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HITRILES By Franco- Ftllon A THESIS Subnittad to u» School of mu sum» of 11161113“ Stun College of Agicnlturo and Applied 831m- 1n mull mun-ant or the remnant. for the degree or M813 0 SINCE Input-taunt of (Shani-try 1953 /o-4'§¢/ EWGfiR-N m author with“ to thunk Dr. ”but I. [mat for his add” and guidance dmdng the carrying out or thin lurk. -W W W W H G 3mm TABLEG'CCKTMS PAGE IHTRDRICTIOH....................................................... 1 DISCUSSION............................‘............................ 2 EIPERIMEEIAL................................... ...... . ..... ........ 13 Re;gent0..................................................... 13 I-Banqyl-S-aninototrasole.................................... 13 Honolution or (Lrothyloqproio acid........................... 15 Inactivo c£yothy1onrqyl chloride............................ 1? Ihlotlvn c£pathyloapron1ir110................................ 17 (~)-aL-Ethvlcnproy1oh1auao 18 (-).oL-my1oapron1trm..................................... 13 (+)«1 (3'-hapty1)-S-am1nototrtsolc........................... 19 Optical rotution............................................. 21 Woo...00000000000000006000.000.0000.0.00000000000000000.00.00 22 RBWBQOCCOOOOOOO0.00.0...IIOOOCIOIOOOOIOOIDO00....IOOOOOOOO... 2’ II'IRODUCTIOU WON Alkyl cyenidee ere kncvn to rcect 11th we nclee ct hydreccic ecid, in the preeence of We ecid, to give l-elkyl-S-eninctetre- eclee (1). It ie apparent thet the .3331 m bee lhfltcd rm cerbon to nitrcgen in the couree ct thie reecticn. imbeci- heebeeneuggeeiedbynerbet,lcbene, endfienill (2) releting thie reel-rennet“ to the ecccelled "1-2 ehifie ,' net of which elec proceed in the preeence of eulIuric acid. In the cue cf the Echean, Bechenn, Canine, Lceeen, end Schidt MW optical: eetive netting neteriele heve been chum to for- cpticelly ective pmdncte. It ne the pupcee ct mic work to etndy the tarmac-eat e: Opuoflly ectivc lam-nu in the pmencc ct hydreeoic ecid end We ecid . The fomflon of en optically ective 1-dkyl-5-ninctetruole undo:- theee condition! wuld be predicted on the belie of the muni- propoeed for thie muon. ”dinner: “11th Iere nede Inning benlyl cyanide to determine the effect of mildew in reection manure end order of eddition ct reegente on the yield of l-benlyl-S-uinctetrucle . The uitrile choeen tor the min pert of we etudy no eL-etlwlceprcnitrile, eince the comeponding inletive tetrucle bed elreedy been prepared by thie mm (2), end procedure. for the recolution or cL-euwlcepreic ecid end propereticn of the active nitrile were known (3 ,h,5) . DISZUSSION DISUBSIC'N The reaction of S-eninotetruole end cone of ite eubetitution products has been cheerved in.e nunbcr of reactions. Thicle (6) see the firet to deecribe coupounde of thin type when.he noted the forncticn of the parent compound, Sauninctctrenolc, Ihcn.lninogunnidine‘vee treeted.eith nitrous acid. .A nether unstable gunnyleeide nee formed an en intenncdiete in thie reaction. ”in. -> ”1:“ 7 W 3? ‘l Although thie reeetien hee not been applied to the prepereticn.cf ether S-Ilinotetreeolee in Ihioh the uino m is mounted, it hee been need with cone encceee in.the preperetion of e.nniher er enh- etiteted deviating. Fec- inetenoo, Bunch end liner (7) he” deecribed the preparetion or l-u'yl-S-eryl—inotetreeolee m: 1-! ' «nu-11.x ' '«Inincguenidinee on internationaeith nitrous cold. Gama max-great.) ca.-m-g;;-0.n. Similarly the interaction.of’l-nitro-l'neninoguenidine end nitroue acid hee'heen.rcported to lend to the nor-etiontof Sinitroeninctetrep sole (8). loan-94m -——> loan-gum -—--> roam-g ——- I In thie mercury, Wl-I'minognenidiee hee been oheerved to give l-Iethyl-S-uinotetreeole on mam tith nitrcne eeid (9) . 03% own-24m 93,-; 1-13. e e ¢ , l The {auction at S-uinctetreecle by eddition ct bydruoic eeid to cyenenide tne dcecribed by lenteech end 7m. (10). The epplioetion o: e eieiler emotion to eonoelkylcyenenidee end to dielhlcyen-idee ha been obeerved to leed to l-elkyl-S-eninotatmolee end S—fldkyluim. tetreeclee , rcepectively (9) . f 8.1m .22.; {Ia-gm --? 