Supporting information for: Rational design of dinitroxide biradicals forefficientcross-effectdynamicnuclearpolarization

DominikJ.Kubicki,†aGillesCasano,†cMartinSchwarzwälder,dSébastienAbel,cClaireSauvée,cKarthikeyan Ganesan,c Maxim Yulikov,d Aaron J. Rossini,a Gunnar Jeschke,d ChristopheCopéret,dAnneLesage,bPaulTordo,*cOlivierOuari,*candLyndonEmsley.*a

†Theseauthorscontributedequallytothiswork.aInstitutdesSciencesetIngénierieChimiques,EcolePolytechniqueFédéraledeLausanne(EPFL),CH-1015Lausanne,Switzerland.bUniversitédeLyon,InstitutdeSciencesAnalytiques(CNRS/ENSdeLyon/UCB-Lyon1),CentredeRMNàTrèsHautsChamps,69100Villeurbanne,France.cAixMarseilleUniversité,CNRS,ICRUMR7273,13397Marseille,France.dETHZurich,DepartamentofChemistry,LaboratoryofInorganicChemistry,8093Zurich,Switzerland.

Table of contents

SampleCompositionsforDNPExperimentsandrecordedTDNP(1H).....................................2

Acquisitionparameters......................................................................................................3

MAS-DNPNMRspectra......................................................................................................4

EPRmeasurements............................................................................................................6

Quenchingfactormeasurements.......................................................................................8

Synthesisofreportedmolecules........................................................................................9Descriptionofthesyntheticschemes...........................................................................................9

SyntheticroutetobTurea-diMe(5),bTurea-diCD3(6),PyPol-DiMe(20),PyPol-diCD3(22),TEKurea(10),TEKurea-diMe(11)andPyPol-CD3(21).....................................................................9Syntheticroutetobp-EtCO2CTurea(12)andTetraPEG(13)........................................................10SyntheticroutetoKbCTurea(PEG)4(14).......................................................................................10SyntheticroutetoPyPolPEGNH2(17)...........................................................................................11Generalsyntheticroutetob-3,5-diMePyTbK(38),TEKPol2(34),TEKPol3(35),TEKPol4(36),TEKPol5(37),(Adm)2TbK(31),bEtTbk(29),bPEtTbK(30)andbTbK-d24(28)...............................12Syntheticroutetob-3,5-diMeAMUPol(26)..................................................................................14

ExperimentalSection.................................................................................................................15EPRspectraofreporteddinitroxides..........................................................................................41

Electronic Supplementary Material (ESI) for Chemical Science.This journal is © The Royal Society of Chemistry 2015

Sample Composit ions for DNP Experiments and recorded TDNP(1H)

Theconcentrationofradicalsolutionswas(16.0±1.0)mM.Ineachcasearound24μLofsolutionwasplacedinarotor.

TableS1.SampleCompositionsforDNPExperimentsandMaximum(afterdegassing)DNPBuild-upTimesTDNP(1H).

Numbera Radical Solvent Maximum TDNP(1H) / s b

1 bTurea TCE 1.2

2 bTurea(PEG)2 TCE 1.4

3 bTurea(PEG)4 TCE 1.1

4 bTurea(PEG)8-12 TCE 1.2

5 bTurea-diMe TCE 1.5

6 bTurea-diCD3 TCE 2.3

7 bTurea-C6 TCE 1.2

8 bCTurea(PEG)2 TCE 1.5

9 bCTurea(PEG)4 TCE 1.4

10 TEKurea TCE 1.5

11 TEKureaDME TCE 1.5

12 bp-EtCO2CTurea TCE 1.0

13 TetraPEG TCE 1.0

14 KbCTurea(PEG)4 TCE 0.8

15 AMUPol TCE 1.7

16 PyPolPEG2OH TCE 2.0

17 PyPolPEGNH2 TCE 2.9

18 AMUPol(PEG)8-12 TCE 1.8

19 PyPol TCE 2.5

20 PyPol-diMe TCE 1.8

21 PyPol-CD3 TCE 2.4

22 PyPol-diCD3 TCE/methanol-d4(93:7v/v) 2.9

23 PyPol-C6 TCE 1.8

24 PyPol-C6OH TCE 2.8

25 AMUPol-C6 TCE 2.3

26 b-3,5-diMeAMUPol TCE 1.8

27 bTbK TCE/methanol-d4(93:7v/v) 2.6

28 bTbK-d24 TCE 4.8

29 bEtTbK TCE 2.2

30 bPEtTbK TCE 3.7

31 (Adm)2TbK TCE 3.4

33 TEKPol TCE 3.2

34 TEKPol2 TCE 3.1

35 TEKPol3 TCE 4.2

36 TEKPol4 TCE 2.4

37 TEKPol5 TCE 3.1

38 b-3,5-diMePyTbK TCE 3.8acf.Fig.1inthemaintext.bTheerrorofthe1HTDNPfitwassmallerthan1%.

Acquisit ion parameters

TableS2.Acquisitionparameters

PulseSequence CP-MASNucleus 13C

Numberofscans 8-64RecycleDelay(s) 4.0

Dwell(us) 12-17Spectralwidth(kHz) 30-41Spinningspeed(kHz) 8.0

Numberofpoints 888-20481Hπpulselength(us) 4.8-5.0

Contactpulselength(us) 7501Hrffieldduringcontactpulse(kHz) 85-120Xrffieldduringcontactpulse(kHz) 60-72

1HrffieldduringSPINAL-64decoupling(kHz) 85-120

MAS-DNP NMR spectra

TheuncertaintyofεCCPwasevaluatedtobe10%usingtheS/Nratioofthespectrainallcases.

FigureS1.SpectrausedtomakeFigure2ofthemaintext(thebTureaseries).ThenumberatthetopofeachspectrumcorrespondstothenumberinginFigure1inthemaintext.Both13CCPMASspectraacquiredwith(topspectrum,inred)andwithout(bottomspectrum,inblack)microwaveirradiationareshownandthedeterminedvalueofεCCP isgiven.Numberofscans:8-32formicrowaveonand16-64formicrowaveoffspectra.ForotheracquisitionparametersseeTableS2.

FigureS2.SpectrausedtomakeFigure2ofthemaintext (thebCTureaseries).Thenumberatthetopofeach spectrumcorresponds to thenumbering inFigure1 in themain text.Both 13CCPMASspectra acquiredwith (top spectrum, in red) andwithout (bottom spectrum, in black)microwaveirradiation are shown and the determined value of εC CP is given. Number of scans: 8-32 formicrowaveonand16-64formicrowaveoffspectra.ForotheracquisitionparametersseeTableS2.

FigureS3.SpectrausedtomakeFigure2ofthemaintext(thePyPolseries).Thenumberatthetopofeachspectrumcorrespondstothenumbering inFigure1 inthemaintext.Both13CCPMASspectraacquiredwith(topspectrum,inred)andwithout(bottomspectrum,inblack)microwaveirradiationareshownandthedeterminedvalueofεCCP isgiven.Numberofscans:8-32formicrowaveonand16-64formicrowaveoffspectra.ForotheracquisitionparametersseeTableS2.

FigureS4.SpectrausedtomakeFigure2ofthemaintext(thebTbKseries).Thenumberatthetopofeachspectrumcorrespondstothenumbering inFigure1 inthemaintext.Both13CCPMASspectraacquiredwith(topspectrum,inred)andwithout(bottomspectrum,inblack)microwaveirradiationareshownandthedeterminedvalueofεCCP isgiven.Numberofscans:8-32formicrowaveonand16-64formicrowaveoffspectra.ForotheracquisitionparametersseeTableS2.

FigureS5.SpectrausedtomakeFigure2ofthemaintext(theTEKPolseries).ThenumberatthetopofeachspectrumcorrespondstothenumberinginFigure1inthemaintext.Both13CCPMASspectraacquiredwith(topspectrum,inred)andwithout(bottomspectrum,inblack)microwaveirradiationareshownandthedeterminedvalueofεCCP isgiven.Numberofscans:8-32formicrowaveonand16-64formicrowaveoffspectra.ForotheracquisitionparametersseeTableS2.

EPR measurements

AllpulseexperimentswererecordedatWband(94GHz)onaBrukerElexsysE680EPRspectrometer.The temperature was stabilized with an Oxford helium flow cryostat and was held at 100 K. Thelongitudinal relaxation timeT1ewasdeterminedperformingan inversion-recoveryexperiment. Theused pulse sequence is shown in Fig. S6. Pulse lengths usedwere 240 ns for the inversion pulse,100nsforthe𝜋/2and200nsfortherefocusing𝜋pulse.Theinitialdvarwassetto2000nsandthetime increment was varied depending on the relaxation time between 352 up to 3900 ns. 1024pointswererecordedforeachtrace.The2-pulseechodelaydwas212ns.Errorbarsareestimatedto be on the order of 1% as good signal to noise spectra were recorded for all samples. Theconcentration of the radical solutions was (16.0 ± 0.5) mM. The solvent was 1,1,2,2-tetrachloroethane(TCE).

FigureS6.PulsesequenceappliedinpulseEPRforinversion-recoveryexperimentstodetermineT1e.

