T HE DISC OVERY OF CR O W N ET HERS

Nobel lect ure, Dece mber 8, 1987 b y C H ARLES J. PE DERSE N

E. I. d u Pont de Ne mo urs an d Co m pany, Wil mington, Dela ware 19898

La dies an d Gentle men, Dear Colleag ues, T his is a w o n d erf ul d a y i n m y lif e, a n d I a m l o o ki n g f or w ar d t o s h ari n g m y t ho ug hts wit h yo u. Before I be gi n, I wo ul d li ke to co n ve y t he war m greeti n gs of t he peo ple of S al e m C o u nt y, N e w J ers e y - w h er e I h a v e li v e d f or m a n y y e ars - t o t h e p e o pl e of S we den. Sale m Co unty is where a very early S we dish settle ment was est a blis h e d i n 1 6 4 3. N e xt y e ar w e will j oi n wit h t h e p e o pl e of o ur n ei g h b ori n g state of Dela ware to celebrate t he 350t h a n ni versary of t he first la n di ng of S we des in the Ne w Worl d at The Rocks in Wil mington, Dela ware. We look for war d to t he visit of His Majesty Ki ng Carl X VI G ustaf a n d Her Majesty Q uee n Sil via a n d ot hers fro m S we de n to o ur celebratio n next A pril. N o w I w o ul d li k e t o dis c uss t h e dis c o v er y of t h e cr o w n et h ers. I will di vi d e m y l e ct ur e i nt o t hr e e p arts. First, beca use e ver y disc o ver y ta kes place i n m ore t ha n a scie ntific c o ntext, I wo ul d like to to uc h o n my life a n d backgro u n d. I n t he weeks si nce it was a n no u nce d t hat I wo ul d s hare t his year’s prize i n c he mistry, peo ple ha ve e x pr ess e d as m u c h i nt er est i n m y e arl y lif e as t h e y h a v e i n m y l at er w or k. S o I t hi n k it a p pr o pri at e t o e x pr ess m ys elf o n t h e m att er. It m a y als o b e t h at d et ails of m y past ha ve more t ha n cas ual beari n g o n m y wor k. Seco n d, I wo ul d like to describe for yo u my researc h progra m a n d so me of t h e s p e cifi c e v e nts t h at l e d t o t h e dis c o v er y of t h e first cr o w n et h er. Si n c e I a m t he o nly o ne w ho k no ws at first ha n d t he excite me nt a n d pleas ure of t he disco ver y, I will de vote a portio n of m y ti me to s hari n g t his ex perie nce wit h y o u. A n d t hir d, I wo ul d li ke to disc uss t he pro perties a n d pre paratio n of cro w n et h ers. I n d oi n g s o, I h o p e I will c o n v e y t o y o u t h at I w as al w a ys a “ h a n ds- o n ” c h e mist; I t o o k s atisf a cti o n fr o m w h at I di d i n t h e l a b or at or y. Als o, I w as v er y m uc h a n i n d ustrial c he mist a n d was al wa ys i ntereste d i n t he pote ntial a p plica- tio n of my work. I n fact, w he n I s ub mitte d my first major pa per o n t he dis c o v er y of t h e cr o w n et h ers, t h e e dit or of t h e Journal of the A merica n Che mical S o ciet y, Mars hall Gates, re marke d t hat my descri ptio ns were re plete wit h i n d ustrial jargo n. Fort u nately he p ublis he d t he pa per a ny way. 4 9 6 Che mistry 1987