8.11 - 33 a . ‘1" A procedure of Mt different ehereoter hee been deeeribed by Stone (11,12) . It invelved mum. of l-enbetitnted thioeree derivetivee eith eodinn eeide in the meence c! leed oxide or leed cerbenete in e m «enc- etnoephere. Under theee condition phenyl- thicm-ee wee cheer-red to give léphewl-S-uinotetreeole end It ,l'odiphenyl- thionree gen l-phenyl-Sophenyl—inotetreeole . The eeqeence or reeetiene bee been repreeented ee involving the initiel commicn of the thienree into e mutated cerhodiinide tollmd by addition of We“ eeid to the eerbm-nltro gen uneeturetion . smug—=7 cyan-ma. ——>c.n.m-%;ec.a.——> 0mg - l$2.3. s' ,, cannula. ——-‘I nun-an ”*7 canning, -—~—7 03.1. £43. ‘I’ lore recently, won Ireun end Keller (1) here etudied the reaction betleen elkyl end eryleyeudee end hydreeoic ecid in the preeence of enlmric acid. It m the hope of these investigate“ to prepero S-elkyl end 5-eryltetreeolee in thie my. Hydrceoie eeid hed been cbeenved to odd to the eerbcn nitrogen metnretion or hydrocyenio eoid (13) , cream (11:) , cyenoaen bromide end ethyl cyeneforeete (15) eith the retention, reepeotively, of tetreeole, Schructetreecle end etlvl tom- eclc—S-cerhozylete. In the preeence of enlhu-ic ecid, however, the reaction followed Quite e different oouree with the reenlt thet l-elkyl end lcuyl-S-eninotetreeolee me toned tron the elkyl end eryl cyeeidee . non an. > n m (3.32.) 1;}. ' at the eeverel “than for the eyntheeie of 5~eninctetreeole derintim 1t ‘11). be obeemd thet the von Bram end Keller method ie the only one thet involvee e remengenent end e chengo or the poezltiea o: ettechent or e eubetitnent group. Thie reection hee been need by Herbet , Roberte end Rex-v11]. to prepero end etndy e eeriee of l-elkyl- Seeminotetreeolee (2). Thcee «mm have tuggeetcd thet the nimticn of the eubetitnent poop involvce e typicel 1,2 ehitt einilr to thet poetuleted tor other canon remengeeente involving edJecent cerhon end nitrogen eta-e each ee the Boolaenn, Curtine, lohmn, Louen end Bcheidt reectione. On thie belie they heve poetuleted tetreecle foru- neticn ecccrdin‘ to the rollovinx necheni-e m .217 act «a 22.7, [mg]’n_7 {Wyn}? + 3:17‘1'8‘“' I” 11’ 4'13 s‘ I It the ebove picture ie the correct one, it ehould be poeeible to obtein en opticelly eetive tetreeole by eterting eith en opticelly active nitrile . In the etndy of the necheni-e of each reerrengeeente the nee or optioelly ective conponnde bee been pertioulerly ”mending. It ie eeeentiel thet the country of the nigreting gmup ehould involve the point of ettechnent. Under thin condition it bee been eeeuned thet complete detechnent of the ligating group during the couree of remnge- nent would leed to menintion of the group, end function of en optioelly ective product he been eeeuned to indioete thet the lighting group he: never been coupletely deteched from the eclecule. In e11 eeeee thet heve been ceretnlly etudied, aptioel ectivity bee elveye been obeerved in the product... ‘ Jonee end Vellie (16) ehoeed thet the Curtiue remengenent or (e)-beneylnethyleoeteeide geve (+)-phew'lilopropyl-ieooynnete . with unonie the ieoeyenete nee converted into the correeponding (+)~l~pheny1- ieopropyl nree. o a. J: —7 Gm.{ «4-0-0 9 H. tne wen-£5383“. $3. I, when“; «4:: Biniler etudiee on the One-tine management were done with the eeidee or (+)-bydretr0plc ecid (17) end or both (+)- end (dd-mm- tacthyl-diphewl-E'ooerbexylio ecid (18). Opticel ectivity in the toner instence ie due to the preeence of en eeyneetric cerbon etc- while in the letter eeee reetricted rotetion ebout e oerben-cerbon bond gives rise to noloouler eeynnetry. There use no evidence of mmieetion in my cue. Kellie end Drippe (19) prepared (+)~N-phenylieopropyl uree through the Loecen reerrengenent or (+)-benzy1methyleoethydromio ecidt H o 3 0.3.03. 