High-Throughput Experimentation in Atom Transfer RadicalPolymerization: A General Approach Toward a DirectedDesign and Understanding of Optimal Catalytic Systems

HUIQI ZHANG, VERONICA MARIN, MARTIN W. M. FIJTEN, ULRICH S. SCHUBERT

Laboratory of Macromolecular Chemistry and Nanoscience, Eindhoven University of Technology and Dutch PolymerInstitute, P.O. Box 513, 5600 MB Eindhoven, The Netherlands

Received 3 December 2003; accepted 11 December 2003

ABSTRACT: High-throughput experimentation (HTE) was successfully applied in atomtransfer radical polymerization (ATRP) of methyl methacrylate (MMA) for the rapidscreening and optimization of different reaction conditions. A library of 108 differentreactions was designed for this purpose, which used four different initiators [ethyl2-bromoisobutyrate, methyl 2-bromopropionate, (1-bromoethyl)benzene, and p-toluene-sulfonyl chloride], five metal salts (CuBr, CuCl, CuSCN, FeBr2, and FeCl2), and nineligands (2,2�-bipyridine and its derivatives). The optimal reaction conditions for Cu(I)halide, CuSCN, and Fe(II) halide-mediated ATRP systems with 2,2�-bipyridine and its4,4�-dialkyl-substituted derivatives as ligands were determined. Cu(I)-mediated sys-tems were better controlled than Fe(II)-mediated ones under the examined conditions.A bipyridine-type ligand with a critical length of the substituted alkyl group (i.e.,4,4�-dihexyl 2,2�-bipyridine) exhibited the best performance in Cu(I)-mediated systems,and p-toluenesulfonyl chloride and ethyl 2-bromoisobutyrate could effectively initiateCu(I)-mediated ATRP of MMA, resulting in polymers with low polydispersities in mostcases. Besides, Cu(I) halide-mediated ATRP with 4,5�-dimethyl 2,2�-bipyridine as theligand and p-toluenesulfonyl chloride as the initiator proved to be better controlled thanthose with 4,4�-dimethyl 2,2�-bipyridine as the ligand, and polymers with much lowerpolydispersities were obtained in the former cases. This successful HTE example opensup a way to significantly accelerate the development of new catalytic systems for ATRPand to improve the understanding of structure–property relationships of the reactionsystems. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 1876–1885, 2004Keywords: atom transfer radical polymerization (ATRP); high-throughput experi-mentation (HTE); catalysis; methyl methacrylate; bipyridine derivatives; structure-property relation

INTRODUCTION

In the last years, the field of free-radical polymer-ization has been revolutionized with the advent ofcontrolled/living radical polymerization techniques,which provide polymers with predetermined molec-

ular weights, low polydispersity indices (PDIs), spe-cific functionalities, and various architectures un-der relatively mild reaction conditions.1–4 One ofthe most versatile systems is atom transfer radicalpolymerization (ATRP) because of the easy avail-ability of many kinds of catalysts, initiators, andmonomers.1,2 However, many parameters in ATRPsuch as the used monomers, catalysts (metal salts/ligands), initiators, solvents, reactant ratios, andreaction temperatures can significantly influence

Correspondence to: U. S. Schubert (E-mail: u.s.schubert@tue.nl)Journal of Polymer Science: Part A: Polymer Chemistry, Vol. 42, 1876–1885 (2004)© 2004 Wiley Periodicals, Inc.

1876

the controllability of the polymerization, whichmakes the optimization of reaction conditionsvery time-consuming, particularly when a newreaction system is investigated. Moreover, theidentification of the best catalytic system for acertain ATRP system is rather difficult becauseof the different polymerization conditions de-scribed. Therefore, new techniques such ashigh-throughput experimentation (HTE), whichallows a fast and efficient optimization of thereaction conditions in an automated parallelsynthesizer under comparable and reproducibleconditions, are highly suitable for this researchdirection. Although HTE has had an enormousimpact on pharmaceutical and catalyst develop-ment5–11 and is receiving rapidly increasing in-terest in the field of polymer science,12–21 thepossible application of this technique in ATRPhas only received very limited attention up tonow.13,21–23 To the best of our knowledge, thereal application of HTE in ATRP was onlybriefly described by Nielsen et al.13 (SymyxTechnologies), but no other literature (includ-ing patent) on this topic is available.