Perso nal backgro u nd Let me start t he n wit h ho w I bega n life a n d we nt o n to disco ver t he cro w n et hers. My fat her, Bre de Pe derse n, was bor n i n Nor way i n 1865 a n d trai ne d as a mari ne e n gi neer. D ue to si bli n g dis har mo n y, he left ho me for goo d as a yo u n g ma n a n d s hi p pe d o ut as a n e n gi neer o n a stea m frei g hter t o t he Far East. He e v e nt u all y arri v e d i n K or e a a n d j oi n e d t h e fl e et of t h e K or e a n c ust o ms, w hi c h was a d mi nistere d b y t he Britis h. He r ose i n ra n k a n d later j oi ne d o ne of t he largest Ja pa nese stea ms hi p li nes a n d beca me a c hief e ngi neer. T he n a trage dy o c c urr e d t h at c h a n g e d t h e c o urs e of his lif e. A c hil d h o o d dis e as e t o o k t h e lif e of my el der brot her w hile my fat her was a way fro m ho me o n a lo ng jo ur ney. He aba n do ne d t he sea a n d beca me a mec ha nical e ngi neer at t he U nsa n Mi nes i n w hat is no w t he nort h wester n sectio n of prese nt- day Nort h Korea. My mot her, Taki no Yas ui, was bor n i n 1874 i n Ja pa n. S he ha d acco m pa nie d h er f a mil y t o K or e a w h e n t h e y d e ci d e d t o e nt er a l ar g e-s c al e tr a d e i n s o y b e a ns an d silk wor ms. They establishe d hea dq uarters not far fro m the Unsan Mines, w here s he met m y fat her. The Unsan Mines were an A merican gol d an d lu mber concession, 500 s q uare miles i n area. It ha d bee n gra nte d b y t he E m peror of Korea to a n A merica n merc ha nt na me d Ja mes R. Morse prior to 1870. I was co nceive d t here i n mi d- wi nter j ust before t he start of t he R usso-Ja pa nese war. Freq ue nt i nc ursio ns b y Cossac ks across t he Yal u Ri ver i nto t he re gio n of t he mi nes were consi dere d to en danger my mother, so she an d several A merican la dies were s e nt s o ut h b y c arri a g e t o t h e r ail h e a d f or s af et y. I w as t h us b or n o n O ct o b er 3, 1904, i n t he s o ut her n P ort of F usa n, t he lar gest i n K orea. M y arri val was do ubly welco me d beca use mot her was still grievi ng t he loss of her firstbor n. S h e d e v ot e d t h e n e xt 1 0 y e ars t o o v ers e ei n g m y e d u c ati o n a n d t h at of m y sist er, Astri d, fi v e y e ars m y s e ni or, i n f or ei g n l a n g u a g e s c h o ols. I s pe nt m y first a n d last wi nter at t he mi nes w he n I was 4 years ol d. T he regio n was k no w n for severe weat her d ue to t he co nfl ue nce of t he Siberia n ste p pes, Mongolian Gobi Desert an d the mo untains of Korea. Large Siberian ti g ers still r o a m e d t h e c o u ntr ysi d e a n d w er e fri g ht e n e d a w a y wit h b ells o n t h e p o n y h ar n ess es. W ol v es kill e d c hil dr e n d uri n g t h e c ol d wi nt er ni g hts, a n d f o x es sl e pt o n r o ofs a g ai nst t h e c hi m n e ys t o k e e p w ar m. Beca use the Unsan Mines were an A merican enclave - the to p manage ment being all A mericans - great e m phasis was place d o n maki ng life as A merica n as p ossi ble. T he c o u ntr y cl u b was t he ce nter of s ocial acti vities a n d life was co nsi derably more ge ntle t ha n at t he ty pical gol d mi ne of t he lege n dary A merica n West. So my co ntacts wit h A merica ns bega n early, a n d I s poke E n glis h w hi c h w a s t h e c o m m o n l a n g u a g e at t h e mi n e s. I d o n ot k n o w if s uc h a n e n vir o n me nt ha d a lifel o n g i nfl ue nce o n me, b ut I c a n s p e c ul at e t h at p er h a ps it di d. Fr e e d o m of t h e A m eri c a ns t o a d mi nist er t h eir affairs i n taki ng care of t he msel ves i n t he wil ds w here t hi ngs co ul d not be or dere d for o ver nig ht deli very no do ubt ta ug ht a certai n i n de pe n de nt a p proac h t o pr o bl e m s ol vi n g. As f or c h e mistr y, I r e c all t h at t h e g ol d w as r e c o v er e d b y t h e cyani de process, an d the monthly clean u p day was marke d by the pervasive C. J. Pe derse n 4 9 7 o dor of t he process. T he po uri ng of t he molte n gol d was al ways a bea utif ul sig ht, a n d t hat mig ht ha ve starte d my i nterest i n c he mistry. Also, my sister cl ai m e d t h at I l o v e d t o pl a y wit h a c oll e cti o n of c ol orf ul Si b eri a n mi n er als. F or ei g n la n g u a g e s c h o ols di d n ot e xist i n K or e a t h e n, a n d s o at t h e a g e of 8, I w as s e nt t o a c o n v e nt s c h o ol i n N a g as a ki. W h e n I w as 1 0 y e ars ol d, m y m ot h er took me to Yoko ha ma w here s he re mai ne d wit h me for a year as I bega n my st u dies at St. Jose p h College. St. Jose p h was a pre paratory sc hool r u n by a Ro ma n Cat holic religio us or der of priests a n d brot hers calle d t he Society of Mar y. T here I recei ve d a ge neral seco n dar y e d ucatio n a n d too k m y first co urse i n c he mistr y. W he n it ca me ti me for me to start my hig her e d ucatio n, t here was no q uestio n of w here it wo ul d be obtai ne d. I ha d li ve d a mo ng A merica ns a n d ha d deter mi ne d, wit h my fat her’s e nco urage me nt, to st u dy i n A merica. I selecte d t h e U ni v ersit y of D a yt o n i n O hi o f or t w o r e as o ns: First, w e h a d f a mil y fri e n ds i n O hi o, a n d s e c o n dl y, t h e s a m e or g a ni z ati o n, t h e S o ci et y of M ar y, r a n b ot h St. Jose p h College a n d t he U niversity of Dayto n. My fo ur years i n Dayto n a n d a year i n gra d uate sc hool at Massac h usetts I nstit ute of Tec h nology were pleasa nt a n d take n u p wit h activities t hat ma de me i nto a n A merica n. T his per ha ps also mol de d my scie ntific c haracter a n d re presente d so mething of a personal meta mor phosis. The sequence - Dayton first a n d t he n MI T - was also goo d, maki ng a false start by a yo u ng ma n m uc h less li kel y. T he U ni versit y of Da yto n was a colle ge of 400 me n, most of t he m li vi n g i n dor mitories u n der strict mo nastic re gi me n. Trai ni n g of t he s pirit was c o nsi d er e d as i m p ort a nt as tr ai ni n g of t h e b o d y a n d s o ul. I e nj o y e d all p h as es of t he trai ni ng. I beca me vice presi de nt of my gra d uati ng class, wo n letters i n t e n nis a n d tr a c k a n d a g ol d m e d al f or e x c ell e n c e t h at r efl e ct e d m y f o ur y e ars of perfor ma nce t here. Excelle nce i n ge neral was e nco urage d; I was eve n a war de d a g ol d m e d al f or c o n d u ct. MI T was a n ot her matter. B ost o n, w here I li ve d, is a n ol d cit y of great c har m a n d a c e nt er of t h e arts. I di d n ot a p pl y m ys elf t o m y c o urs es as I s h o ul d, b ut my extrac urric ular acti vities co ntrib ute d to t he for matio n of my ulti mate c h ar a ct er. It w as w hil e st u d yi n g at MI T t h at I first f elt t h e e x hil ar ati o n of utt er free do m. MI T was co nsi dere d deficie nt i n t he h u ma nities, b ut wit h a little effort t hat deficie ncy co ul d be re me die d delig htf ully by visiti ng seco n d- ha n d book stores. Why secon d-han d books a p peale d to me more than library books still re mai ns a mystery - t ho ug h it possibly was t he pros pect of fi n di ng u nex- pecte d treas ures. I celebrate d my gra d uatio n fro m MI T as a c he mist by taki ng a w al ki n g t o ur of t h e Pr esi d e nti al R a n g e i n N e w H a m ps hir e. I n s pite of t he ur gi n g of Ja mes F. Norris - a ver y pr o mi ne nt pr ofess or a n d m y r es e ar c h a d vis or - I di d n ot r e m ai n at MI T t o t a k e a P h. D. M y bills w er e still b ei n g p ai d b y m y f at h er, a n d I w as a n xi o us t o b e gi n s u p p orti n g m ys elf. I n 1927, I obtai ne d e m ploy me nt at D u Po nt t hro ug h t he goo d offices of Professor Norris, a n d I was fort u nate e no u g h to be directe d to researc h at Jac kso n Laboratory by Willia m S. Calcott. My career of 42 years ha d beg u n. T he researc h e nviro n me nt at D u Po nt d uri ng t hose years was not altoget her ty pical of i n d ustrial laboratories of t he ti me. T he co m pa ny ha d for me d t he 4 9 8 Che mistry 1987 n ucle us of a basic researc h de part me nt t hat i n a fe w years’ ti me wo ul d ha ve scie ntists s uc h as Wallace Carot hers a n d t he yo u ng Pa ul Flory worki ng o n t he pol y mer st u dies t hat le d to n ylo n a n d ot her brea kt hro u g hs. A n d i n ge neral, D u Po nt was a pro d uctive ce nter of researc h w here ma ny i nteresti ng a n d i m por- ta nt proble ms were bei ng solve d. For exa m ple, o ne day w hile visiti ng J ulia n Hill at t h e D u P o nt E x p eri m e nt al St ati o n i n Wil mi n gt o n, D el a w ar e, I o bs er v e d hi m p ull t h e first ori e nt e d fi b er of a p ol y est er. O n a n ot h er o c c asi o n, at J a c ks o n Laboratory, across t he Dela ware River i n Ne w Jersey w here I worke d, I n oti c e d c o m m oti o n i n t h e l a b or at or y of R o y Pl u n k ett, w hi c h w as a cr oss t h e h all fr o m m y o w n. I i n v esti g at e d a n d wit n ess e d t h e s a wi n g o p e n of a c yli n d er fr o m w hic h was obtai ne d t he first sa m ple of Teflo n  fl uoro poly mer. At Jackson Laboratory, d uri ng t hat ti me, ot her i m porta nt a dva nces were taki ng place i n tetraet hyl lea d a n d ne w petrole u m c he micals, ne w elasto mers, a n d a ne w series of fl uorocarbons for refrigeration an d aerosols. The at mos phere was vibrant a n d exciti n g, a n d s uccess was ex pecte d. It was i n t his at mos p here I be ga n m y c areer. As a n e w s ci e ntist I w as i niti all y s et t o w or k o n a s eri es of t y pi c al pr o bl e ms, t he s uccessf ul sol utio n of w hic h b uo ye d m y researc h career ( Ref. l-5). After a w hil e, I b e g a n t o s e ar c h f or oil-s ol u bl e pr e ci pit a nts f or c o p p er, a n d I f o u n d t h e first goo d metal deacti vator for petrole u m pro d ucts ( Ref. 6-8). As a res ult of t his w or k, I d e v el o p e d a gr e at i nt er est i n t h e eff e cts of v ari o us li g a n ds o n t h e catal ytic pro perties of co p per a n d t he tra nsitio n ele me nts ge nerall y, a n d I w or k e d i n t h at fi el d f or s e v er al y e ars. I n oti c e d a v er y u n us u al s y n er gisti c aff e ct w herei n a metal deacti vat or greatl y i ncrease d t he efficac y of a nti oxi da nts ( Ref. 9 - 1 0 ) . So more a n d more, I beca me i ntereste d i n t he oxi dati ve degra datio n of t he s ubstrates the mselves, partic ularly petrole u m pro d ucts an d r ubber. As my i nterests m o ve d i n t hat directi o n, I left off w or ki n g o n metal deacti vat ors a n d coor di natio n c he mistry. By t he mi d-1940s, I was i n f ull career, ha vi ng estab- lis he d m yself i n t he fiel d of oxi dati ve de gra datio n a n d sta bilizatio n ( Ref. 11- 13). I was i n de pe n de nt i n ter ms of t he proble ms I mig ht c hoose a n d ha d ac hie ve d t he hig hest no n- ma nage me nt title t he n a vailable to a scie ntist at D u Po nt. D uri ng t he 1940s a n d 1950s, my i nterests beca me more varie d. For exa mple, I beca me intereste d in the photoche mistry of ne w phthalocyanine a d d ucts a n d of q ui no nei mi ne dioxi des. I fo u n d so me poly merizatio n i nitiators, discovere d t hat ferroce ne was a goo d a ntik nock age nt for gasoli ne, a n d ma de so me novel poly mers ( Ref. 14-23).