Theinversion-recoverytimetraceswerefittedusingastretchedexponentialfunction:

𝐼 𝑡 = 𝐼! + 𝐼!𝑒𝑥𝑝 − 𝑡 𝑇!!∗ !

whereI0istheinitialintensity,I1theproportionalityfactor,T1e*thedecaytimeparameterandβthestretchingparameter.Thefirstmoment<T1e>ofthedistribution isconsideredtobethemeanrelaxationtime,calledtheinversion-recoverytimeTirandisgivenby:

𝑇!! ≡ 𝑒𝑥𝑝 − 𝑥 𝑇!!∗ !

!

!

𝑑𝑡 =𝑇!!∗

𝛽Γ1𝛽

ThephasememorytimeTmwasdeterminedusingavariable-delayHahn-echopulsesequence.TheusedpulsesequenceisshowninFig.S7.Pulselengthsusedwere100nsforthe𝜋/2and200nsfortherefocusing𝜋pulse.Theinitialdvarwassetto344ns,thetimeincrementwasvarieddependingonthe relaxation timebetween 4 up to 16 ns. 800 pointswere recorded for each trace. The 2-pulseechodecaytraceswerefittedusingamonoexponentialfunction.Errorbarsareestimatedtobeontheorderof1%asgoodsignaltonoisespectrawererecordedforallsamples.

FigureS7.PulsesequenceappliedinpulseEPRfor2-pulseHahn-echodecayexperimentstodetermineTm.

TableS3.Summaryoftherecordedelectronrelaxationpropertiesofthebiradicals.

Numbera Radical T1e*/

μsβ Tir/

μsTm/ns Saturation

factor/·1012s2

1HT1/s Relaxationfactor/·1012s3

3 bTurea-PEG4 12 0.44 31 1082 34 1.1 374 bTurea-PEG8-12 8 0.46 19 474 9 1.2 115 bTureadiMe 13 0.46 30 375 11 1.5 176 bTureadiCD3 13 0.46 29 326 10 2.3 2213 TetraPEG 17 0.42 48 528 26 1.0 2615 AMUPOL 59 0.55 99 1202 119 1.7 20319 PyPol 26 0.54 45 1160 52 2.5 13020 PyPoldiMe 30 0.50 61 1181 72 1.8 13021 PyPolCD3 50 0.53 91 961 88 2.4 21122 PyPoldiCD3 45 0.54 79 1487 117 2.9 34023 PyPolC6 36 0.50 70 1562 109 1.8 19725 AMUPOLC6 26 0.48 56 1144 64 2.3 14828 bTbK-d24 24 0.56 40 578 23 4.6 107

29 bEtTbK 28 0.60 42 433 18 2.2 4034 TEKPol2 48 0.55 81 1210 99 3.2 31535 TEKPol3 41 0.59 63 957 61 4.2 25536 TEKPol4 35 0.52 66 1105 73 2.4 17438 b-3,5-diMEPytbK 43 0.50 86 563 48 3.1 14927b bTbK(14.7mM) 2 0.36 10 588 6 2.6 1532b bCTbK(13.3mM) 18 0.49 37 1128 42 3.2 13433b TEKPol(13.0mM) 21 0.47 46 1416 65 3.7 241

acf.Fig.1inthemaintext.bThesedatapointscomefromapreviousworkbyZagdounetal.(A.Zagdoun,G.Casano,O.Ouari,M.Schwarzwälder,A.J.Rossini,F.Aussenac,Y.M.,J.G.,C.Copéret,A.Lesage,P.TordoandL.Emsley,J.Am.Chem.Soc.,2013,135,12790-12797)

Quenching factor measurements

Thequenchingmeasurementswereperformedsimilarlytotheproceduredescribedpreviously.aThefractionofNMRsignalobservedinasampledopedwitharadicalcomparedtopureTCEisdenotedasθ.TherelaxationdelayD1wassettobeatleast5·T1inordertoallowcompleterelaxation.Thesolventintegralwasnormalizedbymassandbynumberofscans.Accordinglythequenchingfactor1-θisthefractionofnucleiinthesamplewhichdonotcontributetotheobservablesignal.TheoverallsensitivityenhancementΣCCPwascalculatedaccordingtothefollowingformula:

Σ! !" = 𝜀! !" ⋅ 𝜃 ⋅𝑇! !"#$ !"#

𝑇!"# !!"#$!% !"#$%&"'= 𝜀! !" ⋅ 𝜃 ⋅ 𝜅

WithrespecttoroomtemperatureNMRexperiment,theoverallsensitivityenhancementincludingtheBoltzmannfactorΣ♱CCPreads:

Σ! !"! =

298 𝐾105 𝐾

⋅ 𝜀! !" ⋅ 𝜃 ⋅ 𝜅 = 2.8 𝜅

Allsolutionswere16.0mM(±0.5mM).

b Sample

Conc

.

/ mM

nse

Mass of

solution

/ mg

1H TDNP

/ s

D1f /

s εC CP

Seen

signal

θ / %

Quenched

signal (1-θ)

/ %

κ ΣC CP Σ✝C CP

- pure TCE - 64 32.9 50±10c 300 - 100 0 - - -

19 PyPol 16.0 64 32.5 3.2 20 26±3 70±7 30±3 16±3 72±13 201±36

27 bTbK 16.1 128 33.6 2.6 20 62±6 52±5 48±5 19±4 141±24 395±67

32 bCTbK 15.8 128 31 3.0 20 93±9 45±5 55±6 17±3 170±28 477±78

33 TEKPol 16.3 128 30.5 3.0 20 205±21 35±4 65±7 17±3 290±49 812±137

34 TEKPol2 16.0 16 35.5 3.3 17 155±16d 51±5 49±5 15±3 310±54 868±151 aA.J.Rossini,A.Zagdoun,M.Lelli,D.Gajan,F.Rascon,M.Rosay,W.E.Maas,C.Copéret,A.LesageandL.Emsley,ChemicalScience,2012,3,108-115.bcf.Fig.1inthemaintext.c1HT1.Thevalueforthedegassedsamplevarieddependingontheglassquality,hencethelargeerrorassociatedwithit.Theerrorof1HTDNPfitwassmallerthan1%.dMeasurementperformedonadifferentDNPsystemwheretheradicalwasnotsaturatedwithmicrowavesevenatthehighestavailableMWpower.eNumberofscansfRelaxationdelay

TheerrorsofεCCPandθwereevaluatedtobe10%bytakingtheS/Nratioofspectra.Theerrorsofκ,ΣCCP,Σ✝CCPwerecalculatedusingthepropagationoferror.

Synthesis of reported molecules

Description of the synthetic schemes

Synthetic route to bTurea-diMe (5), bTurea-diCD 3 (6) , PyPol-DiMe (20), PyPol-diCD 3 (22), TEKurea (10), TEKurea-diMe (11) and PyPol-CD 3 (21) bTurea-diMe(5),bTurea-diCD3(6),PyPol-DiMe(20),PyPol-diCD3(22),TEKurea(10),TEKurea-diMe(11)weresynthesizedinatwo-stepssequencestartingfromketones40,43and46.First,aminoderivatives41,44,48,aminoderivatives42,45andaminocompound47werepreparedbyreactingketone40,43and46withmethylaminehydrochloride,methylamine-D3-hydrochlorideorammoniumacetateinthepresenceofsodiumcyanoborohydride.Then,thecompounds41,42,44,45,47and48werethenreactedwithtriphosgenetoyielddinitroxidesbTurea-diMe(5),bTurea-diCD3(6),PyPol-DiMe(20),PyPol-diCD3(22),TEKurea(10),TEKurea-diMe(11)respectively.PyPol-CD3(21)wasobtainedbycondensationofaminocompound49andmethyl-D3-amine45inthepresenceoftriphosgene.

N

O

ON

NH

O

R

NO

N N

O

RR

NO

R= -CH3 bTurea-diMe (5)R= -CD3 bTurea-diCD3 (6)

R= -CH3 (41)R= -CD3 (42)

40

N

O

ON

NH

O

R

NO

N N

O

RR

NO

R= -CH3 PyPol-diMe (20)R= -CD3 PyPol-diCD3 (22)

R= -CH3 (44)R= -CD3 (45)

43

O O O O O

O O

O

N

O

ON

NH

O

R

NO

N N

O

RR

NO

R= -H TEKurea (10)R= -CH3 TEKureaDMe (11)

Ph Ph Ph Ph Ph

Ph Ph

Ph

46 R= -H (47)R= -CH3 (48)

(i)

(i)

(i)

(ii)

(ii)

(ii)

N

NH2

ON

NH

O

D3C

NO

N N

O

CD3H

NO

PyPol-CD3 (21)49

O O O O O

O O

O

45

(iii)

SI-Scheme1:syntheticroutetodinitroxides5,6,10,11,20,21,22.Reagentsandconditions:(i)RNH2.HClorAcONH4,NaBH3CN,MeOH,25°C.(ii)Triphosgene,TEA,CH2Cl2,reflux,6h.(iii)Triphosgene,TEA,CH2Cl2,25°C,12h.