36' new ——? chasm-E inc-o '3' 7 $3. [,0 cm—g all: ~33. II‘he eubetituted one tree the lawn remengenent of (+)—beneylnethyl- eocttvdromio loid (19) one identical with the product obteined efter the 0mm- reu-nngeeont of (+)-beneylnethyleceteeide (16). Solutione or equal concentretion of both products geve the one rotetion velnee within the linite of experimental error. the Loeeen rearrangement hee eleo been etudied tiling (+)-phcnyl- eettnrlecethydromic eeid (20) . The product reteined ite opticel ectivity in thie ceee too. A number of etudiee on the Hotnenn reerrengceent heve been node uploying (+)-beneylnetlwleeetenide (21), (+)-hydretmp.ide (22), end the eeide or (0-2 ,s-dmLtz-o-e-(oc ~nephthyl)-benzoio eoid (23) . m- leet emple ie en eepecielly interesting ceee, eince the optioel ectivity in due to metriction of rotetion ebout the bond between the phenyl end nephthelene groupe. If the poop involved were ever completely free during the ehirt tron cerbon to nitnogen, et leeet pertiel rennin- tion ehonld take plece. Since the product hed e very lerge epecific rotation Which ,did not change upon recrystallization, it nee concluded thet no reoenization had occurred, end that the nigreting group had never been Completely free. R0,, 0,: 10-0 The Beckeenn amusement of eeverel . opticelly ective ounce bee been etudied by Kenyon end hie coolorkere (17,20) . Both (Ht-newl- 3r ~hepty1ketoxlne (17) end Moat -pbenylethyl lam]. baton-- (20) euro wronged to the oorreeponding minee with over 99% retention of optioel eotivity. Ueing the letter ee en emplet can-£2; eon CH.-§-HR<§H-’C.H. ca. Since the fornetion of 5~uinotetreeole derivetivee tron nitrilee hee been eeeuned to involve e typicel 1,2 ehirt einiler to thet obeerved in the routine duet diecneeed, e etndy or tetreeole duration from en opticelly ective nitrile nee nnderteken to eeteblieh thie reletionehip note tinny. The emple ehoeen tee the oonvereion of Optically active doettnrloepronitrile to 1-(3'.beptyl)-s-enimtetrate1a. The ineotive tern of the product nee known, lime it bed been prepered by Hex-bet, Roberte, and Hervill (2) . Further-ore, ac-otbvidaprbio ecid was con-- miell: eveileble , ite reeolution into the Optioelly eotive tonne bed been deecribed (3,5), end the transformation or theee letter to the opticelly eo'tive bin-nu had been reported 0:) . The resolution of oL-otlwlcapro ic acid no eccomplished by re- peated crystallization of its quinine salt from 50% eoetone. The yield of (-)-a£-athy1oaproio acid obtained in thie w ne lover then expected from the report or Kenyon end Flatt (S) . Since the quinine salt is readily eoluble in ecotone, this low yield is probably due to the nee or one“ eolvent in the leter recrystallization. Sane mummy u- enaerienoed in obteidng elm! develop-em. of crystal. It the m «touted eolution he elloued to cool undietnrbed, the quinine “1t upmtod u on oily lnyer, much eolidified to e herd cake on out-ring or nodlna. On the other hand, seeding of the eolntion while it we: still very urn no not rmible, since the edded motel :1me die- eolved. The uteriel need for eeeding wee prepared in a preliminary andl-ecnle run end recmtellized nix tine! . Kenyon and Flatt (5) had reported the nolting point or the quinin- colt or (-)-oc-othy1caproic acid an (Sh-65°C. we have observed thet the melting point was subject to considerable vuietion depending on the extent to which the eelt lee dried. in lit-dried couple that melted et 61-71%. m round to melt at 107-108°C. artar drying in a mum dolicoetor. The eelt uppeu‘ed to be hygroeoopic since the nelting point or the noun-dried notoriel no lowered otter expoeure to the euoephed-e for e day. It no found necessary to dry the recrystallised eelt completely before regenerotin; the ecid, eince e sticky we was famed when acetone to: present et the tile or addition of eodiun hydroxide eolntion . The (-)-o£.cthy1caproic acid as converted to ite chloride by troetnent with thionyl chloride . The crude chloride to distilled only once end used Mediately to prepare the aide. The crude mice in turn wee dehydrated to the nitrilo by name of thionyl chloride Without ico- letion or pnrificetion . The echoes outlined ebove follow the procedure of Lorene end lune (h) end leede to e eetiefectory yield of the (~)-nitrile. In prelininery rune, en attenuated verietion in the preparation of the ecid chloride resulted in pertielly or completely reed-iced nitrile. The revieed procedure involved refluxing of the reaction mixture with heet supplied by e microfburner, thee-eel the originel, end eucceeeml, pro- ceduro ellowed the mutants to Itend together overnight before hating. under reflux on e etembeth for one hour. 0 c.a,-§'H:com go‘arg'flimi “*7 cargfilzom. 