physiologically7777dd

PolymerChemistryPAPERCitethis:Polym.
Chem.
,2015,6,5705Received3rdFebruary2015,Accepted6thApril2015DOI:10.
1039/c5py00160awww.
rsc.
org/polymersThesynthesisandaqueoussolutionpropertiesofsulfobutylbetaine(co)polymers:comparisonofsyntheticroutesandtuneableuppercriticalsolutiontemperaturesYichengZhu,Janina-MiriamNoy,AndrewB.
LoweandPeterJ.
Roth*Polysulfobutylbetaine(SBB)(co)polymers,zwitterionicspeciesbearingammoniumandsulfonategroupsseparatedbyabutylspacerineveryrepeatunit,werepreparedthroughthreedierentsyntheticroutesandtheiraqueoussolutionbehaviourwasstudied.
Postpolymerizationquaternizationofpoly[2-(dimethyl-amino)ethylmethacrylate]with1,4-butanesultoneresultedinincompletemodicationduetothelowreactivityofthisalkylatingagent.
RAFTradicalpolymerizationofSBB-functional(meth)acrylatemonomersandtheircopolymerizationwithasulfopropylbetaine(SPB)methacrylateyieldedwell-dened(co)poly-merswithlowdispersities1.
13≤M≤1.
23atmonomerconversionsof75–92%.
ForaseriesofSBBmethacrylatehomopolymerswithincreasingdegreesofpolymerizationfrom66–186measureduppercriticalsolutiontemperature(UCST)cloudpointsincreasedfrom27–77°C.
CloudpointsofstatisticalSPB-SBBcopolymerswithsimilardegreesofpolymerization,butvaryingmolarcompositions,increasedlinearlywithSBBcontentoeringasimplemeansofUCSTtuning.
Additionally,novelSBBacrylamidehomo-andcopolymerswerepreparedbypostpolymerizationmodicationofpoly(pentauorophenylacrylate)withanSBB-functionalamineandinmixtureswithbenzylamineasahydrophobicmodier.
Inallcases,theSBB(co)polymershadsignicantlyhigherUCSTsthantheirmorecommonSPBcounterparts,greatlyextendingthetemperaturerangeoftuneableUCSTtransitionsandmakingtheinvestigatedSBB(co)polymersadvantageousforexploitingtheir'smart'behaviour.
Inthisrespect,combiningSBBfunction-alitywithhydrophobicbenzylacrylamidecomonomersispresentedasasimplemeansofincreasingthemaximumsaltconcentrationatwhichUCSTbehaviour(whichshowsanantipolyelectrolyteeect)canbeobserved,enablingUCSTtransitionsinaqueoussolutionscontainingaphysiologicalconcentration(9gL1)ofNaCl.
IntroductionThermoresponsivepolymershavebeenthefocusofresearchformanydecadesandarangeofapplicationsincludingdrugdelivery,separation,diagnostics,andtissueengineeringarebasedonpolymersexhibitingaqueousinversetemperaturesolubility(lowercriticalsolutiontemperature(LCST)behav-iour,i.
e.
phaseseparationaboveacriticaltemperature).
1Theircounterparts,polymerswithanaqueousuppercriticalsolutiontemperature(UCST)whichphaseseparatebelowacriticaltemperature,havesimilarpotentialinsuchapplications,butonlyafew(co)polymersareknowntoexhibitthistypeof"smart"behaviour.
2Sulfobetainepolymers,3–6whichcarrypermanently(pHindependent)chargedammoniumandsulfonategroupsineveryrepeatunit,arepromisingcandidatesforaqueousUCSTbehaviourbecausetheirzwitterionicsidegroupscancausestronginter-andintrapolymerattractionsthroughelectrostaticinterlockingatlowtemperaturesresult-ingininsolubility.