Discovery of the cro w n ethers B ut t he n t here arose a c halle ngi ng o p port u nity t hat le d me back to liga n d c he mistry. I n res po nse to my desire to co ntrib ute to t he elasto mer fiel d, my colleag ue Her man Schroe der s uggeste d that there was an interesting proble m i n t he coor di natio n c he mistry of va na di u m. T his s parke d my c uriosity, a n d I be ga n wor k wit h t he i nitial goal of u n dersta n di n g factors w hic h go ver n catal yt- ic acti vit y of va na di u m i n oxi datio n a n d pol y merizatio n. T his was a relati vel y u n e x pl or e d ar e a, a n d pr e vi o us w or k h a d b e e n e m piri c al. It w as m y w or k i n t his C. J. Pe derse n 4 9 9

Fi g. 1 ar e a t h at l e d t o t h e dis c o v er y of cr o w n et h ers, w hi c h I will n o w d es cri b e. As I ha ve relate d, I st u die d for ma ny years t he a utoxi datio n of petrole u m pro d ucts a n d r ubber a n d its retar datio n by a ntioxi da nts. A utoxi datio n is greatly catalyze d by trace metals, s uc h as co p per a n d va na di u m. He nce, I ha d develo pe d t he co m po u n ds referre d to earlier, na mely t he “ metal deactivators” w hi c h s u p pr ess t h e c at al yti c a cti vit y of t h e m et al s alts b y c o n v erti n g t h e m i nt o inactive m ulti dentate co m plexes. The first of these was N, N’-(1,2- pro pylene- bis) (s ali c yli d e n ei mi n e) s h o w n i n Fi g ur e 1 - a n e x c ell e nt d e a cti v at or f or c o p p er w hic h has bee n use d i n d ustriall y f or ma n y years. I n 1960 w he n I ret ur ne d to i nvestigatio ns i n coor di natio n c he mistry, I deci de d to st u dy t he effects of bi- a n d m ulti de ntate p he nolic liga n ds o n t he

