Preparation of Amphiphilic Statistical Copolymers of2-Hydroxyethyl Methacrylate with 2-DiethylaminoethylMethacrylate, Precursors of Water-Soluble Copolymers

GERARDO MARTINEZ, MANUEL SANCHEZ-CHAVES, ENRIQUE LOPEZ MADRUGA

Instituto de Ciencia y Tecnologıa de Polımeros (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain

Received 21 February 2002; accepted 29 April 2002Published online 00 Month 2002 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/pola.10329

ABSTRACT: Statistical copolymers of 2-hydroxyethyl methacrylate (HEMA) and 2-di-ethylaminoethyl methacrylate (DEA) were synthesized at 50 °C by free-radical copoly-merization in bulk and in a 3 mol L�1 N,N�-dimethylformamide solution with 2,2�-azobisisobutyronitrile as an initiator. The solvent effect on the apparent monomerreactivity ratios was attributed to the different aggregation states of HEMA monomerin the different solvents. The copolymers obtained were water-insoluble at a neutral pHbut soluble in an acidic medium when the molar fraction of the DEA content was higherthan 0.5. The quaternization of DEA residues increased the hydrophilic character of thecopolymers, and they became water-soluble at a neutral pH when the HEMA contentwas lower than 0.25. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40:2427–2434, 2002Keywords: copolymerization; 2-hydroxyethyl methacrylate/2-diethylaminoethylmethacrylate copolymers; monomer reactivity ratios; quaternization reactions; solventeffect; water-soluble polymers

INTRODUCTION

Linear and crosslinked homopolymers and copol-ymers based on 2-hydroxyethyl methacrylate(HEMA) are among the most studied hydroxy-lated systems because of their applicability in theophthalmic industry,1 as controlled drug-releasematrices,2 as nonthrombogenic materials,3 forsurgical prostheses,4 and so forth.

One of the main characteristics of hydroxylatedpolymers is the possibility of noticeable swellingduring contact with a hydrated medium. When adrug is immobilized within a dry (nonswollen),glassy polymer and the system is exposed to wa-ter, it swells and allows diffusion out of the active

species in a manner controlled by the diffusionrate of the water and, to a lesser extent, by themolecular mobility.5

With respect to the method of controlling theswelling process and, therefore, the diffusion ofthe swelling agent into the gel, the introductionby the copolymerization of an appropriate amountof a second monomer has been proven successful.In a general context, HEMA has been copolymer-ized with hydrophobic monomers,6,7 which reducethe degree of swelling. However, it would be in-teresting to improve the degree of swelling orcontrol the experimental conditions under whichthe swelling is produced.

An increase in the hydrophilic character wouldbe achieved by the copolymerization of HEMAwith a tertiary aminoacrylate monomer becausepolymers derived from monomers are easily quat-ernized.8 Furthermore, the water solubility ofsuch polymers before the quaternization reaction

Correspondence to: G. Martinez (E-mail: gmart@ictp.csic.es)Journal of Polymer Science: Part A: Polymer Chemistry, Vol. 40, 2427–2434 (2002)© 2002 Wiley Periodicals, Inc.

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is dependent on the length of the alkyl groupsbound to the nitrogen. In this way, although di-methylaminoethyl methacrylate (DMA) ho-mopolymer is water-soluble, 2-diethylaminoethylmethacrylate (DEA) homopolymer is water-insol-uble at a neutral pH and only dissolves in acidicmedia.9

Previous experience shows that values for themonomer reactivity ratios of HEMA copolymersystems are apparent because the aggregation ofHEMA is very dependent on the polymerizationmedium.6,10–14

Taking into account these considerations, westudied the statistical copolymerization of HEMAwith DEA in bulk and in N,N�-dimethylform-amide (DMF) solutions. To increase the hydro-philic character of HEMA–DEA copolymers, wealso examined quaternization reactions withmethyl iodide (MeI). Furthermore, preliminarytests were performed of aqueous solution behav-ior before and after quaternization reactions.

EXPERIMENTAL

Materials

HEMA (Fluka) was passed through a column ofactivated basic aluminum oxide (Aldrich) andpurged with high-purity nitrogen before use. DEA(Aldrich) was distilled under reduced pressure,and the middle cut was stored under refrigerationovernight before polymerization. DMF (Scharlau)was purified via shaking with phosphorus pentox-ide for 4 days. It was then washed with potassiumhydroxide pellets and distilled at 47 °C and 14Torr. The middle fraction was used. 2,2�-Azo-bisisobutyronitrile (AIBN; Fluka) was purified bycrystallization from methanol and dried in vacuo(mp � 104 °C). Tetrahydrofuran (THF; Fluka)was purified by distillation under nitrogen withlithium aluminum hydride. MeI (Acros Organics)was used as received without further purification.

