Di-block copolymer of poly[methacrylic acid-block-2-(diethylamino)ethyl methacrylate] [P(MAA-b-DEA)] with narrow molecular weight distribution was synthesized using the atom transfer radical polymerization (ATRP) technique. The micellization behavior of the P(MAA-b-DEA) copolymer in aqueous solution at room temperature and different pH values were examined by potentiometric and conductivity titration, UV-Visible spectrophotometry, ¹H-NMR, static and dynamic laser light scattering. At low pH ( 9.5), core-shell like micelles consisting of hydrophobic DEA core and ionized MAA shell were re-established.Singapore-MIT Alliance (SMA

Dai, S.

Gan, L.H.

Palaniswamy, R.

Tam, Michael K. C.

DSpace@MIT

 Abstract— Di-block copolymer of poly[methacrylic acid-block-2-(diethylamino)ethyl methacrylate] [P(MAA-b-DEA)]with narrow molecular weight distribution was synthesizedusing the atom transfer radical polymerization (ATRP)technique. The micellization behavior of the P(MAA-b-DEA)copolymer in aqueous solution at room temperature anddifferent pH values were examined by potentiometric andconductivity titration, UV-Visible spectrophotometry,  1H-NMR, static and dynamic laser light scattering. At low pH (<4.2), core-shell micelles were formed with MAA core andprotonated DEA shell. At moderate pH values, the polymerprecipitated from water and formed a cloudy solution, wherethe polymer chains aggregated into larger particlesresembling that of a hard sphere induced by electrostaticinteractions. At high pH (> 9.5), core-shell like micellesconsisting of hydrophobic DEA core and ionized MAA shellwere re-established.Index Terms— ATRP, laser light scattering, P(MAA-b-DEA),stimuli-responsiveI. INTRODUCTIONhe stimuli-responsive water-soluble and amphiphilicpolymers have attracted much interest since theirmicelles can be produced or destroyed by changing thetemperature, pH, ionic strength, and solvent polarity.1,2Recently, several research groups have reported on thereversible micellization behavior of block copolymers insolution.3-10 Laschewsky and Armes groups havesuccessfully synthesized di-block copolymers of poly(N-                                                Manuscript received October 23, 2003.Kam C. Tam is with MEBCS of Singapore-MIT Alliance, and Schoolof Mechanical and Production Engineering, Nanyang TechnologicalUniversity, 50 Nanyang Avenue, Singapore, 639798 (phone: 65-67905590; e-mail: mkctam@ntu.edu.sg)Palaniswamy Ravi is with the MEBCS of Singapore-MIT Alliance, 50Nanyang Avenue, Singapore, 639798 (e-mail: ravi@ntu.edu.sg).Dai Sheng is with the MEBCS of Singapore-MIT Alliance, 50Nanyang Avenue, Singapore, 639798 (e-mail: msdai@ntu.edu.sg).Leong H. Gan is with the Natural Science, National Institute ofEducation, Nanyang Technological University, 50 Nanyang Avenue,Singapore, 639798 (e-mail: lhgan@nie.edu.sg).isopropylacrylamide-block-3-(N-(3-ethacrylamidopropyl)-N, N -dimethyl)ammoniopropane sulfonate) (P(NIPAM–b-SPP))  and poly(2-(N-mor-pholino)ethyl methacrylate-block - 2-(sulfobetaine-dimethylamino)ethyl methacrylate)(P(MEMA-b-SBMA)) by reversible addition fragmentationchain transfer (RAFT) and atom transfer radicalpolymerization (ATRP) respectively.3,4 By linkingsegments that possess lower critical solution temperature(LCST) and upper critical solution temperature (UPST)properties, temperature-responsive block copolymers couldbe produced. With increasing temperature, micellescontaining SPP or SBMA hydrophobic core wereconverted to unimers, which then re-established theirmicellar structure consisting of NIPAM or MEMA corerespectively. Armes and co-workers also reported studieson di-block copolymers with temperature- and pH-responsive reversible aggregation properties of the poly(2-(dimethylamino)ethyl methacrylate-block-methacrylicacid) (P(DMA-b-MAA)) synthesized using group transferpolymerization (GTP).6,7 Reversible aggregates containingDMA hydrophobic core and ionized MAA hydrophiliccorona were produced at pH 9.5 and 50oC. The aggregateshas a large hydrodynamic