Synthetic route to bp -EtCO2CTurea (12) and TetraPEG (13) ThespirocyclohexylmoietieswereintroducedaccordingthemethodofYamadaetal.1startingfromethyl4-cyclohexanonecarboxylateandamine50.Theresulting2,6-substituedpiperidin-4-one51wasoxidizedwithhydrogenperoxideinthepresenceofsodiumtungstatetoafford52.Reductiveaminationofketone52usingsodiumborohydrideandammoniumacetateyieldedtoamine53thatwasfurtherreactedwithtriphosgenetoobtainbp-EtCO2CTurea(12).Then,thehydrolysisofthefourethylesterfunctionsgavecompound54.Finally,tetra(ethyleneglycol)methyletherwascoupledattetraacid54inthepresenceofHBTUtoaffordtetraPEG(13).

N

O

NH

O

EtO2C CO2EtN

O

EtO2C CO2EtO

NH

NH2

EtO2C CO2Et

N

CO2Et

O

EtO2CNH

NH

O NO

CO2Et

CO2Et

NO

NH

NH

O NO

50 51 52

53 bp-EtCO2CTurea (12)

TetraPEG (13)

O

CO2Et

N

CO2H

O

HO2CNH

NH

O NO

CO2H

CO2H

54

(i) (ii)

(iii) (iv)

(v) (vi)

HN O

HNO

OO

O

HN

OO

HN

O

4 4

44

SI-Scheme2:syntheticroutetodinitroxides12and13.Reagentsandconditions:(i)NH4Cl,DMSO,60°C,20h.(ii)H2O2(30%),Na2WO4.2H2O,EtOH,25°C,24h.(iii)AcONH4,NaBH3CN,MeOH,25°C.(iv)Triphosgene,TEA,CH2Cl2,reflux,6h.(v)NaOH,EtOH/THF,80°C,8h.(vi)DIPEA,HBTU,H2N(PEG)4OMe.

Synthetic route to KbCTurea(PEG)4 (14) Compound55wassynthesizedaccordingtotheliteratureprocedure.1Amine56waspreparedbyreactingketone55withtetra(ethyleneglycol)methyletherinthepresenceofsodium

triacetoxyborohydride.Ketone55wasachievedbyreductiveaminationusingsodiumcyanoborohydrideandammoniumacetateyieldedtoamine57.Finally,amixtureof56and57wasreactedwithtriphosgenetogiveKbCTurea(PEG)4(14).

NO

O O

OO

O

NO

O O

OO

NHO

4

NO

OO

NH2

NO

N NH

O NO

O

OO OO

O

OO

O

4

55 56

57 KbCTurea(PEG)4 (14)

(i)

O

O

(iii)

(ii)

SI-Scheme3:syntheticroutetoKbCTurea(PEG)4(14).Reagentsandconditions:(i)NH2(CH2CH2)4OCH3,Na(OAc)3BH,AcOH,THF,25°C,16h.(ii)AcONH4,NaBH3CN,MeOH,25°C,20h.(iii)56,Triphosgene,TEA,CH2Cl2,25°C,12h.

Synthetic route to PyPolPEGNH 2 (17) bPyTO(43)andN-acetyl-2,2’-ethylenedioxybis-(ethylamine)werepreparedaccordingtothereportedprocedures.1,2

Dinitroxide59wassynthesizedusingthesamestrategythanKbCTurea(PEG)4(14).First,amine58waspreparedbyreactingketone43withN-acetyl-2,2’-ethylenedioxybis-(ethylamine)inthepresenceofsodiumtriacetoxyborohydride.Then,amixtureof58and49wasreactedinthepresenceoftriphosgenetoobtaindinitroxide59.Finally,acetamidogroupwasremovedinaqueousbasicconditionstogivePyPolPEGNH2(17).

NO O

O

O

NO O

O

HN

N

O

O

O

N NH

O N

O

O

O

43 58

(i)

(ii)

OO

NHAc

O

O

NHAc

N

O

O

O

N NH

O N

O

O

O

O

O

NH2

(iii)

59 PyPolPEGNH2 (17)

SI-Scheme4:SyntheticroutetoPyPolPEGNH2(17).Reagentsandconditions:(i)NH2(OCH2CH2)2NHAc,Na(OAc)3BH,AcOH,THF,25°C,16h.(ii)49,triphosgene,TEA,CH2Cl2,25°C,12h.(iii)KOH,EtOH/Water,50°C,16h.

General synthetic route to b-3,5-diMePyTbK(38), TEKPol2 (34), TEKPol3 (35), TEKPol4 (36), TEKPol5 (37), (Adm)2TbK (31), bEtTbk (29), bPEtTbK (30) and bTbK-d 24 (28) AccordingtothepublishedprocedureforTEKPol(33),aseriesofnewdinitroxides38,34,35,36,37,29,30,31and28waspreparedinathreeorfourstepssequencestartingfrom1,2,2,6,6-pentamethyl-4-piperidinone(50).First,thespiro(hetero)cyclohexylmoietieswereintroducedbyYamada’smethods,usingcis-2,6-dimethyltetrahydropyran-4-one,tetrahydro-4H-thiopyran-4-one,cis-3,5-diphenylcyclohexanone,cis-2,6-bis(phenyl)dihydro-2H-thiopyran-4(3H)-one,4-(4-biphenylyl)cyclo-hexanone,4-(4-methoxyphenyl)cyclohexanone,and4-(4-oxo-cyclohexyl)benzoicacidethylesterasreactant,togive2,6-dispisubstituedpiperidin-4-onederivatives60,61,62,63,70,71,72,respectivelyandamonospirosubstituted76piperidin-4-onewasobtainedwith2-adamantanone.Then,thespirosubstitutedpiperidin-4-onederivativeswerereactedwithpentaerythritoltoaffordbisketals64,65,66,67,73,74,75and77.Thedesulfurizationofcompounds65and67withRaney-Niaffordedcompounds68and69.Finally,thenewbisketalcompoundswereoxidizedbyhydrogenperoxideinthepresenceofsodiumtungstatetoyieldthenewdinitroxidebiradicals38,34,35,36,37,31,29and30.bTbK-d24(28)waspreparedinatwostepssequenceusingthesamestrategydescribedbeforestartingfrom78whichwassynthesizedfollowingthegeneralprocedureofLinetal.3

N

O

NHX X

O

R1 R1

R1R1X

O

R1 R1

60; X=O; R1= CH361; X=S; R1= H62; X=CH2; R1= C6H563; X=S; R1= C6H5

NHX X

O

R1 R1

R1R1 HNO

O

O

ONH

X

X

X

X

R1

R1

R1

R1

R1

R1

R1

R1

NO

O

O

ON

X

X

X

X

R1

R1

R1

R1

R1

R1

R1

R1

O O

HNO

O

O

ONH

R1

R1

R1

R1R1

R1

R1

R1

64; X=O; R1= CH365; X=S; R1= H66; X=CH2; R1= C6H567; X=S; R1= C6H5

b-3,5-diMePyTbK (38); X=O; R1= CH3TEKPOL2 (34); X=CH2; R1= C6H5

68; R1= H69; R1= C6H5

(i)

(ii) (iii)

50

NO

O

O

ON

R1

R1

R1

R1R1

R1

R1

R1

bEtTbK (29); R1= HbPEtTbK (30); R1= C6H5

O O(iii)(iv)65 or 67

N

O

O

R

NH

O

R R

70; R=C6H571; R=OMe72; R=CO2Et

(i)

HNO

O

O

ONH

R R

RR

NO

O

O

ON

R R

RR

O O

TEKPOL3 (35); R=C6H5TEKPOL4 (36); R=OMeTEKPOL5 (37); R=CO2Et

(ii) (iii)

50

73; R=C6H574; R=OMe75; R=CO2Et

N

OO

NH

O

(i)

NH

O

NH

OO

OO

HN

N

OO

OO

NO

O

(ii) (iii)

50 76

77 (Adm)2TbK (31)

NH

O

D3CD3C

NH

OO

OO

HN

CD3CD3

N

OO

OO

N

CD3CD3

D3C

O

O

D3CD3CD3C

(ii) (iii)

78 bTbk-d24 (28)

CD3CD3

D3CD3C

CD3CD3 CD3

CD3

D3CD3C

79

SI-Scheme5:Reagentsandconditions:(i)NH4Cl,DMSO,60°C,20h.(ii)p-TsOH,pentaerythritol,PhMe,reflux,24h.(iii)H2O2(30%),Na2WO4.2H2O,EtOH,25°C,24h.(iv)Ni-Raney,EtOH,reflux,24h.

Synthetic route to b-3,5-diMeAMUPol (26) b-3,5-diMeAMUPol(26)wassynthesizedusingthesimilarstrategythanKbCTurea(PEG)4(14)startingfrom60.

NH

O

O ON

O

O OO

N

NH2

O OO

N

HN

O OO

O4

N

O

O

ON N

H

O N

O

O

O

O4

60

(i) (ii)

(iii)

(iv)

b-3,5-diMeAMUPol (26)

80 81

82

SI-Scheme6:syntheticroutetob-3,5-diMeAMUPol(26).Reagentsandconditions:(i)H2O2(30%),Na2WO4.2H2O,EtOH,25°C,24h.(ii)NH2(CH2CH2)4OCH3,Na(OAc)3BH,AcOH,THF,25°C,16h.(iii)AcONH4,NaBH3CN,MeOH,25°C,20h.(iv)81,Triphosgene,TEA,CH2Cl2,25°C,12h.