Copolymerization Reactions

HEMA–DEA copolymers were synthesized inglass ampules sealed with rubber septa, in bulkand with DMF as a solvent (3.0 mol L�1) and withAIBN as an initiator. The initiator concentrationwas 9.0 � 10�3 mol L�1. Dissolved oxygen wasremoved from the reaction solution by 30 min ofnitrogen purging before immersion in a waterbath at 50 � 0.1 °C. The copolymerization system

was homogeneous in all cases investigated. Afterthe required time interval, the reaction solutionswere poured into a large excess of water or aheptane–diethylether mixture to precipitate thepolymers. All samples were purified by reprecipi-tation with THF as the solvent and with water asthe precipitant and then dried in vacuo in thepresence of phosphorus pentoxide until a constantweight was attained.

Characterization of the Copolymers

The 1H NMR spectra were recorded on a 300-MHzVarian Inova 300 spectrometer with deuterateddimethyl sulfoxide (10 wt % solutions) at 80 °Cunder standard conditions. The proton solventsignal was used as a chemical-shift marker. Therelative signal intensities of the spectra weremeasured from the integrated peak areas calcu-lated with an electronic integrator. The averagemolar fraction composition of the copolymers wasquantitatively determined from the correspond-ing 1H NMR spectra of copolymer samples. Theanalysis was performed by a comparison of theintegrated intensities of the signals that ap-peared between 0.6 and 1.1 ppm (correspondingto the �CH3 group of both HEMA and DEA unitsand the OCH3 protons of the DEA units), withthe peak at 3.60 ppm ascribed to OCH2OOH inthe HEMA units (Fig. 1).

Quaternization Reaction

Both poly(diethylaminoethyl methacrylate) (PDEA)and HEMA–DEA copolymers were modified byquaternization with MeI under a nitrogen flow at30 °C. A precursor polymer (DEA homopolymer orHEMA–DEA copolymer; 0.8–1 g) was dissolved in28 mL of THF, and 1.1 equiv of MeI based on theDEA content was added slowly. The solution wasstirred for 4 h and poured into a large volume ofheptane. The precipitate was filtered, washed,and dried in vacuo at 36 °C for 24 h. The degree ofquaternization was determined by 1H NMR spec-troscopy.

Characterization of the Modified Copolymers

The copolymers were characterized by IR spec-troscopy with a Nicolet 520 Fourier transforminfrared spectrometer equipped with a deuteratedtriglycine sulphide (DTGS) detector. Thirty-twoscans were signal-averaged at a resolution of 2cm�1. The selective quaternized copolymers were

2428 MARTINEZ, SANCHEZ-CHAVES, AND MADRUGA

Figure 1. 1H NMR spectra of homopolymer and copolymer samples of HEMA–DEAprepared by free-radical copolymerization at 50 °C. The monomer molar fractions ofHEMA in the copolymer chain are indicated on the right.

AMPHIPHILIC STATISTICAL COPOLYMERS 2429

investigated by 1H NMR in methanol-d at 50 °Cunder standard conditions. The degree of quater-nization was determined by a comparison of thepeak integrals assigned to the different comono-mers before and after quaternization.

Test of Water Solubility

In all experiments, the concentration of the DEAhomopolymer and HEMA–DEA copolymers in theaqueous phase was 5 wt %. The pH was adjustedby the addition of small amounts of HCl until thecomplete solution at 25 °C of DEA homopolymerswas attained. The copolymers were tested at aneutral pH and in an acidic medium, which dis-solved the DEA homopolymer. The water solubil-ity for quaternized homopolymers and copolymerswas tested in an aqueous phase at a neutral pH.

RESULTS AND DISCUSSION

Free-Radical Copolymerization

The free-radical copolymerization of HEMA–DEAin bulk and with a 3.0 mol L�1 DMF solution and9.0 � 10�3 mol L�1 AIBN as an initiator wascarried out at 50 °C. Conversions lower than 10%were obtained to satisfy the differential copoly-merization equation. The average molar fractioncomposition of the copolymers was quantitativelydetermined from the corresponding 1H NMRspectra of the copolymer as described previously.

Because the monomer reactivity ratios for thissystem are unknown, approximate values in bulkand in solution were obtained from the averagemolar fraction composition of the copolymers, per-formed with the HEMA monomer feed composi-tion ranging from 0.3 to 0.8 with a step of 0.1. Theapproximate monomer reactivity ratios were usedto determine the optimally designed experi-ment,15 in which the value of the molar fractionsin the feed (f �1 and f �1) are given by the followingexpressions:

f�1 �2

2 � r1

f �1 �r2

2 � r2

where r1 and r2 represent the copolymer reactiv-ity ratios of monomer 1 (HEMA) and monomer 2

(DEA), respectively. Finally, the six first compo-sitions along with two replicates of each optimalfeed composition and the HEMA monomer feedcompositions of 0.1 and 0.2 were used to deter-mine the monomer reactivity ratios.