diameter of ~ 400 nm. Otherresearch groups, such as Hatton’s and Jerome’s have alsoreported the pH- and temperature-responsive properties ofP(DMA-b-MAA).11,12 Depending on the blockcomposition, salt and pH, the copolymer is either soluble,insoluble or it forms large non-micellar aggregates.Another di-block copolymer with temperature and pHresponsive reversible micellization property is thepoly(propylene oxide-block-2-(diethylamino) ethylmethacrylate) (PPO-b-PDEA) synthesized by Armes andco-workers using ATRP.10 At high temperature (40oC) andlow pH (5.5), the micelles with hydrophobic PPO corewere formed in aqueous solution, while at low temperature(25oC) and high pH (8.5), micelles containing hydrophobicDEA core were produced. In addition, salt induced pH-responsive block copolymer of P(MEMA-b-DEA) was alsosynthesized by Armes and co-workers using the GTPmethod.8,9 At low pH value (< 6) and high saltNovel pH Responsive Amphiphilic DiblockCopolymers with Reversible MicellizationPropertiesPalaniswamy Ravi1,2, Sheng Dai1,2, Kam Chiu Tam1,2*, Leong Huat Gan31Singapore-MIT Alliance 2School of Mechanical and Production Engineering, Nanyang TechnologicalUniversity, Nanyang Avenue, Singapore 639798, Republic of Singapore 3Natural Sciences, NationalInstitute of Education, Nanyang Technological University, Nanyang Avenue, Singapore 639798,Republic of Singapore.Tconcentration (1 M K2SO4), micellar aggregates consistingof hydrophobic MEMA core and DEA corona shell wereproduced. Removal of salt by dialysis and adjusting the pHto greater than 8 produced reverse micelles containinghydrophobic DEA core and hydrophilic MEMA coronashell. Between the pH of 6 to 8, only unimers were foundto exist. Until recently, there is no published report on thereversible micellization behavior induced only by pHchanges. As we were finalizing this manuscript, wediscovered a recent publication by Armes and co-workers5,where they reported the synthesis of poly(4-vinyl benzoicacid-block-2-(diethylamino) ethyl methacrylate) (P(VBA-b-DEA)) that exhibited pH reversible micellizationproperty. Micelles with hydrophobic VBA core andhydrophilic DEA shell were produced at low pH, whileDEA formed the hydrophobic core with VBA as thehydrophilic shell at high pH.II. EXPERIMENTAL SECTIONWe now report the synthesis and the solution behavior ofa new pH induced reversible micellization of P(MAA-b-DEA). The biocompatibility of MAA and the higherhydrophobicity of DEA as compared to DMA at high pHmake this an polymeric attractive system. As far as we areaware, this is the first reported study on P(MAA-b-DEA).This copolymer system is believed to have potential fordrug delivery applications due to the biocompatibility ofMAA and DEA. In this P(MAA-b-DEA) copolymer, oneof the segments is a weak acid and the other a weak base(pKa 7.3 for DEA and pKa 5.4 for MAA).13 The DEAblock could be protonated at low pH making this segmenthydrophilic, while the MAA block could be ionized andbecomes soluble at high pH. Since either block hasdifferent pKa values and different chain lengths, thehydrophile-lipophile balance (HLB) of the blockcopolymer at high or low pH values are different.The P(MAA-b-DEA) was synthesized by ATRPtechnique using protecting group chemistry, followed byhydrolysis in acid condition. The synthetic scheme isoutlined in Scheme 1. For the first time, we havedemonstrated the synthesis of a well-defined blockcopolymer using either poly(tert-butyl methacrylate)(PtBMA) or PDEA as the macroinitiators.  In the first step,well-defined Cl-terminated PtBMA macroinitiator (Mn =13000 Da & Mw/Mn = 1.11) was synthesised using p-toluene sulfonyl chloride as an a initiator and CuClcomplexed with N,N,N’,N’,N’’,N’’-hexamethyltriethylenetetraamine (HMTETA) as a catalystin 50 vol% anisole at 90°C. The resulting P(tBMA)-Cl wasused as a macro-initiator to synthesize the block copolymerwith DEA using the same reaction condition as in thehomopolymer.  