en-1-yl rad'ical js caused by through space inter- actions of hydrogens at C2 and C6, which bar the format'ion of t.he transjt'ion state for 1,6-cyclisation. (4) Mononrethyl substi tut'ion of the hex-5-en- 1-y'l rad i cal at ei ther C2,or C3,or C4 exerts control' in the selective formatjon of ci.t or üan^ stereo'isomers of dimethy'lcycl opentane. Thi s i s consistent wjth a chaìr-ljke cycl'ic conformation of the transition state in whìch the.: methyl group ìs predonlinantly in an equatorial ori entation . (5) The following free radicals do not undergo intramolecular cyc'l ì sation : 2,2-Dinrethyl pent-4-en- 1-y1, 3, 3-Dimethyl pent-4-en- 1- yl , and 5,6-Epoxyhc'xan-1-yl . II STATEMENT This thesis contains no material previously submitted for a degree or diploma in any University, and to the best of my knowledge and belief, contains no material previous'ly published or written by another person, except where due reference is made in the text. TONY LAWRENCE. III ACKNOI^JLEDGEMTNTS At its best the work presented in this thesis js but a small addition to the results of research in free radical cyclisations, which were available to me during my studjes. 0f particular relevance were the reports jn free radical cycfisa- tions by K.U. Ingold, C. lnlallirg, M. Juìia, and A.L.J. Beckwith. I have endeavoured to do my work as well as they did theirs. This project was supervised by Professor A.L.J. Beckwith, and by Dr. G.E. Gream during the absence of Professor Beckwith in t979. The whole manuscript rvas proof-read by Dr. R.H. Prager. Throughout jts duratjon thjs work was supported by a Commonweal th Postgraduate Scholarshi p. 1 INTRODUCTI ON Backqround chemistry This is a study of carbon radicals. In all cases the unpaired electron is vlhol'ly centred on one carbonl There is no deiocaljsation of the unpa'ired electron onto neìghbouring groups by conjugation. There is no l¡eteroatom within the molecule which could change the free spin density on the radical carbon. l,rlith but one exception all are primary carbon radicals, one beìng a secondary carbon radical. The followjng radicals were investigated in the course of this work. I o a a a ilt * To the e.xte-nt that.Lt. dou ex,í,tt, el..¿ettton de..LocæLtsctlirtn bq hgputcctttiugalion i,s tty.(i]¿c(1¡ .{o lx*,e /¿igt+L(ic.rutt.in{Luer.c.e u¡ttsn thrz next'(-t''s o{ 'l'hi-t LaltLl¿' 3 There are many ways to generate such free spin.bearing reactive inter- medíates in so]ution. Some of the methods used to generate hex-S-en-l-y'l radica'l - the first one listed above - involved the following reactions: (1) Thermoìysis of di-6-heptenoyl perox'ide1. -Þ 2 (2) Reduction of 6-mercapto-1.-hexene with triethy'lphosphite H (3) Kolbe's electrolysis of 6-heptenoic acid 3 + c0, 4 4 (4) Reaction of 6-bromohex-1-ene with sodjum naphthalene (5) Reaction of di-6-heptenoyì peroxide with copper acetates. (6) Reduction cl't 6-chloro or 6-bromohex-1-ene with tri-n-butyl tin hydride6'31. r a l- n Bu SnH + nBu3SnBr + RH (7) Reaction of hex-S-enyl-1-mercuric bromjde with sodjunr borohydricle - reductjve demercurationT. (S) Reduction of hex-5-enyl -1-mercuric bromide with tri-n-buty'lt'in hydr i cleB . Reductìon of aìky1 halides with tri-n-butyltìn hydride js a simpìe and efficient nethod for generatìng free radicals in solution. It is the method of choice, and the only method empìoyed for generating free radicals in thìs work. Some twenty years ago it was known that organotin hyclrides react w'ith al kyl hal ides9'tO On rep'ìacing the aì ky'l halogen vrith tlre t'in hydrogen, thus producing organotin halides and hydrocarbons. In 1962-64 Kuivila and co-workers undertool< mechanist'ic stuCies in the reduction of aìkyl halides by tri-n-butyltìn hydridell-13. Their investigations led them to the conclusjon that the reduction of aìkyl hal'ides by tin hydrìde involves free rad'ical reactjve intermedjates. 0n the basjs of their observations they proposed the following free radi cal cha'in mechani rnl13 . 5 'l.vu,ti¡tiion Initiator + R-X---c> R' Pnopagation R' + BurSnH --Þ RH + Bu3Sñ BurSñ + R-X -_ÞR'+ Bu3SnX TunLwLLon R'+ R'-> p-o R' + Bu3Sh _-Þ> BurSn-R InneÍivø ytrtoduct6 BurSñ + BurSh .---> BurSn-Sn Bu 3 Non-stabilized radicals of the hex-5-en-1-y'l type are hi9h1y reactive. Their free spin bearing carbons are not sterically crolded, and such radicals t^Jil1 undergo coupling reactions at diffusion controlled rates. In a steady state process, where the concentration of free radicals is low and does not change with the reaction time, the extent of coupling reactjons is likewise very low. Once generated a free radical jn solution may undergo one or more of the fol'lovring reactions: {1) Disproportionation (2) Intermolecular hydrogen atom abstraction (3) Intramolecular hydrogen atom abstractÍon (4) Intramolecular rearrangement When a radical in solutjon undergoes two or more irreversjble intermolecular reactions with reactants of identjcal concentrations the relative yield of each product is dependent only on the rate constattt of its formation. Likeu'ise the relative amounts of products frorn two or more irreversible intramolecular reactions of the sarne reactive intermediate are direct'ly related to their respec'bive rate constants. Reduction of bromoal kenes with tri-n-buty'ltin h-vdride i s a steady state process - the concentration of the free radical reactive inter- nlediates is constant throughout the reaction. Here the extent of intrarno.lecular rearrangements depend only on tinle and the reaction rate constani:s. l'ligh conceirtrations 6 of reactants lead to an increased number of intramo'lecular collisions per unjt time, and to relative'ìy higher yields of products from irreversjble intermolecular react'ions.