SUPPLEMEN

TAL MATERIAL
Synthesis of Ibuprofen in the Introductory Organic Laboratory
Richard A. Kjonaas,* Peggy E. Williams, David A. Counce, and Lindsey R. Edenburn De ar!men! o" Chemis!ry and Physics, #ndiana $!a!e %niversi!y, &erre 'au!e, #( )*+,*Richard.Kjonaas.inds!a!e.edu

Contents
'a/ards 0re roduced "rom !he original ar!icle1 $!uden! rocedure Lis! o" re2uired chemicals and e2ui men! #ns!ruc!ors3 no!es CA$ 4 Regis!ry (umbers ' (5R s ec!ra o"6 henone 0commercial sam le8Al"a Aesar -*91 p7isobu!ylace!o 470)7isobu!yl henyl1e!hanol 0s!uden! re ara!ion1 47chloro7470)7isobu!yl henyl1e!hane 0s!uden! re ara!ion1 ibu ro"en 0s!uden! re ara!ion1

4:

C (5R s ec!rum o" ibu ro"en 0combined s!uden! sam les ; <,, mg1 DEP& s ec!rum o" ibu ro"en 0combined s!uden! sam les ; <,, mg1 'E&C=R s ec!rum o" ibu ro"en 0combined s!uden! sam les ; <,, mg1 $!uden! handou!s used >hile !es!ing !his e? erimen!6 $yn!hesis o" #bu ro"en8Par! 4 0bac@ground in"orma!ion and rocedure1 $yn!hesis o" #bu ro"en8Par! 4 0s!uden! re or! shee!1 $yn!hesis o" #bu ro"en8Par! < 0bac@ground in"orma!ion and rocedure1 $yn!hesis o" #bu ro"en8Par! < 0s!uden! re or! shee!1 $am le 2ues!ions "or s!uden!s $yn!hesis o" #bu ro"en8Par! 4 $yn!hesis o" ibu ro"en8Par! <

!a"ards #reproduced fro$ the origina% artic%e&

Care should be !a@en !o avoid inhala!ion, eye con!ac!, or inges!ion o" any o" !he chemicals used in !his e? erimen!. Eye ro!ec!ion, rubber gloves, and a ro ria!e ro!ec!ive a!!ire should be >orn a! all !imes. $odium hydro?ide, sodium borohydride, and hydrochloric acid are corrosive in cases o" s@in con!ac!. 'ydrochloric acid emi!s hydrogen chloride gas >hich resen!s a serious inhala!ion ha/ard. Chloro"orm7d and 4,<7dibromoe!hane are carcinogenic in cases o" chronic e? osure. 5e!hanol, e!roleum e!her, die!hyl e!her, &'A, and )7isobu!ylace!o henone are "lammable. &'A !ends !o "orm ero?ides more readily !han die!hyl e!her and !hese ero?ides are e? losive. Res onsibili!y "or !he handling o" !his solven!, including drying and dis ensing as >ell as overseeing !he "a!e o" any le"!over or!ion un!il i! is ei!her used or dis osed o", should be given only !o someone >ho has !he necessary @no>ledge and e? erience.

