for sustainable NSAIDs synthesis amides organo-catalyzed by trifluoroaceticacid Beckmann of rearrangement acetophenone oximes to thecorresponding Applied Catalysis A: General

ContentslistsavailableatScienceDirect

Applied

Catalysis

A:

General

jo u r n al ho me p a g e :w w w . e l s e v i e r . c o m / l o c a t e / a p c a t a

Beckmann

rearrangement

of

acetophenone

oximes

to

the

corresponding

amides

organo-catalyzed

by

trifluoroacetic

acid

for

sustainable

NSAIDs

synthesis

Giuseppe

Quartarone,

Elia

Rancan,

Lucio

Ronchin

,

Andrea

Vavasori

DepartmentofMolecularSciencesandNanosystems,UniversityCa’FoscariofVenice,Dorsoduro2137,30123,Venezia,Italy

a

r

t

i

c

l

e

i

n

f

o

Received16September2013 Receivedinrevisedform 27November2013 Accepted21December2013 Available online 28 December 2013 Keywords: Trifluoroaceticacid Organocatalysis Beckmannrearrangement Acetaminophen

a

b

s

t

r

a

c

t

The Beckmann rearrangement of acetophenone oximes to the corresponding amides (4-hydroxyacetophenone oxime to N-acetyl-4-hydroxyacetanilide and acetophenone oxime to N-phenylacetamide) is investigated by using trifluoroacetic acid (TFA) as catalyst. The reaction occurseitherinthepresenceorintheabsenceofasuitablesolvent.Highselectivityandpractically quantitativeyieldtoamideisachievedinbothcasesatTFA/substrate>3.BothTFAandthesolvent (wheneverpresent)couldbeeasilyreusedbydistillationsincenoprotonationofamidesoccurs.The reactionproceedsviaamultistepreactionpathandtheroleofTFAisrelatednotonlytoitsacidity butalsomainlytoitsabilityonformingreactivetrifluoroacetylatedintermediates.Inparticular,the highlyreactivetrifluoroacetylatedamideisactuallytheeffectivecatalyst.Finally,alikelyreactionpath isproposed.

© 2014 Elsevier B.V. All rights reserved.

1. Introduction

Acetanilide (N-phenylacetamide) and paracetamol or acetaminophen (N-acetyl-4-aminophenol) are antipyretic– analgesicdrugs.Besidesacetanilidehasbeenemployedindrug formulationsforlongtime,though,nowforthisuseitisalmost completely substituted by acetaminophen [1–5]. In any case, acetanilideisanimportantintermediateintheproductionoffine chemicals,infact,itisusedasaninhibitorofperoxides,stabilizer forcelluloseestervarnishes,asanintermediateforthesynthesis of rubber accelerators, dyeintermediate and as a precursor in penicillinsynthesis[5].

Acetaminophen production is in continuous growth and its industrialsynthesisisbasedonfourdifferentroutes:(i)from phe-nol,(ii)fromchlorobenzene,(iii)fromnitrobenzeneand(iv)from 4-hydroxyacetophenoneoxime(4-HAPO),thelatterknownalsoas theHoechst-Celaneseprocess[2,3].Inthepast,thefirsttwo pro-cesseswerepredominant,whilethelasttwohavebeenevolvingin recentyears[3].Fromeconomicalandenvironmentalpointofview thefirsttwoshowmoreconcerns,duetothelargecoproductionof unwantedbyproducts(suchasisomersandsalts).Inaddition,the processesarecarriedout inbatchreactors,thusimplyingsmall productionwithhighcosts.

∗ Correspondingauthor.

E-mailaddress:ronchin@unive.it(L.Ronchin).

Conversely,both therouteviaselectivenitrobenzene hydro-genationto4-aminophenolandtheHoechst-Celaneseprocessare continuousmultistageplantdevelopedforlargeproductions[1–4]. Theseprocessesinvolvetheuseofacidcatalystsandtheplantsin operationareactuallyusingmineralacids,whichlimittheir sus-tainabilityfrombothenvironmentalandeconomicalpointofview [4].Thelatter,particularly,comprisesseveralstageswhereacid cat-alystsareinvolved:theFriesrearrangementofphenylacetate,the oximationofthe4-hydroxyacetophenoneto4-HAPOandfinally itsBeckmannrearrangementtoparacetamol[1–3].Aboveall,Fries andBeckmannrearrangementrequirestrongacidsandsevere reac-tionconditions [1–3].Boththestages employmineralacidand inorganicbaseseachonewiththenecessaryhold-upoperation, clearlytheirsustainabilityimprovementpassesthroughtheuseof easilyreusableacidcatalyticsystem.

ThestudiesrelatedtotheBeckmannrearrangementhavebeen particularlyfocusedonthecyclohexanoneoximeto␧-caprolactam conversion,sincethisreactionisofparamountimportanceforthe industry,beingthislactamthekeyintermediatefornylon6 pro-duction[6–10].AlargenumberofpapersdealingtotheBeckmann rearrangementof ketoximes are availablein literature employ-ing liquid and solid acidcatalysts(both inorganicand organic) [11–18],butfewpapersarespecificallyavailableontheBeckmann rearrangementofthe4-hydroxyacetophenoneoximeas interme-diateforacetaminophensynthesis[14–17].Inpatentliteraturethe mostimportantapplicationarereferredtotheCelaneseprocessbut therearesomepatentsclaimingtheBeckmannrearrangementof ketoximestothecorrespondingamides[2,3,19,20].

0926-860X/$–seefrontmatter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.apcata.2013.12.026

N OH

+

Scheme1.SchematicreactionmechanismofTFAcatalyzedBeckmannrearrangementofcyclohexanoneoximeto␧-caprolactamseeRef.[28].