In this article, we report our first result onthe development of a high-throughput approachfor the rapid screening and optimization of thereaction conditions for the ATRP of methylmethacrylate (MMA) with an automated paral-lel synthesizer. The described setup is also suit-able for the detailed investigation of the poly-merization kinetics; see refs. 24 and 25, forexample, of living cationic polymerization. Alibrary of 108 different polymerizations explor-ing the main variables (initiators, metal salts,and ligands) was designed for this purpose. Theoptimal reaction conditions for Cu(I) halide,CuSCN, and Fe(II) halide-mediated ATRP sys-tems with 2,2�-bipyridine and its 4,4�-dialkyl-substituted derivatives as ligands were deter-mined. The utilization of a series of commer-cially available as well as tailor-madebipyridine derivatives as ligands allowed thefirst systematic investigation on the effects ofthe substitutents of bipyridine derivatives onATRP under the same reaction conditions. Be-sides, some general rules such as the applica-bility of the halide-exchange effect in Cu(I) ha-lide and Fe(II) halide-mediated ATRP systems,the critical length of the 4,4�-substituted alkylgroup on the bipyridine and the optimal posi-tions of the substitutents on the bipyridine wereestablished.

EXPERIMENTAL

Materials

MMA (Aldrich, 99%) was washed twice with anaqueous solution of sodium hydroxide (5%) andtwice with distilled water, dried with anhydrousmagnesium sulfate overnight, and then distilledover calcium hydride in vacuo. The distillateswere stored at �18 °C before use. CuBr (Aldrich,98%) and CuCl (Aldrich, 98�%) were purified ac-cording to the method described in the literatureand stored in an argon atmosphere before use.26

FeCl2 (Aldrich, anhydrous, beads, �10 mesh,99.99%) was dissolved in degassed methanol, andthen the solvent was evaporated to provide FeCl2powder, which was used in this work. CuSCN(Aldrich, 99%), FeBr2 (Aldrich, 98%), 2,2�-bipyri-dine (bpy, Acros, 99�%), 4,4�-dimethyl 2,2�-bi-pyridine (dMbpy, Aldrich, 99%), 4,4�-dinonyl 2,2�-bipyridine (dNbpy, Aldrich, 97%), ethyl 2-bro-moisobutyrate (EBIB, Aldrich, 98%), methyl2-bromopropionate (MBP, Aldrich, 98%), (1-bro-moethyl)benzene (BEB, Aldrich, 97%), p-toluene-sulfonyl chloride (TsCl, Acros, 99�%), p-xylene(Aldrich, 99�%, anhydrous), aluminum oxide 90(Merck, standardized, for column chromatogra-phy), and all the other chemicals were used asreceived.

4,4�-Dihexyl 2,2�-bipyridine (dHbpy) and 4,4�-ditridecanyl 2,2�-bipyridine (dTbpy) were synthe-sized according to a published procedure for re-lated compounds.27

dHbpy, yield 1H NMR (300 MHz, CDCl3): �� 8.56 (d, 2H), 8.23 (bs, 2H), 7.13 (dd, 2H), 2.69 (t,4H), 1.69 (qv, 4H), 1.41–1.24 (m, 12H), 0.88 ppm(t, 6H). 13C NMR (300 MHz, CDCl3): � � 156.20,152.92, 148.98, 123.90, 121.32, 35.56, 31.64,30.45, 29.00, 22.55, 14.07 ppm. Matrix-assistedlaser desorption/ionization time-of-flight massspectrometry (MALDI-TOF MS) (dithranol):mass-to-charge ratio (m/z) � 325.44 (MH�). ELEM.ANAL. Calcd. C, 81.43%; H, 9.94%; N, 8.63%.Found: C, 81.16%; H, 9.92%; N, 9.05%.

dTbpy, yield: 88%. 1H NMR (300 MHz, CDCl3):� � 8.55 (d, 2H), 8.23 (bs, 2H), 7.13 (d, 2H), 2.69 (t,4H), 1.69 (qv, 4H), 1.32–1.19 (m, 40H), 0.88 ppm(t, 6H). 13C NMR (300 MHz, CDCl3): � � 156.21,152.94, 148.98, 123.91, 121.32, 35.57, 31.93,30.48, 29.66, 29.54, 29.44, 29.35, 22.70, 14.13ppm. MALDI-TOF MS (dithranol): m/z � 521.65(MH�). ELEM. ANAL. Calcd. C, 83.01%; H, 11.61%;N, 5.38%. Found: C, 83.29%; H, 11.92%; N, 5.36%.