Student procedure
Airs! Day. 1-(4-Isobutylphenyl)ethanol. Dissolve 4.,, mL o" p7isobu!ylace!o henone in : mL o" me!hanol in a se ara!ory "unnel. Weigh ou! ,.<B g (aC') and !hen very 2uic@ly add i! !o !he se ara!ory "unnel. Allo> i! !o si! 4, minu!es. While >or@ing in a "ume hood, add 4, mL o" 4,9 'Cl and !hen e?!rac! !he roduc! "rom !his mi?!ure 0CA%&#=(D considerable ressure buildu E1 using : ? B mL o" e!roleum e!her. Remove !he solven! by ro!ary eva ora!ion "rom a B,7mL roundbo!!omed "las@. Place one dro o" !he roduc! in!o an (5R !ube and add abou! ,.B mL o" CDCl:. Record !he 4' (5R s ec!rum. 1-Chloro-1-(4-isobutylphenyl)ethane. While >or@ing in a "ume hood, use a i e! !o care"ully !rans"er !he 470)7isobu!yl henyl1e!hanol "rom !he revious s!e in!o a se ara!ory "unnel and !hen use !>o B7mL or!ions o" 4< 5 'Cl !o hel !rans"er any !ha! remains in !he "las@ and !he i e!. $ha@e !his mi?!ure abou! < minu!es. E?!rac! !he roduc! "rom !his mi?!ure >i!h : ? B mL o" e!roleum e!her, and !hen dry i! >i!h (a<$=). Remove !he solven! by ro!ary eva ora!ion "rom a re7>eighed B,7mL round7bo!!omed "las@, and !hen >eigh !o de!ermine !he yield. Record !he 4' (5R s ec!rum o" one dro o" !his roduc! in abou! ,.B mL CDCl:. $!o er !he "las@. %se a mar@er !o >ri!e your name on i!, and !hen hand i! in on a cor@ ring. $econd Day. 1-(4-Isobutylphenyl)ethylmagnesium chloride. &o an oven7dried B,7mL round7 bo!!omed "las@ add ,.B g o" oven dried magnesium, ,.<B mL o" 47chloro7470)7 isobu!yl henyl1e!hane, 4, mL o" &'A, and !hree dro s o" 4,<7dibromoe!hane. A!!ach a re"lu? condenser 0>i!h !he bo!!om join! greased1 and a!!ach a drying !ube !o !he !o o" !his. Cegin hea!ing under re"lu?. When Frignard "orma!ion has begun, as evidenced by a large amoun! o" "oaming, con!inue hea!ing under re"lu? "or an addi!ional :, minu!es. Cool >i!h a >a!er ba!h, disassemble !he a ara!us, and >i e !he grease "rom !he join!s. 2-(4-isobutylphenyl)propanoic acid 0Gibu ro"enH1. While >or@ing in a "ume hood, bubble abou! a li!er o" C=< in!o !he reac!ion mi?!ure. Decan! !he solu!ion in!o a se ara!ory "unnel. %se B mL o" die!hyl e!her !o rinse !he "las@ and magnesium and !hen decan! !his e!her in!o !he se ara!ory "unnel. Add + mL o" 4,9 'Cl and mi?. Remove !he organic hase and se! i! aside. E?!rac! !he a2ueous hase >i!h < ? B mL die!hyl e!her. Combine !he !hree organic layers and e?!rac! >i!h < ? ) mL B9 (a='. Acidi"y !his ne> +7mL a2ueous layer by adding B mL 4,9 'Cl. %se li!mus or ' a er !o ma@e sure !he mi?!ure is acidic. E?!rac! ibu ro"en "rom !his a2ueous layer >i!h < ? B mL die!hyl e!her and !hen dry >i!h (a<$=). Remove !he solven! by ro!ary eva ora!ion "rom a re7>eighed <B7mL round7bo!!omed "las@, and !hen use a gen!le s!ream o" air !hrough a i e! !o remove any remaining !races o" !he solven!. Weigh !he "las@ !o de!ermine !he yield. %se abou! ,.I mL o" CDCl: !o !rans"er !he en!ire sam le !o an (5R !ube, bu! i" !he solu!ion is cloudy, use a lug o" co!!on in a i e! !o "il!er i! direc!ly in!o !he (5R 4 !ube. Record !he ' (5R s ec!rum.

List of re'uired che$ica%s and e'uip$ent

Chemicals 0amoun! er s!uden!1D p7isobu!ylace!o henone 04.,, mL bu! could be scaled do>n !o ,.B, mL1 me!hanol 0: mL1 $odium borohydride 0,.<B1 4,9 'Cl 0<: mL1 Pe!roleum e!her :,7I, 0:, mL1 $odium sul"a!e anhydrous 0!o dry a 4B7mL e! e!her solu!ion and a 4, mL e!hyl e!her solu!ion1 Chloro"orm7d 04.I7<., mL1 4< 5 'Cl 04, mL1 5agnesium !urnings 0oven dried, ,.B g1 Calcium sul"a!e anhydrous 0as needed "or drying !ube1 Produc! "rom 4s! day 0needed on <nd day, ,.<B mL1 &e!rahydro"uran8very dry and ero?ide "ree 04, mL1 4,<7dibromoe!hane 0: dro s1 Carbon dio?ide gas 0in a gas cylinder >i!h regula!or, 4 li!er1 Die!hyl e!her 0<B mL1 B9 (a=' 0+ mL1 Li!mus or ' a er 0less !han J inch1 Also needed by each s!uden!D 4,7mL gradua!ed cylinder $e ara!ory "unnel 0>e use a 4<B7mL bu! a :, or I, migh! be be!!er1 <B7mL roundbo!!omed "las@ B,7mL roundbo!!omed "las@ >i!h s!o er Cor@ ring sui!able "or a B,7mL roundbo!!omed "las@ (5R !ubes 0< er s!uden! on day 4 and 4 er s!uden! on day <1 Re"lu? condenser and hoses Drying !ube >i!h co!!on $mall Erlenmeyer "las@s 0"or >or@ing u reac!ions1 Pas!eur i e!0s1 04 er s!uden! >ill do, bu! s!uden!s re"er more1 Common e2ui men!D <B7mL bure! 0"or dis ensing 4.,, mL o" s!ar!ing ma!erial !o each o" <) s!uden!s1 4,,7mL bure! 0"or dis ensing : mL o" me!hanol !o each o" <) s!uden!s1 Ro!ary eva ora!or 0a! leas! <, bu! re"erably ), "or a class o" <) s!uden!s1 5ar@er 0"or s!uden!s !o >ri!e !heir name on !heir B,7mL "las@, one "or !he >hole class1 (5R ins!rumen! 0I, 5'/ ermanen! magne! Aourier !rans"orm >or@s "ine1 =ven 0se! a li!!le above 4,, KC1 4,7mL bure! 0"or dis ensing ,.<B mL o" !he "irs!7day roduc! !o each s!uden!1 CalloonLs!o coc@LPas!eur i e! assembly 0see dra>ing in (o!e M4,, N+ "or <) s!uden!s1 Pas!eur i e! secured !o a : inch hose a!!ached !o an air su ly 0N) er <) s!uden!s1