Amongthe liquid acidsTFA appears tobe really interesting forsyntheticpurposes, becauseof itslow boilingpoint(346K), whichallowsaneasyrecoveryand recyclingoftheacidby dis-tillationwithoutproductsdecomposition[21,22].Inaddition,TFA isnontoxic,quitestable,itsdecompositiondoesnotgive harm-ful products and it doesnot giveaccumulation phenomena in theenvironment [23].However,except thepaperof Cossy and coworkers,whoemployedTFAfortherearrangementofketoxime carbonate[24],TFA wasnot usedforthis reactionasa catalyst and only in few cases it was employed in thesolvent system butnot recognizedascatalyst[25].During thelast5 yearsour researchgrouphasstudiedtheBeckmannrearrangementof cyclo-hexanoneoximeto␧-caprolactaminthepresenceofTFAascatalyst [26–29].For instance, we showedthat TFA in CH3CN asa

sol-ventgivespracticallyquantitativeconversionwithhighselectivity in theBeckmannrearrangement of cyclohexanoneoximeto ␧-caprolactam[27–29].Furthermore, thesolventcatalytic system CH3CN-TFAisfullyreusablebecauseoftheacidityoftheTFAdoes

notallowtheformationofthecaprolactamsalt,typicallyobserved withmineralacids,thusitdoesnotneedneutralization[26–29]. Thosepapers clearly evidenced that the reaction occursvia an organocatalyzedpathduetotheformationofcompoundsinvolving TFAesters[26–29].Theproposedreactionmechanismenvisages theformationoftheoximeesterofthetrifluoroaceticacid,which, afterrearrangement,formsatrifluoroacetylacetamide.Thelatter isthekeyintermediateofthecatalysisbeingthe trifluoroacetylat-ingcompoundoftheoxime,whichcontinuouslyreformstheester sustainingthecatalyticcycle(Scheme1).

VeryrecentlyLuoand co-workersdepositedapatentforthe synthesisofamides,basedontheuseofTFA-CH3CNsystem[30].

Asamatteroffact,theapplicationclaimsaprocedurequitesimilar tothatproposedinourpreviouspapersandthefinalresultsare practicallyoverlapping[26–30].

In this work we study TFA as catalyst for the Beckmann rearrangementofaromaticketoximestothecorrespondingamides, employingbothAPOand4-HAPOassubstratesandweshowthat TFAactsinbothcasesasanorganocatalyst.Inaddition,we inves-tigatetheinfluenceof differentsolvents(also neat TFA)and of theoperativevariablesonreactionrateconversionandselectivity. Finally,onthebasisofthereactivityoftheintermediateswe pro-poseareactionmechanism,whichexplainsthebehaviorsofboth theoximes.

2. Experimental 2.1. Materials

Allsolvents and products wereemployed as received with-out further purification. Acetophenone≥98%, trifluoroacetic acid 99%, trifluoroacetic anhydride>99%, nitroethane 96% and

hydroxylamine hydrochloride 99%, dimethyl carbonate were Aldrich products; 4-hydroxiacethophenone≥98% (HPLC), dichloromethane, acetonitrile, nitroethane, were all HPLC grade Fluka products. Dimethyl sulfoxide (DMSO) 99% and 1,2-dichloroethane 99% were ACS reagent Aldrich. Deuterated chloroform,deuteriumoxideanddeuterateddimethylsulfoxide (DMSO-d6)wereEurisoTopproducts.

2.2. Instruments

The gas-chromatograph (GC) Agilent model 6890, equipped withaHP5,filmthickness2.65_␮m,30m_×530_␮mcolumn; detec-tor:flameionizationdetector(FID);carriergas:N2,0.9mL/min;

oven:333–523K(5min)at5K/minwasusedmainlyforthe anal-ysisofAPOreactions.

Thequantitativeanalysesof4-HAPOrearrangementwere car-riedoutexclusivelybyhighperformanceliquidchromatography (HPLC),because4-HAPOandacetaminophendecomposeintothe GCinjector.TheHPLCinstrumentemployedwasaPerkinElmer binaryLCpump250withphenomenexLuna,5␮mC18100 ˚A,LC column300mm×4.6mm(detector:PerkinElmerLC235CDiode Array,wavelengths:255nmand220nm;carrier:mixwater– ace-tonitrile witha concentrationgradient 60% water (9min), 50% water(5min)and30%water(1min)).

DespiteofbothAPOandacetanilidearestablebyGCanalysis therearrangementwasfollowedbyusingeitherGCorHPLC,since intermediatesappearstodecomposebyusingboththetechniques. Thegas-chromatograph coupledmass spectroscopy (GC-MS) Agilent model 5975C interfaced with GC Agilent model 7890 equippedwithaHP5filmthickness0.5␮m,30m×250␮mwas usedthroughouttheexperimentsforcheckingreactionproducts. ThereactioncarriedoutinthepresenceofH2SO4andCH3SO3H

were analyzed after dilution with water and extraction with dichloromethane,therestwereanalyzedwithoutany neutraliza-tion.

The1_{HNMRspectrawererecordedonaBrukerAC200}

spec-trometeroperatingat200.13MHz,thesample temperaturewas maintainedat298K.Thereagentconcentrationswerechosenin ordertosimulatetherealcatalytic conditions.Allthechemical shiftswerereferredtointernaltetramethylsilane.

2.3. Ketoximesynthesis

4-HAPO and APO were synthesized from thecorresponding ketone (4-hydroxyacetophenone and acetophenone) by follow-ing the procedure described in literature [27,28]. In a typical preparation, aflask equipmentequippedwithrefluxcondenser wascharged with170mLof water, 0.51mol of hydroxylamine hydrochloride,0.81molofsodiumacetateand0.15molof4-HAPO. Thereactionwasheatedatca.363Kfor1handthen,aftercooling,

thesolidwasfilterandwashedwithasaturatedsolutionofNaCl andNaHCO3at273K.Thecrude4-HAPOwasdissolvedinwater

andextractedwithdiethylether.Afterevaporationofthesolvent thesolidwastwicerecrystallizedwithdiethyletherandhexane.

