Radical Polymerizations II Special Cases

Home , Living polymerization, Polymerization, Radical polymerization

Devon A. Shipp Department of Chemistry, & Center for Advanced Materials Processing Clarkson University Potsdam, NY 13699-5810 Tel. (315) 268-2393, Fax (315) 268-6610 [email protected]

• Objectives • Requirements – Initiation must be fast – Continuous chain • Ri >> Rp growth – Termination must be – No termination eliminated • Or at least reduced to – Well-defined chains insignificance • Chain structure • Chain length • Problems with free • Molecular weight radical polymerization distribution – Initiation is slow • Block copolymer – Radical-radical synthesis termination is fast

47 Reversible-Deactivation Radical Polymerizations (RDRP)

• Often called living radical polymerization

activation Dormant polymer Active polymer radical + capping group deactivation Monomer (Propagation) t P h o g l i y

e Δ[M] Monomer repeat unit Functional terminal d

DP = i W s ( ω ) end ("capping") group [In] r

0 p a e l r u s c

X i t e y In l n o M Y Y < 1.5 Initiator ( α ) end 48 % Monomer Conversion Features of Living Polymerizations

• Linear increase in • Low polydispersity

molecular weight – Mw/Mn < 1.5 (often ~ 1.1) – Vs. monomer conversion

• First-order monomer • Pre-defined molecular consumption weight – Same as conventional radical polymerization – DPn = Mn/FWM = Δ[M] / [Initiator]

49 Terminology/Tests for Living Polymerization

• Controversy over terminology – Controlled, living, pseudo-living, quasi-living, living/controlled, living/controlled, reversible-deactivation,… • IUPAC definition of living polymerization: – Absence of irreversible transfer and termination • Cannot be applied to any radical polymerization! • Some tests for RDRP: – Continued chain growth after addition monomer added – Molecular weight increases linearly with conversion – Active species (i.e. radicals) conc. remains constant

– Narrow molecular weight distributions (low Mw/Mn) – Block copolymers may be prepared (subset of first test) – End groups are retained – yields end-functionalized chains

50 Moad and Solomon The Chemistry of Radical Polymerization, 2nd edition, 2006, page 453. Examples of RDRP Data

• Atom transfer radical polymerization (ATRP)

– Styrene. Mn at 100% (theoretical) = 10,000 (DP = 100)

T.E. Patten, J. Xia, T. Abernathy, K. Matyjaszewski, Science, 1996, 272, 866. 51 K. Matyjaszewski, T.E. Patten, J. Xia, J. Am. Chem. Soc., 1997, 119, 674. Calculated MWDs

52 Moad and Solomon The Chemistry of Radical Polymerization, 2nd edition, 2006, page 454. Materials From RDRP

53 D.A. Shipp, Polym. Rev., 2011, 51, 99-103. RDRP: Types & Requirements

• Main types • Requirements – Nitroxide-Mediated – All chains begin at the Polymerization same time • NMP • Fast initiation – Atom Transfer Radical Polymerization – Little or no termination • ATRP • Low radical concentration – Reversible Addition- – All chains grow at the Fragmentation Chain same rate Transfer Polymerization • RAFT • Fast exchange • Other types – Metal-mediated polymn – Iniferter – Iodo and methacrylate-based – Group transfer polymn degenerate transfer 54 Nitroxide-Mediated Polymerization

• Nitroxides • TEMPO – Stable free radicals – 2,2,6,6 – Do not react with O-centered N O tetramethylpiperidim-N- radicals oxyl – React fast with C-centered radicals – Only good for styrene 6 9 -1 -1 (co)polymers • kd ~ 10 – 10 M s – Do not initiate polymerization • αH nitroxides