Instructors( notes
041 Starting material. We al>ays dis ense !he 4.,, mL o" p7isobu!ylace!o henone 0Al"a Aesar -*91 and !he :.,, mL o" me!hanol each "rom a bure! in a "ume hood. 0<1 Glassware. We use a 4<B7mL se ar!ory "unnel because !ha! is >ha! our dra>ers are s!oc@ed >i!h. A :,7mL or I,7mL >ould robably be be!!er. We also use glass>are >i!h 4)L<, ground7glass join!s. 0:1 !". We use an Anasa/i E"!7I, (5R >i!h a Oarian E5:I,L magne!. Each s!uden! runs hisLher o>n sam les. &he ins!ruc!or is sea!ed ne?! !o !he ins!rumen! so !ha! on !hose rare occasions >hen !he alcohol is con!amina!ed >i!h @e!one or !he al@yl chloride is con!amina!ed >i!h alcohol, !he s!uden!3s a!!en!ion can be dra>n !o !his, and !he s!uden! can be ins!ruc!ed !o subjec! !he roduc! !o !he reac!ion condi!ions again and !hen run ano!her (5R. &here is len!y o" !ime. 0)1 #asteur #ipetsD When >e "irs! began doing !his e? erimen! >e >ere "rus!ra!ed by !he "ac! !ha! so many s!uden!3s (5R s ec!rum o" !heir chloride sho>ed con!amina!ion >i!h small amoun!s o" !he alcohol. We soon reali/ed !ha! !he roblem >as no! !ha! !he reac!ion didn3! go !o com le!ion. &he roblem >as !ha! so many s!uden!s >ould no! clean !heir Pas!eur i e! be"ore !rans"erring !he chloride !o !he (5R !ube. &heir revious use o" !he i e! >as !o !rans"er !he alcohol. Al!hough >e have changed !he rocedure !o have !hem no> use !he !>o B7mL or!ions o" 4< 5 'Cl !o hel !rans"er any remaining !races o" !he alcohol "rom !he "las@ and the pipet, i! is s!ill a good idea !o remind !hem o" !he im or!ance o" using a clean dry i e! >hen !rans"erring any sam le !o an (5R !ube. 0B1 $and in the chloride%& A! !he end o" !he "irs! day some s!uden!s have a lo! o" roduc!, some have only a li!!le. $ome have a dry roduc! and some, in s i!e o" using a drying agen!, have a >e! roduc!. &ha!3s >hy >e have !he s!uden!s hand in !he chloride a! !he end o" !he "irs! dayP !his allo>s us !o level !he laying "ield "or !he day7!>o rocedure. We assign J oin! er 4,, mg u !o a ma?imum o" : oin!s and !hen sub!rac! J ! i" !he sam le is >e! 0cloudy1. &he ins!ruc!or !hen !rans"ers !hese sam les !o ano!her con!ainer, adds some e!roleum e!her, dries !his solu!ion >i!h a drying agen!, decan!s or "il!ers, and !hen removes !he solven! by ro!ory eva ora!ion. We re"er !o use a 4, mL bure! "or dis ensing !his ma!erial !o !he s!uden!s 0,.<B mL each1 on !he second day. &he ins!ruc!or also rinses each s!uden!3s B,7mL round7bo!!omed "las@ >i!h ace!one and !hen oven dries i! rior !o !he second day. &he s!uden!s could ge! !heir "las@s ou! o" !he oven, bu! >e re"er !o go in!o !he lab abou! an hour be"ore each lab sec!ion mee!s, remove !he "las@s "rom !he oven, "lush !hem >i!h dry ni!rogen 0no! essen!ial, bu! a good idea1, s!o er !hem >i!h !he s!uden!s3 &e"lon s!o ers, and se! !hem in !he cor@ rings "or !he s!uden!s !o ic@ u . #! has been our e? erience !ha! s!uden!s !end !o dro and brea@ ho! glass>are. 0I1 !agnesium. #n our o>n hands, Gdry7s!ir magnesiumH is convenien! and e""ec!ive "or re aring ben/ylic Frignards in high yield. Cu! "or our so homore organic chemis!ry lab course, >e s!rongly re"er oven7dried magnesium !urnings 0Aisher $cien!i"ic1.