Experimental Section Compounds43,49,50,55,bTurea(1),bTurea(PEG)2(2),bTurea(PEG)4(3),bTurea(PEG)8-12(4),bTurea-C6(7),bCTurea(PEG)2(8),bCTurea(PEG)4(9),AMUPol(15),PyPolPEG2OH(16),AMUPol(PEG)8-12(18),PyPol(19),PyPol-C6(23),PyPol-C6OH(24),AMUPol-C6(25),bTbK(27),bCTbK(32),TEKPol(33)andTOTAPOL(39)weresynthesizedaccordingtoreportedprocedures.1,4,5,6,7,8,9,10

Tetra(ethyleneglycol)methyl,Cis-2,6-dimethyltetrahydropyran-4-one,cis-3,5-diphenylcyclohexanone,cis-2,6-bis(phenyl)dihydro-2H-thiopyran-4(3H)-one,4-(4-biphenylyl)cyclohexanone,4-(4-methoxyphenyl)cyclohexanone,4-(4-oxo-cyclohexyl)-benzoicacidethylesterwerepreparedaccordingtotheliteratureprocedures.11,12,13,14,15,16,17,18AllchemicalsusedinsynthesiswerepurchasedfromAldrichChemicalCo.Commerciallyavailablestartingmaterialswereusedwithoutfurtherpurification.Purificationofproductswasaccomplishedbyflashchromatographyonsilicagel(Mercksilicagel60,230-400Mesh).NMRmeasurementswererecordedonaBrukerAVL300spectrometer(1H-NMR300.1MHzand13C-NMR75.5MHz)usingCDCl3asthesolvent(internalreference).Splittingpatternsareindicatedasfollows:br,broad;s,singlet;d,doublet;t,triplet;q,quadruplet;m,multiplet;dd,doubletofdoublets.MassspectraanalyseswerecarriedoutusingaQ-STAReliteattheAix-MarseilleUniversitéMassspectrumfacility,spectropoleSaintJérômeMarseille.MeltingpointweredeterminedusingaBibbySMP3apparatusandwereuncorrected.Thefinalwerepurifiedto≥95%andwereconfirmedbyelementalanalysisorHPLC.HPLCexperimentswereperformedusingAgilent1200systemequippedwithUV-Visabsorptiondetector.AfusedcoreRPC18column(Phenomenex,KinetexC18,100mmx4.6mm,2.6µm)wasused.Typicallyagradientelutionusingaqueousmobilephasewithincreasingfractionofacetonitrile(from10%to40%over5minandfrom40to100%over5min)inthepresenceof0.1%TFAwasused.Thecompoundswereelutedusingaflowrateof1.5mL/min.

Generalprocedureforsynthesiscompound41,42,44,45and48.

Underargonatmosphereasolutionofketone(1mmol),methylaminehydrochlorideormethylamine-D3-hydrochloride(6mmol)indryMeOHwasstirredat25°Cduring3h.Afterthistime,NaBH3(CN)(0.8mmol)wasaddedandthereactionwasstirred24hatroomtemperature.Thena10%K2CO3aqueoussolutionwasadded.ThemixturewasconcentratedunderreducedpressureandtheremainingaqueousphasewasextractedtwicewithCH2Cl2,driedoverNa2SO4andconcentratedunderreducedpressure.ThecrudeproductwaspurifiedbySiO2columnchromatographyusingCH2Cl2/EtOHaseluentinincreasingpolaritytoyieldthedesiredcompounds.

Compound41.Atotalof80mg(43%)of41wasobtainedasaredsolid.HRMS-ESI:calcdforC10H22N2O.([M+H]+)186.1727found186.1727.

Compound42.Atotalof100mg(53%)of42wasobtainedasaredsolid.HRMS-ESI:calcdforC10H19D3N2O.([M+H]+)189.1915found189.1914.

Compound44.Atotalof180mg(67%)of44wasobtainedasaredsolid.HRMS-ESI:calcdforC14H26N2O3

.([M+H]+)270.1938found270.1938.

Compound45.Atotalof260mg(85%)of45wasobtainedasapaleredsolid.mp131°C.ESI-MSm/z=273[M+H]+;295[M+Na]+.

Compound48.Atotalof300mg(71%)of48wasobtainedasapaleredsolid.mp185°C.ESI-MSm/z=418[M+H]+;440[M+Na]+.

Generalprocedureforsynthesiscompounds47,53,57and82.Underargonatmosphere,asolutionofammoniumacetate(10mmol)indryMeOH(3mL)wasstirredfor10minutes.Then,asolutionofketone(1mmol)indryMeOH(5mL)wasaddedandthereactionwasstirredatroomtemperatureduring5h.Then,NaBH3(CN)(0.72mmol)wasaddedat0°Candthereactionwasstirredat25°Cduring20h.Afterthistime,20mLof10%K2CO3aqueoussolutionwasadded.ThemixturewasconcentratedunderreducedpressureandtheremainingaqueousphasewasextractedwithCH2Cl2(2x60mL).TheorganiclayerwasdriedonNa2SO4,concentratedunderreducedpressureandtheresiduewaspurifiedbySiO2columnchromatographyusingCH2Cl2/EtOHaseluentaseluentinincreasingpolaritytoyieldthedesiredcompounds.

Compound47.Atotalof271mg(66%)of47wasobtainedasaredsolid.mp218°C.ESI-MSm/z=404[M+H]+;426[M+Na]+.

Compound53.Atotalof170mg(43%)of53wasobtainedasaredsolid.ESI-MSm/z=396[M+H]+;418[M+Na]+.

Compound57.Atotalof150mg(41%)of57wasobtainedasaredsolid.ESI-MSm/z=368[M+H]+.

Compound82.Atotalof130mg(42%)of82wasobtainedasaredsolid.ESI-MSm/z=312[M+H]+;[M+Na]+.

Generalprocedureforsynthesiscompounds5,6,10,11,12,20,22.Toasolutionofsecondaryamineorprimaryamine(0.5mmol)andTEA(1.2mmol)inCH2Cl2wasaddedat0°Ctriphosgene(0.1mmol)underargonatmosphere.Themixturewasstirredunderrefluxduring6h.Attheendofreaction,a10%K2CO3aqueoussolutionwasaddedandthesolutionwasextractedtwicewithCH2Cl2,driedoverNa2SO4andconcentratedunderreducedpressure.Thecrude

productwaspurifiedbySiO2columnchromatographyusingCH2Cl2/EtOHaseluentinincreasingpolaritytoyieldthedesiredcompounds.

bTurea-diMe(5)Atotalof23mg(58%)of5wasobtainedasaredsolid.HRMS-ESI:calcdforC21H41N4O3

2.([M+H]+)397.3173found397.3173.

bTurea-diCD3(6)Atotalof21mg(52%)of6wasobtainedasaredsolid.HRMS-ESI:calcdforC21H34D6N4O3

2.([M+H]+)403.3550found403.3546.

PyPol-diMe(20)Atotalof20mg(35%)of20wasobtainedasaredsolid.HRMS-ESI:calcdforC29H49N4O7

2.([M+H]+)565.3596found565.3595.

PyPol-diCD3(22)Atotalof27mg(47%)of22wasobtainedasaredsolid.HRMS-ESI:calcdforC29H43D6N4O7

2.([M+H]+)571.3972found571.3971.

TEKurea(10)Atotalof38mg(46%)of10wasobtainedasaredsolid.HRMS-ESI:calcdforC55H69N4O3

2.([M+H]+)833.5364found833.53.

TEKureaDME(11)Atotalof43mg(50%)of11wasobtainedasaredsolid.HRMS-ESI:calcdforC57H73N4O3

2.([M+H]+)861.5677found861.5671.

bp-EtCO2CTurea(12)Atotalof58mg(71%)of12wasobtainedasaredsolid.HRMS-ESI:calcdforC43H72N5O11

2.([M+NH4]+)834.5223found834.5228.

Synthesisofcompound58.Toasolutionof43(0.75g,2.94mmol)andN-acetyl-2,2’-ethylenedioxybis-(ethylamine)(0.6g,3.18mmol)indryTHFwasaddedAcOH(0.10mL)toobtainpHaround4.After5hat25°C,NaBH(OAc)3wasaddedandthereactionwasstirred16hat25°C.Afterthistime,themixturewasconcentratedunderreducedpressure.TheresiduewassolubilizedinCH2Cl2,washedwithasaturatedaqueoussolutionofNaHCO3,driedoverNa2SO4,concentratedunderreducedpressureandthecrudeproductwaspurifiedbySiO2columnchromatographyusingCH2Cl2/EtOH(98/2)aseluenttogive58(0.65g,51%)asaredoil.ESI-MSm/z=429[M+H]+;451[M+Na]+.

Generalprocedureofcompounds14,21,26,59.Asolutionofsecondaryamine(1mmol),primaryamine(0.5mmol),NEt3(1.2mmol)andtriphosgene(0.5mmol)wasstirredatroomtemperatureinCH2Cl2underargonatmosphereduring12h.Attheendofreaction,thesolutionwaswashedwithasaturatedNaHCO3aqueoussolution,driedoverNa2SO4andconcentratedunderreducedpressure.ThecrudeproductwaspurifiedbySiO2columnchromatographyusingCH2Cl2/EtOHaseluentinincreasingpolaritytoyieldthedesiredcompounds.