NMRassignments:

4-HAPO, white solid, m.p. 413-418K, 1_{H NMR: (200MHz,}

(CD3)2SO),ı10.84(s,1H,N OH),9.60(s,1H, OH),7.49–7.45(d,

2H),6.78–6.73(d,2H),2.09(s,3H)[31];

APO,whitesolid,m.p.331-333K,1_{HNMR:(200MHz,CDCl} 3),ı

9.04(brs,1H, OH),7.68–7.63(m,2H),7.43–7.40(m,3H),2.34(s, 3H)[32].

2.4. SynthesisofO-trifluoroacetyloximesester,N-trifluoroacetyl acetanilide,N-trifluoroacetyl4-hydroxyacetanilide

An attempt to obtain O-trifluoroacetyl-4-hydroxy-acetophenoneoxime (4-HAPO-TFA) byfollowing the procedure reportedforcyclohexanoneoximeinpreviouspapersdoesnotgive satisfactorilyresults[27,28].Infact,theformationof4-HAPO-TFA byreactingtrifluoroaceticanhydridewith4-HAPOisnotobserved since, the instantaneous rearrangement to acetaminophen is observedalsoat298K.

The reactivity of trifluoroacetic anhydride with acetophe-none oxime at 353K gives in few minutes acetanilide but, O-trifluoroacetyl acetophenone oxime (APO-TFA) is formed at 298K by following the procedure reported for cyclohexanone oximeinpreviouspapers[27,28].Thereactionoccursalmost quan-titativelyinvarioussolventinatypicalpreparation 25mmolof APOreactswithanequimolaramountoftrifluoroaceticanhydride in3mLofCH2Cl2.Toavoid fastdecompositionoftheproducts,

APO-TFAismaintainedinaDMSOsolutioninthepresenceofan over-stoichiometricamountoftrifluoroaceticanhydride(1.1equiv. withrespecttoAPO-TFA).Theproductisidentifiedby1_HNMR,

GC–MSandHPLC(seesupplementarymaterials).

N-Trifluoroacetyl-4-hydroxyacetanilide (AcP-TFA) or N-trifluoroacetyl-acetanilide (AcA-TFA) are obtained by triflu-oroacetylation of acetaminophen or acetanilide in acetonitrile, theproductsareidentifiedviaGC–MSandNMR(see supplemen-tarymaterials).Inatypicalpreparation26mmolofparacetamol wasdissolved with3mLof acetonitrile and added 26mmol of trifluoroaceticanhydride in aglass flask,thenthereactionwas stirredfor1hat298K.Thesolventwaseliminatedundervacuum byarotaryevaporatorat298K; adeliquescentwhitesolidwas obtainedand analyzedby HPLC,GC–MSand NMR (see supple-mentarymaterials).Analogousprocedurewasfollowedtoprepare N-trifluoroacetyl acetanilide (see supplementary materials). It is noteworthy that all the compounds are moisture sensitive. Toavoid fastdecompositionof theproducts, both AcP-TFAand AcA-TFA are maintained in a DMSO or CH3CN solution in the

presenceofanover-stoichiometricamountofTFA(1.1equiv.with respecttoAcP-TFAorAcA-TFA).

NMRassignments:

APO-TFA, 1_{H NMR (200MHz, CDCl}

3), ı 7.75–7.70 (m, 2H),

7.54–7.26(m,3H),2.51(s,3H);

acetanilide,whitesolidm.p.385–389K,1_{HNMR(200MHz,CDCl} 3), ı8.19(brs,1NH),7.55–7.51(m,2H),7.33–7.25(m,2H),7.13–7.06 (m,1H),2.15(s,3H)[33]; AcA-TFA, 1_{H NMR (200MHz, CDCl} 3), ı 7.52–7.47 (m, 3H), 7.25–7.20(m,2H),2.55(s,3H);

acetaminophen,whitesolidm.p.440–443K1_HNMR((CD 3)2SO,

200MHz),ı9.63(s,1H, OH),9.12(brs,1H, NH),7.36–7.31(d, 2H),6.69–6.65(d,2H),1.98(s,3H)[34];

AcP-TFA,1_{HNMRı9.64(s,1H, OH),7.45–7.32(d,2H),6.70–6.65}

(d,2H),1.97(s,3H).

2.5. Beckmannrearrangementreactions

Alltheoperationswerecarriedoutundernitrogen(chargedat atmosphericpressure)inajacketedsealedglassreactor(10mL) atseveraltemperaturesandautogenouspressure.Thecourseof reactionswascheckedsamplingtheliquidphasebyasyringeat establishedintervals.AlltheanalyseswerecarriedoutbyGCand GC–MSwhen APOwasemployedas substrate,while HPLCand GC–MSwereusedwhenthesubstratewas4-HAPO.Thepotentialof themethodasanalternativesyntheticrouteforobtainingdifferent amideshasbeentestedonseveraloximesgiving,inanycase,high yieldinthecorrespondingamides(seesupplementarymaterials).

In a typical experiment, a glass reactor was charged with 1.3mmolof4-HAPO,9mLofnitroethaneand 12.5mmolofTFA under nitrogen.Thereaction time wascomputedafter theTFA addition.

The firstderivativeat time 0 ofthe third orderpolynomial, obtainedbyfittingthetimedecreasingconcentrationof4-HAPO, givestheoverallinitialreactionrate,thusallowingthecontrolof theinfluenceoftheoperativevariableonthereactionkinetics.In thiscasesubstrateconsumptionandamideformationhasbeen fol-lowedbyHPLCanalysissinceGCcannotbeemployedsinceeither 4-HAPOoracetaminophendecomposeintheGCinjectionsystem, givingnotreliableresultsinthequantitativeanalysis.

TheinitialrateofAPOrearrangementwasmeasuredbythefirst derivativeattime0ofthethirdorderpolynomialobtainedbyfitting thetimevs.acetanilideformationdata.Thedifferentmethodsinthe calculationoftheinitialrateofreactionforthetwosubstrateisdue thefactthatAPOshowsacomplexreactionpath,thenacetanilide formationappearstobeasimpleandreproducibleparameterfor measuringtheoverallreactionrate.