Ca techol Dihydropyran

Partially protected catechol I Fi g. 2. 5 0 0 Che mistry 1987

catalytic pro perties of t he va na dyl gro u p, V O ( Ref. 24). T he m ulti de n date liga n d I selecte d is t he bis[2-(o- hy droxy p he noxy)et hyl] et her w hose sy nt hesis is de picte d i n Fig ure 2. As I procee de d, I k ne w t hat t he partially protecte d catechol was conta minate d with abo ut 10 percent unreacte d catechol. B ut I d e ci d e d t o us e t his mi xt ur e f or t h e s e c o n d st e p a n y w a y si n c e p urifi c ati o n w o ul d be re q uire d at t he e n d. T he reacti o ns were carrie d o ut as o utli ne d a n d ga ve a pr o d uct mixt ure i n t he f or m of a n u nattracti ve g o o. I nitial atte m pts at p urifica- tio n ga ve a s mall q ua ntity (abo ut 0.4 perce nt yiel d) of w hite crystals w hic h dre w atte ntio n by t heir silky, fibro us str uct ure a n d a p pare nt i nsol ubility i n hy droxylic sol ve nts. T he a p peara nce of t he s mall q ua ntit y of t he u n k no w n s ho ul d ha ve p ut me i n a q uan dary. I probably was not the target co m po un d beca use that wo ul d be o btai ne d i n a hi g her yiel d. M y o bjecti ve was to pre pare a n d test a partic ular co m po u n d for a partic ular p ur pose. Ha d I follo we d t his li ne, I wo ul d have doo me d t he cro w n et hers to obli vio n u ntil s uc h a ti me as a not her i n vesti gator wo ul d retrace my ste ps a n d make t he better c hoice at t he critical mo me nt. Cro w n et hers, ho wever, were i n no da nger, beca use of my nat ural c uriosity. Wit ho ut hesitatio n, I bega n st u dy of t he u nk no w n It was fort u nate t hat I use d a n ultra violet s pectro p hoto meter to follo w t he reactio ns of t he p he nols. T hese co m po u n ds a n d t heir et hers i n ne utral met ha- nol sol utio ns absorb i n t he re gio n of 275 milli micro ns. O n treat me nt wit h al k ali, t h e a bs or pti o n c ur v e is n ot si g nifi c a ntl y alt er e d if all t h e h y dr o x yl gr o u ps ar c c o v er e d, b ut it is s hift e d t o l o n g er w a v el e n gt hs a n d hi g h er a bs or pti o n if o n e or m ore h y dr ox yl gr o u ps are still free, as s h o w n b y t he das he d c ur ve i n Fi g ure C. J. Pe derse n 5 0 1

Fi g. 3.

T he u nk no w n pro d uct was very little sol uble i n met ha nol, a n d t he ne utral sol utio n gave a n absor ptio n c urve c haracteristic for a p he nolic co m po u n d. T he sol utio n was ma de alkali ne wit h so di u m hy droxi de wit h t he ex pectatio ns t hat t he c urve wo ul d eit her be u naffecte d or s hifte d to lo nger wavele ngt hs. T he res ulti n g s pectr u m, ho we ver, s ho we d neit her effect, b ut rat her t he o ne s ho w n i n Fi g ure 4. At t he sa me ti me, I notice d t hat t he fibro us cr ystals were freel y sol uble i n met ha nol i n t he prese nce of so di u m hy droxi de. T his see me d stra nge si nce t he co m po u n d di d not co ntai n a free p he nolic gro u p, a fact co nfir me d b y its i nfr ar e d a n d N M R s p e ctr a. I t h e n f o u n d t h at t h e c o m p o u n d w as s ol u bl e i n met ha nol co ntai ni ng a ny sol uble so di u m salt. T h us, t he i ncrease d sol ubility was d ue not to alkali nity b ut to so di u m io ns. B ut t here was no ob vio us ex pla natio n for t he be havior of t he co m po u n d beca use its ele me ntary a nalysis corres pon de d with that for a 2,3-benzo-1,4,7-trioxacyclononane, (Fig ure 5) a pla usible pro d uct fro m t he reactio n of catec hol a n d bis(2-c hloroet hyl)et her i n the presence of so di u m hy droxi de. Ho wever, the mo ment of revelation ca me w he n I lear ne d t hat its molec ular wei g ht was exactl y t wice t hat of t he a bo ve co m po un d. The tr ue str uct ure was that of an 18- me mbere d ring, dibenzo-18- 5 0 2 Che mistry 1987

cro w n-6, t he first a n d most versatile of t he aro matic cro w n co m po u n ds, de pict- e d i n Fi g ur e 6. T h e s h a p e is t h at of a t or us or a d o u g h n ut. It s e e m e d cl e ar t o m e n o w t h at t h e s o di u m i o n h a d f all e n i nt o t h e h ol e i n t h e ce nter of t he molec ule a n d was hel d t here by t he electrostatic attractio n bet wee n its positi ve c har ge a n d t he ne gati ve di polar c har ge o n t he six ox y ge n ato ms sy m metrically arra nge d aro u n d it i n t he polyet her ri ng. Tests s ho we d t h at ot h er al k ali m et al i o ns a n d a m m o ni u m i o n b e h a v e d li k e t h e s o di u m i o n s o that, at long last, a ne utral co m po un d ha d been synthesize d which for me d stable co m plexes wit h alkali metal io ns. U p to t hat poi nt, no o ne ha d ever foun d a synthetic co mpoun d that for me d stable co mplexes with so diu m an d potassi u m.