The molar fraction composition of the monomerfeed (fHEMA), final conversion, and average molarfraction composition of the copolymer (FHEMA) foreach low-conversion bulk and DMF solution copo-lymerization are listed in Table 1. The monomerreactivity ratios were determined from the aver-age compositions of the copolymers listed in Table1 with the nonlinear least-squares analysis sug-gested by Tidwell and Mortimer.15 The valuesobtained for HEMA–DEA in bulk and in DMF aregiven in Table 2.

On the basis of the values listed in Table 2,both reactivity ratios apparently changed withthe solvent in which the copolymerization exper-iments were performed. To determine if the ob-served differences in apparent reactivity ratioswere significant, we calculated joint confidence

Table 1. Molar Feed Composition (fHEMA),Conversion, and Experimentally DeterminedCopolymer Composition (FHEMA) for the Free-RadicalCopolymerization of HEMAand DEA at 50 °C in Bulk and DMF

Solvent fHEMA Conversion FHEMA

Bulk 0.80 0.05 0.8980.70 0.04 0.8080.60 0.06 0.7340.50 0.05 0.6320.481 0.07 0.5950.481 0.07 0.5820.40 0.04 0.5340.30 0.05 0.3950.288 0.06 0.3760.288 0.06 0.3590.20 0.05 0.2400.10 0.05 0.115

DMF 0.80 0.07 0.8280.70 0.08 0.7200.637 0.07 0.6540.637 0.07 0.6570.60 0.08 0.6270.50 0.06 0.5170.40 0.06 0.4290.322 0.06 0.3530.322 0.06 0.3310.30 0.06 0.3130.20 0.06 0.1660.10 0.05 0.091

2430 MARTINEZ, SANCHEZ-CHAVES, AND MADRUGA

intervals. These confidence intervals are showngraphically in Figure 2. It is clear that the valuesobtained in bulk and in DMF do not overlap;therefore, the solvent significantly influenced thereactivity ratios.

The apparent monomer reactivity ratios col-lected in Table 2 appear to indicate that the re-activity ratio of HEMA decreases but the reactiv-ity ratio of DEA slightly increases from bulk toDMF. When the HEMA–DEA copolymerizationwas performed in DMF, both monomer reactivityratios had apparent values higher than unity,although values lower than unity for r2 were in-side the confidence interval. However, some sys-tems appear in the literature for which the calcu-lated r1 and r2 values were greater than 1. In thisrespect, Saini et al.16,17 found values greater than

1 for monomer reactivity ratios of acrylamide/methyl methacrylate, methacrylamide/methylmethacrylate, acrylamide/styrene, and methac-rylamide/styrene when the copolymerization wascarried out in dioxane. Values for both r1 and r2greater than 1 were also reported by Johnstonand McCarthy18 for the free-radical copolymeriza-tion of styrene/acrylamide carried out in acetoni-trile. In contrast, reactivity ratios for the whichthe products (r1 � r2) were lower than unity wereobtained for acrylamide/styrene or methacrylam-ide/styrene when ethanol or mixtures of dioxaneand ethanol were used as solvents.16–18 There-fore, it is clear that a solvent effect gives rise tochanges in the reactivity ratios of acrylamide/styrene or methacrylamide/styrene.

Variation of the monomer reactivity ratio val-ues for other HEMA copolymerization systems asa function of the solvent has also been observed.Therefore, a significant solvent effect has beennoted for the copolymerization of HEMA with sty-rene,10,11 dodecyl methacrylate (DMA),12 butylmethacrylate,6,13 and tert-butyl acrylate.14 In allof these copolymer systems, the monomer reactiv-ity ratio of HEMA presents a higher value with adecreasing polarity of the medium. This behavior

Table 2. Apparent Monomer Reactivity Ratios forthe HEMA–DEA System in Various Solvents

Solvent rHEMA rDEA

Bulk 2.208 0.912DMF 1.217 1.045

Figure 2. Joint 95% confidence intervals for monomer reactivity ratios of the HEMA–DEA system in different solvents: (�) bulk and (E) DMF.