N O – Styrene, acrylates, ka Pn-X Pn + X acrylonitrile, 1,3- kd Ph butadiene kp Monomer

ka O N O N n k n Rizzardo, Solomon, et al. Ph Ph Ph d Ph Ph Ph US Patent 4,581,429, 1986. TEMPO Aust. J. Chem., 1990, 43, 1215-1230. Ph 55 Chem. Aust., 1987, 54, 32. Propagation Georges/Xerox Approach to NMP

N O O O O O Heat O O n N O O O n Ph Ph Ph Ph TEMPO BPO n+1 Ph Heat

O O O n N Ph Ph

Propagation

Molecular weight distributions of polystyrene produced by NMP using BPO and M.K. Georges et al., Macromolecules, 56 n TEMPO. M and Mw/Mn of samples I – IV are as follows: (Mn:Mw/Mn) 1700:1.28, 1993, 26, 2987-2988. 3200:1.27, 6800:1.21, 7800:1.27. Hawker Approach to NMP (Using TEMPO)

Alkoxyamine

57 C.J. Hawker, J. Am. Chem. Soc., 1994, 116, 11185-11186. Newer108 Nitroxides: R. B. Grubbs α-Hydrido-Derivatives commercialized by Arkema in 2005 points to the continued interest in NMP from re- searchers who would rather not synthesize their own alkoxyamine initiators. As TIPNO and related alkoxyamines are now also commercially available (Sigma-Aldrich), research • Widerinvolving polymers range prepared by NMPof should monomers continue to grow. & functionalities

Common nitroxides/ alkoxyamines

110 R. B. Grubbs Scheme 3.

2.2.1 In Situ Generation of Nitroxide Radicals and Alkoxyamines. In the earliest examples of NMP, alkoxyamines were generated during the course of the polymerization through the use of conventional radical initiators in the presence of nitroxides.51 Shortly thereafter, strategies to isolate unimolecular alkoxyamines from nitroxides and radical precursors were Functional developed.9,54 This general strategy has recently been modified to allow the low temperature R alkoxyamines synthesis of the BlocBuilder⃝ alkoxyamine by photolysis of a diacid-functional azo initiator in high yield.55 Anumberofsyntheticroutestoalkoxyamineshavebeendevelopedinwhichan active alkoxyamine is generated during the course of the polymerization from precursors that are not nitroxides (Scheme 4, color scheme available online).13 The propensity of nitric oxide (Scheme 4a), nitrosoalkanes/arenes (Scheme 4b) and nitrones (Scheme 4c) to react with two equivalents of a carbon-centered radical to form alkoxyamines has been exploited as an alternative route to new nitroxide controlling agents that have allowed the controlled preparation of polymers and block copolymers,56–58 including copolymers of methyl methacrylate (MMA), and, in some cases, have facilitated polymerization at lower temperatures.59 Density functional theory has been used in combination with electron spin 58 Figure 2. Structures of selected new alkoxyamines used for NMP: 17–18,69 19–20,70 21–22,71 P. Tordo, Y. resonanceGnanau, et spectrometry al., J. Am. Chem. to better Soc. understand, 2000, 122 these, 5929-5939 systems. and to predictR.B. Grubbs, the properties Polym. ofRev., 2011, 51, 104-137. 23–24,61 25,20 26,62 27.63 C.J. Hawker,the et resultingal., J. Am. nitroxides. Chem. Soc.60 , 1999, 121, 3904-3920. Downloaded By: [Grubbs, Robert B.] At: 13:14 2 May 2011 alkoxyamine to other polymers (to form block copolymers), to surfaces (to create polymer brushes), and to fluorescent labels (Figure 2).62,69,72–75 Alcohol (17),69 carboxylic acid (18),62,69 thiol/disulfide (20, 21),70 bis(thioether) (21),71 pyridyl (22),71 ketone (25),20 and carboxylate ester (24, 26, 27)20,61–63 functionalized alkoxyamines are among such NMP initiators recently prepared. In a number of these examples, the functional alkoxyamines (24–27) were prepared by the addition of functional group-bearing radical species to nitrosoalkanes.20,61–63