Polysulfobetaineshaveadditionallyattractedattentionbecauseoftheirsuperiorhaemocompatibilityandantibiofoulingproperties,7,8whichhavebeenexploitedforsurfacemodificationofultrafiltrationmembranes9andblood-contactingdevices10,11andwounddressingappli-cations.
12Sincefirstdescribedinthe1950s,13awiderangeofpolysulfobetaineswithvariousbackbonetypes,sidegroupgeo-metries,ammoniumalkylsubstituents,andspacerlengthsElectronicsupplementaryinformation(ESI)available:Heatingandcoolingcurvesshowingreproducibilityandhysteresis,19FNMRmeasurementsindicat-ingfullconversionofPFPprecursors.
SeeDOI:10.
1039/c5py00160aPresentaddress:NanochemistryResearchInstitute(NRI),DepartmentofChemistry,CurtinUniversity,Bentley,PerthWA6102,Australia.
CentreforAdvancedMacromolecularDesign(CAMD),SchoolofChemicalEngineering,UniversityofNewSouthWales,Kensington,Sydney,NSW2052,Australia.
E-mail:Peter.
Roth@curtin.
edu.
auThisjournalisTheRoyalSocietyofChemistry2015Polym.
Chem.
,2015,6,5705–5718|5705hasbeenprepared.
3,4,6,14–18Notably,asignificantfocusofpre-viousresearcheortswasonfullywatersoluble(co)polymerswithmiscibilitygapsoftenbeingconsideredanuisanceratherthananopportunity.
Consequently,aqueousUCSTbehaviourhasonlybeenreportedforasmallsubsetofzwitterionic(co)polymers.
3,19–25Whiletheinfluenceofspacerlengths,includingthelengthoftheionbridgebetweenthechargedsites,onhydrophilicityhasbeeninvestigatedforsmallmole-cule(sulfo)betaines,15,26–29detailedstudiesofaqueoussolu-tionbehaviourofsulfobetainepolymershaveinvariablydealtwithsulfopropylbetaine(SPB)polymers,i.
e.
structureswiththreemethylenegroupsbetweenthechargedgroups.
19–21,23,24,30–32ThemajorityofrecentstudiesonpolysulfobetaineUCSTbehaviouris,infact,largelybasedonthetwocommerciallyavailablemonomers3-((2-(methacryloyloxy)-ethyl)dimethylammonio)propane-1-sulfonate(MA2-3)21,30,33–35and3-((3-methacrylamidopropyl)dimethylammonio)propane-1-sulfonate(MAm3-3).
21,31,36,37Zwitterionicmonomersaretypicallypolymerizedinaqueoussolution,3,16,38whichposeslimitationsfortheincor-porationofhydrophobicsegmentsincludingco-monomers.
39Also,characterizationofzwitterionicpolymers,especiallybysizeexclusionchromatography(SEC),suersfromthelimitedsolubilityofsuchpolymersinorganicsolvents.
32Forthesereasons,quaternizationofaminogroupsorinstallationofzwitterionicsegmentsthroughpostpolymerizationmodifi-cationof(easiertocharacterize)precursorscanbepreferen-tial.
6Commonly,tertiaryaminefunctionalpolymers,suchashomo-16,40orcopolymers41,42of2-(dimethylamino)ethylmethacrylate(DMAEMA)arereactedwithsultones,cyclicsulfo-nicesters,inorganicsolventsproducing,inthecaseofpDMAEMAand1,3-propanesultone,poly[3-((2-(methacryloyl-oxy)ethyl)dimethylammonio)propane-1-sulfonate],p(MA2-3).
Forreactioninmostorganicsolvents,suchasTHF,theresult-ingpartiallybetainized(co)polymersprecipitatewithreactioncontinuing,considerablyslower,16underheterogeneouscon-ditions.
Werecentlyreported43thepostmodificationoftheactivatedesterprecursorpoly(pentafluorophenylacrylate),pPFPA,44withazwitterionicfunctionalprimaryamine,3-((3-aminopropyl)dimethylammonio)propane-1-sulfonate,amine3-3,asanovelandversatilesyntheticroutetowardzwitterionichomo-andhydrophobicallymodifiedcopolymers.