The well-defined P(tBMA-b-DEA) had aMn of 24800 Da and Mw/Mn of 1.22. P(MAA-b-DEA)was obtained by specific hydrolysis in acid condition(HCl/1,4-dioxane). Under this condition, DEA isinsensitive towards hydrolysis.14 The complete hydrolysisof the P(tBMA-b-DEA) was confirmed by FTIR. The 1HNMR spectrum (Figure 1) of the block copolymer(unhydrolyzed) allows the degree of polymerization of theindividual blocks to be determined from the relativeintensity of the peaks at 1.45 ppm (-C(CH3)3 of the tBMAblock) and 2.60-2.74 ppm (-N(CH2)3 of DEA block). Basedon the GPC and NMR results, the composition of the blockcopolymer was obtained. The copolymer is represented byP(MAA95-b-DEA65).Figure 2 shows the potentiometric and conductivitytitration curves of 0.04 wt% P(MAA-b-DEA) with NaOHat 25oC. Two transition points (pH ~ 4.2 and 9.8) indicatedby “A” and “B” were evident in the conductivity curve.The first transition corresponds to the beginning of theneutralization of –COOH groups of MAA segment, whilethe second transition is related to the  end  of  thedeprotonation on  the  DEA block. During the titration, itwas found that the transparent solution at low pH valuesbecomes cloudy at moderate pH (between 6 to 9), butturned transparent again at high pH. The % transmittance atwavelength of 488 nm was used to monitor the turbidityassociated with the phase behavior at different pH values(Figure 3).  It is evident that the solution is transparent atthe two extreme pH values, i.e. pH < 5.5 and pH > 9.2. CH3CCCH2 CCH3COOCH3C CH3CH3H2C TsCl, CuCl/HMTETAAnisole, 90oCnOOCH3CCH3CH3CH3CCH2COOCH2CH2N CH2H2CCH3 CH3CH2 CCH3COOCH3C CH3CH3 nCH3CCH2COOCH2CH2N CH2H2CCH3 CH3 mCH2 CCH3COHOnCH3CCH2COOCH2CH2N CH2H2CCH3 CH3 mAnisole, 90oC CuCl/HMTETAHCl/1,4-dioxaneClScheme 1. Synthetic outline for P(MAA-b-DEA)c  b  d  a  e  f  CH2 CCH3COOCH3C CH3CH3nCH3CCH2COOCH2CH2N CH2H2CCH3 CH3 ma abbcdf ffeeFigure 1. 1H-NMR spectrum of P(tBMA-b-DEA) inCDCl3Between pH range of 5.5 to 9.2, the solution becomescloudy, with the maximum turbility observed at pH 7.5.From the potentiometric and conductivity titration results,it is clear that the phase separation occurs after theneutralization of MAA segment and before thedeprotonation of DEA segment.Based on the chemical structure and the observedphenomena described above, pH-dependent reversiblemicelles are produced at low pH (Figure 2, below “A”) andhigh pH (Figure 2, above “B”) solutions. In the titration,the added NaOH first neutralizes the free HCl, followed bythe neutralization of MAA segment (between 0 to0.08mmol of NaOH). At low pH (below point “A”),micelles of hydrophobic MAA core and protonated DEAcorona shell are formed. By increasing the pH beyond point“A”, the -COOH groups of MAA segment areprogressively neutralized, thereby producing morehydrophilic –COO- groups. These –COO- groups interactwith the protonated DEA segments through electrostaticattraction, which giving rise to the precipitation of thepolymer in solution. As the pH increases beyond the IEP(iso-electric point)5, where the total negative charge equalsto total positive charge (at electrically neutral condition),the DEA segment is progressively deprotonated, and theelectrostatic balance is destroyed. The cloudy solution turnsclear again due to the formation of reverse micellescontaining deprotonated hydrophobic DEA core andneutralized hydrophilic MAA corona shell. Beyond point“B”, the DEA segment is completely deprotonated andonly NaOH dilution is observed henceforth.The 1H NMR spectra of the P(MAA-b-DEA) at low andhigh pH are shown in Figure 4a. In the spectrum recordedat low pH, the signals at 1.29(-CH3)2, 3.29(-N(CH2CH3)2,and 3.62 ppm (-NCH2CH2-) correspond to thecharacteristic of DEA segments. These peaks are clearlydetected in the 1H-NMR spectrum indicating that the DEAblock is solvated in the solvent (D2O/DCl). At high pHvalue (adjusted using NaOD), all the DEA peaks havedisappeared and only the -CH3 protons of methacrylic acidat 0.76-0.89 ppm are observed. This confirms thatreversible micelles are formed since the non-solvated DEAblock is now in