2.6. Products,solventandcatalystrecovery

Thereactedmixtureistransferredtoaminidistillation appara-tusequippedwithmembranepump,operatingat130Paandwitha condenserchilledat273Kwithacirculatingthermostat.The mix-tureisheatedat353K,thanthesolventquicklydistils.Thesolvent recoveredisover95%oftheinitialsolvent,therestisinthe distil-lationapparatus.Theresidueisrecoveredandtheisolatedyieldof acetanilideandacetaminophenareca.90–95%.

3. Resultsanddiscussion

3.1. InfluenceofthesolventontheBeckmannrearrangementof 4-HAPOandAPOcatalyzedbyTFA

Table1reportstheinfluenceofthesolventontheBeckmann rearrangementreactionof4-HAPOandAPOafter2hofreaction.

Itisnoteworthythatconversionsareclosetocompletenessin thepresenceofvarioussolvents,insomecasesthereactionis prac-ticallyquantitativetothedesiredamide,exceptentries4,6and 8thatarecarriedoutinthepresenceofethanol,DMCandDMSO, respectively.Asregardthereactivityin ethanol,thebehavioris expected,since TFA reacts almostinstantlywith thealcohol to giveethyltrifluoroacetate,thussubtractingtheacidtothe reac-tionenvironment.InthepresenceofDMCthereactiondoesnot proceed but no byproductswere observed. Thisstrong solvent effect is generally related toa stabilizationof a charged inter-mediate, whose stability increases theactivation energy of the overallprocess[35].Thisstrongsolventinteractioninhibitsalso allthereactionsinvolvedintheprocess(oximehydrolysisand/or

Table1

Beckmannrearrangementof4-HAPOandAPOcatalyzedbyTFAinthepresenceofvarioussolvent.

Entry Solvent 4-HAPO APO

Conv.a_{(%) Select.}b_{(%) T(K) Conv.}a_{(%) Select.}c_{(%) T(K)}

1 Acetonitrile 99 99 343 >99 60.2d ₃₅₈ 2 Nitromethane >99 99 343 >99 99 358 3 Nitroethane >99 >99 343 >99 >99 358 4 Ethanol /e _{/ 343 /}e _{/ 358} 5 1,2-Dichloroethane 97 96 343 96 95 358 6 DMC <1 / 343 <1 / 358 7 DMSO / / 343 / / 358 8 Chloroform 96 96 343 96 98 358 9 TFA 97 96 343 >99 99 358 10 CH3SO3H 98 99 343 99 99 358 11 H2SO475% 99 99 343 99 99 358

Runcondition:molarratioTFA/substrate=10,TFA=13.2mmol,totalvolume=10.8mL,timeofreaction120min.

a_{Oximeconversion.} b _{Selectivitytoacetaminophen.} c _{Selectivitytoacetanilide.}

d _{FormationofAPO-TFAareobserved;after18hofreactionacetanilideyield99%.} e_{TFAisconvertedquantitativelytoitsethylesterandreactiondoesnotproceedfurther.}

esterification).Infact,thesereactionsareobservedforAPO(entry1) aswellasforcyclohexanoneoximerearrangementinTFA–CH3CN

[26–29].Correspondingly,inDMSO(entry7),thereactiondoesnot proceed,likelyforasimilarsolventreason[35].Entry8showshigh conversionandselectivityforboth4-HAPOandAPOinchloroform asthesolvent.

ReactionscarriedoutinneatTFA(entry9)showhighconversion andselectivitytothedesiredamideforeither4-HAPOorAPO.

Entries10and11showthereactivityinCH3SO3HandH2SO4

70%, as expected in both cases high conversion and selectiv-ity are achieved but dilution in water and extraction with dichloromethaneneedstorecovertheproducts.

Theprocedurehasalsobeentestedonseveralketoximesand aldoximesgivinghighyieldinthedesiredamides,some prelim-inaryresultsareavailableonsupplementarymaterialsbutthisis beyondthescopeofthepresentresearchandfurtherinvestigations areincourse.

3.2. Timevs.concentrationsprofileoftheTFAcatalyzed Beckmannrearrangementinnitroethaneasasolvent

Fig.1showsthetimevs.concentrationsprofileoftheBeckmann rearrangementof4-HAPOandAPOcatalyzedbyTFAinnitroethane asasolvent.

ThecomparisonofthetwoplotsofFig.1showsapparentlytwo completelydifferenttrends.The4-HAPOrearrangementshowsthe disappearingoftheoximewiththeconcomitantincreaseofthe rel-ativeamide(acetaminophen).Onthecontrary,therearrangement ofAPOshowsacomplexreactionpattern,inwhichisevidenced thatpartofthestartingoximeistransformedalmostimmediately invariousintermediatesaftertheadditionoftheTFA.Furthermore, acetanilideformationpresentsaninductionperiod;thissuggests thattheformationofacatalyticallyactiveintermediaterequiresa certaintimetoreachtheminimumconcentrationforstartingthe catalysisoftherearrangementtoacetanilide.Suchaninduction periodistemperaturedependant(seesupplementarymaterials) anddecreasesastemperatureraises.TheintermediateofFig.1(b) hasbeenidentified(GC–MS,NMRandcomparedwithastandard seesupplementarymaterials)asAPO-TFAandAcA-TFA,while ace-tophenonederivefromAPOhydrolysisduetothereactionofthe protonatedformofAPO(APOpKa=2.52,TFApKa≈0.47)withthe

waterderivingfromtheformationoftheAPO-TFA(esterification), orfromasecondaryreactionpathalreadydescribedinaprevious paper[27–29,36–38].

Thisclass of products, suggestsa reaction path for theAPO Beckmannrearrangement,similartothatproposedfor cyclohex-anoneoxime[27,28].Onthecontrary,thetimevs.concentration profileofthe4-HAPOrearrangementwould suggesta Brønsted

a

b

Fig.1. Timevs.concentrationsprofileoftheBeckmannrearrangementof4-HAPO(a)andAPO(b)innitroethane.Runconditions:reactiontemperature343K,molarratio TFA/substrate=10,nitroethane/substrate=100,TFA=13.2mmol(14mmolforAPO).In(a):()=4-HAPO,(䊉)=AcP;in(b):()=APO,()=acetophenone,()=APO-TFA, ()=AcA-TFA,(䊉)=acetanilide.