Notably,alsointhisstudyonlypropyl-spacedderivativeswereinvestigated.
Thoughpromising,applicationsoftheUCSTbehaviourofpolysulfobetainesarelimitedcomparedtothoseofLCST-typepolymerssuchaspoly(N-isopropylacrylamide)ornon-linearpoly(ethyleneglycol)sfortworeasons.
Firstly,UCSTtransitionsgenerallyshowastrongpositivedependenceonmolecularweight.
AsthecommonlystudiedMA2-3andMAm3-3basedpolysulfopropylspeciescanexhibitgoodsolubilityinpurewater,relativelyhighmolecularweightsofseveralhundredkgmol1arenecessarytoachievecloudpointsashighas30–40°C.
21,35Polymerswithlowermolecularweightshavelowercriticaltemperaturesormaybefullysoluble,notexhibit-ingthedesired"smart"behaviouratall.
Secondly,zwitterionicpolymersshowanantipolyelectrolyteeect:addedsaltsscreentheinter-andintraionicinteractions,reducingelectrostaticinterlockingeciencywhichresultsinadecreaseofUCSTcloudpointsand,ultimately,atsucientlyhighsaltconcen-trations,intemperatureindependentaqueoussolubility.
4Con-sequently,itisofconsiderableinteresttodevelop(co)polymerswithsignificantlyhigherUCSTtransitionsthanthoseofcom-parableMA2-3andMAm3-3basedpolysulfopropylbetaines—possiblytoanextentthatpolymersareinsolubleinpurewaterovertheentiretemperaturerangeupto100°Cat1atm.
"Smart"behaviourinapracticaltemperaturerangewouldthenbeobservablefor(moreconvenientlyavailable)lowermolecularweightsamples,and,importantly,inaqueoussaltsolutions,mostideallyextendingtoaphysiologicallyrelevantionconcentration(e.
g.
154mMNaCl).
OurpreviouslyreportedpostpolymerizationpreparationofhydrophobicallymodifiedsulfopropylbetainecopolymersrepresentsafirststudyaimedatincreasingUCSTtransitionsthroughtuningofcopolymercompositionwhichenabledsharptransitionsofacopolymerwithMn=27kgmol1inaqueoussolutionscon-tainingupto76mMNaCl.
43Herein,wepresentadetailedstudyintotheUCSTbehav-iourofsulfobutylbetaine(SBB)(co)polymersandshowthatincreasingtheionbridgebyjustonemethyleneunitre-presentsasimplemeansofsignificantlyincreasingcriticalsolutiontemperaturesofhomopolymers.
SBB(co)polymersandseveralSPBreferencesampleswerepreparedthroughdirect(co)polymerizationofcommercialandpreparedzwit-terionicmonomers,throughpostmodificationofpDMAEMAwithsultones,andthroughpostmodificationofanactivatedesterprecursorusinganovelzwitterionicamineallowingustocomparethesemethodswithregardstotheireciencyinproducingtheSBBspeciesandprovidingaccesstoalibraryof(novel)zwitterionicacrylate,methacrylateand(hydropho-bicallymodified)acrylamide(co)polymerswithtuneableUCSTtransitionsspanninganimpressivetemperaturerangeandextendinguptophysiologicallyrelevantNaClconcentrations.
ExperimentalsectionMaterialsAllreagents,includingmethacryloxyethyldimethylammoniopropanesulfonate(MA2-3)and2-cyano-2-propyldithiobenzoate(CPDB)werepurchasedfromSigma-Aldrichandwereusedasreceivedunlessstatedotherwise.
Propylenecarbonate(99.
7%,anhydrous)wasstoredinaglovebox.
Azobis(isobutyronitrile)(AIBN)wasrecrystallizedfrommethanolandstoredat24°C.