PyPol-CD3(21)

Atotalof162mg(58%)of21wasobtainedasaredsolid.HRMS-ESI:calcdforC28H43D3N4O72.

([M+H]+)554.3628found554.3623.

KbCTurea(PEG)4(14)Atotalof130mg(26%)of14wasobtainedasaredsolid.ESI-MSm/z=951[M+H]+;968[M+NH4]+;973[M+Na]+.HRMS-ESI:calcdforC48H78N4O15

2.([M+H]+)951.5536found951.5532.HPLC:rt=11.07min.

b-3,5-diMeAMUPol(26)Atotalof140mg(33%)of26wasobtainedasaredsolid.HRMS-ESI:calcdforC44H78N4O11

2.([M+H]+)839.5740found839.5740.HPLC:rt=11.13min.

PyPolPEGNHAc(59)Atotalof165mg(47%)of59wasobtainedasapurpleoil.ESI-MSm/z=710[M+H]+;732[M+Na]+.

SynthesisofPyPolPEGNH2(17).Toastirredsolutionof59(165mg,0.23mmol)inethanolwasaddedasolutionofKOH(1.27g,19.2mmol)inwater(0.8mL)at25°C.Themixturewasstirredat50°Cfor16h.Afterthistime,themixturewasconcentratedunderreducedpressure,dilutedinCH2Cl2,washedwithbrine(20mL),driedoverNa2SO4andconcentratedunderreducedpressure.ThecrudeproductwaspurifiedbySiO2columnchromatographyusingCH2Cl2/EtOH/NH4OH(9/1/1)togive17(0.1g,65%)asapurplesolid.ESI-MSm/z=668[M+H]+;690[M+Na]+.HRMS-ESI:calcdforC33H58N5O9

2.([M+H]+)668.4229found668.4225.

Synthesisofcompound51.Toastirredmixtureof1,2,2,6,6-pentamethypiperidin-4-one50(1.69g,10.00mmol)andethyl4-cyclohexanonecarboxylate(5.0g,29.40mmol)indimethylsulfoxide(50mL),NH4Cl(3.3g,61.68mmol)wasaddedatroomtemperature.Themixturewasheatedat60°Cduring20h,thenitwasdilutedwithwater(200mL),pHwasadjustedat2with1NHClaqueoussolution(40mL)andthemixturewasextractedwithdiethylether(2x100mL).TheaqueouslayerwasadjustedtopH11byadding50mLofsaturatedK2CO3aqueoussolutionandthenextractedwithchloroform(2x100mL).Theorganicphasewasconcentratedunderreducedpressure,washedwithbrine(100mL),driedoverNa2SO4,andthesolventwasdistilledunderreducedpressure.ThecrudeproductwaspurifiedbySiO2columnchromatographyusingpentane/ethylacetate(1/1)toafford51(0.56g,15%)asawhitesolid.1HNMR(300MHz,CDCl3)δ1.15-1.19(t,6H),1.65-1.85(m,16H),2.15-2.25(m,2H),2.33(s,4H),4.02-4.07(q,4H).13CNMR(300MHz,CDCl3)δ14.05,24.63,39.19,41.72,49.65,56.37,60.13,175.06,209.98.ESI-MSm/z=380[M+H]+;402[M+Na]+.

Synthesisofcompound52.Compound51(0.5g,1.32mmol)andNa2WO4.2H2O(52mg,0.16mmol)werestirredinethanol(15mL)andH2O2(30%,5.46mmol,625μL)wasslowlyaddedat0°C.Themixturewasstirredfor24hatroomtemperature,thenK2CO3(0.80g)wasaddedandthesolutionwasextractedtwicewithchloroform(50mL).TheorganiclayerwasdriedoverNa2SO4anddistilledunderreducedpressure.ThecrudeproductwaspurifiedbySiO2columnchromatographyusingChloroform/MeOH(99/1)aseluenttoprovidecompound52(0.43g,50%)asapaleredsolid.ESI-MSm/z=395[M+H]+;412[M+NH4]+;417[M+Na]+.

Synthesisofcompound80.Compound60(0.8g,2.71mmol)wasoxidizedaccordingtothegeneralproceduredescribedabovefortheoxidationof51.ThecrudeproductwaspurifiedbySiO2columnchromatographyusingCH2Cl2/EtOH(99/1)aseluenttoprovidecompound80(0.75g,89%)asayellowsolid.mp165-170°C.X-bandEPRspectrum(293K,inCH2Cl2):triplet,AN=1.47mT.HRMS-ESI:calcdforC17H28NO4

.([M+H]+)311.2091found311.2089.

Synthesisofcompound54.Asolutionof12(0.25g,0.3mmol)andNaOH(0.24g,6.1mmol)inamixtureEtOH/THF(1mL/1mL)wasstirredat80°Cfor8h.Itwasthenallowedtocooltoroomtemperature.At0°C,a6MHClsolutionwasaddeduntilpH3andtheproductprecipitated.Itwasthenfilteredoff,washedwithEtOHandH2Oanddriedtogive54(0.15g,71%).HRMS-ESI:calcdforC35H52N4O11([M+Na]+)727.3525found727.3525.

SynthesisofTetraPEG(13).

Toasolutionof54(50mg,0.07mmol),DIPEA(0.15mL,0.84mmol)andHBTU(0.32mg,0.84mmol)indryDMF(2mL)wasaddedaminePEG(118mg,0.57mmol)andthesolutionwasstirredatroomtemperaturefor16h.BrinewasaddedandthesolutionwasextractedwithCH2Cl2,driedoverNa2SO4andthesolventwasevaporatedunderreducedpressure.Then,theresiduewasdriedunderhighvacuumtoremovetheremainingDMF.ItwasthenpurifiedbySiO2columnchromatographyusingCH2Cl2/EtOH(9/1)aseluenttogiveTetraPEG(13)(70mg,69%)asaredoil.HRMS-ESI:calcdforC71H136N10O23([M+2NH4]2+)748.4884found748.4888.

Generalprocedureforcompounds56and81.Toasolutionofketone(1mmol),tetra(ethyleneglycol)methyetheramine(1.3mmol)indryTHFwasaddedAcOHtoadjustpHataround6-7andthesolutionwasstirredatroomtemperaturefor2h.Then,Na(OAc)3BH(1.5mmol)wasaddedandthereactionwasstirredat25°Cfor16h.Afterthistime,themixturewasconcentratedunderreducedpressure.TheresiduewassolubilizedinCH2Cl2,washedwithasaturatedaqueoussolutionofNaHCO3,driedoverNa2SO4,concentratedunderreducedpressureandthecrudeproductwaspurifiedbySiO2columnchromatographyusingCH2Cl2/EtOHaseluentinincreasingpolaritytoyieldthedesiredcompounds.

Compound56.Atotalof280mg(50%)of56wasobtainedasaredsolid.ESI-MSm/z=558[M+H]+;564[M+Li]+;580[M+Na]+.

Compound81.Atotalof290mg(57%)of81wasobtainedasaredsolid.ESI-MSm/z=502[M+H]+;524[M+Na]+.

Synthesisofcompound60.Compound60waspreparedaccordingtothegeneralproceduredescribedfor51,usingcis-2,6-dimethyltetrahydropyran-4-one(3.84g,30.00mmol)inplaceofethyl4-cyclohexanonecarboxylate.ThecrudeproductwaspurifiedbySiO2columnchromatographyusingpentane/ethylacetate(90/10)toafford60(0.36g,12%)asawhitesolid.Thestructureofcompound60wasdeterminedbysinglecrystalX-raydiffraction.mp126-128°C;1HNMR(300MHz,CDCl3)δ1.11(s,6H),1.13(s,6H),1.15-1.26(m,5H),1.59-1.66(m,4H),2.46(s,4H),3.44-3.52(m,4H).13CNMR(300MHz,CDCl3)δ21.84,48.09,49.55,55.82,69.05,209.66.ESI-MSm/z=296[M+H]+.HRMS-ESI:calcdforC17H29NO3([M+H]+)296.2220found296.2219.

Synthesisofcompound61.Compound61waspreparedaccordingtothegeneralproceduredescribedfor51,usingtetrahydro-4H-thiopyran-4-one(3.48g,30.00mmol)inplaceofethyl4-cyclohexanonecarboxylate.ThecrudeproductwaspurifiedbySiO2columnchromatographywithpentane/ethylacetate(90/10)toafford61(0.89g,33%)asawhitesolid.mp156°C(lit.,1155-157°C).1HNMR(300MHz,CDCl3)δ0.8(brs,1H),1.75-1.91(m,8H),2.28(s,4H),2.44-2.50(m,4H),2.88-2.96(m,4H).13CNMR(300MHz,CDCl3)δ24.03,41.40,53.00,55.71,208.99.ESI-MSm/z=272[M+H]+.