39.1.1? rial- c.n «cu Herbet, Roberta end flervill (2) properod l-elkyloS-uinotetreeolee by adding We laid to e benzene mint-ion of the nitrile end hydro- eoic eeid. Since the principel lay-product of the reection m the aide correeponding to the nitrile, it eeemed poeeible thet enide-tornetion light be minimised by changing the order of eddition of the mgonte. Prelilinery experiments with bencyl cyenide thawed thet the order-ct eddition of the reegente did not nerkedly effect the yield of l-elkyl-S- nimtetruole. However, in prectice, it no found convenient for the 10 fine]. nell-eoele reeotion tith ag-ethyloepronitrile to odd the nitrilc to e mixture of hydreeeie eoid dieeolved in bemeno end nlfnrio ecid. Althom the yielde of tetreeole derivetim ere lee due to the tor-etion of the eoneepcndins enidee, in thie eeee ditticnltiee in eeperetion end pm-iticetion or the product lowered the yield etill acre. The or genie neteriele an be eepereted tron inorganic eelte eetietectorily by extreetion with impropyl eloohol. louver, eveporetion or the ertreot leevee e dork red, new neee ehioh doee not eryetelliee tree either eeetic aid or ieopropyl eloohol . the a: n-heptene ee e oryetellieing eolvent , ee euggeeted by Herbet, Roberto end fiervill, did not give e good ”pere- tion iron the aide, eince the letter dieeolved eere reedily in hot eelvent then the deeired product . Hanover , cold n-heptene proved meeeeo t‘cl in owning the retention of oryetelline uteriel fro. the originel eon-like reeidue. the elerry or eryetele eo tee-nod nee then deeented end filtered . Repetition of thie proceee reduced the residue to e very eeell eeount of highly colored uteriel. The crude oryetelline product reeryetellieed reedily tree eeetie eoid, but here egein, no eetiefectory enbetitnte wee found for neohenioel eeperetion o: the colored impurity tree the urine e: the eooling eixture. Ihie purifioetion procedure leede to eeohenieel loee, but etteepte to inprove or einplity it hove co he been mencoeeetul . the leeorotetory cLoethyleeproic eoid geve e levorotetory nitrile , each furniehed e dextrorotetory tetreeole derivetive, nth e nelting point eignificently higher then thet of the inective product. “thin tetreeole derivetive hee not previouely been propered in optically ective lll‘l'llll'llll' torn, end no method for roeolntion of the ineotive compound in «oil-- eble. Consequently, it 1e not poeeible et preeent to ehcv conclusively thet no recnnieetion took pleoe during this reerrengenent. Hoe-var, the optioel ectivity of the product obteined eupporte the necheniae nuggeeted by Eel-bet, Roberto end fiervill. Thmughout the etudiee on the related rec-rengenente eentioned above, the nuggeetion hee repeetodly been eede thet configuretion, ee well u eeynetry, ie reteined in the nigreting redicel. The evidence in fever or this view ie reviewed by lemon end teen; (17) end :1» by Leno end Kellie (2h,25) . The ooncleeion ie drevn thet configuretion ie retuned in ell intrmohcnler reerrengenente . To this evidence night he edded the my given by cupbon end Kenyon (20), in which they ehoe thet (+)-hydretropio ecid hoe been converted, by new or editable internedietee, to the one (dab-phenol ethylenine through the Curtiue, nor-em, Loeeen end Beck-en reerrengenente, with better then 99$ retention of eeylnetry in en eeeee except the Hohenn, more the drop to 953$ retention of opticel activity in expleined by enolieetion. The noet conclusive evideme ie reported by Leno end Hollie (2h) , mo cerried out e bolt! reerrengenent or en opticelly ective dieeoketone, end degreded the product to the cane ecid need to propere the eterting dieeoketone. In thin cycle the only etep involving the eeyuetrio center one the reerrengenent iteeli’. Since no inversion wee obeerved in the cycle, the reerrenaenent proceeded lithout invereion. On the halo of thie evidence, it «one Quite probable thet both eeynnetry end contiguretion ere eleo reteined in the toreetion or 12 opticelly ective l—elkyl-S-eminotetrezolee , though rigid proof is inpoeeible in the ebeence of en independent synthesis of the optioelly ective product . 