Thesynthesesofthechaintransferagent(CTA)benzylpropyltrithiocarbonate(BPTC),45theCTApentafluorophenyl4-cyano-4-((phenylcarbonothioyl)thio)valerate,46theactivatedesterinitiatorbis(pentafluorophenyl)4,4′-(diazene-1,2-diyl)bis-(4-cyanopentanoate),46andtheamine-functionaldye4-nitro-7-piperazin-1-yl-2,1,3-benzoxadiazole(NBDamine)47aredescribedelsewhere.
PaperPolymerChemistry5706|Polym.
Chem.
,2015,6,5705–5718ThisjournalisTheRoyalSocietyofChemistry2015MethodsNMRspectroscopicmeasurementsinD2OwereperformedonaBrukerAvance300MHzinstrumentin5mmNMRtubes.
MeasurementsofpolymersweredoneonD2Osolutionscon-tainingupto0.
5MNaCl.
Theinternalsolventsignalδ(D2O)=4.
79ppmwasusedasreference.
Sizeexclusionchromatography(SEC)inN,N-dimethyl-acetamide(DMAc)wasperformedonaShimadzusystemwithfour300*7.
8mm2linearphenogelcolumns(105,104,103,and500)operatingataflowrateof1mLmin1.
Thesystemwascalibratedwithaseriesoflowdispersitypolystyrene(PS)standardswithmolarmassesrangingfrom0.
58–1820kgmol1.
AqueousSECwasperformedonaShimadzusystemwithtwoAgilentAquagelcolumnswith0.
2MNaClsolutioncontaining0.
02mass%sodiumazideaseluentataflowrateof1mLmin1.
Thissystemwascalibratedwithaseriesofnarrowmolarmassdistributionpoly(ethyleneglycol)(PEG)standards.
ChromatogramswereanalysedbyCirrusSECsoftwareversion3.
0.
Fouriertransforminfraredspectroscopy(FT-IR)wasper-formedonaBrukerIFS66/Sinstrumentunderattenuatedtotalreflectance,anddatawasanalysedwithOPUSsoftwareversion4.
0.
TurbiditymeasurementswereperformedonaVarianCary300ScanspectrophotometerequippedwithaCarytemperaturecontrollerandaPeltierheatingelementinquartzcuvettesof10mmpathlengthatawavelengthof520nmwithheating/coolingratesof1°Cmin1.
Unlessotherwisenoted,polymerconcentrationswere10gL1.
Forclearsolutionsthebaselinewascorrectedtozeroabsorbance,A.
Transmittance,t=10A,wasplottedagainsttemperature,andcloudpoints,CP,weredeterminedattheonsetoftransmittancedecrease.
Electrosprayionization(ESI)massspectrometrywasper-formedonaScientificLTQOrbitrapXLmassspectrometeroperatinginpositiveionmodewithasprayvoltageof1.
2kV,acapillaryvoltageof45V,acapillarytemperatureof200°C,andatubelensvoltageof120V.
Poly[2-(dimethylamino)ethylmethacrylate],pDMAEMA,waspreparedaspreviouslydescribed.
48Mtheor.
n=31.
8kgmol1,DPtheor.
=201,MSECn=22.
3kgmol1(DMAc,PSstandard),M=MSECw/MSECn=1.
14.
1HNMR(D2O,300MHz),δ/ppm=4.
11(–OCH2CH2–),2.
67(–OCH2CH2–),2.
27,2.
04(backbone–CH2–),1.
08,0.
90(backbone–CH3).
PostpolymerizationofpDMAEMAwithsultones.
Poly[3-((2-(methacryloyloxy)ethyl)dimethylammonio)propane-1-sulfonate],p(MA2-3):pDMAEMA(100mg,0.
636mmolofrepeatunits,1eq.
)wasdissolvedin2,2,2-trifluoroethanol(2mL).