0 50 100 150 200 250 300 350 0 25 50 75 100 S pec ies, (m ole %)

Time, (minutes)

Fig.2.Timevs.concentrationsprofileoftheBeckmannrearrangementofAPOin nitroethanebyusingGCanalysis.Runconditions:reactiontemperature353K,molar ratioTFA/substrate=12,nitroethane/substrate=100,TFA=14.0mmol;()=APO, ()=acetophenone,(䊉)=acetanilide,()=acetanilideGC.

acidcatalyzedrearrangementsimilartothatobservedinmineral acid[38–41].Nevertheless,thismarkeddifferenceinthereaction pathbetweenAPOand4-HAPO,evidencedinFig.1couldbeonly apparent,becauseofthedifferentmethodofanalysisemployedfor thetwosubstrates(GCandHPLC,respectively).Infact,theneed ofusing HPLCfor analyzingthesamplesof reactionof4-HAPO rearrangement may cause the hydrolysis of the intermediates, which,onthecontrary,areactuallypresentintothereaction mix-ture.Thisisdemonstratedbyfollowing4-HAPOrearrangementvia NMRinCDCl3,thespectrashowcomplexreactionpattern,where

severalintermediatesareobserved,butanunambiguous identifi-cationoftheintermediatesisnotpossible(seesupplementary).A furtherhintthatthelackoftheintermediatesofthetimevs. con-centrationsprofileof4-HAPOrearrangementisduetoananalytical problemisevidentbynotinginFig.2(comparewithFig.1(b))that thetimevs.profileofAPOrearrangementisdifferentifthereaction courseisfollowedbyHPLCorbyGC.Asamatteroffact,thevarious intermediates,evidencedbyGCanalysisdisappear.Fig.1(b)shows theformationofAcA-TFA,immediatelyaftertheadditionofTFA thussuggestingafastrearrangementofAPO-TFA.

Inordertohighlightthisbehaviorsthereactivityofreagents and intermediateswithoximes,water and theirstability under differentconditionsarereportedinTable2.

The trifluoroacetylation of both the molecules occurs easily withtrifluoroaceticanhydride.Infact,theanhydridereactswith 4-HAPOat298Kgivingseveralcompounds,whoseequilibriaafter dilution give acetaminophenquantitatively (see supplementary materials).Incontrast,APOreactswithtrifluoroaceticanhydride giving APO-TFA, which is stable at 298K, but it rearranges at 343KinthepresenceofTFA.Inthegasphase,intotheGC injec-tor,APO-TFArearranges promptlytoAcA-TFA (yield70%),thus explaining theinstantaneousformation ofAcP-TFAobserved in Fig.1(b).APO-TFA,AcP-TFAandAcA-TFAaremoisturesensitive givingfasthydrolysistoAPOandtothecorrespondingamidesand releasingTFA.Intheabsenceofwater,AcP-TFAandAcA-TFAreact almostquantitativelywithAPOtoAPO-TFAand/ortoacetanilide and acetaminophen. Furthermore,AcP-TFA and AcA-TFAin the presenceof4-HAPOmediateitsrearrangementtoacetaminophen also at 298K (see Table 2). This explains the trend of Fig. 2, wherenointermediatesareobservedbutonlyAPOconsumption andacetanilideformationduetothehydrolysisofthe interme-diatesduringHPLCanalysis.Startingfromtheseresultsitisclear

0.00280 0.00285 0.00290 0.00295 0.00300 0.00305 0.00310 -0.018 -0.016 -0.014 -0.012 -0.010 -0.008 TC = -53 kcal mol-1 TC = -32 kcal mol-1 R ln r0 , ( kc al K -1 mo l -1 ) T-1_{, ( K}-1₎ TC = -20 kcal mol-1

Fig. 3.Arrhenius plot of initial rate from Beckmann rearrangement from 4-HAPO in nitroethane. Run conditions: molar ratio TFA/substrate=10, nitroethane/substrate=100,TFA=13.2mmol.

thataprecisequantificationofreactionintermediatescannotbe obtained,sincethermalrearrangementandhydrolysisalter signif-icantlytheirdistributionvs.time.Thisbehaviorsuggeststhatthe formationofthetrifluoroacetylated-amideintermediateisthekey stepintherearrangementofbothoximesinagreementwithour previousinvestigation[26–29].

In addition, the reactivity of the trifluoroacetylated amides allowsproductsrecoverywithoutwork-upoperations,whichare converselyindispensableinthepresenceofmineralacids[26–29]. 3.3. EffectoftemperatureontheinitialrateofBeckmann

rearrangementinnitroethaneasasolvent

Theeffectofthetemperatureoninitialratesofrearrangement of 4-HAPOis reported in Fig.3. The Arrheniusplot of 4-HAPO rearrangement(Fig.3)showsanoticeablenonlineartrend,thus suggestingacomplexreactionpath,whichisinagreementwith themultistepmechanismproposedintheprevioussection.From anestimateofthetemperaturecoefficient(TC),calculatedby divid-inginzonesthecurveoftheArrheniusplot,itappearsvaluesofTC rangingfrom20to50kcalmol−1.Thisconfirmsthatseveralstages influencetheoverallkinetics, thusthevariationoftemperature causesthechangesoftheactivationenergyoftheratedetermining step.

Atdifferenceofwhatobservedfor4-HAPO,theinitialrateof theBeckmannrearrangementofAPOislinear(seesupplementary materials).ApparentlythisdisagreeswiththeresultsofFig.1(b), whichshowstheformationofseveralintermediates.Thevalueof theTCofabout20kcalmol−1issimilartothatmeasuredfor4-HAPO athighertemperaturesandispracticallythesamewithrespectto thatmeasuredinmineralacid[38–41].