13 Emma." Reagents sediu Aside m ebtained tro- E. I. Dupont delta-ours and Gamay, Explosives Division. Hydrasoie acid solutions in bensane m prepared by treating a vigorously stirred sludge of equal weights of sedim aside and eater under banana with concentrated sulfuric acid, added slam, while the t-pmtnra vu kept bales 25°C. The bansana solution In separated tre- tha aqueous sludge and dried over sodim snltata . The concentration or the hydraaeie acid depended on the value of banssns upland aui us detox-lined by titration at an aliquot of the banana solution with a standard aqueous sodiu- hydrexida solution using phenolphthslain as indicator. Banal cyanide as obtained tron Eastman Kodak Calpany. eta-Ethyloapreie acid as obtained tro- ths Distillation Products Industries, Division of East-an Kodak Celpaw. l-Banabe-uinetatrasole OMB-'3 ‘— g‘ma \‘/ I 1 All melting points are uncorrected, unless otherIiaa stated. flatbed i . Bmylcyenide (29 g.) and 250 .1. of a 13.11 solution a: hwdrasoic acid in benaene ears placed in a one-liter three-necked flask snipped Vith thermneter, nechenical. stirrer, and dropping funnel. The ther- neaeter res held in a glass tube vith a side-era open to the at-oephere, and the dropping fennel us extended by runs of a thick-called capillary tube inch dipped below the surface or the Ivdraaoic acid solution. Concentrated sulfuric acid (15 :1.) was added slowly with stirring, and reaction temperature was controlled vhen necessary with a cold Inter bath. Stirring as continued about eight hours after addition of the sulfuric acid was couplets. The acid layer see separated and diluted by pouring over ice. The reaction flask and tumel were rinsed with a nall snount of sulfuric acid, which was added to the diluted mixture. This solution us neutraliaed to litlus with 501 potassius Ivdrexide, cooled, and filtered. “the filter cake, ehicb consisted of the predict lined eith such potassiue sulfate, res enracted vith hot iecpropyl alcohol. Il‘he alcohol extract was evaporated to a snaller volue , cooled, and the crude product filtered off. The filtrate us than evaporated further to give a second crop. Apparently the corresponding uide is none soluble in isoprOpyl alcohol than the tetrssole, since the first crop consistently shows a higher nelting point than later ones . A typi- cal preparation gave the tolloning and. yield! 12.3 g., I.p. 187-19o°c. and 2.0 3., -.p. 163-183°c. The crude product was recrystallised tro- iscpropyl alcohol. In sue runs, the bet alcohol solutions rare decolorised aith charcoal 15 before filtering. Iielda by this nethod were 21-27: of theory. Tee runs were aade at SID-35°C., one at 20-25°C., but no significant effect an the yield was noticed. melting points after one recrystallisation of the first crop varied froa 187-189°C. to 189-19336. (Herbst, mm, and Harvill (2) give 186.5-187.5°C .) However, percentage yields include an oncedrscrystallissd products melting at 150%. and above. thcd 3 Apparatus and quantities used were the ace as in the above nethcd. the solution of hydreacio acid in benaene was placed in the flask and stirred rapidly while first the sulfuric acid, than the hensyl cyanide were added, with the telperature controlled at 20-25% . Il'otsl addition required 15 ainutes and temperature control was such easier than in lethod A. Stirring was continued nine hours longer, with taperature controlled below 25°C. Iron this point on, the reaction airture was treated as described above. The crude yield us obtained in two crops. 7.5 g. nelting' at 170-186°C ., and is.) z. nelting it. 167-170°c . Accidental loss of one of the fractions prevented comparison of yields on the purified asterisl , but the crude yield is clearly no better than in lethod i, and nay be somewhat lower. Resolution of aL-etm'lcaproic acid (3,5) A finaliter flask equipped with a reflux condenser was charged with 160 g. of quinine, 173 ;. cfaLv-ethylcaproic acid, 900 ll. of acetone and 900 ll. of uter. The mixture was heated on the eteanbath until the l6 quinine dissolved, the solution was clarified with a .all additional nount of acetone, and allond to cool. While the solution was still slightly were, it was seeded with the quinine salt of the (-) acid, obtained froa a preliainary small-scale min, and allowed to stand over- night. The salt which crystallised was filtered and