Inasepa-ratevial,1,3-propanesultone(155.
4mg,1.
272mmol,2eq.
)wasdissolvedinTFE(1mL)andthenaddedintothepolymersolu-tion.
Themixturewasstirredat40°Cfor3days.
Brinewasaddedtothereactionmixtureandtheaqueousphasewaswashedseveraltimeswithdiethylether,subjectedtodialysisutilizingregeneratedcellulosemembraneswitha3500gmol1molecularweightcut-oinultrapurewaterfor3daysfollowedbyfreezedrying,yielding163mg(92%)ofawhitesolid.
1HNMR(D2O,500mMNaCl,300MHz),δ/ppm=4.
54(–OCH2CH2–),3.
86(–OCH2CH2–),3.
65(–N+(CH3)2CH2CH2–),3.
28(–N+(CH3)2–),3.
03(–CH2SO3),2.
34(–N+(CH3)2CH2CH2–),2.
06(backbone–CH2–),1.
20,1.
06(backbone–CH3).
Poly[4-((2-(methacryloyloxy)ethyl)dimethylammonio)butane-1-sulfonate],p(MA2-4),waspreparedinananalogouspro-cedureusing1,4-butanesultone(173.
2mg,1.
272mmol,2eq.
)withheatingtoreflux(oilbathat103°C)for4days.
Workupasdetailedaboveyielded125mg(67%)ofawhitesolid.
1HNMR(D2O,500mMNaCl,300MHz),δ/ppm=4.
57(–OCH2CH2–),3.
86(–OCH2CH2–),3.
56(–N+(CH3)2CH2CH2CH2–),3.
28(–N+(CH3)2–),3.
03(–CH2SO3),2.
08(–N+(CH3)2CH2-CH2CH2–andbackbone–CH2–),1.
90(–N+(CH3)2CH2CH2CH2–),1.
20,1.
06(backbone–CH3).
Monomer4-((2-(methacryloyloxy)ethyl)dimethylammonio)-butane-1-sulfonate(MA2-4).
492-(Dimethylamino)ethylmeth-acrylate(DMAEMA,4.
43mL,26.
3mmol),1,4-butanesultone(2.
44mL,23.
9mmol),inhibitor3,5-di-tert-butyl-4-hydroxy-toluene(BHT,50mg),andacetonitrile(50mL)werecombinedandrefluxedfor48h.
Theconsumptionof1,4-butanesultonewasmonitoredbythin-layerchromatography(TLC)usingn-hexane–ethylacetate50:50asthemobilephase.
Thecrudematerialwhichprecipitatedthroughoutthecourseofthereac-tionwasfiltered,washedwithacetonitrile(150mL),anddriedinvacuoatroomtemperature.
5.
32g(76%)ofawhitesolidwereobtained.
1HNMR(D2O,300MHz),δ/ppm=6.
18(m,1H,CHHvC(CH3)–,cis),5.
80(m,1H,CHHvC(CH3)–,trans),4.
65(m,2H,–OCH2CH2–),3.
80(m,2H,–OCH2CH2–),3.
48(m,2H,–N+(CH3)2CH2CH2CH2–),3.
20(s,6H,–N+(CH3)2–),2.
99(t,2H,–CH2SO3),2.
00(m,5H,–N+(CH3)2CH2CH2CH2–and–CH2C(CH3)–),1.
82(m,2H,–N+(CH3)2CH2CH2CH2–).
Monomer4-((2-(acryloyloxy)ethyl)dimethylammonio)butane-1-sulfonate(A2-4).
2-(Dimethylamino)ethylacrylate(DMAEA,4.
19mL,27.
6mmol),1,4-butanesultone(2.
56mL,25.
1mmol),BHT(50mg),andacetonitrile(50mL)werecombinedandrefluxedfor48h.
Theconsumptionof1,4-butanesultonewasmonitoredbyTLCwithn-hexane–ethylacetate50:50asthemobilephase.