HIGH-THROUGHPUT EXPERIMENTATION 1877

4-Methyl 2,2�-bipyridine (4Mbpy), 6-methyl2,2�-bipyridine (6Mbpy), 5,5�-dimethyl 2,2�-bi-pyridine (5,5�-dMbpy), and 4,5�-dimethyl 2,2�-bi-pyridine (4,5�-dMbpy) were prepared according toa procedure described elsewhere.28

Instruments and Measurements

The reactions were carried out in a computer-controlled Chemspeed, Ltd. ASW 2000 automatedparallel synthesizer (Fig. 1). Two reactor blockswere used in parallel and each block had 16 reac-tion vessels (13 mL). Each reaction vessel wasjacketed with an oil bath and was equipped witha cold-finger reflux condenser. The temperature ofthe oil bath was controlled by a Huber Unistat390 W Cryostat and varied from �90 to 150 °C,and the temperature of the reflux liquid was con-trolled by a Huber ministat compatible controland changed from �10 to 50 °C. The reactionvessels were connected with a membrane pump,which can be used for inertization or evaporationprocesses. Mixing was performed by a vortex pro-cess (0–1400 rpm). A glovebox was available,which kept an argon atmosphere outside the re-action system. The automated synthesizer wasconnected to an online size exclusion chromato-

graph (SEC) and an offline gas chromatograph(GC). A Gilson liquid handling system was usedin the automated synthesizer.

The monomer conversion was determined fromthe concentration of the residual monomer withan offline Interscience Trace GC with an au-tosampler, equipped with an Rtx-5 (Crossbond 5%diphenyl-95% dimethyl polysiloxane) capillarycolumn (30 m � 0.25 mm i.d. � 0.25 �m df) withp-xylene as an internal reference. After optimiza-tion, the GC measurement of one sample required5 min. Molecular weights and molecular weightdistributions were measured with an online SECsetup [Shimadzu gel permeation chromatograph(GPC) equipped with an LC-10AD VP pump andan RID-6A differential refractometer] at ambienttemperature. Tetrahydrofuran (THF) was used asthe eluent at a flow rate of 1.0 mL/min. A linearcolumn (PLgel 5 �m Mixed-D, Polymer Labora-tories, 30 cm) was used. The calibration curvewas prepared with poly(methyl methacrylate)(PMMA) standards. The GPC measurement ofone sample required 15 min. An automated, on-line purification method was used for the removalof catalysts from the polymers before the onlineSEC measurements, as reported previously.22

The purification steps had no influence on the

Figure 1. Visualization of the experimental setup: (a) automated synthesizer incombination with online SEC and offline GC, (b) detailed view of the automatedsynthesizer, (c) filtration column in SPE unit, and (d) reactors containing reactionmixtures of ATRP of MMA.

1878 ZHANG ET AL.

observed molecular weights and PDIs of the poly-mers as checked by several control experiments.

Polymerization Procedure

A typical ATRP of MMA in the automated syn-thesizer was carried out as follows. CuBr/CuCl(0.125 mmol) was manually added to the reactionvessels (13 mL). Inertization [three cycles of vac-uum (15 min)/argon filling] of these reaction ves-sels was conducted at 120 °C to remove oxygenand moisture. The jacketed oil bath temperaturewas lowered to 25 °C, and degassed MMA (1.8722g, 18.70 mmol) as well as degassed solutions ofligands (dMbpy, dHbpy, dNbpy, and dTbpy)(0.249 mmol) in anhydrous p-xylene (2.5980 g, 3mL) were added subsequently. After the refluxcondensing liquid was cooled to �5 °C and thereaction temperature was increased to 90 °C, thereaction mixtures were vortexed at 600 rpm for 20min. The degassed solutions of initiators (EBIB,MBP, BEB, and TsCl) (0.125 mmol) in anhydrousp-xylene (0.8660 g, 1 mL) were added into thereactors in 2 min, respectively. The referencesamples (for the calculation of monomer conver-sion) were taken from the reaction systems imme-diately after the addition of the correspondinginitiators was finished. The reaction mixtureswere then vortexed at 600 rpm, and the polymer-izations were sampled at predetermined times(284, 261, 238, and 215 min for EBIB, MBP, BEB,and TsCl-initiated ATRP system, respectively).The samples were diluted with THF, and parts ofthem were used for GC measurements to deter-mine monomer conversions. The remaining sam-ples were purified automatically by passing themthrough aluminum oxide columns (0.5 cm long) insolid-phase extraction (SPE) cartridges (length:5.6 cm, diameter: 0.6 cm) including porous poly-ethylene frits and ASPEC caps (Chemspeed) (2mL of THF as the eluent) and then used for theonline SEC measurements to determine the mo-lecular weights and PDIs of the resulting poly-mers.