recrystallised six tines from 505 acetone, with a decrease in the snout of solvent each tine. The yield (50.? e) was lower than expected, probably due to assess solvent in the later recrystallisations. the quinine salt has a strong tendency to separate as an oil. If the nixture is swirled er scratched after it has cooled and separated into two lqers, the oily layer nay for- a hard solid cake, difficult to remove fro- the flask. The aelting point of this salt depends largely on the degree of drying. Bone naterial, recrystallised six tines and dried in a mural desiccator Ialtad 107-108’0 ., nhile material allowed to dry in air nelted 67-71%. If the crystals are dried in a mode desicatcr and than M . ”3 7. . . ~ .' .1: ~I". 5 ,‘ ,U “gal-t {- axposed to the air, the selting point again drops. i‘hedryeuininssalt Uta.) usetirndinanopenbeamwitha solution of 20 g. of solid sodiu- hydreidde in 500 ll. of water. After standing a while, the sisters was filtered by auction and the filter cake again treated with a solution of sodium hydroxide as before. after the second filtration, the filter cane should consist of reecvered minim. The combined filtrates were acidified to Congo Red and extracted with ether. The ether extracts were dried over ankydrous sodiun sulfate, 17 the other renewed at reduced pressure, and the acid distilled, 11.13. 108- llh°c. at an n. Heating was done through an oil bath saintained loo-165°C. The yield was 113.8 g.) [051007.913 at roon twerature. Inactive cL-ethcaproyl chloride A Monte!- flask equipped with dropping funnel and reflux condenser use charged with 210 g. (1&8 n1.) of thionyl chloride. the tunnyl chloride was heated to reflux temperature; the flue was moved, and 216 a. of inactive eL-etlvlcaproic acid was added slowly over a period of 20 ainutes. The Iixture us refluxed with a free flame for two hours, then distilled at Wed pressure. The Iain distillate was colorless, b.p. 77.78%. at 28 an. on. yield was 188.7 s. (77.6: of theory). Inactive (oathylcaprenitrile The inactive cL-ethylcaproyl chloride (188.7 e.) no added dropwise with atirrin; over a period of four hours to 600 al. of alcohol saturated with meals, dththatenperature kept bole-5°C. hyseans cfan ice- alcohcl bath. The precipitate cf moniua chloride us filtered off, and the alcohol recoved fru the filtrate under rechlced pressure with slight warning on a steel hath. The unoniun chloride filter cake ens washed with benaene, and the mailings added to the residue left after evaporation of the alcohol. the benzene was then renewed under reduced pressure. The crude amide thus obtained was dissolved in 260 ll. of thiolvl chloride and reflund one hour on the stembath. Thiorwl chloride 18 eas removed at reduced pressure and the residue was dissolved in ether, waehed with three lOO-Il. portions oi’ eater, and dried over anhydroue sodiua sulfate. After filtration, the ether was renoved at reduced preseure and the midee distilled. The run fraction boiled loo-102°C. at 27 no. The yield was 106.9 a. (73.7% of theory heeed on acid chloride). (~)~ oL-Ettwlceproyl chloride (1;) (-)-oL~lttvloaproio acid (tht e.) was added with swirling to 135 :1. of thiowl chloride and allowed to etand oral-night, then rennnd two been on the steenbath. Erness thioxvl chloride wee reamed at rec duced preeenre end the acid chloride distilled, b.p. 11—78%. at 25 en. (Oil hath tenpereture 1.174%.) the yield an 113.9 3. (91.“ of sheen). (-)-oL-Ettylcapronitrile (h) (-)~oL-Ethy1caproyl chloride (11:3 a.) wee eddcd slowly, over 20 aimtee, to 50 al. of 95X ethyl alcohol saturated with mania, wile aixture wee aaintained below 10° . in en ice-salt hath. monie- chloride waefiltoredcff,andthealcoholfiltrate eeeporatedtodryneeeunder reduced preesure. II'he mania chloride was washed with hsnaene and the solution added to the solid residue fro- the alcohol filtrate. ‘fhe result- ing mixture was again evaporated to dryness. The crude aide thus obtained was reflond one hour on the atembeth with 25 ml. of thionyl chloride. After filtration, mace thionyl chloride wee removed at reduced preasure. The residue was diesolved in 25 ml. of ether, washed with three lo I1. 