Thecrudematerialwhichprecipitatedthrough-outthecourseofthereactionwasfiltered,washedwithaceto-nitrile(150mL)anddriedinvacuoatroomtemperature.
6.
20g(89%)ofawhitesolidwereobtained.
1HNMR(D2O,300MHz),δ/ppm=6.
49(dd,1H,trans,2Jgem=1.
2Hz,3Jcis=17.
4Hz,CHHvCH–),6.
25(dd,1H,gem,3Jtrans=17.
1Hz,3Jcis=17.
1Hz,CHHvCH–),6.
06(dd,1H,cis,2Jgem=0.
9Hz,3Jtrans=10.
5Hz,CHHvCH–),4.
66(m,2H,–OCH2CH2–),3.
79(m,2H,–OCH2CH2–),3.
48(m,2H,–N+(CH3)2CH2CH2CH2–),3.
20(s,6H,–N+(CH3)2–),2.
99(t,2H,–CH2SO3),2.
00(m,2H,–N+(CH3)2CH2CH2CH2–),1.
82(m,2H,–N+(CH3)2CH2CH2CH2–).
Monomer4-((3-methacrylamidopropyl)dimethylammonio)-butane-1-sulfonate(MAm3-4).
3-(Dimethylamino)propylmethacrylamide(DMAPMAm,3.
05g,17.
9mmol),1,4-butane-sultone(1.
67mL,16.
3mmol),BHT(50mg),andacetonitrile(50mL)werecombinedandheatedto45°Cfor3days.
Thecrudematerialwhichprecipitatedthroughoutthecourseofthereactionwasfiltered,washedwithacetonitrile(150mL)PolymerChemistryPaperThisjournalisTheRoyalSocietyofChemistry2015Polym.
Chem.
,2015,6,5705–5718|5707anddriedinvacuoatroomtemperature.
2.
63g(53%)ofawhitesolidwereobtained.
1HNMR(D2O,300MHz),δ/ppm=5.
73(m,1H,CHHvCCvO),81.
21(–C(CH3)3),63.
35,61.
67(–CH2N+(CH3)2CH2–),50.
74(–N+(CH3)2–),49.
95(O3SCH2–),36.
82(–CH2CH2NHBOC),27.
63(–C(CH3)3),22.
68(–N+(CH3)2CH2CH2–),21.
06(O3SCH2CH2CH2–),20.
82(O3SCH2CH2–).
Aftertreatmentwithaq.
HClandanionexchangebeads,0.
99g(74%)freebaseamine3-4wasobtained.
1HNMR(300MHz,D2O),δ/ppm=3.
39–3.
32(m,4H,–CH2N+(CH3)2CH2–),3.
09(s,6H,–N+(CH3)2–),2.
99(t,2H,O3SCH2–),2.
72(t,2H,–CH2NH2),2.
01–1.
77(m,6H,–CH2CH2CH2N+(CH3)2CH2CH2CH2NH2).
13CNMR(300MHz,D2O),δ/ppm=63.
47,62.
20(–CH2N+(CH3)2CH2–),50.
63(–N+(CH3)2–),49.
93(O3SCH2–),37.
61(–CH2CH2NH2),24.
96–CH2CH2NH2),21.
07(O3SCH2CH2CH2–),20.
80(O3SCH2CH2–).
GeneralprocedureforpostpolymerizationmodificationofpPFPAwithzwitterionicamines.
pPFPA(44.
7mg,0.
188mmolofrepeatunits,1equiv.
)wasdissolvedinanhydrouspropylenecarbonate(1.
5mL)at60°Candhydroxyethylacrylate(5L)wasaddedtoscavengethiolsreleasedfromtheRAFTendgroupsthroughaminolysis.
50Inparallel,3-((3-aminopropyl)di-methylammonio)propane-1-sulfonate,(amine3-3,63.
2mg,0.
282mmol,1.
5equiv.