AMPHIPHILIC STATISTICAL COPOLYMERS 2431

has been interpreted as a result of the aggrega-tion of HEMA through hydrogen bonding: HEMAis clearly aggregated in nonpolar solvents (ben-zene, toluene), whereas no association has beenfound in a polar solvent (DMF).12 However, bothpolar solvents and nonpolar solvents such as di-oxane, which has the possibility of forming hydro-gen bonds, can prevent the aggregation of HEMAmolecules.14

Although it is well known that the degree ofassociation of HEMA monomer has an importanteffect on the values of the reactivity ratios foundin different solvents, a bootstrap effect has alsobeen claimed to explain the solvent effects on theapparent variation of monomer reactivity ratiosfor the free-radical copolymerization of HEMAwith hydrophobic monomers.11–14

We can get some insight into the solvent effectsif the copolymerization results obtained in bulkare compared with those obtained in solution.Therefore, a copolymer chain of the same compo-sition was produced in bulk and in solution fromdifferent feed compositions. Differences betweenbulk and solution monomer feed compositions asa function of the copolymer chain compositiongive us an indication of the variation in the mono-mer feed composition necessary to obtain in solu-tion the same copolymer composition as in bulkcopolymerization, and so the monomer that pref-

erentially sorbed can be qualitatively deter-mined.19 For the same copolymer composition, itis clear from the apparent reactivity ratios thatwhen copolymers are prepared in DMF, it is nec-essary to use a higher HEMA molar fraction inthe feed than that used in bulk. This means thatwhen the copolymerization is carried out in bulk,HEMA associates strongly with the poorly sol-vated polymer chain, whereas the addition ofDMF to the reaction medium solvates the chainmore effectively and avoids its selective associa-tion with HEMA.20 As a result, the HEMA localconcentration around the growing radical dimin-ishes, and an apparent enrichment of the DEAmonomer at the polymerization site is operative.

Quaternization of PDEA and HEMA–DEACopolymers

Butun et al.9 recently showed that the quater-nization of polymers with pendant tertiary aminogroups by alkyl halides is dependent on the struc-ture of the amino substituent. In this way, meth-ylation of the DMA homopolymers was essentiallycomplete within 10–20 min at 20 ° C in eitherTHF or water, whereas methylation of DEA ho-mopolymers required 2–4 h in THF at 20 °C.9 Thequaternization reaction of HEMA–DEA copoly-mers was carried out with THF as a solvent at30 °C according to the following scheme:

PDEA was quaternized in a similar way. Thestructure of the resulting copolymers was con-firmed by IR and 1H NMR spectroscopy. The IRspectra of quaternized HEMA–DEA copolymersshow the absence of the bands at 2810 and 2726cm�1 due to the tertiary amine.

Figure 3 shows the 1H NMR spectra of a copol-ymer sample before and after quaternization,with all the relevant signals assigned. Peaks a, b,and c after quaternization [Fig. 3(b)] are shifted

downfield from 4.25, 3.0, and 2.82 ppm to 4.75,4.12, and 3.85 ppm, respectively. A new peak, e,appeared at 3.45 ppm because of the quaternarymethyl group. The peak labeled d at 1.28 ppm isshifted to 1.65 ppm and represents the six dim-ethylamino protons in the tertiary amine group.9

In addition, peak f at 1.15 ppm, due to all the�-CH3 in both DEA and HEMA comonomers, issplit into two bands after quaternization, one at1.14 ppm due to �-CH3 in DEA and the other at

2432 MARTINEZ, SANCHEZ-CHAVES, AND MADRUGA

1.31 ppm due to �-CH3 for HEMA. The degree ofquaternization was determined by a comparisonof the integrals of peaks e and d, and the quater-nization reaction was found to be quantitative inall cases.

Aqueous Solution Behavior

PDEA and HEMA–DEA copolymers are water-insoluble polymers at a neutral pH. However,PDEA and HEMA–DEA copolymers with DEAmolar fractions in the copolymer chain higherthan 0.48 are water-soluble in acidic media (pH� 0.9). Quaternization reactions in both PDEAand HEMA–DEA copolymers produce significant

changes in the solubility in the aqueous medium.Preliminary experiments at room temperaturehave shown that PDEA and HEMA–DEA copoly-mers with HEMA contents lower than 0.25 areperfectly soluble in water at a neutral pH.

CONCLUSIONS

The results presented here provide an easy way ofimproving the degree of swelling and solubility ofcopolymers based on HEMA, opening a path forcontrolling the balance between the hydrophilicand hydrophobic characters of this kind of mate-

Figure 3. 1H NMR spectra of the HEMA–DEA copolymer with a 0.313 DEA molarfraction in the copolymer chain (a) before and (b) after quaternization with MeI.

AMPHIPHILIC STATISTICAL COPOLYMERS 2433

rial with potential applications in drug delivery,separation, and biological activity.

Financial support from the Comision Interministeralde Ciencia y Tecnologıa (Mat 2000-1008) is gratefullyacknowledged.

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