3.4. Effectofsubstrateconcentrationontheinitialrateof Beckmannrearrangementinnitroethaneasasolvent

Fig.4reportstheinfluenceofthesubstrateconcentrationon theinitialrateofBeckmannrearrangementof4-HAPOandAPO. Asexpectedinbothcases,theinitialrateofreactionincreasesas substrateconcentrationraise.Apowerlowequationrate satisfac-torilyfitexperimentaldatabecauseofthelinearityofthedouble logarithmicplot(seesupplementarymaterials)andthecalculated

Table2

Stabilityofthereagentsandintermediatesafter60minofreactionsundervariousconditions.

Compoundtested Stabilityundervariousconditions Reagent

Liquid298K Liquid343K GasGC533K APO343K 4-HAPO343K H2O298K

Yield%

4-HAPO NR Est/Rea _Decb _{/ / Hy}c_/Re=1/2

APO NR Est/30 NR / / Hyc₌₁

4-HAPO-TFA Re=100 Re=100 Decb _{/ / /}

APO-TFA NR Re=30 Re=70 / / Hy=100d

AcP-TFA NR NR Decb _{Ex/Re=100/30 Ex/Re=100/40 Hy=100}e

AcA-TFA NR NR NR Ex=100 Ex/Re=100/40 Hy=100e

Runconditions:solventCH3CN,reactionvolume10mL,TFAconcentration0.1molL−1,TFA/substrate=1,substrate/reagent=1.

Est=esterification,GasGC=GCinjector,Re=rearrangement,Dec=decomposition,NR=noreaction,Ex=exchange,Hy=hydrolysis.

a_ViaNMR.

b _{Tracesoftrifluoroacetylatedcompoundsareobservedbutextensivedecompositionoccursduetothepoorthermalstabilityofphenolsandaminophenols.} c _{Hydrolysistoketone.}

d _{Hydrolysistooxime.} e_{Hydrolysistoamide}

reactionordersare0.7and0.6for4-HAPOandAPO,respectively.A nonintegerreactionordersuggeststhattherearesomestepsthat influencetheratedeterminingstepofthereaction[42,43].Thisis evidentfortherearrangementofAPO,whosetimevs. concentra-tionprofile(Fig.1(b))showssomeintermediates.Forinstance,the formationofAPO-TFA,whichisanester,isastepwhose contribu-tioneasilyexplainsanonintegerreactionorder[42,43].Itislikely thatalsofor4-HAPOrearrangementthekineticsshouldbe influ-encedbyanalogousesterificationandprotonationequilibria,thus explainingthenonintegerreactionorderandthevariationofthe TCwithtemperature.

3.5. InfluenceofTFAontheinitialrateofBeckmann rearrangementinnitroethaneasasolvent

InTable3theinfluenceoftheTFA/substrateratioonconversion andselectivityafter18hofreactionisreported.Itisnoteworthy thatataratiohigherthan3theconversionispractically quantita-tiveandselectivityisashighas95%inthedesiredamideandonly atTFA/substrateratioof1ketoneformationoccursnoticeably.The reasonofsuchabehaviorislikelyduetotheesterificationequilibria oftheoxime,whichisfavoredatthehighestTFA/substrate.

InFig.5thetrendoftheinitialrateofrearrangementof4-HAPO andAPOvs.theconcentrationofTFAisreported.

In both cases the trend of theinitial rateof rearrangement increaseswithrespecttoTFAconcentrationupto2molL−1.AtTFA

concentrationshigherthan2molL−1,therateofrearrangement of 4-HAPOreachesa plateauand after 2.5molL−1 alsoa slight decreasecanbenoted.AnalogoustrendisobservedalsoforAPO, withaconstantincrease till3.2molL−1,athigherconcentration two phases is observed. It is likely that, as already observed for the Beckmann rearrangement of cyclohexanone oxime in TFA–CH3CN,protonation,esterificationandexchangebetweenthe

trifluoroacetylatedamideandthestartingoxime,areallreactions affectingtheoverallreactionrate[26–29].

3.6. BeckmannrearrangementinTFAascatalystandsolvent Fig.6showsthetimevs.concentrationprofilesregardingtothe Beckmannrearrangementof4-HAPOandAPO,respectively, cat-alyzedbyneatTFA,whichactsalsoasthesolvent.Bothreaction profilesaresimilartothoseobservedinthepresenceofnitroethane asasolvent(seeFig.1), excepttheabsenceofacetophenoneas byproduct,fortherearrangementofAPO,whichcausesafurther increaseoftheselectivitytowardtheacetanilide(seeFig.6(b)). Thesamebehaviorofthereactioncarriedoutinthepresenceof nitroethane(Fig.2)isobservedbyanalyzingthesamplesviaHPLC (seesupplementary)inwhichnointermediatesareobservedfor APOrearrangement.Thisisinagreementwithwhatalready dis-cussed in Section 3.2 suggesting that HPLC analysiscausesthe hydrolysisofthetrifluoroacetylatedintermediates(4-HAPO-TFA andAcP-TFA)alsointhecaseof4-HAPO.

Fig.4.Influenceof4-HAPO(a)andAPO(b)concentrationontheinitialrateofBeckmannrearrangementof4-HAPOinnitroethane.Runconditions:reactiontemperature 343K,molarrationitroethane/TFA=10,TFA=13.2mmol(14mmolforAPO).

Table3

InfluenceoftheTFA/substrateratio.