0*1

0+1

0-1

04,1

'$(. Cecause i! is a <K ben/ylic Frignard !ha! is being made, i! is es ecially im or!an! !ha! !he &'A be scru ulously dry and ero?ide "ree. We se! u a recycling solven! s!ill in one o" !he "ume hoods in !he lab. &his rovides an o or!uni!y "or s!uden!s !o see ho> one o" !hese >or@s. We use ben/o henone @e!yl and >e ma@e sure !ha! !he con!en!s o" !he s!ill o! are ur le ra!her !han jus! blue. Convenien!ly, our s!uden! dra>ers are e2ui ed >i!h B, mL roundbo!!om "las@s !ha! have a circle 0"or >ri!ing on >i!h a encil1, and i! !a@es almos! e?ac!ly 4, mL o" li2uid !o "ill !he "las@ u !o !he bo!!om o" !his circle. $o, >e run &'A "rom !he side arm o" !he s!ill righ! in!o !he "las@ u !o !he bo!!om o" !he circle and !his is close enough !o 4, mL o" &'A. Al!hough >e have no! used commercially available re7dried &'A, i! should >or@ jus! as >ell and !his >ould elimina!e !he need !o have a recycling solven! s!ill. Cer!ainly, ho>ever, i! >ould be advisable !o dis ense !he commercially available re7dried &'A >i!h a syringe, and !he se !um on !he bo!!le should have a needle !ha! is a!!ached !o a ni!rogen or argon source so !ha! as &'A is removed, ni!rogen or argon can re lace i!. Also, !he bo!!le should be very securely clam ed !o a la!!ice rod. We have no! used &'A "rom a solven! uri"ica!ion sys!em. 1)2-dibromoethane. &hree dro s "rom a Pas!eur i e! is len!y. =ne >ould e? ec! !ha! i" !oo much 4,<7dibrome!hane is used !he resul!ing bromide ion could conver! !he ben/ylic chloride !o a bromide and !his >ould lead !o even more cou ling. We !ried using addi!ional 4,<7dibromobu!ane, and indeed, !he yield o" ibu ro"en >as lo>er. (oaming. Reali/ing !ha! "oaming occurs >hen !he Frignard has begun !o "orm >as a major brea@!hrough on !his rojec!E =" course righ! a"!er >e reali/ed !his >e ran across some e?am les o" i! in !he li!era!ure. Ac!ually, once !he "oaming s!ar!s i! !a@es a minu!e or !>o "or i! !o go "rom !he Gis !his >ha! you call "oamingQH s!age !o !he Gyu , i!3s de"ini!ely "oaming no>H s!age. A B,7mL round7 bo!!omed "las@ is large enough !o con!ain !he "oaming >i!hou! i! going in!o !he condenser, bu! i!3s a good idea !o @ee an eye on i!, es ecially near !he end o" !he re"lu?. C*2. Aor <, s!uden!s >e have several o" !he a ara!us sho>n belo>. &he !eaching assis!an! runs C=< in!o !he balloon !hrough !he rubber !ube, a!!aches a dis osable i e!, and hands i! !o !he s!uden!. We use 4<7inch round balloons !ha! >e buy a! a local scien!i"ic su ly com any called GDean3s Par!y 5ania.H

0441

Stream o+ air. &'A is no!oriously di""icul! !o remove com le!ely by ro!ary eva ora!ion. Aor !his reason, i! is im or!an! !o have !he s!uden!s use a gen!le s!ream o" air !hrough a i e! "ollo>ing ro!ary eva ora!ion so !ha! any small amoun!s o" &'A >ill be removed be"ore !he "inal >eighing and be"ore !he "inal (5R is !a@en. #! is sa"er !o use a las!ic i e! because some s!uden!s !urn on