the core and the solvated methacrylic acidblock forms the shell of the micelles.Figure 4. (a) 1H NMR of P(MAA-b-DEA) at low pH andhigh pH values, and (b) The hydrodynamic radiusdistributions and the possible structures of P(MAA-b-DEA) at different pH values.012345δ  (ppm)CH2 CCH3COHOnCH3CCH2COOCH2CH2N CH2H2CCH3 CH3 ma abbcdeeabcdeno ano b & cpH = 3pH = 12(a)0.1 10 1000Rh (nm)f(R h)pH = 3pH = 7pH = 12(b)Figure 4. (a) 1H NMR of P(MAA-b-DEA) at low pH and highpH values, and (b) The hydrodynamic radius distributions andthe possible structures of P(MAA-b-DEA) at different pH values.234567891011120 0.1 0.2 0.3 0.4[NaOH] (mmol)pH0100200300400500600700800λ (mS/cmpHCondaABFigure 2. The potentiometric titration of 0.05 wt%P(MAA-b-DEA) by NaOH at 25oC.01020304050607080901002 4 6 8 10 12pHT (%)Figure 3.   The UV-Vis transmittance of 0.05wt% P(MAA-b-DEA) at different pHs. The micellization behavior of the block copolymer atdifferent pH was also studied by laser light scattering(Figure 4b). At low pH of 3, the dynamic light scattering(DLS) data revealed two translational diffusion modes inthe decay time distribution functions. Based on the Stokes-Einstein relationship, the hydrodynamic radii of twospecies determined to be 2.7 nm and 70 nm, were for theunimers and micelles respectively. The composition of theunimers is estimated to be about 8 %wt. The radius ofgyration Rg determined from static light scattering (SLS)was found to be 46 nm, giving rise to a Rg/Rh of 0.66,which is smaller than 0.774 for hard sphere. This suggests athicker hydration layer within the core-shell micelle. Sincethe HLB value of P(MAA-b-DEA) at the prevailing pHvalue may not be low enough and the pKa of MAA is 5.4, amixture of unimers and micelles was observed. Byincreasing the pH from 6 to 9, the solution became cloudydue to phase separation as indicated by the abrupt increasein the scattering intensity. The DLS data indicates theformation of large aggregates with an averaged size of 800nm. At high pH (> 9), the solution became clear again andthe scattering intensity decreased. It was observed theexistence of only one narrow q2 dependent peak in thedecay time distribution function. The Rh and Rg weredetermined to be 17.5 and 12 nm respectively, giving riseto Rg/Rh = 0.686, which indicates again that the micellepossesses a core shell structure. Due to the high pKa valueof the DEA (7.3) associated with the lower HLB values, theCMC is extremely small. The aggregation numbermeasured using static light scattering technique was foundto be ~ 50. The hydrodynamic radius distribution and thepossible microstructure of the reversible pH-responsivemicelles of P(MAA-b-DEA) in solution are shown inFigure 4b. To further clarify the pH dependentmicellization properties, electrophoresis, steadyfluorescence spectroscopy and time- resolved fluorescencequenching studies are currently in progress.ACKNOWLEDGMENTPR and DS wish to acknowledge the financial support inthe form of a postdoctoral fellowship provided by theSingapore-MIT Alliance (SMA).REFERENCES[1]   (a) Kwon, G. S.; Naito, M.; Yokoyama, M.; Okano, T., Sakurai, Y.;Kataoka, K. Pham. Res. 1995, 12, 92. (b) Kataoka, K.; Kwon, G. S.;Yokoyama, M.; Okano, T.; Sakurai, Y. J. Controlled Release 1993,24,119. (c) Harada, A.; Kataoka, K. Macromolecules 1995, 28,5294. (d) Scholz, C.; Iijima, M.; Nagasaki, Y.; Kataoka, K.Macromolecules 1995, 28, 7295.[2]  (a) Sukhorukov, G.B.; Antipov, A.A.; Voigt, A.; Donath, E.;Mohwald, H. Macromol. Rapid Commun. 2001, 22,44. (b) Sauer,M.; Meier, W. Chem. Commun. 2001, 1, 55.[3]    Zhang, X.; Matyjaszewski, K. Macromolecules 1999, 32, 1763.[4]    (a) Misra, S.; Varanasi, S.; Varanasi, P. P. 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Novel pH Responsive Amphiphilic Diblock Copolymers with Reversible Micellization Properties

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Novel pH Responsive Amphiphilic Diblock Copolymers with Reversible Micellization Properties

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