)or4-((3-aminopropyl)dimethyl-ammonio)butane-1-sulfonate,(amine3-4,67.
1mg,0.
282mmol,1.
5equiv.
)wasdissolvedinpropylenecarbonate(1.
5mL)withheating.
Afterdissolving,theaminesolutionwasquicklyaddedintothepolymersolutionandthemixturestirredat40°Covernight.
Asample(100μL)waswithdrawn,dilutedwithDMSO(550μL)andanalysedby19FNMRspectroscopyindicatingcompleteconversionofPFPestersshowingonlysignalsoffreepentafluorophenolatδ/ppm=167.
4(2F,ortho),170.
2(2F,meta),181.
7(1F,para).
Thesolutionwastransferredintoadialysisbag(molecularweightcut-o3500gmol1)anddialyzedagainstultrapurewaterfor3daysatRT(p(Am3-3))or60°C(p(Am3-4)),followedbyfreeze-drying.
Poly[3-((3-acrylamidopropyl)dimethylammonio)propane-1-sulfonate],p(Am3-3):1HNMR(D2O,500mMNaCl,300MHz)δ/ppm=3.
55(bs,–N+(CH3)2CH2CH2–),3.
43(bs,–NHCH2CH2CH2–),3.
28(bs,–NHCH2CH2CH2–),3.
18(bs,–N+(CH3)2–),3.
03(bt,–CH2SO3),2.
26(bs,–N+(CH3)2CH2CH2–),2.
11,2.
07(backbone–CH80mM.
Here,aseriesofSBBcopolymerswithmolarBzAmcontentsof50%,62%,and69%,asdeterminedby1HNMRspectroscopyin500mMNaClinD2O,wasprepared.
Notably,samplep[(Am3-4)0.
31-co-BzAm0.
69]withthehighestBzAmcontentdidnotformaclearsolutioninthissolvent(norathigherNaClcon-centrations)—thedeterminedcompositionmaythusbelessaccurate—indicatinganupperlimitofobservablezwitterionicbehaviourforhydrophobicmodification.
Theremainingtwosamples,however,whilebeinginsolubleinpure(hot)water,didexhibitsharp,reversibleUCSTtransitionsbetweenclearsolutionsandcloudymixturesinaqueousNaClsolution.
Asexpected,thephasebehaviourofthesesamplesextendedtohigherNaClconcentrationsthanfortheSPBcopolymer,withUCSTtransitionsmeasuredonsolutionscontainingupto128mM(7.
5gL1)NaClforp[(Am3-4)0.
50-co-BzAm0.
50]and154mM(9.
0gL1,concentrationofisotonicsaline)NaClforp[(Am3-4)0.
38-co-BzAm0.
62],seeFig.
8.
Theseresultsdemon-Fig.
7FT-IRspectraofthepPFPAprecursor(top),ap(Am3-4)homo-polymerpreparedthereof(middle),andaRAFT-madep(MA2-4)homo-polymerforcomparison(bottom).
ThecharacteristicbandsoftheactivatedesterCvOstretching(1780cm1,grey),theesterCvOstretching(1720cm1,pink),andtheamideCvOstretching(1650cm1,yellow)aremarked.
Fig.
8InuenceofNaClconcentrationonthephaseseparationtemperatureofp(Am3-4)-benzylacrylamidecopolymers;(A)plotofUCSTcloudpointversusNaClconcentrationforp[(Am3-3)0.
47-co-BzAm0.
53](valuestakenfromourpreviousstudy)43(greentriangles),andtheSBBspeciespre-paredherep[(Am3-4)0.
50-co-BzAm0.
50](blacksquares)andp[(Am3-4)0.
38-co-BzAm0.
62](redcircles);(B)exemplaryturbiditycurvesforp[(Am3-4)0.
50-co-BzAm0.
50]atdierentNaClconcentrations.
PaperPolymerChemistry5716|Polym.
Chem.