04<1

!he air "ull blas! and !he i e! goes "lying o"" !he end o" !he hose. &he s!ream o" air is used !o gen!ly ush !he roduc! 0an oil1 around !he bo!!om o" !he "las@. $ome!imes !he ibu ro"en solidi"ies >hile doing !his 0li!. m. . *IK C1. 1, C) -.#' and $.'C*". Whereas 4' and 4:C (5R are discussed in every so homore organic lec!ure course, DEP& and 'E&C=R are no! even included in some o" !he !e?!boo@s "or !hose courses. &he ibu ro"en e? erimen! should s!and on i!s o>n >i!hou! doing !he 4:C, DEP&, or 'E&C=R, bu! "or !hose >ho >ish !o have !heir s!uden!s e? erience !he use o" DEP& or 'E&C=R or bo!h, !his is an e?cellen! o or!uni!y "or !he reason given in !he ar!icle. Perha s !he bes! >ay !o do !his >ould be !o discuss DEP& and 'E&C=R brie"ly in !he lec!ure ar! o" !he course and !hen, in !he relab lec!ure, oin! ou! !ha!, >i!h ibu ro"en, !hey should e? ec! !o no!ice some missing signals in !he 4:C and DEP& bu! !ha! !he 'E&C=R should reveal !he reason "or !his. &he s!uden!s could be as@ed !o e? lain !his reason in !heir lab re or! or, al!erna!ively, one o" !he assigned 2ues!ions migh! as@ !hem abou! !his. &ha!3s !he easy ar!. &he roblem lies in hysically running !he !hree s ec!ra >i!h only <,, mg. &he !hree 4' (5R s ec!ra 0< on day 4 and 4 on day <1 re2uire very li!!le !ime even i" !he s!uden! has as li!!le as :, mg, bu! !his ho>ever is no! !rue "or !hese o!her !hree (5R !echni2ues. &he da!a ac2uisi!ion !ime alone "or !he 4:C, DEP&, and 'E&C=R is abou! :.B minu!es, :.B minu!es, and - minu!es res ec!ively >i!h a <,,7mg sam le 0!he combined sam les o" !hree s!uden!s or so1. $o "ar, >e have incor ora!ed !hese !hree !echni2ues >i!h a ermanen! magne! ins!rumen! only during !he summer >hen !here is jus! one sec!ion >i!h only abou! a do/en s!uden!s. We divided !he s!uden!s in!o grou s o" !hree !o combine !heir sam les, ro!ova !hem do>n, !rans"er !o a clean (5R !ube >i!h "resh CDCl:, and !hen run a 4:C, DEP&, and 'E&C=R 0see a sam le o" each belo>1. $ome ossible scenarios "or ac2uiring one or more o" !hese s ec!ra >i!h a class o" <) s!uden!s are given belo>. 0A1 Dove!ail !he 4:C, DEP&, and 'E&C=R s ec!ra >i!h ano!her e? erimen! !he "ollo>ing >ee@. &his e? erimen! >ould have !o be one "rom >hich !he s!uden!s could !a@e abou! a :,7minu!e brea@ a! any !ime !o go !o !he ins!rumen!. Dividing <) s!uden!s in!o I grou s o" ) each >ould leave len!y o" !ime "or each grou during a :7hour lab eriod. 0C1 Five !he s!uden!s !he 4:C and DEP& resul!s and call !heir a!!en!ion !o !he "ac! !ha! !here are some missing signals. &hen have !hem, in maybe ) grou s o" I, combine sam les !o ac2uire jus! !he 'E&C=R s ec!rum. #n !heir lab re or!, !he s!uden!s can use !he 'E&C=R da!a !o e? lain !he missing signals. 0C1 $ho> and discuss !he 4:C, DEP&, and 'E&C=R s ec!ra during !he lec!ure and !hen give e?!ra credi! !o !hose s!uden!s >ho >ish !o !a@e !he !ime !o run !hem during ano!her !ime such as during a Gma@e7u dayH a! !he end o" !he semes!er. 0D1 'ave !he s!uden!s submi! !heir sam les !o an (5R ins!rumen! !ha! is e2ui ed >i!h an au!osam ler. #n some o" our o!her e? erimen!s >e have s!uden!s submi! !heir sam les !o a ),,75'/ ins!rumen! "or !heir 4' and 4:C s ec!ra >hich are !hen au!oma!ically e7mailed !o !hem. 0E1 $chedule some !imes on nonlab days "or grou s o" : s!uden!s !o come in and run !he 4:C, DEP&, and 'E&C=R s ec!ra.

CAS Registry Nu$bers

p7#sobu!ylbu!ylace!o henone 5e!hanol $odium borohydride 'ydrochloric acid Pe!roleum e!her 0:,7I,1 Chloro"orm7d 470)7#sobu!yl henyl1e!hanol $odium sul"a!e 47Chloro7470)7isobu!yl henyl1e!hane &e!rahydro"uran 5agnesium 4,<7Dibromoe!hane Carbon dio?ide Die!hyl e!her $odium hydro?ide <70)7#sobu!yl henyl1 ro anoic acid 0ibu ro"en1 R:++I47*+7+S RI*7BI74S R4I-),7II7<S R*I)*7,47,S RI+)*I7B,7IS R+IB7)-7IS R),4B,7-<7:S R**B*7+<7IS RI<,)-7IB7)S R4,-7--7-S R*):-7-B7)S R4,I7-:7)S R4<)7:+7-S RI,7<-7*S R4:4,7*:7<S R4BI+*7<*74S

! NMR spectra #Anasa"i Eft*+,- ) scan&

p7isobu!ylace!o henone 0commercial sam le1 =

470)7isobu!yl henyl1e!hanol 0s!uden! re ara!ion1 ='

47chloro7470)7isobu!yl henyl1e!hane 0s!uden! re ara!ion1 Cl

ibu ro"en 0s!uden! re ara!ion1 = ='

).

C NMR spectra #Anasa"i Eft*+,&

$am le si/eD abou! <,, mg 0!hree combined s!uden! sam les o" I,7*, mg each1 $olven!D CDCl: 0a ro?ima!ely ,.B mL1 Da!a ac2uisi!ion and rocessingD abou! IJ minu!es 0bu! hal" !ha! !ime >or@s "ine1
= ='

(o!ice !ha! !here a ears !o be only nine resonances ra!her !han !en. (o!ice also !ha! DEP& does no! clear u !his dilemma, bu! 'E&C=R does.

<B,

<,,

4B,

4,,

B,

PP5

).