Fi g. 5. C. J. Pe derse n 5 0 3

My excite ment, which ha d been rising d uring this investigation, no w reac he d its pea k a n d i deas s war me d i n m y brai n. O ne of m y first actio ns was m oti vate d b y est hetics m ore t ha n scie nce. I deri ve d great est hetic pleas ure fr o m the three- di mensional str uct ure as portraye d in the co m p uter-si m ulate d mo del i n Fig ure 7. W hat a si m ple, elega nt a n d effecti ve mea ns for t he tra p pi ng of hit hert o recalcitra nt al kali cati o ns! I a p plie d t he e pit het “cr o w n” t o t he first me mber of t his class of macrocyclic polyet hers beca use its molec ular mo del looke d like o ne a n d, wit h it, catio ns co ul d be cro w ne d a n d u ncro w ne d wit ho ut p h ysi c al d a m a g e t o eit h er as s h o w n f or t h e p ot assi u m c o m pl e x i n Fi g ur e 8. As my st u dies progresse d, I create d the syste m of cro wn no menclat ure chiefly b e c a us e t h e offi ci al n a m es of t h e cr o w n et h ers w er e s o c o m pl e x a n d h ar d f or m e to re me m ber. It is a so urce of s pecial satisfactio n to me t hat t his s yste m of abbre viate d na mes, de vise d solely for t he rea dy i de ntificatio n of t he macrocy- clic p ol yet hers, has bee n retai ne d b y t he scie ntific esta blis h me nt. I n Fi g ure 9 I have ill ustrate d ho w the no menclat ure syste m is ma de u p of the si de-ring s u bstit u e nts, t h e t ot al n u m b er of o x y g e n at o ms i n t h e m ai n ri n g a n d t h e si z e of t h e ri n g. A not her as pect of t his disco ver y fille d me wit h wo n der. I n or di nar y or ga nic r e a cti o ns o nl y ri n gs of 5, 6, or 7 m e m b ers f or m e asil y. H er e a ri n g of 1 8 at o ms ha d bee n for me d i n a si ngle o peratio n by t he reactio n of t wo molec ules of catec hol, w hic h was prese nt as a mi nor i m p urity, wit h t wo molec ules of bis(2- chloroethyl)ether. Further experi ments reveale d that dibenzo-18-cro wn-6 can be s y nt hesize d fro m t hese i nter me diates i n a 45 perce nt yiel d wit ho ut resorti n g to hig h dil utio n tec h niq ues. T his was most u nex pecte d a n d so me goo d reaso n m ust exist for s uc h a n u n us ual res ult. I co ncl u de d t hat t he ri n g-closi n g ste p, eit her b y a sec o n d m olec ule of catec h ol or a sec o n d m olec ule of bis(2-c hl or oet h- yl)et her, was facilitate d by t he so di u m io n w hic h, by io n- di pole i nteractio n, “ wra p pe d” t he molec ular pieces aro u n d itself to for m a t hree- q uarter circle a n d Che mistry 1987

Fi g. 7

dis p os e d t h e m f or t h e fi n al ri n g cl os ur e i n m u c h t h e s a m e f as hi o n as is i n v ol v e d in the synthesis of the por phyrins an d phthalocyanines. Later ex peri ments a p pear to s u p port t his hy pot hesis. T he yiel ds of dibe nzo-18-cro w n-6 are hig her w he n it is pre pare d wit h so di u m or potassi u m hy droxi de t ha n w he n lit hi u m or tetra methyla m moniu m hydroxide is used. Lithiu m and the quaternary a m mo- ni u m io ns are not stro ngly co m plexe d by t he polyet her. T he best co m plexi ng a ge nts are ri n gs of 15 to 24 ato ms i ncl u di n g 5 to 8 ox y ge n ato ms. T he y are f or m e d i n hi g h er yi el d s t h a n s m all er or lar g er ri n g s, or ri n g s of e q u al si z e s wit h o nly fo ur oxyge n ato ms. Fi nally, e ve n o pe n-c hai n polyet hers s uc h as 3,4,12,13- diebenzo-2,5,8,11,14-pentaoxapenta deca-3,12- dienc (Figure 10) were foun d to for m co m plexes with so di u m an d potassi u m ions.

Fi g. 8 C. J. Pe derse n 5 0 5

Some Macrocyclic Polyethers

Fi g. 9

T h us di d I disco ver dibe nzo-18-cro w n-6, t he first cro w n et her a n d t he first ne utral synthetic co m po un d ca pable of co m plexing the alkali metal cations ( Ref. 2 5- 2 6, 3 6). Wit h t h e r e ali z ati o n t h at I h a d s o m et hi n g v er y u n us u al a n d wit h t h e ut m ost c uri osit y a n d a ntici pati o n, I de v ote d all m y e ner gies o ver t he next se veral years t o t he st u d y of t his fasci nati n g class of li ga n ds a n d t heir i nteracti o n wit h i norga nic catio ns. Every s uccessf ul ex peri me nt pro d uce d a sig nifica ntly novel r es ult a n d l e d t o n e w t h o u g hts o n w h at t o s y nt h esi z e a n d als o as t o t h e m a n y pote ntial uses of t hese extraor di nar y s ubsta nces. I w as es p e ci all y i nt er est e d i n t h e st a bilit y of t h e “ c o m pl e x es ” a n d t h e r e as o n f or t h eir b e h a vi or. F or e x a m pl e, I f o u n d t h at f or m a xi m u m st a bilit y of its s alt co m plex, eac h catio n has a n o pti m u m size of t he ri n g of t he pol yet her. A co mplex can for m even if the fit is not the best by for ming a san d wich consisting of t wo molec ules of polyet her per catio n. T he t her mal stability of so me salt c o m pl e x es, f or e x a m pl e, t h at wit h K C N S, is att est e d t o b y t h eir h a vi n g m elti n g poi nts hi g her t ha n t hose of t he co m po ne nts. Preparatio n a nd properties of macrocyclic polyethers S p urre d b y c uri osit y re gar di n g t he fact ors i n v ol ve d i n t he sta bilit y of t he salt c o m pl e x es (s u c h as t h e r el ati v e si z es of t h e h ol e a n d t h e c ati o n, a n d t h e n u m b er a n d sy m metrical arra nge me nt of t he oxyge n ato ms i n t he polyet her ri ng), I i nitiate d a n exte nsive progra m of sy nt heses. Ulti mately, abo ut 60 macrocyclic pol yet hers were pre pare d co ntai ni n g 12 to 60 ato ms to a pol yet her ri n g i ncl u d- i ng 4 to 10 oxyge n ato ms a n d so me wit h nitroge n a n d s ulf ur ato ms. Ma ny of these co m po un ds were fo un d to be useless as co m plexing agents, b ut they 5 0 6