19 portione of water, and dried over anhydrouslsodiu sulfate. The ether ens rencved at reduced pressure and the nitrile distilled, b.p. 77-78%. at 18 in. the yield was 5.8 a. (50.111 of theory iron ecid chloride); [pun-9.85" at too. beeper-com. (0-1 (3'-hcptyl)~S-aniaotetrasole In a preliminary preparation of the tetraeole , a 36 3. sample of partially resolved acid, ($14.9, en converted to the acid chloride by the nethod wood with the inactive acid. the yield was 37 g. (91.14:! of theory) 3 hp. los-lO9°c. at 75 en. the acid chloride was converted, by the above procedure to the corresponding nitrile, b.p. “(h—78°C. at 16 en. the yield vee 21.5 3., [oL]D+O.2°. the pin-ile was converted to l-(3'-heptyl)-Soaninotetraaole by the neihcd dcecribed below for prepara- tion of the dextrorotatory compound. The yield us 3.7 x. , I.p. 1147- lh6°c. i one-gen sample in ethanol exhibited no optical activity. the aelting point of this aaterial was the sue as that of the inactive tetraaole derivative . the nelting point reported for the inactive tetra- sole derivative is 1116-1146500. (2) . A line: solution of hydreecie acid in heneene (M :1.) was placed in a 300 ll. two-necked flask equipped with a dropping funnel and ther- neaeter , arranged as described for the preparation of l-beneyl-S-snino- tetrasole. The flask was swirled in an ice bath during the gradual addition of 13,5 al. of concentrated sulfuric acid, followed by 5.11 g. of (-)-oL-othylcapronitrile (lea)n -9.85) . the dropping funnel wee then 20 replaced by a neohanical stirrer, and the reaction was stirred overnight. the tapereturs ass minteinod et 20.30% . with a cutter bath. The acid layer as separated, diluted with ice, and neutralized to litmus with 50‘ potassium hydroxide. After cooling, the resulting nix- tars was filtered and the filter cake extracted with a total of 100 ml. of hot isoprcpyl alcohol. "this extract use evaporated to dryness at reduced pressure. . The solid residue was rinsed out of the flask lith a uall haunt or n—heptsne and the: slurry of crystals _ toned was decanted tre- thslcser layerotyellovoil. ball-ountsofheptane vereadded to theeilanddecantednntilnoaore erystdssereobtainahle. Thecrude product (3.2 g.) eee altered, dissolved in 1h :1. or 505 eeetic eoid, filtered, and treated sith 1 ll. of water. The solution was heated on the ate—bath until clear and allcssd to cool slowly. is the solution cooled a red , aw Iaterial separated and collected on the surface. mar this material was resoved mechanically, the desired product separated iron the renaming solution as colorless crystals . 0n repeated treatment or thered, materiel tithe-inure or tel. oteeter endzel. or glacial acetic acid, further separation of the product from the colored impunity was accomplished. The several fractions of colorless product were eonbined, eeehed Iith enter and air-dried, e.p. 153-156°c., yield 1.6 8. This product was recrystallised a second tine fro- the sane solvent mixture, filtered on a eintored glass towel, and dried ho einutee et 100%., e. p. lso-ls7°c. the yield en 0.8 g. [cl-1048.05 (in ethyl alcohol). 21 Ami} Calculated for c.8141... c, 52mg; 3, 9.33%; x, 38.21% coon. c, 52M, 52.35; a, 9.1;3, 9.20; a, 37.93, 37.98 Optical rotation ill readings were taken at room tenperature using a om-decineter tube and the sodiu- D-line. Reading on the acid and the nitrile wars lads on the halogenoous liquid. The tetrasole sulpls Ias dissolved without heating in 955 ethyl alcohol to make 10 ll. of solution . Substance m fill) (-)-oL-etrqleeproio acid -7 .17 -7 .9h (4- drsthylcapronitrile -7 .915 .9 .85 (e)-l(3'-heptyl)-S-aninotetraa ole e0 .68 +9 .05 (0.1511 x.) 1 Analysis was done by Micro-Tech Laboratories, Skokie, Illinois. sum! 22 SWEAR? 1. An Optically active l-ellql-Sominotetrazole has been prepared by the reaction of an Optically active nitrile with hydrazoic acid in the pmence of sulfuric acid. 2 . This observation supports the idea that the tournament involved is intranolocular and proceeds by a nechanien similar to that currently eccepted for the Hormann, Loseen, Curtius and Bookworm rearrangements . REFEREECES 23 HEFIEENCES 1. Von Bram and Keller, Ben, 35, 1677 (1932). 2. Herbst, Roberts, and mu, J. Org. Che-1., .13, 139 (1951). 