C /EPT #Anasa"i Eft*+,&

$am le si/eD abou! <,, mg 0!hree combined s!uden! sam les o" I,7*, mg each1 $olven!D CDCl: 0a ro?ima!ely ,.B mL1 Da!a ac2uisi!ion and rocessingD abou! :.B minu!es
= ='

&o D DEP&74:B 0C': and C' u , C'< do>n1 5iddleD 1 , and C' u 1 Co!!omD DEP&7-, DEP&7)B 0C' 0C' u , C'
: <

(o!ice !ha! !he DEP&74:B s ec!rum a ears !o be missing !>o signals8one o" !hem osi!ive 0u 1 and one o" !hem nega!ive 0do>n1. &ha! >ould be only one missing signal i" you coun! >ha! a ears !o be a very small osi!ive signal a! )B mP ho>ever, in some runs !here is no signal a! all a! )B m, and in some !here is a very small nega!ive signal a! )B m ins!ead o" !he very small osi!ive one seen here.

).

C !ETCOR #Anasa"i Eft*+,&

$am le si/eD abou! <,, mg 0!hree combined s!uden! sam les o" I,7*, mg each1 $olven!D CDCl: 0a ro?ima!ely ,.B mL1 Da!a ac2uisi!ion and rocessingD less !han - minu!es
= ='

(o!ice !ha! !he !>o ben/ylic resonances 0C'< and C'1 are bo!h a! )B m. &his e? lains !he a aren! missing resonance in !he 4:C and !he DEP&7)B and !he !>o missing resonances 0one u and one do>n1 in !he DEP&74:B.

<

P P 5 # n d i r e

4, <,, 4B, 4,, PP5 Direc! Dimension B,

Synthesis of Ibuprofen0Part )
1ac2ground Infor$ation ro"en >as develo ed !he Coo!s Pure Chemical Com any = and !hen#bu a!en!ed in 4-I4. #! is a by non7s!eroidal an!i7in"lamma!ory drug =' 0($A#D1 and is mar@e!ed under a >ide varie!y o" !rade names including AdvilT and 5o!rinT. #bu ro"en is one o" several <7aryl ro anoic acids !ha! are curren!ly on !he mar@e!. =!hers include @e!o ro"en, "lurbi ro"en, and na ro?en. &he name Gibu ro"enH originally came "rom !he name isobu!yl ro anoic henolic acid, bu! !his nomencla!ure has no! been Uibu ro"enU used "or many years and, in "ac!, vir!ually all chemis!s !oday are <70)7isobu!yl henyl1 ro anoic acid un"amiliar >i!h i!. Aor!una!ely, ho>ever, !he name is s!ill a reasonably good ma!ch "or !he curren!ly acce !ed name <70)7isobu!yl henyl1 ro anoic acid. 5any me!hods "or ma@ing ibu ro"en have been ublished, bu! !he one !ha! is curren!ly used "or large scale roduc!ion is one develo ed join!ly by Coo!s and 'oechs! Celanese. &his me!hod leads !o very li!!le chemical >as!e and, because o" !his, i! earned !he GPresiden!ial Freen Chemis!ry Challenge A>ardH in 4--*. Curren!ly, CA$A uses !his rocess !o manu"ac!ure *.* million ounds o" ibu ro"en er year in Cisho , &e?as. %n"or!una!ely, !his very e""icien! me!hod re2uires !he use o" carbon mono?ide a! B,, si. Aor !his reason, >e >ill use ano!her rou!e !o ma@e i!. =ur rou!e >ill em loy only reac!ions !ha! are !radi!ionally !augh! in mos! !>o7semes!er in!roduc!ory organic chemis!ry courses. We >ill begin >i!h commercially available p7isobu!ylace!o henone >hich is also >ha! !he 'oechs! rocess begins >i!h. &oday = you >ill reduce !his @e!one !o an alcohol and !hen conver! !he alcohol !o an al@yl chloride. Vou >ill record !he I, 5'/ 4' (5R s ec!rum o" bo!h o" !hese roduc!s. &he I, 5'/ 4' (5R s ec!rum o" !he s!ar!ing ma!erial is sho>n here "or com arison. (e?! >ee@ you >ill conver! !his al@yl chloride !o ibu ro"en 8 7 5 4 3 2 1 by >ay o" carbo?yla!ion o" a Frignard reagen!. 6 0 PPM Procedure 1-(4-Isobutylphenyl)ethanol. Dissolve 4.,, mL o" p7isobu!ylace!o henone in : mL o" me!hanol in a se ara!ory "unnel. Weigh ou! ,.<B g (aC' and !hen very 2uic@ly add i! !o !he se ara!ory "unnel. Allo> i! ) !o si! 4, minu!es. While >or@ing in a "ume hood, add 4, mL o" 4,9 'Cl and !hen e?!rac! !he roduc! "rom !his mi?!ure 0CA%&#=(D considerable ressure buildu E1 using : ? B mL o" e!roleum e!her. Remove !he solven! by ro!ary eva ora!ion "rom a B,7mL round7bo!!omed "las@. Place one dro o" !he roduc! in!o an (5R !ube and add abou! ,.B mL o" CDCl . Record !he 4' (5R s ec!rum. : 1-Chloro-1-(4-isobutylphenyl)ethane. While >or@ing in a "ume hood, use a i e! !o care"ully !rans"er !he 470)7isobu!yl henyl1e!hanol "rom !he revious s!e in!o a se ara!ory "unnel and !hen use !>o B7 mL or!ions o" 4< 5 'Cl !o hel !rans"er any !ha! remains in !he "las@ and !he i e!. $ha@e !his mi?!ure abou! < minu!es. E?!rac! !he roduc! "rom !his mi?!ure >i!h : ? B mL e!roleum e!her, and !hen dry i! >i!h (a $= . Remove !he solven! by ro!ary eva ora!ion "rom a re7>eighed B,7mL round7bo!!omed "las@, < ) and !hen >eigh !o de!ermine !he yield. Record !he 4' (5R s ec!rum using one small dro o" !his roduc!