Entry TFA/substrate 4-HAPO APO

Conv.a_{(%) Selectivity(%) Conv.}a_{(%) Selectivity(%)}

Amide Ketone Othersb _{Amide Ketone Others}c

1 1 64 29 70 1 55 5 75 20 2 1.5 90 51 31 18 84 27 60 13 3 2 99 76 14 10 91 46 20 14 4 3 99 95 3 2 99 94 3 3 5 5 99 98 / 2 99 96 / 3 6 10 99 99 / 1 99 98 / 2

Runconditions:solventCH3CH2NO2,reactionvolume10mL,TFAconcentration0.1molL−1,T=353K,timeofreaction18h. a_{Oximeconversion.}

b_{Condensationproducts.}

c _{Othersaremainlytrifluoroacetylatedamideandketoxime.}

3.7. EffectoftemperatureoninitialrateofBeckmann rearrangementinTFA

The trend of the Arrhenius plot of the initial rate of rearrangementof4-HAPOandAPOaresimilarofthoseobtained innitroethane(seesupplementarymaterials),withanonconstant valueoftheTCfor4-HAPOcomprisedbetween7and30kcalmol−1. Asalreadypointedoutforthereactioncarriedinthepresenceof

nitroethaneasasolvent,thisbehaviorsuggestsacomplexreaction path,whereseveralstagesinstationarystateareinvolved.Thenon homogeneousvaluesoftheTCforAPOrearrangementarefurther evidencesthatthereactionismultistepwithequilibria[42,43].

ThevalueofTCfortherearrangementof4-HAPOinneatTFAis lowerthanthatobservedinthepresenceofnitroethane, suggest-ingastabilizationeffectoftheactivatedstateinthepresenceof neatTFA.TheTCforAPOrearrangementispracticallythesame

Fig.5.InfluenceofTFAconcentrationontheinitialrateofBeckmannrearrangementof4-HAPO(a)andAPO(b)innitroethaneasasolvent.Runconditions:reaction temperature363K,molarrationitroethane/TFA=10,nitroethane/substrate=100,TFA=13.2mmol(14.0mmolforAPO),molarrationitroethane/substrate=100.

a

b

Fig.6. Timevs.concentrationsprofileoftheBeckmannrearrangementof4-HAPO(a)andAPO(b)inneatTFA.Runconditions:reactiontemperature343K,molarratio TFA/substrate=10,TFA=33.1mmol.In(a):()=4-HAPO,(䊉)=AcP;in(b):()=APO,()=AcA-TFA,()=APO-TFA,(䊉)=acetanilide.

Table4

InfluenceoftheTFA/substrateratio.

Entry TFA/substrate 4-HAPO APO

Conv.a_{(%) Selectivity(%) Conv.}a_{(%) Selectivity(%)}

Amide Ketone Othersb _{Amide Ketone Others}c

1 1 66 70 29 1 56 8 16 62 2 1.5 99 85 3 12 99 58 2 40 3 2 99 94 2 4 99 93 2 5 4 3 99 96 2 2 99 95 2 2 5 5 99 98 / 2 99 98 / 2 6 10 99 99 / 1 99 99 / 1

Runconditions:substrate1mmolT=353K,timeofreaction18h.

a_{Oximeconversion.} b _{Condensationproducts.}

c _{Othersaremainlytrifluoroacetylatedamideandketoxime.}

of that measured in the presence of nitroethane as a solvent (TF=21kcalmol−1).

3.8. Effectofsubstrateconcentrationontheinitialrateof BeckmannrearrangementinTFA

InTable4theinfluenceoftheTFA/substrateratioonconversion andselectivityafter18hofreactionisreported.Asinthepresence ofnitroethaneasasolventataratiohigherthan3theconversion ispracticallyquantitativeandwithamidesselectivityhigherthan 95%.

InFig.7arereportedtheinitialrateof4-HAPOandAPO.Fig.7 shows in both cases an increasing trend of the initial rate of rearrangementastheconcentrationofsubstrateraise.Asregard 4-HAPO,thepowerlawkineticsgivesagoodfitofthe experimen-taldatawithareactionorderof1.72(seesupplementarymaterials), atdifferenceofwhatobservedinnitroethaneasasolvent,where thekineticsshowsareactionorderlowerthan1(0.72).This behav-iorislikelyduetothesolventeffectontheequilibria(forinstance protonationand/oresterificationofoxime)inwhichthesubstrate isinvolved,andnotfromachangeofreactionmechanismforthe absenceofthesolvent[42,43].

Fig.7(b)reportsthetrendofinitialrateofrearrangementvs. APOinitialconcentration;thepowerlawkineticsfitsthedata giv-inganoverallreactionorderofabout1.78,whichisalsointhis casegreaterthan1.Inthisway,thereactionorderisincreasedof anunitycomparedtothatmeasuredinthereactioncarriedoutin nitroethane.Alsointhiscase,asolventeffectislikelyactingonthe variousequilibriapresentinthereactionenvironment[35,42,43].

3.9. Hypothesisonreactionmechanismandreactivityofthe intermediates

The reaction path for APO rearrangement is clearly via the intermediatesAPO-TFAandAcA-TFA,whichareevidencedinthe reactionmixture (Figs. 1(b)and 6(b))and isolated(see supple-mentary).Inadditions,thereactivityoftheintermediatessuggests theactiveroleofTFAasorganocatalystbeingtheessential com-ponentintheirformationandnotonlytheprotondonor.Inany case,areactionpathviaapurelyBrønstedacidcatalysiscannot becompletelyruledoutbeingtheoximeeasilyprotonatedinthis rangeofacidity[38,39].Inaddition,theFT-IRspectraofthe 2,4,6-trimethylacetophenoneoximeinthepresenceofTFAat298Kdo notshowformationofnitriliumion(seespectrainsupplementary materials),whichisobservedinstrongmineralacidunderthesame conditionswiththisoxime[38–41].