3. Levene, Rothen and Meyer, J. Biol. Chem, E5, 1411 (1936). h. Levene, Ind tuna, J. Biol. Chem., _lh_g, 263 (19181). 5. Kenyon and Flatt, J. Chen. 500., 2.222, 633. 6. mm, 41111., 312, 5h (1892). 7. can): end Bauer, 2.9., a, 1069 (1900). 8. Leibe, Shensn, Henry and Oohen, J. Al. Chen. 300., 1;, 2327 (1951). 9. Mbreoht, The Reaction of Hydrazoic Acid with abstituted C . ides: The S thesis and ' ”Rina " one rive van 0 1.91... asoe. '1..' es e,"c. - e o ego, " ,p. ,,55. 10. nanteechand Vagt, Ann... 25,, 339 (1901). i1. suns, J. putt. on... 1.23, 282 (1932). 12. stolfl, Ber" 25, 1289 (1922). 13. Dimth and hater, 2a., 52, 2219 (1910). 11.. 011mm; and Pun-looms, Glee. chin. no“, 51, n, no (1911); Lg. 11. 1.65 (1913). 15. cum-14mm, am. cm. mm, 3;, I, 59 (1911). 16. Jones and Hallie, J. 1-. cm. 306., 1.3}, 169 (1926). 1?. lemon and 101111;, J. Chen. 500., 392.19,, 363. 18.134111, 4. Chen. 300., ELM, 835. 19. 11-111- and Dripps, J. n. chem. 800., 25, 1701 (1933). 20. Gumbel]. and Kenyon, J. Chem. Soc... £113, 25. 21. 21. van- and 82361, J. 1-. Chem. Soc., 22: 2787 (1931). 22. irons and Kenyon, J. Chen. 800., $222, 916. 23. 2.111. and Ham, J. 1-. Chem. 800., 25. 2598 (1933). 21.. Leno end Hallie, J. 1-. Chem. 506., 63, 167k (19111). 25. Wellis and Lane, “The Harmon Reaction,“ 93391:: Reacticng, vol. III, p. 268-273. This; STEMHEXISTR! OF THE P01222110! W Wormwoms FRO! 1113338 By fiancee Pollen All ABSTRACT snbdtted to the School of mu studiee e: lichim State College of Agriculture ma Applied Science in pert-ill fulfill-ant cf the Wants for the degree of M23 0? $15305} nap-rum or Cheeistry Iear 1953 . Approved drwflfm}{ A105 if“ T‘IE STJREJCK ‘ _..."I$1"iY 03‘ "3’3 ng‘LE HT 02?. U? M'Zli-éUTISTRAZUb’fiS FFi‘Jfll EC 1‘1‘1’2114‘33 The l-alkyl-fieaninotetrazolee may be foamed from a number of different etarting‘aateriale. Of the reactions employed. only one iamolvee a rearrangement and a change ih the poaiticn of attachment of a sat- etituent group. This ie the reaction.betveen alkyl and eryl cyanide. and hylrazoic acid in the preeence of eulfurie acid. 2 HR, RC2; ) R‘i-‘i" 91-2212 19 (“2902.) H \\ ’ i mechanic: for thie reaction has been suggested by Herhet. Roberts and Hervill, ae rollovea 2m ”:6“? g on] Eli—‘7 [it-uh “EJ L227 .,. __ + * + [2:5me 221., > a}. ’21 «a ‘7 3-2:”: 9-2.1: u Wan-1mg ‘ u’ , The migration.ot the substituent group involves a typical 1.2 shift eiuiler to that poetulated for other common rearrangemente in! volein‘ adjacent carbon and nitrogen atone ouch ae the 3 eokmcnn, Curtiue, Hotmann, Loeeen and Schmidt reactione. If the above picture ie the correct one, it ehould be poeeible to obtain an OfitiCllly.fiOt1VO tetrazole by etnrting with an optically active nitrileo The example chosen woe the conversion or oytically active o(-ethylcapronitrile to l-{S'-heyty1)- 5-eninotetrazole. The resolution ofciéethylceproic acid woe accomplished by repeated cryetallizetion or its quinine colt from 5b % acetone. The (-)-oieethyl- caproic acid thue obtained wee converted to ite chloride by treatment with thionyl chloride. The crude chloride wee distilled only once and need iaaedi- etely to prepare the amide. The crude amide in turn nae dehydrated to the nitrile by meene of thionyl chloride without isolation or vurifioetioe. The levorotntory nitrile, on treatment with culturic acid and a eolutioe of hydrezoic ecid in benzene, yielded dextrorotctory l(5’-heptyl)-5-eaino~ tetrezole. Thie tetrazole derivative hoe not proviouely been gregcrod in optically active form. and no method for reeolutioe of the inactive campound ie available. Consequently. it ie not possible at preeent to chow conclueively that no racenization took place during thie rearrange- ment. However. the Optical activity of the oroduct obtained eupporte the mechanism suggeeted by Rel-bet, Fioborte and Hamill. Coneidcrable evidence hge been preeonted to show that the related arrangemente mentioned ebove ;roceed with retention or configuration so well ae eeymcetry. 0n the baeie of this evidence, it $803. quite probable that both aeymnetry and configuration are also retained in the formation of oyticelly active l-alkyl-fi-ecinotctvecoloo. though rigid proof ie impoeeible in the abeence of an independent eyntheeie of the optically active product.