Synthesisofcompound62.Compound62waspreparedaccordingtothegeneralproceduredescribedfor51,usingcis-3,5-diphenylcyclohexanone(8.90g,35.60mmol)inplaceofethyl4-cyclohexanonecarboxylate.ThecrudeproductwaspurifiedbySiO2columnchromatographyusingpentane/ethylacetate(90/10)toafford62(0.51g,8%)asawhitesolid(asamixtureofdiasteroisomers).1HNMR(300MHz,CDCl3)δ1.48-1.70(m,4H),1.90-2.18(m,8H),2.37-2.65(m,4H),2.82-3.49(m,4H),7.10-7.40(m,20H).ESI-MSm/z=540[M+H]+;546[M+Li]+.

Synthesisofcompound63.Compound63waspreparedaccordingtothegeneralproceduredescribedfor51,usingcis-2,6-bis(phenyl)dihydro-2H-thiopyran-4(3H)-one(8.04g,30.00mmol)inplaceofethyl4-cyclohexanonecarboxylate.ThecrudeproductwaspurifiedbySiO2columnchromatographywith

CH2Cl2/EtOH(95/5)toafford63(0.43g,8%)asawhitesolid.(asamixtureofdiasteroisomers).1HNMR(300MHz,CDCl3)δ1.92-2.68(m,12H),4.13-4.80(m,4H),7.20-7.45(m,20H).ESI-MSm/z=576[M+H]+;598[M+Na]+.

Synthesisofcompound70.Compound70waspreparedaccordingtothegeneralproceduredescribedfor51,using4-(4-biphenylyl)cyclohexanone(7.5g,30.00mmol)inplaceofethyl4-cyclohexanonecarboxylate.ThecrudeproductwaspurifiedbySiO2columnchromatographywithpentane/ethylacetate(70/30)toafford70(0.16g,3%)asawhitesolid.1HNMR(300MHz,CDCl3)δ1.60-1.70(m,8H),1.84-2.00(m,9H),2.50-2.59(m,6H),7.28-7.62(m,18H).13CNMR(300MHz,CDCl3)δ29.27,40.22,42.17,48.07,55.77,125.99,126.33,127.69,138.13,139.99,144.45,209.81.ESI-MSm/z=540[M+H]+;546[M+Li]+.

Synthesisofcompound71.Compound71waspreparedaccordingtothegeneralproceduredescribedfor51,using4-(4-methoxyphenyl)cyclohexanone(6.20g,30.00mmol)inplaceofethyl4-cyclohexanonecarboxylate.ThecrudeproductwaspurifiedbySiO2columnchromatographyusingpentane/ethylacetate(70/30)toafford71(180mg,4%)asawhitesolid.1HNMR(300MHz,CDCl3)δ1.44-2.00(m,17H),2.40-2.55(m,6H),3.78(m,6H),6.83(d,J=8.34Hz,4H),7.12(d,J=8.44Hz,4H).13CNMR(300MHz,CDCl3)δ30.50,41.25,42.62,49.09,55.26,56.77,113.81,127.58,138.56,157.93,211.02.ESI-MSm/z=448[M+H]+;554[M+Li]+.

Synthesisofcompound72.Compound72waspreparedaccordingtothegeneralproceduredescribedfor51,using4-(4-oxo-cyclohexyl)-benzoicacidethylester(7.38g,30.00mmol)inplaceofethyl4-cyclohexanonecarboxylate.ThecrudeproductwaspurifiedbySiO2columnchromatographywithDCM/EtOH99/1toafford72(0.55g,10%)asawhitesolid.mp193°C.1HNMR (300MHz,CDCl3)δ =1.36(t,J=7.10Hz,6H),1.54-1.66(m,8H),1.75-2.01(m,8H),2.53(s,4H),4.33(d,J=7.10Hz,4H),7.22(d,J=8.25Hz,2H),7.93(d,J=8.25Hz,4H).13CNMR (75MHz,CDCl3)δ =14.32,29.95,40.97,43.53,49.00,56.72,60.76,126.70,128.48,129.72,151.51,166.53,210.55.ESI-MSm/z=532[M+H]+;554[M+Na]+.

Synthesisofcompound76.Compound76waspreparedaccordingtothegeneralproceduredescribedfor51,using2-adamantanone(4.5g,30.00mmol)inplaceofethyl4-cyclohexanonecarboxylate.ThecrudeproductwaspurifiedbySiO2columnchromatographyusingpentane/ethylacetate(95/5)toafford76(0.13g,5%).1HNMR(300MHz,CDCl3)δ1.17(s,6H),1.40-1.90(m,15H),2.20(s,2H),2.47(s,2H).13CNMR(CDCl3)δ26.97,27.13,31.95,32.90,33.43,38.40,38.46,49.94,54.33,54.73,61.51,211.68.ESI-MSm/z=248[M+H]+;270[M+Na]+.

Generalprocedureofsynthesisofcompound64,65,66,73,74,75,77and79.Ketone(1mmol)wasdissolvedintoluene(60mL),pentaerythritol(0.40mmol)andp-toluenesulfonicacid(0.8mmol)wereaddedtothestirredsolution.ThemixturewasheatedatrefluxinaDeanStarksystemfor24h.Aftercooling,thesolutionwasconcentratedunderreducedpressureand10%Na2CO3aqueoussolutionwasadded.Themixturewasextractedtwicewithchloroform(40mL),driedoverNa2SO4andthesolventwasdistilledunderreducedpressure.ThecrudeproductwaspurifiedbySiO2columnchromatographyusingCH2Cl2/EtOHaseluentinincreasingpolaritytoyieldthedesiredcompounds

Compound64.Atotalof85mg(31%)of64wasobtainedasawhitesolid.13CNMR(CDCl3)δ22.16,32.83,38.19,48.43,51.75,63.39,69.53,99.18.HRMS-ESI:calcdforC39H66N2O8([M+H]+)691.4892found691.4888.

Compound65.

Atotalof182mg(70%)of65wasobtainedasawhitesolid.1HNMR(CDCl3)δ1.67(s,8H),1.70-1.88(m,16H),2.39-2.47(m,8H),2.88-2.99(m,8H),3.72(s,8H).13CNMR(CDCl3)δ24.08,32.72,41.41,42.71,51.45,63.37,99.05.ESI-MSm/z=643[M+H]+.

Compound66.Atotalof345mg(73%)of66wasobtainedasawhitesolid(asamixtureofdiasteroisomericcompounds).1HNMR(CDCl3)δ1.50-2.20(m,32H),2.70-3.28(m,8H),3.50-3.92(m,8H),7.00-7.56(m,40H).ESI-MSm/z=1179[M+H]+;590[M+2H]2+.

Compound73.Atotalof200mg(42%)of73wasobtainedasawhitesolid..1HNMR(CDCl3)δ1.50-1.73(m,18H),1.80-2.13(m,25H),2.57(m,4H),3.83(s,8H),7.25-7.60(m,40H).13CNMR(CDCl3)δ30.63,33.19,37.84,41.12,43.19,52.46,63.72,99.78,126.97,127.04,127.13,128.67,138.94,141.03,145.90.ESI-MSm/z=1179[M+H]+;590[M+2H]2+.

Compound74.Atotalof190mg(47%)of74wasobtainedasawhitesolid.1HNMR(CDCl3)δ1.20-2.00(m,40H),2.34-2.48(m,4H),3.70(s,20H),6.77(d,J=8.16Hz,8H),7.07(d,J=8.34Hz,8H).13CNMR(CDCl3)δ30.81,33.16,37.70,40.93,42.59,52.72,55.22,63.67,99.67,113.70,127.53,138.91,157.80.ESI-MSm/z=995[M+H]+.

Compound75.Atotalof390mg(84%)of75wasobtainedasawhitesolid..1HNMR (300MHz,CDCl3)δ1.32(t,J=7.1Hz,12H),1.35-1.65(m,16H),1.70-1.85(m,8H),1.89(s,8H),1.95-2.05(m,8H),2.52(m,4H),3.77(s,8H),4.29(q,J=7.1Hz,8H),7.22(d,J=8.2Hz,8H),7.90(d,J=8.2Hz,8H).13CNMR(75MHz,CDCl3)δ14.42,30.46,33.16,37.89,41.03,43.76,52.44,60.81,63.78,99.75,126.80,128.39,129.72,152.10,166.62.ESI-MSm/z=1163[M+H]+.

Compound77.Atotalof173mg(73%)of77wasobtainedasawhitesolid.13CNMR(CDCl3)δ27.35,31.97,32.27,32.69,34.08,34.12,37.97,38.35,38.91,40.85,41.06,50.62,56.52,63.27,63.55,100.03.ESI-MSm/z=595[M+H]+;298[M+2H]2+.

Compound79.Atotalof150mg(86%)of79wasobtainedasawhitesolid.1HNMR(CDCl3)δ1.59(s,8H),3.68(s,8H).13CNMR(CDCl3)δ30.82(m),32.29,42.64,50.37,63.18,99.28.ESI-MSm/z=435[M+H]+;452[M+NH4]+;457[M+Na]+;473[M+K]+.