abou! ,.B mL o" CDCl . $!o er !he "las@. %se a mar@er !o >ri!e your name on i!, and !hen hand i! in in : on a cor@ ring.

(ame

Synthesis of Ibuprofen0Part )
Com le!e !he "ollo>ing !able. &he only densi!y needed is given. $ho> your calcula!ions 0e?ce ! !he calcula!ion o" "ormula >eigh!s1 in !he s ace belo> !he !able. Each calcula!ion should be done in a nea! and easy7!o7"ollo> manner. All uni!s should be included and signi"ican! "igures should be given close a!!en!ion. &.V means !heore!ical yield.
= (aC'
)

'Cl

='

'Cl

Cl

A.W. amoun! moles densi!y ,.-B< 4.,, mL

5ass o" RC "las@ 5ass o" roduc!

g g

5ass o" RC "las@ lus roduc! 9 Vield o" roduc!

Attach the )! NMR spectra o" !he alcohol and !he al@yl chloride !o !he bac@ o" !his shee!. =n each one, dra> !he com ound and indica!e >hich ro!ons are res onsible "or each signal. #" !here are any im uri!ies, iden!i"y !hem also. =n !he bac@ o" !his shee!, ans>er !he 2ues!ions !ha! >ere assigned "or !his e? erimen!.

Synthesis of Ibuprofen0Part 3
1ac2ground Infor$ation Las! !ime you made 47chloro7470)7isobu!yl henyl1e!hane. &oday you >ill conver! !his ben/ylic halide in!o a Frignard reagen! and !hen in!o ibu ro"en.
Cl
W<

5gCl
5g

5g

Cl
C =

= = '

= = '

Cl

5gCl<

Cu! !here is a major roblem >i!h doing !his. Cen/ylic and allylic halides are reac!ive enough !o reac! easily >i!h Frignard reagen!s. #n o!her >ords, in !oday3s e? erimen! a molecule o" 47chloro7470)7 isobu!yl henyl1e!hane can reac! >i!h a molecule o" !he corres onding Frignard !o give a dimer 0"rom !he ancien! Free@ di meaning G!>iceH and meros meaning G ar!PH i.e., a molecule >i!h !>o iden!ical halves1.
5gCl Cl

5gCl
<

Cy ma@ing a chloride ra!her !han a bromide in !he revious s!e >e have already !a@en one s!e !o>ards minimi/ing !his un>an!ed Gcou lingH !o give a dimer. &o "ur!her minimi/e cou ling >e >ill use !e!rahydro"uran 0&'A1 as !he solven! ins!ead o" die!hyl e!her. Any dimer !ha! does "orm can be easily removed. &his is ossible because !he sodium sal! o" ibu ro"en is soluble in >a!er bu! no! in e!her, >hereas !he dimer is soluble in e!her bu! no! in >a!er. Procedure 1-(4-Isobutylphenyl)ethylmagnesium chloride. &o an oven7dried B,7mL round7bo!!omed "las@ add ,.B g o" oven dried magnesium, ,.<B mL o" 47chloro7470)7isobu!yl henyl1e!hane, 4, mL o" &'A, and !hree dro s o" 4,<7dibromoe!hane. A!!ach a re"lu? condenser 0>i!h !he bo!!om join! greased1 and a!!ach a drying !ube !o !he !o o" !his. Cegin hea!ing under re"lu?. When Frignard "orma!ion has begun, as evidenced by a large amoun! o" "oaming, con!inue hea!ing under re"lu? "or an addi!ional :, minu!es. Cool >i!h a >a!er ba!h, disassemble !he a ara!us, and >i e !he grease "rom !he join!s. 2-(4-isobutylphenyl)propanoic acid 0Gibu ro"enH1. While >or@ing in a "ume hood, bubble abou! a li!er o" C= in!o !he reac!ion mi?!ure. Decan! !he solu!ion in!o a se ara!ory "unnel. %se B mL o" die!hyl < e!her !o rinse !he "las@ and magnesium and !hen decan! !his e!her in!o !he se ara!ory "unnel. Add + mL o" 4,9 'Cl and mi?. Remove !he organic hase and se! i! aside. E?!rac! !he a2ueous hase >i!h < ? B mL die!hyl e!her. Combine !he !hree organic layers and e?!rac! >i!h < ? ) mL B9 (a='. Acidi"y !his ne> +7mL a2ueous layer by "rom adding B a2ueous mL 4,9 'Cl. %se li!mus ormL 'die!hyl a er e!her !o ma@e sure !he mi?!ure is $= acidic. E?!rac! ibu ro"en !his mi?!ure >i!h <?B and !hen dry >i!h (a . < ) Remove !he solven! by ro!ary eva ora!ion "rom a re7>eighed <B7mL round7bo!!omed "las@, and !hen use a gen!le s!ream o" air !hrough a i e! !o remove any remaining !races o" !he solven!. Weigh !he "las@ !o de!ermine !he yield. %se abou! ,.I mL o" CDCl !o !rans"er !he en!ire sam le !o an (5R !ube, bu! i" !he solu!ion is : cloudy, use a lug o" co!!on in a i e! !o "il!er i! direc!ly in!o !he (5R !ube. Record !he 4' (5R s ec!rum.