RESULTS AND DISCUSSION

High-throughput experimentation of the ATRP ofMMA (Scheme 1) was carried out in a ChemspeedASW 2000 automated parallel synthesizer to rap-idly screen and optimize the reaction conditions(Fig. 1). A library of 108 different polymerizationswith different initiators [ethyl 2-bromoisobu-

tyrate (EBIB), methyl 2-bromopropionate (MBP),(1-bromoethyl)benzene (BEB), and p-toluenesul-fonyl chloride (TsCl)], metal salts (CuBr, CuCl,CuSCN, FeBr2, and FeCl2), and ligands (2,2�-bi-pyridine and its derivatives with dimethyl, di-hexyl, dinonyl, or ditridecanyl groups on 4,4�-po-sitions, dimethyl groups on 4,5� or 5,5�-positions,and one methyl group on the 4- or 6-position) wasdesigned for this purpose (Fig. 2). In this study,three parameters were used to evaluate the con-trollability of an ATRP system, that is, monomerconversion (CMMA), initiation efficiency of the re-action (i.e., f � Mn,th/Mn,SEC, see Table 1), andPDIs of the polymers. An offline GC (5 min persample) and an online conventional SEC (15 minper sample) were used to determine these param-eters. The computer-based planning and roboticperforming of the reactions as well as the utiliza-tion of fast characterization techniques dramati-cally decreased the research time for the designedlibrary from several months in the conventionalsetup to 2 weeks. Moreover, because all the reac-tions were carried out under the same conditions,the obtained experimental results could be com-pared and used for elucidation of the structure–property relationships of monomer, initiator, andcatalytic systems.

The polymerizations were carried out in p-xy-lene at 90 °C. The volume ratio of p-xylene to

Scheme 1. Representation of the ATRP of MMA.[MMA]0/[initiator]0/[metal salt]0/[ligand]0 � 150:1:1:2,MMA/p-xylene � 1:2 v/v.

HIGH-THROUGHPUT EXPERIMENTATION 1879

MMA was 2:1 in each reaction, and the molarratio of MMA to initiator to metal salt to ligandwas 150:1:1:2. The reproducibility of the resultsobtained from parallel reactions in the automatedsynthesizer and their comparability with thoseobtained in the conventional setup are two impor-tant issues for the application of HTE in ATRPand have to be checked in advance.29 Three par-allel reactions for two ATRP systems (i.e.,[MMA]0/[TsCl]0/[CuCl]0/[bpy or dNbpy]0 � 150:1:1:2, MMA/p-xylene � 1:2 v/v, 90 °C) were carriedout in the automated synthesizer to test the re-producibility of the results. Figure 3 demon-strates the good reproducibility of the parallel

reactions in the automated synthesizer, and themaximum differences of the experimental resultswere within 6%. Most importantly, the resultsobtained from the automated synthesizer werealso comparable with those obtained in conven-tional experiments in the laboratory. For in-stance, three parallel reactions of the ATRP ofMMA (with TsCl as the initiator and CuCl/dNbpyas the catalyst) carried out in the automated syn-thesizer resulted in a CMMA of (67.5 � 0.6)% at510 min and polymers with an Mn,SEC of 11,790� 160 and PDI of 1.09 � 0.01 (Fig. 3), whereas thesame reaction conducted in the conventional lab-oratory setup led to a CMMA of 61% at 480 min anda polymer with an Mn,SEC of 11,000 and PDI of1.13.

Cu(I)-Mediated ATRP of MMA with 2,2�-Bipyridineand Its 4,4�-Dialkyl-Substituted Derivatives asLigands

With the previously described knowledge andsetup, a high-throughput evaluation and optimi-zation of the reaction conditions for the ATRP ofMMA was performed, and the results are shownin Figure 4. Varying the described ligands, initi-ators, and metal salts revealed a strong influenceon CuBr/CuCl-mediated ATRP. The homogeneityof the reactions varied largely with the reactionconditions. The ATRP systems with dHbpy, dN-bpy, and dTbpy as ligands were homogeneous andusually provided polymers with much lower PDIvalues than the heterogeneous systems with bpyand dMbpy as ligands. The polymerization ratesof the ATRP systems were, however, not so muchinfluenced by the homogeneity of the systems.The polymerization rates of the heterogeneoussystems were comparable with those of the homo-geneous systems and were even higher in somecases. The initiators used had only a slight influ-ence on the polymerization rates of the ATRP inmost cases but had much influence on the PDIs ofthe obtained polymers and initiation efficiency ofthe reactions, especially in the CuBr-mediatedATRP systems. MBP- and BEB-initiated ATRPresulted in lower initiation efficiencies and pro-vided polymers with relatively higher PDIs ascompared with those initiated by TsCl and EBIB,which could be ascribed to the relatively slowinitiation of MBP and BEB for the ATRP ofMMA.30 Percec et al found that TsCl was a goodinitiator for the ATRP of MMA, providing poly-mers with low PDIs (usually �1.2).31 Herein,TsCl proved to be the best initiator for the inves-