,2015,6,5705–5718ThisjournalisTheRoyalSocietyofChemistry2015stratethatthecombinationofSBBsidechainswithhydrophobicmodificationfurtherincreasesthetemperature/saltrangeinwhichsharpUCSTtransitionscanbeachieved.
Specifically,UCSTtransitionsofzwitterioniccopolymersataphysiologicalNaClconcentrationarepromisingfortheexploitationofsuchsmartmaterialsinbiomedicalapplications.
However,thecomplexcompositionofbiologicalfluidsandthestrongdepen-denceoftheUCSTphasebehaviouronthetypeofions20,21,23,31or,likely,othersolutesneedstobeconsidered.
Inthepresentcase,forexample,p[(Am3-4)0.
38-co-BzAm0.
62]wasfoundtoremainsolubleinphosphatebueredsaline(137mMNaCl,2.
7mMKCl,10mMNa2HPO4,1.
8mMKH2PO4)andHEPESbuer(150mMNaCl,10mM4-(2-hydroxyethyl)-1-piperazine-ethanesulfonicacid)whencooledto0°C.
Conversely,thisstrongdependenceofthephasebehaviouronpotentiallyminutechangesoftheenvironmentmaybeexploitedforthedevelop-mentofmaterialsthatrespondselectivelytospecificbiologicalmicroenvironmentswith(slightly)dierentionconcentrations.
ConclusionAdetailedcomparativestudyoftheaqueoussolutionbehav-iourofsulfobutylbetaine(SBB)(co)polymerswaspresented.
Inallcases,samplesshowedsignificantlyhigherUCSTtran-sitions,i.
e.
theywerelesssolubleinwater,thantheirrespect-ivesulfopropylbetaine(SPB)counterparts.
WhereastheUCSTtransitionsofthecommonSPBhomopolymersp(MA2-3)andp(MAm3-3)arelimitedtorelativelyhighmolecularweightsamplesand/ortosolutionsinultrapurewater,thecorres-pondingSBB-functionalhomopolymersinvestigatedhereoeramuchlargertemperatureandsaltconcentrationrangeforobservingsharp,reproducibleUCSTtransitions.
ScopeandlimitationsofthreedierentsynthetictechniquestowardSBBhomo-andcopolymerswerecompared.
ThequaternizationofpDMAEMAwith1,4-butanesultonein2,2,2-trifluoroethanol(TFE)sueredfromlowreactivityofthisalkylatingagentresultinginincompletemodificationmakingthisprocedurelessattractiveforthesynthesisofpristineSBBspecies.
RAFTradicalpolymerizationofSBB-functional(meth)acrylatemono-mersandtheircopolymerizationwithSPBmonomersinTFEproceededsmoothlywithhighconversions,lowmeasureddis-persitiesM,andfacilitatedaccesstoaseriesof(co)polymerswithcloudpointsfrom13.
2–76.
5°C.
LowcompatibilityofSBB-functionalmonomerswithnon-proticsolventsincludingpro-pylenecarbonate(PC),however,limitstheincorporationofnon-polaroralcohol/water-sensitivecomponentsinthismethod.
Post-modificationofpoly(pentafluorophenylacrylate)withaSBB-functionalamineinPCprovidedzwitterionicpoly-acrylamidesandallowedfortheintroductionofhydrophobiccomonomerunits,butrequiredthemulti-stepsynthesisoftheaminereagent.
ASBB-functionalcopolymercontaining62mol%ofbenzylacrylamidecomonomerunitsshowedUCSTbehaviouruptoaphysiologicalconcentrationof9gL1NaClmakingsuchmaterialspromisingforexploitingtheirsmartbehaviourinthebiomedicalarena.
FundingsourcesP.
J.
R.
acknowledgesfundingfromtheUniversityofNewSouthWales(UNSW)andtheAustralianResearchCouncil(ARC)throughaDiscoveryEarlyCareerResearcherAward(DE120101547).
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