Synthesisofcompound68.AsuspensionofRaneyNi(50%inwater)wasaddedtoasolutionof65(0.20g,0.31mmol)inethanol(25mL).Themixturewasstirredatrefluxduring24h.Aftercooling,thesolutionwasfilteredthroughapadofCeliteandthefiltratewasconcentratedunderreducedpressure.Theresiduewasdissolvedinchloroform(30mL),washedwith10%K2CO3aqueoussolution(30mL),driedoverNa2SO4andthesolventwasdistilledunderreducedpressuretoyield68(30mg,19%)asawhitesolid.1HNMR(CDCl3)δ0.70-0.76(m,24H),1.26-1.34(m,8H),1.43-1.51(m,8H),1.58(s,8H),3.66(s,8H).13CNMR(CDCl3)δ8.04,32.17,32.74,39.49,54.83,63.49,99.79.ESI-MSm/z=523[M+H]+.

Synthesisofcompound69.Compound63(0.43g,0.74mmol)wasdissolvedintoluene(80mL),pentaerythritol(45mg,0.33mmol)andp-toluenesulfonicacid(0.13g,0.65mmol)wereaddedtothestirredsolution.ThemixturewasrefluxedinaDeanStarksystemfor24h.Aftercooling,thesolutionwasconcentratedunderreducedpressureand10%Na2CO3aqueoussolution(100mL)wasadded.Themixturewasextractedtwicewithchloroform(150mL),driedoverNa2SO4andthesolventwasdistilledunderreducedpressure.TheresiduewaspurifiedbySiO2columnchromatographywithCH2Cl2/EtOHaseluent(90/10)toafford67(0.16g,38%)asawhitesolid.ESI-MSm/z=1251[M+H]+;626[M+2H]2+.

Then,asuspensionofRaney/Ni(50%inwater)wasaddedtoasolutionof67(0.16g,0.12mmol)inethanol(60mL).Themixturewasstirredatrefluxduring24h.Aftercooling,thesolutionwasfilteredthroughapadofCeliteandthefiltratewasconcentratedunderreducedpressure.Theresiduewasdissolvedinchloroform(30mL),washedwith10%K2CO3aqueoussolution(30mL),driedoverNa2SO4andthesolventwasdistilledunderreducedpressure.TheresiduewaspurifiedbyAlO2columnchromatographywithCH2Cl2/EtOH(99/1)togive69(50mg,37%)recrystallizedfromDCM/pentaneasawhitesolid.1HNMR(CDCl3)δ1.80-1.99(m,24H),2.62-2.72(m,16H),3.76(s,8H),7.10-7.30(m,40H).13CNMR(CDCl3)δ30.45,33.09,40.00,43.12,55.09,63.61,99.48,125.67,128.36,128.39,142.73.ESI-MSm/z=1132[M+H]+.566[M+2H]2+.

Synthesisofcompound78.Compound78waspreparedusingamodifiedprocedurereportedbyLinetal.17.2,2,6,6-Tetraperdeuteromethyl-3,3,5,5-tetradeuteropiperidinewasstirredinpurewater(H2O)andfreezedried(repeated2times)toobtain78.1HNMR(CDCl3)δ2.16(s).13CNMR(300MHz,CDCl3)δ31(m),53.82,54.79,210.81.ESI-MSm/z=168[M+H]+;190[M+Na]+.

Synthesisofb-3,5-diMePyTbK(38).Compound64(35mg,0.05mmol)andNa2WO4.2H2O(2mg,0.006mmol)werestirredinethanol(5mL)andH2O2(30%,0.21mmol,24μL)wasslowlyaddedat5°C.Themixturewasstirredfor24hatroomtemperature,thenK2CO3(0.10g)wasaddedandthesolutionwasextractedtwicewithchloroform(30mL).TheorganiclayerwasdriedoverNa2SO4anddistilledunderreducedpressure.ThecrudeproductwaspurifiedbySiO2columnchromatographyusingChloroform/MeOH(99/1)aseluenttoprovidepureb-3,5-diMePyTbK(38)(18mg,50%)asapaleredsolid.X-bandEPRspectrum(293K,inCH2Cl2):triplet,AN=1.53mT.ESI-MSm/z=721[M+H]+.HRMS-ESI:calcdforC39H64N2O10

..([M+H]+)721.4634found721.4637.HPLC:rt=10.28min.

SynthesisofTEKPOL2(34).Thediamine66(85mg,0.07mmol)wasoxidizedaccordingtothegeneralproceduredescribedabovefortheoxidationof64.ThecrudeproductwaspurifiedbySiO2columnchromatographyusingchloroformaseluenttoprovidepureTEKPol2(34)(39mg,45%),whichwasrecrystallizedfromacetonetoyieldpaleredsmallcrystals.X-bandEPRspectrum(293K,inCH2Cl2):triplet,AN=1.48mT.mp230-233°C.ESI-MSm/z=1209[M+H]+;1231[M+Na]+.HRMS-ESIcalcdforC83H88N2O6

..([M+NH4]+)1226.6981found1226.6956.Elementalanalysis:C,82.04;H,7.34;N,2.32calcdforC83H88N2O6

2.:C,82.41;H,7.33;N,2.32.

SynthesisofbEtTbK(29).Thediamine68(30mg,0.06mmol)wasoxidizedaccordingtothegeneralproceduredescribedabovefortheoxidationof64.ThecrudeproductwaspurifiedbySiO2columnchromatographyusingCH2Cl2/EtOH(99/1)aseluenttoprovidepurebEtTbK(29)asapaleyellowsolid(19mg,57%).X-bandEPRspectrum(293K,inCH2Cl2):triplet,AN=1.445mT.mp140-142°C.ESI-MSm/z=553[M+H]+;575[M+Na]+;591[M+K]+.HRMS-ESI:calcdforC31H56N2O6

..([M+H]+)553.4211found553.4211.HPLC:rt=12.731min.

SynthesisofbPEtTbK(30).Thediamine69(50mg,0.044mmol)wasoxidizedaccordingtothegeneralproceduredescribedabovefortheoxidationof64.ThecrudeproductwaspurifiedbySiO2columnchromatographyusingCH2Cl2aseluenttoprovidebPEtTbK(30)asaredsolid(30mg,60%).X-bandEPRspectrum(293K,inCH2Cl2):triplet,AN=1.42mT.ESI-MSm/z=1161[M+H]+;1199[M+K]+.HRMS-ESI:calcdforC79H88N2O6

..([M+NH4]+)1178.6981found1178.6980.

SynthesisofTEKPOL3(35).Thediamine73(25mg,0.02mmol)wasoxidizedaccordingtothegeneralproceduredescribedabovefortheoxidationof64.ThecrudeproductwaspurifiedbySiO2columnchromatographyusingchloroformaseluenttoprovidepureTEKPol3(35)(13mg,54%)asapaleredsolid.X-bandEPR

spectrum(293K,inCH2Cl2):triplet,AN=1.51mT.mp275-278°C.ESI-MSm/z=1209[M+H]+;1226[M+NH4]+.HRMS-ESIcalcdforC83H88N2O6

..([M+H]+)1209.6715found1209.6720.Elementalanalysis:C,81.91;H,7.57;N,2.19calcdforC83H88N2O6

..:C,82.41;H,7.33;N,2.32.

SynthesisofTEKPOL4(36).Thediamine74(40mg,0.04mmol)wasoxidizedaccordingtothegeneralproceduredescribedabovefortheoxidationof64.ThecrudeproductwaspurifiedbySiO2columnchromatographyusingchloroformaseluenttoprovidepureTEKPol4(36)asaredsolid(19mg,46%).X-bandEPRspectrum(293K,inCH2Cl2):triplet,AN=1.506mT.mp245-248°C.ESI-MSm/z=1025[M+H]+;1047[M+Na]+.HRMS-ESIcalcdforC63H80N2O10

..([M+H]+)1025.5886found1025.5901.Elementalanalysis:C,73.96;H,8.05;N,2.69calcdforC63H80N2O10

2.:C,73.80;H,7.86;N,2.73.

SynthesisofTEKPOL5(37).Thediamine75(0.2g,0.17mmol)wasoxidizedaccordingtothegeneralproceduredescribedabovefortheoxidationof64.ThecrudeproductwaspurifiedbySiO2columnchromatographyusingCH2Cl2/EtOH(99/1)aseluenttoprovidepureTEKPol5(37)asaredsolid(0.16mg,80%).X-bandEPRspectrum(293K,inCH2Cl2):triplet,AN=1.505mT.HRMS-ESI:calcdforC71H90N2O14

2.([M+2H]2+)597.3191found597.3186.

Synthesisof(Adm)2TbK(31).Thediamine77(50mg,0.08mmol)wasoxidizedaccordingtothegeneralproceduredescribedabovefortheoxidationof64.ThecrudeproductwaspurifiedbySiO2columnchromatographyusingchloroformaseluenttoprovidepure(Adm)2TbK(31)(23mg,46%)asapaleredsolid.X-bandEPRspectrum(293K,inCH2Cl2):triplet,AN=1.53mT.ESI-MSm/z=625[M+H]+;642[M+NH4]+;647[M+Na]+.

SynthesisofbTbK-d24(28).Thediamine79(100mg,0.23mmol)wasoxidizedaccordingtothegeneralproceduredescribedabovefortheoxidationof64.ThecrudeproductwaspurifiedbySiO2columnchromatographyusingCH2Cl2/EtOH(99/1)aseluenttoprovidebTbK-d24(28)(90mg,84%)asapaleredsolid.mp180-182°C.X-bandEPRspectrum(293K,inCH2Cl2):triplet,AN=1.55mT.ESI-MSm/z=465[M+H]+.HRMS-ESIcalcdforC23H17D24N2O6

2.([M+H]+)465.4466found465.4460.1HNMRofreducedbTbK-d24(CDCl3)δ2.33(s,8H),3.71(s,8H).