Figure 2. Schematic setup of the automated synthe-sizer and combinations of metal salts, initiators, andligands used in this study. The symbols used in thefigure are as follows: dMbpy, M; dHbpy, H; dNbpy, N;dTbpy, T; CuBr, CB; CuCl, CC; CuSCN, CS; FeBr2, FB;FeCl2, FC; CuBr � ligand � TsCl (ligand � 4,5�-dMbpy, 1; 5,5�-dMbpy, 2; 4Mbpy, 3; and 6Mbpy, 4), andCuCl � ligand � TsCl (ligand � 4,5�-dMbpy, 5; 5,5�-dMbpy, 6; 4Mbpy, 7; and 6Mbpy, 8).

1880 ZHANG ET AL.

tigated systems, resulting in relatively fast poly-merizations and polymers with the lowest PDIs(usually �1.2). The combinations of TsCl withligands such as dHbpy, dNbpy, and dTbpy allrevealed reasonable results, whereby the best re-sult was obtained in the case of dHbpy (Table 1,entries 1 and 2), which suggested the existence ofa critical length of alkyl substitutent for the bestperformance of bipyridine-type ligands, probablybecause of the competition between the solubilityof metal salt/ligand complexes and their sterichindrances. CuBr-catalyzed ATRP were slightlyfaster than those with CuCl in most cases, but thePDIs of the resulting polymers were usually lowerin the latter cases, particularly when EBIB, MBP,and BEB were used as initiators (consistent withthe halide-exchange effect32). The optimal reac-tion conditions identified here (i.e., CuBr/TsCl/dHbpy, Table 1, entry 1) agreed with a previousreport by Matyjaszewski et al.,30 who found thatthe combination of CuBr, TsCl, and 4,4�-di(5-nonyl) 2,2�-bipyridine (d5Nbpy) provided the bestresults for the ATRP of MMA in diphenyl ether at90 °C among all the studied conditions [i.e., CuX(X � Br, Cl)/d5Nbpy/initiators such as EBIB,TsCl, benzhydryl chloride, 1-phenylethyl chlo-ride, and BEB]. This further demonstrates thereliability of the HTE results.

To date, only one CuSCN-mediated ATRP ofMMA with 4,4�-diheptyl 2,2�-bipyridine as ligandand EBIB as initiator at 100 °C was reported,which provided fast reactions and high f. How-ever, the resulting polymers revealed relatively

high PDIs (1.36).33 Our systematic studies onCuSCN-mediated ATRP demonstrated that theywere heterogeneous for all the used ligands. Veryslow reactions were observed when bpy was usedas the ligand (CMMA � 20% at ca. 4 h). The effectsof initiators on the initiation efficiency of the re-actions and PDIs of the polymers were almost thesame as those in Cu(I) halide-mediated systems.TsCl-initiated ATRP also provided polymers withthe lowest PDI values (usually �1.2) in all thesystems, but the reactions were relatively slow(CMMA ca. 40% at 215 min) as compared with theATRP systems with other initiators. The combi-nation of CuSCN, EBIB, and the substituted bi-pyridines with longer alkyl groups such as dH-bpy, dNbpy, and dTbpy all led to reasonable re-sults with only slightly higher PDI values (�1.3),whereby the best controllability was againachieved in the case of dHbpy, as demonstrated inTable 1 (entry 7).

Fe(II) Halide-Mediated ATRP of MMA with 2,2�-Bipyridine and Its 4,4�-Dialkyl-SubstitutedDerivatives As Ligands

In contrast to Cu(I)-mediated ATRP systems,Fe(II) halide-mediated ones were ill-controlled inmost cases. The reactions catalyzed by FeCl2 re-sulted in polymers with much higher PDI values(1.4) than FeBr2-catalyzed ones, demonstratingthe failure of the halide-exchange effect. Althoughall the combinations of FeBr2, EBIB/TsCl, andd5Nbpy in the ATRP of MMA ([MMA]0/[initia-

Table 1. Selected Results for the ATRP of MMA Obtained by the Automated Synthesizera