The induction period in the acetanilide formation is a fur-therevidencethat a Brønsted acidcatalysisfor APOBeckmann rearrangementispoorlyprobable.Asamatteroffact,protonation isafastreaction,andthenitdoesnotexplaintheinductionperiod observedinacetanilideformation.Onthecontrary,theexplanation ofaninductionperiodcouldbeconnectedwiththeformationofa longlivingintermediate,whichretardstheconversiontothefinal product[42,43].Anotherpossibleexplanationofthelong induc-tionperiodcouldberelatedtoanautocatalyticphenomena[42,43]. For thesereasonsit is morelikely that theinductionperiod in acetanilideformationiscausedbytheneedsofformingAcA-TFA, whichistheintermediatethatclosethecatalyticcycle(Scheme2). Theseevidencessuggestareactionmechanism(Scheme2),which

Scheme2. MechanismoftheBeckmannrearrangementcatalyzedbyTFA.

isinagreementwiththatproposedforthecyclohexanoneoxime andincludingthefollowingsteps:

(i)APO reacts with TFA to give the ester APO-TFA (equilib-rium)[26–29].Thiscompoundhasahighlyelectrondeficient nitrogenatom,thusallowingeasyBeckmannrearrangement [38–41].

(ii)APO-TFArearrangestoAcA-TFA(irreversible)[38–41]. (iii)AcA-TFAreactswithAPOtogiveacetanilideplusAPO-TFAand

withwatertogiveTFAplusacetanilide.

Unfortunately,itisnotpossibleastraightparallelismbetween the reactivity of 4-HAPO with that of APO, since the time vs. concentration profileof theformer present apparently no evi-dentintermediates,thenitdoesnotallowanydirectcomparison. However,asalreadypointedoutinSection3.2,theabsenceof inter-mediatesisduetotheirhydrolysisduringsamplespreparationfor carryingoutHPLCanalysis.4-HAPOrearrangementhasbeen fol-lowedbyNMRinCDCl3 anditshowscomplexreactionpattern,

whereseveralintermediatesareobserved,butasureidentification oftheseintermediatesisnotpossible(seesupplementary materi-als).Inaddition,thereactivityofAPOand4-HAPOwithAcP-TFA givesalmostinstantlyatroomtemperatureexchangereactionto acetanilideplusacetaminophenanda furtherrearrangementto acetaminophenisobservedfor4-HAPO(seeTable2).Startingfrom theseevidences,eventhough,AcP-TFAhasnotbedirectlyobserved duringthereaction,itislikelythatAcP-TFAcouldbeinvolvedin 4-HAPOrearrangement,thussuggestingtofollowthesame mecha-nismproposedforAPO(Scheme2).Fig.8reportssomeNMRspectra

relatingthetransformationof4-HAPOintrifluoroaceticanhydride toAcP-TFA.

AtdifferenceofAPO-TFA,wearenotabletoisolate 4-HAPO-TFA(seeTable2),buttheNMRspectraofthereactionof4-HAPO withtrifluoroaceticanhydrideat298KinDMSOgivessome use-fulinformation.Forinstance(seespectra3–4),inthepresenceof 0.3and0.7equiv.oftrifluoroaceticanhydride(withrespecttothe 4-HAPO)itappearstwospecies:AcP-TFAandthesecondonehas thesamespectrumofthe4-HAPOinthepresenceofTFA (com-parewithspectrum2).Increasingto0.9equiv.oftrifluoroacetic anhydride,thesignaloftheAcP-TFAremainspracticallytheonly one(comparewithspectra5and6).Itisnoteworthyto remem-berthatthereactiondoesnotoccurinthepresenceofTFAand inDMSOasasolvent(seeTable1),butisfastinthepresenceof trifluoroaceticanhydrideat298K,too.Itislikelythatacharged intermediate isnot necessary,inthepresence oftrifluoroacetic anhydride,sinceitisaquitestrongneutralelectrophilewhose reac-tivityislessinfluencedbysolventpolarity[35].Thisbehavioris inagreementwiththeformationofaneutralintermediatesuchas theester(forinstanceAPO-TFAand/or4-HAPO-TFA),which under-goesrearrangementwithouttheinvolvementofanacidcatalysis. ThepresenceofthestronglysolvatingDMSOorDMCstabilizesthe protonatedoximes,whicharenotinvolvedinthecatalyticprocess. ThecomplexbehavioroftheTCisaclearevidencethatthe4-HAPO rearrangementfollowsamultistepmechanism,sincethis behav-iorcannotbeexplainedmerelyintermsofaBrønstedacidcatalysis [42,43].Themultisteporganocatalyzedreactionmechanism,which isevidentforAPO,explainswithoutcontradictionsalsothe reactiv-ityof4-HAPO,ofAcP-TFAandthecomplexbehavioroftheTC,for

Fig.8.1_HNMR((CD

3)2SO,200MHz)spectrarelatingthetransformationof4-HAPOinthepresenceoftrifluoroaceticanhydride(ATF)andTFAandthecomparisonwith

AcP-TFAandacetaminophen(AcP)inthepresenceofTFA.

thisreasons,itappearsmorelikelythantheBrønstedacidcatalyzed path.

4. Conclusions

TheuseofTFAinthesynthesisofparacetamolandacetanilide withrespecttothetraditional processeswhichemploymineral acidorthionylchloridepresentsthefollowingbenefits:

i.lowertoxicity;

ii. easierseparationofreactionmixtureandrecyclablesolvent; iii.TFAmaybeusedpureorincombinationwithotheraqueousor

notaqueoussolvent.

Besides,thenewfeaturesofthesyntheticprocedure,we pro-poseareactionpathwaywhereTFAactsasanorganocatalystby formingtheoximeester,whichrearrangetothecorresponding tri-fluoroacetylamide,beingthelatter,inturn,responsibleforthe trifluoroacetylationoftheoxime,closing thecatalytic cycleand

givingfinallythedesiredamide.Thisreactionmechanismseemsto bequiteevidentforAPO,butbytakingintoaccountthebehavior oftheTC,thereactivityof4-HAPOintrifluoroaceticanhydrideand thatofAcP-TFA,suchpathwaycouldbereasonablyextendedalso toacetaminophenformation.

Acknowledgements

FinancialsupportbyCa’FoscariUniversityofVeniceisgratefully acknowledged(ADIRfund2011).AspecialthanktoMr.Claudio Tortatoforthehelpfuldiscussions.

AppendixA. Supplementarydata

Supplementary data associated with this article can be found,intheonlineversion,athttp://dx.doi.org/10.1016/j.apcata. 2013.12.026.

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