NMR spectra

Whenreported,NMRspectraofbiradicalswereobtainedafteraddingadropofphenylhydrazinedirectlyintheNMRtubes.

9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

6.508.277.942.074.004.01

TMS

CHLOROFORM-d

4.07

4.05

4.03

4.02

2.33

1.80

1.79

1.72 1.

691.

51 1.40

1.37

1.19

1.17

1.15

0.00

1HNMR(CDCl3,300MHz)spectrumof51.

200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

CHLOROFORM-d

209.

98

175.

06

77.4

377

.00

76.5

8 60.1

356

.37

49.6

5

41.7

239

.19 24

.63

14.0

5

13CNMR(CDCl3,75MHz)spectrumof51.

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)

0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

Nor

mal

ized

Inte

nsity

18.804.034.003.97

CHLOROFORM-d

7.27

3.50 3.

483.

463.

45

2.46

1.65

1.60

1.25

1.20

1.13

1.11

1HNMR(CDCl3,300MHz)spectrumof60.

200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

209.

66

77.4

277

.00

69.0

5

55.8

2 49.5

548

.09

21.8

4

13CNMR(CDCl3,75MHz)spectrumof60.

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

5.627.143.964.0021.10

TMS

7.33

7.31 7.

297.

277.

257.

217.

20 7.19

7.16

7.15

7.14

3.48

3.45

3.42

3.32

3.29 2.

862.

65

2.39

2.37

2.25

2.10 2.04 1.

931.

901.

651.

621.

601.

58 1.51

1.48

0.00

1HNMR(CDCl3,300MHz)spectrumof62.

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

12.024.2121.63

7.43

7.41 7.

37 7.34

7.31

7.28

7.26

7.25

7.24

4.78

4.73 4.69

4.20 4.

194.

174.

15

2.61

2.45

2.41

2.32

2.31

2.21 2.16

2.05

2.01

1HNMR(CDCl3,300MHz)spectrumof63.

136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Nor

mal

ized

Inte

nsity

CHLOROFORM-d

99.1

8

77.0

0

69.5

3

63.3

9

51.7

548

.43

38.1

9

32.8

3

22.1

6

13CNMR(CDCl3,75MHz)spectrumof64.

4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

7.9316.318.018.208.00

3.72

2.91

2.47

2.45

2.44

1.94

1.78

1.67

1HNMR(CDCl3,300MHz)spectrumof65.

112 104 96 88 80 72 64 56 48 40 32 24Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

CHLOROFORM-d

99.0

5

77.0

0

63.3

7

51.4

5

42.7

141

.41

32.7

2

24.0

8

13CNMR(CDCl3,75MHz)spectrumof65.

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

25.798.818.047.698.00

CHLOROFORM-d

7.27

3.72

1.64

1.55 1.

531.

39 1.37

1.35

0.81

0.79

0.78

1HNMR(CDCl3,300MHz)spectrumof68.

140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

CHLOROFORM-d

99.7

8

77.0

0

63.4

8

54.8

2

39.4

8

32.7

232

.16

8.03

13CNMR(CDCl3,75MHz)spectrumof68.

7 6 5 4 3 2 1 0 -1 -2Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

24.1916.008.2944.51

TMS

grease

n-pentane

n-pentane

7.27

7.25

7.22 7.15

7.15

7.12

3.76

2.70

2.67

2.64

1.96 1.93

1.89

1.86

1.84

1.26

0.86

0.07

0.00

1HNMR(CDCl3,300MHz)spectrumof69.

140 130 120 110 100 90 80 70 60 50 40 30 20 10Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Nor

mal

ized

Inte

nsity

CHLOROFORM-d

142.

73

128.

3912

5.67

99.4

8

77.0

0

63.6

1

55.0

9

43.1

240

.00

33.0

930

.45

13CNMR(CDCl3,75MHz)spectrumof69.

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

7.838.796.0019.15

CHLOROFORM-d

7.60

7.58

7.56 7.44 7.

31

2.60

2.53

1.99

1.96

1.89

1.69

1.66

1HNMR(CDCl3,300MHz)spectrumof70.

200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)

0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

Nor

mal

ized

Inte

nsity

CHLOROFORM-d

210.

82

145.

4614

0.99

139.

13

128.

7012

7.14

126.

99

77.0

0

56.7

7 49.0

8 43.1

741

.23

30.2

8

13CNMR(CDCl3,75MHz)spectrumof70.

13 12 11 10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

16.655.776.003.973.88

CHLOROFORM-d

7.14

7.12 6.86

6.84

3.79

2.55

2.46

1.91

1.60

1.58

1HNMR(CDCl3,300MHz)spectrumof71.

200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Nor

mal

ized

Inte

nsity

CHLOROFORM-d21

0.93

157.

84

138.

47

127.

49

113.

71

77.4

277

.00

76.5

8

56.6

855

.16

49.0

0 42.5

341

.16 30

.41

13CNMR(CDCl3,75MHz)spectrumof71.

10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

6.1719.226.054.005.583.97

TMS

7.98 7.

96

7.28

7.26

7.25 4.38 4.35

4.33

2.56

1.93

1.81

1.65

1.61 1.

411.

391.

36

0.00

1HNMR(CDCl3,300MHz)spectrumof71.

200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)

0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

Nor

mal

ized

Inte

nsity

CHLOROFORM-d

210.

55

166.

53

151.

51

129.

8412

9.72

126.

70 77.4

277

.00

76.5

8

60.7

656

.72 49

.00 43

.53

40.9

7

29.9

5 14.3

2

13CNMR(CDCl3,75MHz)spectrumof72.

9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

18.8025.414.568.0040.36

TMS

grease

n-pentane

n-pentane

toluene7.

587.

557.

547.

447.

32

3.83

2.57

2.35

2.12 2.08

1.98

1.86

1.67

1.64 1.60

1.56

1.50

1.26 0.

88

0.08

1HNMR(CDCl3,300MHz)spectrumof73.

150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

Nor

mal

ized

Inte

nsity

CHLOROFORM-d

145.

9014

1.03

138.

94

128.

6712

6.97

99.7

8

77.0

0

63.7

2 52.4

6

43.1

941

.12

37.8

4

33.1

930

.63

13CNMR(CDCl3,75MHz)spectrumof73.

12 11 10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

40.914.3120.007.877.91

CHLOROFORM-d

7.27

7.18 7.

15 6.87

6.84

3.80

2.56 2.

48

2.08

1.95

1.81 1.

57

1HNMR(CDCl3,300MHz)spectrumof74.

200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Nor

mal

ized

Inte

nsity

CHLOROFORM-d

157.

80

138.

91

127.

52 113.

70

99.6

7

77.0

0

63.6

7

55.2

2

42.5

840

.93

37.7

030

.80

13CNMR(CDCl3,75MHz)spectrumof74.

9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

Nor

mal

ized

Inte

nsity

16.2539.604.168.518.008.267.99

TMS

pentane

pentane

7.89

7.86

7.21

7.18

4.27

4.25

3.73

2.47

1.98 1.

951.

851.

72

1.40

1.28

1.25

1.16

0.78

1HNMR(CDCl3,300MHz)spectrumof75.

180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

CHLOROFORM-d

166.

40

151.

89

129.

5112

6.58

99.5

3

77.0

0

63.5

560

.59

52.2

1

43.5

440

.80

37.6

532

.94

30.2

3

22.1

5

14.1

9

13CNMR(CDCl3,75MHz)spectrumof75.

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)

0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

Nor

mal

ized

Inte

nsity

5.9714.981.952.00

CHLOROFORM-d

7.27

2.47

2.25

2.20

1.84

1.75

1.60

1.47

1.43

1.17

1HNMR(CDCl3,300MHz)spectrumof76.

200 180 160 140 120 100 80 60 40 20Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

CHLOROFORM-d

211.

68

77.0

0

61.5

154

.73

54.3

3 49.9

4

38.4

638

.40

33.4

331

.95

27.1

326

.97

13CNMR(CDCl3,75MHz)spectrumof76.

120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

CHLOROFORM-d

100.

03

77.0

0

63.5

563

.27

56.5

2

50.6

2

41.0

640

.85 38

.91 38

.35

34.0

832

.69

32.2

731

.97

27.3

5

13CNMR(CDCl3,75MHz)spectrumof77.

9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

7.738.00

CHLOROFORM-d

7.27

3.68

1.59

1HNMR(CDCl3,300MHz)spectrumof79.

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

CHLOROFORM-d

99.2

8

77.0

0

63.1

8

50.3

7

42.6

4

32.2

930

.82

13CNMR(CDCl3,75MHz)spectrumof79.

8 7 6 5 4 3 2 1 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8N

orm

aliz

ed In

tens

ity

8.008.28

TMS

TMS

3.71

2.23

1HNMR(CDCl3,300MHz)spectrumofbTbK-d24(28)afteradditionofadropofphenylhydrazine.

EPR spectra of reported dinitroxides 1mMinTCE,293K,9GHz(Xband)EPR

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