Entry Metal Salt Ligand Initiator tb (min) CMMA (%) Mn,thc Mn,SEC

d fe PDI

1 CuBr dHbpy TsCl 215 55 8,450 9,320 0.91 1.122 CuCl dHbpy TsCl 215 52 8,030 9,830 0.82 1.113 CuBr dNbpy TsCl 215 41 6,360 7,830 0.81 1.144 CuCl dNbpy TsCl 215 28 4,370 7,190 0.61 1.125 CuBr dTbpy TsCl 215 41 6,370 9,600 0.66 1.106 CuCl dTbpy TsCl 215 40 6,200 9,460 0.66 1.097 CuSCN dHbpy EBIB 284 71 10,800 11,430 0.94 1.308 CuSCN dNbpy EBIB 284 65 10,020 10,790 0.93 1.339 CuSCN dTbpy EBIB 284 65 10,030 11,530 0.87 1.29

10 FeBr2 dTbpy EBIB 284 50 7,650 10,570 0.72 1.28

a [MMA]0/[initiator]0/[metal salt]0/[ligand]0 � 150:1:1:2, MMA/p-xylene � 1:2 v/v, 90 °C.b Reaction time.c Theoretical molecular weights Mn,th � ([MMA]0/[RX]0)CMMAMMMA � MRX, where [MMA]0 and [RX]0 are the initial concen-

trations of monomer and initiator, respectively, and MMMA and MRX are the molecular weights of monomer and initiator,respectively.

d Number-average molecular weights determined by SEC against PMMA standards.e f � Mn,th/Mn,SEC.

HIGH-THROUGHPUT EXPERIMENTATION 1881

tor]0/[FeBr2]0/[d5Nbpy]0 � 200:1:1:1; MMA/tolu-ene � 1:1 v/v, 90 °C) were reported to providecontrolled reactions with relatively high CMMAand f as well as relatively low PDIs of the result-ing polymers,34 the combination of FeBr2, EBIB,and dTbpy was the only one to provide reasonableresults in our case (Table 1, entry 10), whereasthe reaction rates of TsCl-initiated ATRP systems([MMA]0/[initiator]0/[FeBr2]0/[ligand]0 � 150:1:1:2; MMA/p-xylene � 1:2 v/v, 90 °C) in our studywere very slow (CMMA � 15% at 215 min). Thisdiscrepancy was likely caused by the differentreaction conditions used.

Cu(I) Halide-Mediated ATRP of MMA with otherBipyridine Derivatives as Ligands

In addition to the described symmetrical 4,4�-di-alkyl-substituted bipyridine derivatives, one sym-metrical 5,5�-dimethyl-substituted bipyridinederivative (5,5�-dMbpy), for the first time oneasymmetrical dimethyl-substituted bipyridinederivative (4,5�-dMbpy), and two monomethyl-substituted bipyridine derivatives (4Mbpy and6Mbpy) were also used as ligands in CuBr/CuCl-mediated ATRP of MMA with TsCl as the initia-tor (Scheme 1). Cu(I) halide-mediated ATRP sys-tems with 4,5�-dMbpy, 5,5�-dMbpy, 4Mbpy, and6Mbpy as ligands and TsCl as the initiator wereall heterogeneous. The metal salts had little in-fluence on the ATRP of MMA under the examinedconditions. However, the position of the methylgroup on bipyridine greatly affected the experi-mental results. The ATRP systems with 4Mbpy,4,5�-dMbpy, and 5,5�-dMbpy as the ligands showedcomparable polymerization rates, whereas the in-troduction of only one methyl group in the 6-po-sition of bipyridine led to a significant decrease ofthe reaction rates because of the steric hindrance[Fig. 5(a)]. The initiation efficiency of the reactionwith 6Mbpy as the ligand was also much lowerthan that with 4Mbpy, 4,5�-dMbpy, or 5,5�-dMbpyas the ligand [Fig. 5(b)]. The ATRP systems withmonomethyl-substituted bipyridine derivativesas ligands (i.e., 4Mbpy and 6Mbpy) resulted inpolymers with higher PDIs (�1.4) than that with4,5�-dMbpy or 5,5�-dMbpy as the ligand (�1.3),especially when 6Mbpy was used as the ligand[PDI 1.8, Fig. 5(c)]. However, because the PDIsof the polymers prepared via ATRP usually de-creased with increasing monomer conversions, itis hard to discern whether the high PDIs of thepolymers obtained from the ATRP with 6Mbpy asthe ligand were due to the poor controllability of

Figure 3. (a) Monomer conversions (CMMA), (b) mo-lecular weights (Mn,SEC), and (c) PDIs of the polymersin the ATRP of MMA during the reproducibility tests inthe automated synthesizer. The ligands in reactions1–3 and 4–6 are bpy and dNbpy, respectively. [MMA]0/[TsCl]0/[CuCl]0/[ligand]0 � 150:1:1:2, MMA/p-xylene� 1:2 v/v, 90 °C, reaction time: 510 min.