serve d to defi ne t he effective o nes w hic h are co m po u n ds co ntai ni ng 5 to 10 ox y ge n ato ms i n t he ri n g, eac h se parate d fro m t he next b y 2 car bo n ato ms. I also note d t hat eve n w hole molec ules s uc h as t he t hio ureas for me d co m plexes wit h so me cro w n co m po u n ds. I acco m plis he d all t his worki ng alo ne wit h t he h el p of m y a bl e t e c h ni ci a n, T e d M ali n o ws ki. So me of t he ge neral pro perties of t he aro matic macroc yclic pol yet hers are as follo ws: T hey are ne utral, colorless co m po u n ds wit h s har p melti ng poi nts, a n d ar e littl e s ol u bl e i n w at er a n d al c o h ols, f airl y s ol u bl e i n ar o m ati c s ol v e nts, a n d very sol uble i n met hyle ne c hlori de a n d c hlorofor m. T hey u n dergo s ubstit utio n reactio ns c haracteristic for aro matic et hers ( haloge natio n, nitratio n, etc.), a n d for m for maldehyde resins when treated with parafor maldehyde under acid co n ditio ns. T hey are deco m pose d by reactio ns w hic h ca use t he scissio n of et hers. T he sat urate d macrocyclic polyet hers are obtai ne d most si m ply by catalyt- ically hydrogenating the aro matic co mpounds using rutheniu m catalyst. Bridge-bond iso mers are obtained fro m co mpounds containing t wo or more aro matic si de-ri ng s ubstit ue nts. For exa m ple, dibe nzo-18-cro w n-6 gives a mix- t ure of stereoiso mers of dicyclo hexyl-18-cro w n-6. T he sat urate d polyet hers are c ol orl ess, vis c o us ills or s oli ds of l o w m elti n g p oi nts. T h e y ar e t h er m all y st a bl e b ut, like t he aro matic co m po u n ds, m ust be protecte d fro m oxyge n at hig h te m perat ures. T hey are, as a gro u p, very m uc h more sol uble t ha n t he aro matic co m po u n ds i n all solve nts, a n d most of t he m are eve n sol uble i n petrole u m et h er. T he u niq ue pro perty of t he macrocyclic polyet hers as co m plexi ng age nts is t heir prefere nce f or al kali metal i o ns, w hic h do not for m co m plexes wit h t he n u mero us ligan ds use d for the transition metal ions. The cro wn co m po un ds for m stable crystalli ne co m plexes a n d sol utio ns of t he co m plexes wit h so me or T a bl e I. all of t h e c ati o ns of al k ali a n d al k ali n e e art h m et als pl us a m m o ni u m i o ns a n d others. So me of the m, for exa m ple, dicyclohexyl-18-cro wn-6, also for m co m- pl e x e s wit h C o(II), a n d so me ot her tra nsitio n metal io ns. T he sat urate d co m po un ds are better co m plexing agents than the corres pon ding aro matic co mpounds. T hree criteria have bee n use d for t he for matio n of co m plexes bet wee n macr oc yclic p ol yet hers a n d salts: (a) is olati o n of t he c o m plexes as cr ystals; ( b) c haracteristic c ha nges i n t he ultraviolet s pectra of t he aro matic co m po u n ds; a n d (c) c ha n ges i n t he s ol u bilities of t he p ol yet hers a n d salts i n differe nt s ol v e nts. As is e vi de nt fro m Table 1, t hese co m po u n ds ha ve holes of differe nt dia me- t ers i n t h e c e nt er of t h e p ol y et h er ri n gs. T h e u n c o m pl e x e d c ati o ns als o diff er i n size, give n i n Table 2 i n A ngstro ms u nits: so di u m 1.94, potassi u m 2.66, a m m o ni u m 2. 8 6, r u bi di u m 2. 9 4, a n d c esi u m 3. 3 4. D e p e n di n g, t h er ef or e, o n t h e relati ve sizes of t he h ole a n d t he cati o n, cr ystalli ne c o m plexes wit h p ol yet her / cati o n rati os of 1:1, 3:2, a n d 2:1 ha ve bee n pre pare d as ill ustrate d i n Ta ble 3. T he aro matic macrocyclic polyet hers te n d to give hig h melti ng co m plexes w hic h are not rea dily sol uble i n a protic sol ve nts, w hile t he sat urate d co m po- u n ds give lo wer melti ng co m plexes w hic h are more sol uble. Most of t he p ure co mplexes are deco mposed by water, the rate an d extent of deco m position de pe n di ng o n t he pro portio n of water a n d t he te m perat ure. It was post ulate d fro m t he begi n ni ng t hat co m plexes of macrocyclic po- lyet hers co ntai ni ng less t ha n seve n oxyge n ato ms co nsiste d of a catio n s ur- ro u n de d by t he oxyge n ato ms arra nge d sy m metrically i n a si ngle pla ne. T he esse ntial correct ness of t his vie w of t he str uct ure has bee n co nfir me d by Professor M. R. Tr uter a n d her collaborators w ho ha ve bee n t he first to deter mi ne t he str uct ures of a n u mber of crystalli ne salt co m plexes of cro w n co m po un ds by X-ray diffraction metho ds ( Ref. 27). All macrocyclic polyet hers co ntai ni ng o ne or more be nzo gro u ps have a characteristic absor ption maxi m u m at 275 milli microns in methanol, an d the s ha pes of t he c ur ves are altere d b y t he a d ditio n of co m plexable salts as was s h o w n i n Fi g ure 4 . T he s pectral evi de nce is nearly al ways co nfir me d by t he ot h er t w o crit eri a. 5 0 8 C he mistry 1987

T a bl e 2.