(ame

Synthesis of Ibuprofen0Part 3
Com le!e !he "ollo>ing !able. &he only densi!y needed is given. $ho> your calcula!ions 0e?ce ! !he calcula!ion o" "ormula >eigh!s1 in !he s ace belo> !he !able. Each calcula!ion should be done in a nea! and easy7!o7"ollo> manner. All uni!s should be included and signi"ican! "igures should be given close a!!en!ion. &.V means !heore!ical yield.
Cl = = C= 5g
<

= =' 'Cl

5gCl

A.W. amoun! moles densi!y ,.-I ,.<B mL

5ass o" RC "las@ 5ass o" roduc!

g g

5ass o" RC "las@ lus roduc! 9 Vield o" roduc!

Attach the )! NMR spectru$ o" ibu ro"en !o !he bac@ o" !his shee!. Dra> !he s!ruc!ural "ormula on !he shee! and !hen indica!e >hich ro!ons are res onsible "or each signal. #" !here are any im uri!ies, iden!i"y !hem also. =n !he bac@ o" !his shee!, ans>er !he 2ues!ions !ha! >ere assigned "or !his e? erimen!.

Sa$p%e 'uestions for students #day )&

4. Al!hough >e s!ar!ed >i!h a commercially available sam le o" p7 isobu!ylace!o henone in !his e? erimen!, >e could have s!ar!ed >i!h isobu!yl ben/ene and our "irs! s!e >ould have been !o conver! !his !o p7 isobu!ylace!o henone. Wri!e an e2ua!ion sho>ing ho> !his could be done and !hen >ri!e a mechanism "or !he reac!ion. Ac!ually, >e could have s!ar!ed >i!h ben/ene in our syn!hesis o" ibu ro"enP >e could have conver!ed !his !o isobu!ylben/ene and !hen roceeded as in 2ues!ion M4. Wri!e e2ua!ions sho>ing !he !>o s!e rocedure "or conver!ing ben/ene !o isobu!ylben/ene. 0'in!D &his >ill involve a Clemmensen Reduc!ion.1 Conver!ing an alcohol !o an al@yl chloride in !his e? erimen! could be achieved by sim ly sha@ing in a se ara!ory "unnel a! room !em era!ure, >hereas !he las! !ime you conver!ed an alcohol !o an al@yl halide, i! !oo@ much harsher condi!ions. Why did !his one go so "as! a! room !em era!ure Wri!e a mechanism "or each s!e !ha! >as carried ou! in !he conversion o" p7isobu!ylace!o henone !o 470)7isobu!yl henyl1747chloroe!hane. When deciding >he!her or no! !o sho> a carboca!ion in !he s!e involving !he alcohol >i!h 'Cl, @ee in mind !ha! !his carboca!ion 0i" i! "orms1 >ould be secondary and ben/ylic.

<.

:.

).

Sa$p%e 'uestions for students #day 3&

4. $u ose a s!uden! added >a!er ins!ead o" carbon dio?ide !o !he Frignard reagen! in !his e? erimen!. Dra> !he roduc! !his s!uden! >ould ob!ain. #nclude !he mechanism. $u ose !here >as a ain reliever named i ro ro"en. 0#n !his case, Gi roH s!ands "or iso ro yl jus! as GibuH s!ands "or isobu!yl in ibu ro"en.1 $ho> ho> !o ma@e i! s!ar!ing >i!h ben/ene. E? lain !he me!hod >e used !o ge! reasonably ure ibu ro"en "rom a mi?!ure o" ibu ro"en and <,:7di0)7isobu!yl henyl1bu!ane 0!he GdimerH1. 0< !s1 Loo@ u ibu ro"en in Wi@i edia and s!udy !he Gs!ereochemis!ryH sec!ion. &hen, in your own words, summari/e >ha! i! says. #n ar!icular, address !he "easibili!y o" mar@e!ing jus! one enan!iomer o" ibu ro"en. Ano!her ain reliever in !he same "amily as ibu ro"en is Gna ro?en sodium.H Dra> !his com ound and !hen based on !his, dra> >ha! Gibu ro"en sodiumH >ould be. Dra> a cu!7a>ay vie> o" a recycling solven! s!ill. E? lain ho> i! >or@s.

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).

B.

I.