1882 ZHANG ET AL.

the reaction systems or just because of the lowmonomer conversions. Further kinetic studies areneeded to explain this phenomenon. The ATRPwith 4,5�-dMbpy or 5,5�-dMbpy as the ligand pro-vided even better controlled systems than thosewith dMbpy as the ligand (PDI � 1.4), and poly-mers with lower PDIs were obtained in the formercases [in particular, in the case of 4,5�-dMbpy/CuCl (PDI � 1.15)] although their polymerizationrates were comparable. This might suggest that4,5�-dialkyl 2,2�-bipyridines could lead to better-controlled ATRP than 4,4�-dialkyl 2,2�-bipyri-dines.

CONCLUSIONS

HTE has been demonstrated to be a valuable toolfor the rapid screening and optimization of thereaction conditions for ATRP. The optimal reac-tion conditions for Cu(I) halide, CuSCN, andFe(II) halide-mediated ATRP with 2,2�-bipyridineand its derivatives with dialkyl groups on 4,4�-positions as ligands were determined. Cu(I)-cata-lyzed systems were more effective than Fe(II)-catalyzed ones under the studied conditions. Abipyridine-type ligand with a critical length of thesubstituted alkyl group (i.e., dHbpy) demon-strated the best performance in Cu(I)-mediatedsystems, and EBIB and TsCl could initiate Cu(I)-mediated ATRP of MMA effectively, providingpolymers with low PDIs in most cases. Addition-ally, the halide-exchange effect proved to be ap-plicable in Cu(I) halide-mediated systems insteadof Fe(II) halide-mediated ones. Furthermore,Cu(I) halide-mediated ATRP with 4,5�-dMbpy asthe ligand and TsCl as the initiator were bettercontrolled than those with dMbpy as the ligand,and polymers with much lower PDIs were ob-tained in the former cases. This successful HTEexample opens up the way to greatly accelerateprogress in developing new catalytic systems forATRP and in understanding structure–propertyrelationships of the reaction systems. We are now

Figure 4. Effects of metal salts, ligands, and initia-tors on (a) CMMA’s, (b) f, and (c) PDIs of the polymers inthe ATRP of MMA in p-xylene at 90 °C. [MMA]0/[initi-ator]0/[metal salt]0/[ligand]0 � 150:1:1:2, MMA/p-xy-lene �1:2 v/v, 90 °C. EBIB, MBP, BEB, and TsCl wereused as the initiator from right to left in each ligandcolumn, respectively.

HIGH-THROUGHPUT EXPERIMENTATION 1883

using this method for the screening of other metalsalts and ligands for ATRP systems. Moreover,matinformatics tools are being introduced intoour research efforts. Using already existing data,combined with information derived from molecu-lar modeling, will allow the development of quan-titative structure-property relationship (QSPR)models. These can then be used in combinationwith design-of-experiment methodologies to fur-ther optimize polymerization conditions and todesign second-generation libraries.

This work was financially supported by the Dutch Poly-mer Institute (DPI), NWO, and the Fonds der Che-mische Industrie. The authors thank Chemspeed, Ltd.for the collaboration.

REFERENCES AND NOTES

1. Matyjaszewski, K.; Xia, J. Chem Rev 2001, 101,2921.

2. Kamigaito, M.; Ando, T.; Sawamoto, M. Chem Rev2001, 101, 3689.

3. Hawker, C. J.; Bosman, A. W.; Harth, E. Chem Rev2001, 101, 3661.

4. Chong, Y. K.; Krstina, J.; Le, T. P. T.; Moad, G.;Postma, A.; Rizzardo, E.; Thang, S. H. Macromole-cules 2003, 36, 2256.

5. Wang, X. D.; Sun, X.; Briceno, G.; Lou, Y.; Wang,K. A.; Chang, H.; Wallace-Freedman, W. G.; Chen,S. W.; Schultz, P. G. Science 1995, 268, 1738.

6. Danielson, E.; Golden, J. H.; McFarland, E. W.;Reaves, C. M.; Weinberg, W. H.; Wu, X. D. Nature1997, 389, 944.

7. Senkan, S. M. Nature 1998, 394, 350.8. Jandeleit, B.; Schaefer, D. J.; Powers, T. S.; Turner,

H. W.; Weinberg, W. H. Angew Chem 1999, 111,2648.

9. Jandeleit, B.; Schaefer, D. J.; Powers, T. S.; Turner,H. W.; Weinberg, W. H. Angew Chem Int Ed 1999,38, 2494.

10. Senkan, S. Angew Chem 2001, 113, 322.11. Senkan, S. Angew Chem Int Ed 2001, 40, 312.12. Brocchini, S.; James, K.; Tangpasuthadol, V.;

Kohn, J. J Am Chem Soc 1997, 119, 4553.13. Nielsen, R. B.; Safir, A. L.; Petro, M.; Lee, T. S.;

Huefner, P. Polym Mater Sci Eng 1999, 80, 92.14. Bosman, A. W.; Heumann, A.; Klaerner, G.; Benoit,

D.; Frechet, J. M. J.; Hawker, C. J. J Am Chem Soc2001, 123, 6461.