Macrocyclic polyet hers a n d co m plexable salts m ut ually i ncrease t heir sol u- bilities i n sol ve nts w herei n t he co m plexes are sol uble. So meti mes t hese effects are s pectac ular, for i nsta nce, t he sol ubility of t he potassi u m t hiocya nate co m- plex is a b o ut a te nt h of a m ole per liter, a 100-f ol d i ncrease. S o me of t he sat urate d polyet hers, s uc h as dicyclo hexyl-18-cro w n-6, have t he usef ul pro per- t y of s ol u bili zi n g al k ali m et al s alts, p arti c ul arl y t h os e of p ot assi u m, i n a pr oti c solvents. Crystals of potassi u m per manganate, potassi u m tertiary-b utoxi de, an d potassi u m palla do us tetrachlori de ( P d C12 +2 K Cl) can be ma de to dis- solve in liq ui d aro matic hy drocarbons merely by a d ding dicyclohexyl-18- cro wn-6. This is dra matic for the cro wn co m plex of potassi u m per manganate w hic h colors tol ue ne p ur ple. Be nzyl potassi u m is re n dere d sol uble i n n- he pta ne by t he polyet her, b ut t he polyet her ri ng is gra d ually deco m pose d by t his organo metallic co m po un d. The sol ubilizing po wer of the sat urate d macrocyclic p ol y et h ers p er mits i o ni c r e a cti o ns t o o c c ur i n a pr oti c m e di a. It is e x p e ct e d t h at t his pro pert y will fi n d practical use i n catal ysis, e n ha nce me nt of c he mical reacti vit y, se paratio n a n d reco ver y of salts, electroc he mistr y, a n d i n a nal ytical c he mistry. T he co m plexi ng efficie ncies of sat urate d macrocyclic et hers ca n be ra nke d n u m eri c all y b y m e as uri n g t h e r el ati v e distri b uti o n of a c ol or e d al k ali m et al s alt (s uc h as picrate) bet wee n a n i m miscible orga nic sol ve nt a n d water i n t he prese nce of t he cro w n et her as de picte d. If t he pol yet her is i neffecti ve, t he or ga nic p hase will be c ol orless; if t he p ol yet her is ver y p o werf ul, m ost of t he c ol or will b e i n t h e or g a ni c p h as e. T h e effi ci e n ci es of t h e p ol y et h er will li e bet wee n t hese t wo li mits as s ho w n i n Ta ble 4 ( Ref. 28-35). Dr. H. K. Fre ns d orff has deter mi ne d t he sta bilit y c o nsta nts f or 1: 1 c o m plex- es of ma n y macroc yclic pol yet hers wit h al kali metal io ns b y pote ntio metr y wit h C. J. Pe ders o n 5 0 9 Crystalline Co mplexes of P ol y e t h er s

Crystalli ne C o m plex M ol e R ati o’

T a bl e 3.

catio n-selecti ve electro des. Selecti vity to war d t he differe nt catio ns varies wit h p ol y et h er ri n g si z e, t h e o pti m u m ri n g si z e b ei n g s u c h t h at t h e c ati o n j ust fits i nt o t h e h ol e, t h at is 1 5- 1 8 f or s o di u m i o n, 1 8 f or p ot assi u m i o n, a n d 1 8- 2 1 f or c esi u m i o n ( R ef. 3 3). T hat co ncl u des my re marks o n t he discovery, pro perties a n d pre paratio n of t he cro w n et hers. It re mai ns o nly for me to me ntio n certai n i n divi d uals w ho co ntrib ute d to t he s uccess of my researc h a n d to a d d a fe w wor ds co ncer ni ng m y i nt er est a n d h o p e f or t h e f ut ur e of r es e ar c h i n t his ar e a. First, I w a nt t o r e m e m b er o n t his o c c asi o n m y wif e S us a n w h o di e d i n 1 9 8 3. It w o ul d ha ve bee n w o n derf ul t o s hare wit h her all t hat has ha p pe ne d t o me of late as we s hare d e ver yt hi n g else d uri n g o ur marria ge of 36 years. N e xt, I w o ul d li k e t o t h a n k t h e D u P o nt C o m p a n y. T h e y e n c o ur a g e d m e t o p urs ue my researc h o n cro w n et hers, e ve n w he n it was e vi de nt t hat, at least i nitially, my work mig ht not have a sig nifica nt practical i m pact. At a not her co m pa ny, I mig ht not have met wit h s uc h e nco urage me nt a n d latit u de. Wit hi n t he co m pa ny I recei ve d s u p port fro m certai n i n di vi d uals. I a p preci- ate t he a d vice a n d co u nsel of m y close frie n d, Dr. Her ma n Sc hroe der, w ho was 5 1 0 Che mistry 1987

Extracti o n Res ults”

T a bl e 4. al ways i ntereste d i n my researc h a n d w hose co m pa nio ns hi p has mea nt so m uc h t o m e d uri n g t h e m a n y y e ar s w e h a v e k n o w n e a c h ot h er. I al s o t h a n k m y fri e n d Dr. R u d ol p h Pariser, w h o has bee n tireless i n his eff orts t o ass ure rec o g niti o n for my acco mplish ments. Fi n all y, I w a nt t o t h a n k t h e a n al yti c al gr o u ps of t h e c o m p a n y f or m a ki n g all t heir res o urces a vaila ble t o me; m y tec h nical c ollea g ues f or t heir scie ntific co ns ultatio n; a n d o ur aca de mic frie n ds for t heir i nterest. Of co urse, I m ust me ntio n m y res pect a n d a d miratio n for t he t wo scie ntists wit h w ho m I s hare t his year’s prize. If I may use a n a nalogy reflecti n g m y yo ut h at t he U nsa n gol d mi nes, I see t he disco ver y of t he cro w n et hers as c o m p ar a bl e t o t h e fi n di n g of a n e w fi el d wit h a l ot of a cti o n i n it. Pr of ess or Cra m a n d Pr ofess or Le h n sta ke d clai ms t o partic ular vei ns of ric h ore a n d we nt o n t o dis c o v er g ol d mi n es of t h eir o w n. I k no w t hat t he cro w n et hers co nti n ue to create great i nterest a mo n g biolo- gists for st u dyi ng t he mec ha nis m of tra ns port of io ns across cell me mbra nes ( R ef. 3 6). B ut w h et h er it b e i n bi ol o g y or s o m e ot h er fi el d, it is m y f er v e nt wis h t hat before too lo ng it matters not by w ho m t he cro w n et hers were disco vere d b ut rat her t hat so met hi ng of great be nefit to ma nki n d will be de velo pe d a b o ut w hi c h it will b e s ai d t h at w er e it n ot f or t h e cr o w n c o m p o u n ds it c o ul d n ot b e. C. J. P e d ers e n 5 1 1