15. Lavastre, O.; Lllitchev, L.; Jegou, G.; Dixneuf, P. H.J Am Chem Soc 2002, 124, 5278.

16. Komon, Z. J. A.; Diamond, G. M.; Leclerc, M. K. L.;Murphy, V.; Okazaki, M.; Bazan, G. C. J Am ChemSoc 2002, 124, 15280.

17. Potyrailo, R. A.; Pickett, J. E. Angew Chem 2002,114, 4399.

Figure 5. (a) CMMA’s, (b) f, and (c) PDIs of the poly-mers in the ATRP of MMA carried out in the automatedsynthesizer. The metal salts used in reactions 1–4 and5–8 are CuBr and CuCl, respectively, and the ligandsused in reactions 1 and 5, 2 and 6, 3 and 7, and 4 and 8 are4,5�-dMbpy, 5,5�-dMbpy, 4Mbpy, and 6Mbpy, respec-tively. [MMA]0/[TsCl]0/[metal salt]0/[ligand]0 � 150:1:1:2,MMA/p-xylene �1:2 v/v, 90 °C, reaction time: 510 min.

1884 ZHANG ET AL.

18. Potyrailo, R. A.; Pickett, J. E. Angew Chem Int Ed2002, 41, 4230.

19. See, for example, contributions in Macromol RapidCommun 2003, 24(1).

20. Boussie, T. R.; Diamond, G. M.; Goh, C.; Hall, K. A.;LaPointe, A. M.; Leclerc, M.; Lund, C.; Murphy, V.;Shoemaker, J. A. W.; Tracht, U.; Turner, H.;Zhang, J.; Uno, T.; Rosen, R. K.; Stevens, J. C.J Am Chem Soc 2003, 125, 4306.

21. Hoogenboom, R.; Schubert, U. S. J Polym Sci PartA: Polym Chem 2003, 41, 2425.

22. Zhang, H.; Fijten, M. W. M.; Hoogenboom, R.; Rein-ierkens, R.; Schubert, U. S. Macromol Rapid Com-mun 2003, 24, 81.

23. Zhang, H.; Fijten, M. W. M.; Hoogenboom, R.;Schubert, U. S. Advances in Controlled/Living Rad-ical Polymerization; ACS Symposium Series 854;American Chemical Society: Washington, DC,2003; p 193.

24. Hoogenboom, R.; Fijten, M. W. M.; Meier, M. A. R.;Schubert, U. S. Macromol Rapid Commun 2003, 24,92.

25. Hoogenboom, R.; Fijten, M. W. M.; Brandli, C.;Schroer, J.; Schubert, U. S. Macromol Rapid Com-mun 2003, 24, 98.

26. Keller, R. N.; Wycoff, H. D. Inorg Synth 1946, 2, 1.27. Griggs, C. G.; Smith, D. J. H. J Chem Soc Perkin

Trans 1 1982, 3041.28. Schubert, U. S.; Eschbaumer, C.; Heller, M. Org

Lett 2000, 2, 3373.29. The reproducibility of the parallel reactions in the

automated synthesizer and the comparability ofthe results obtained from the automated synthe-sizer with those from the conventional experimen-tal setup (including kinetics, CMMA and Mn,SEC andPDIs of the resulting polymers) have been checkedin a previous article (ref. 22), but the reactor vol-ume was 75 mL in that case.

30. Matyjaszewski, K.; Wang, J. L.; Grimaud, T.;Shipp, D. A. Macromolecules 1998, 31, 1527.

31. Percec, V.; Barboiu, B.; Kim, H. J. J Am Chem Soc1998, 120, 305.

32. Matyjaszewski, K.; Shipp, D. A.; Wang, J. L.; Gri-maud, T.; Patten, T. E. Macromolecules 1998, 31,6836.

33. Singha, N. K.; Klumperman, B. Macromol RapidCommun 2000, 21, 1116.

34. Matyjaszewski, K.; Wei, M.; Xia, J.; McDermott,N. E. Macromolecules 1997, 30, 8161.

HIGH-THROUGHPUT EXPERIMENTATION 1885