R E F E R E N C E S

1. F. B. Do wning, A. E. Par malee and C. J. Pedersen, U. S. P. 2,004,160 (6/11/35) to D u P o nt. 2. F. B. Do wning and C. J. Pedersen U. S. P. 2,008,753 (7/23/35) to Du Pont; also 2,087,103 (7113137). 3. R. G. Clarkson and C. J. Pedersen, U. S. P. 2,054,282 (7/15/36) to Du Pont. 4. L. Spiegler and C. J. Pedersen, U. S. P. 2,087,098 (7/13/37) to Du Pont. 5. F. B. Do wning and C. J. Pedersen, U. S. P. 2,121,397 (6/21/38) to Du Pont. 6. F. B. Do wning and C. J. Pedersen, U. S. P. 2,181,121 (11/28/39) to Du Pont. 7. C. J. P e d ers e n, Oil & G as J o ur n al , p. 9 7, J ul y 2 7, ( 1 9 3 9). 8. C. J. P e d ers e n, Ind. & Eng. Che m ., 4 1, 8 2 4 , (1949). 9. C. J. P e d ers e n, Dela ware Che mical Sy mposiu m , D e c. 1, ( 1 9 4 8). Pr o o xi d a nt C at al yti c Activity of Metal Chelates. 1 0. C. J. P e d ers e n, Sy mposiu m on Chelate Che mistry . Centenary Celebration of Brooklyn P ol yt e c h ni c I nstit ut e, N e w Y or k, N. Y. P u blis h e d i n Advances in Chelate Che mistry , p. 1 1 3 ( 1 9 5 4). 1 1. C. J. P e d ers e n, Dela ware Che mical Sy mposiu m , Jan. 21, ( 1950). Mechanis m of Deco m- position of Perbenzoic Acid Co mpared with Benzoyl Peroxide. 1 2. C. J. P e d ers e n, A nti o xi d a nts, Encyclopedia Britannica, (1953). 1 3. C. J. P e d ers e n, J. Or g. C h e m ., 2 2, 1 2 7 (1957); U. S. P. 2,662,895-7 (12/15/53); U. S. P. 2,681,347 (6/15/54); U. S. P. 2,741,531 (5/12/56); U. S. P. 2,831,805 (4/22/58) all to D u P o nt. 1 4. C. J. P e d ers e n, I n d. & E n g. Che m ., 4 8, 1 8 8 1 ( 1 9 5 6). 1 5. C. J. P e d ers e n, J. A m. C h e m. S o c ., 7 9, 2 2 9 5 (1957). 1 6. C. J. P e d ers e n, J. A m. C h e m. S o c . , 79, 5014 (1957); U. S. P. 2,681,918 (6/22/54); U. S. P. 2,741,625 (4/10/56); U. S. P. 2,831,805 (4/22/58) all to Du Pont. 17. C. J. Pedersen, U. S. P. 2,867,516 (l/6/59) to Du Pont. 1 8. C. J. P e d ers e n, U. S. P. 3, 3 4 1, 3 1 1 ( 9/ 1 2/ 6 7) t o D u P o nt. 19. C. J. Pedersen, U. S. P. 3,038,299-300 (6/12/62) to Du Pont. 2 0. C. J. P e d ers e n, J. Or g. C h e m ., 2 3, 2 5 2 & 2 5 5 (1958). 2 1. J. Di e k m a n n a n d C. J. P e d ers e n, J. Or g. C h e m ., 2 8, 2 8 7 9 ( 1 9 6 3). See als o Che m. Rev ., 6 7, 6 1 1 ( 1 9 6 7, p. 6 1 7). 22. C. J. Pedersen, U. S. P. 3,232,914 (2/l/66) to Du Pont. 2 3. C. J. P e d ers e n, U. S. P. 3, 3 2 0, 2 1 4 ( 5/ 1 6/ 6 7) t o D u P o nt. 24. C. J. Pedersen, U. S. P. 3,361,778 (l/2/68) to Du Pont. 2 5. C. J. P e d ers e n, J. A m. C h e m. S o c. , 8 9, 2 4 9 5, 7017 (1967). 2 6. C. J. P e d ers e n, Al dri c hi mi c a A ct a , ( 4) 1, 1 ( 1 9 7 1). 27. M. R. Truter and C. J. Pedersen, Endeavor, X X X (111), 142 (1971). 2 8. C. J. P e d ers e n, F e d. Pr o c., F e d. A m. S o c. E x p. Bi ol. , 2 7, 1 3 0 5 ( 1 9 6 8). 2 9. C. J. P e d ers e n, J. A m. C h e m. S o c ., 9 2, 3 8 6 (1970). 3 0. C. J. P e d ers e n, J. A m. C h e m. S o c ., 9 2, 3 9 1 ( 1 9 7 0). 3 1. C. J. P e d ers e n, J. Or g. C h e m., 3 6, 2 5 4 (1971). 3 2. C. J. P e d ers e n, J. Or g. C h e m ., 3 6 , 1 6 9 0 ( 1 9 7 1). 3 3. C. J. P e d ers e n a n d H. K. Fr e ns d orff, Ange w. Che m ., 8 4, 1 6 ( 1 9 7 2); i bi d. (i nt. E d.), 1 1, 1 6 ( 1 9 7 2). 3 4. C. J. P e d ers e n, Or g. S y n ., 5 2, 6 6 (1972). 35. C. J. Pedersen, U. S. P. 3,562,295, (2/9/71); U. S. P. 3,622,577 (11/23/71); U. S. P. 3,686,225 (8122172); U. S. P. 3,687,978 (8129172); with M. Bro meis U.S.P. 3,847,949 (1 l/12/74); U. S. P. 3,856,813 (12/24/74); U. S. P. 3,873,569 (3/25/75); U. S. P. 3,987,061 (10/19/76); U. S. P. 3,998,838 (12/21/76); with M. Bro meis U. S. P. 4,031,111 (6/21/77); all to Du Pont. 36. C. J. Pedersen in Current Topics in Macrocyclic Che mistry in Japan, Ed. E. Ki mura, Hiroshi ma Univ. School of Medicine (1987), p. 1. H. E. Schroeder 5.