2.3 Improving NMP Rates Scheme 4. In general, efforts to increase the rate and/or lower the temperature for NMP have involved pushing the equilibrium between the dormant alkoxyamine and the active radical toward 2.2.2 One Step Routes to Alkoxyamines. When the above reactions of radicals with amine the propagating radical (increasing k /k in Scheme 1). In all of these manipulations, there oxide derivatives are carried out atd temperaturesa below those where alkoxyamine dissocia- Downloaded By: [Grubbs, Robert B.] At: 13:14 2 May 2011 is a ﬁnetion occurs, line between alkoxyamine a slow initiators but well-controlled can be prepared polymerization in one step—a number and a of fast, such uncontrolled examples polymerization; any changes that increase the concentration of propagating radicals are likely to decrease the livingness of the polymerization. As the earliest published examples of NMP were centered on bimolecular benzoyl per- oxide/TEMPO initiating systems, most of the earliest rate acceleration strategies involved the use of various additives (e.g., camphorsulfonic acid,76,77 2-ﬂuoro-1-methylpyridinium 78 79 p-toluenesulfonate, acetic anhydride )toincreasetherateofhomolysis(increasekd in Scheme 1) of the alkoxyamine, to retard the recombination of the nitroxide radical with the polymer radical (decrease ka in Scheme 1), or to decompose excess nitroxide that might build up due to polymer radical termination.9 Nitroxides, such as TIPNO and DEPN, that are believed to decompose at polymerization temperatures at a slow enough rate to prevent the build up of excess nitroxide without negatively affecting control over the polymerization process have similarly proven useful in increasing NMP rates.37,80 Subsequent approaches have used a wider range of initiating radicals and mediating nitroxides to control the dormant alkoxyamine/active radical equilibrium. With bimolecular initiating systems, the use of lower temperature radical initiators, such as tert-butylperoxy 2-ethylhexyl carbonate with TEMPO,81 has shown some success. It has been demonstrated ARTICLE IN PRESS W.A. Braunecker, K. Matyjaszewski / Prog. Polym. Sci. 32 (2007) 93–146 101

successful moderators of vinyl acetate polymeriza- cross-coupling (deactivation) of the transient radical tion, although the mechanism of control is not R with persistent radical Y (kc), and termination of based on the SFRP principle but rather follows a two transient radicals to form product P (kt). degenerative transfer mechanism (cf. below) [73–76]. In this case, the rates of formation of the persistent radical and of loss of the transient radical 4.2.4. Metal mediated polymerization are given by the expressions in Eq. (3) (where the Transition metal compounds that can mediate term 2kt is used because a single termination step radical polymerization include those based on Co consumes two radicals) [47],Mo[77], Os [78], and Fe [79]. Controlled dR 2 d kdI kcRY 2ktR ; polymerization of methyl acrylate with Co porphyr- t ¼ À À (3) dY k I k RY dR 2k R2: ins is one of the most successful SFRP systems, dt ¼ d À c ¼ dt þ t having produced well-defined high molecular weight The two coupled differential equations were polyacrylates. Recently, Co(acac) derivativesARTICLE were IN PRESS 2 solved analytically by Fischer and independently used to control theW.A. polymerization Braunecker, of vinyl K. Matyjaszewski acetate / Prog. Polym. Sci. 32 (2007) 93–146 101 by Fukuda. Both proposed that the increase in and N-vinylpyrrolidone (Fig. 3a) [80–83]. Co- concentration of deactivator ( ) should be propor- porphyrin and glyoxime derivatives do not control Y tional to t1/3 and the loss of transient radical (R) successful moderatorsthe SFRP of methacrylates of vinyl but acetate rather lead polymeriza- to very cross-coupling1/3 (deactivation) of the transient radical proportional to tÀ according to tion, althoughefficient the catalytic mechanism chain transfer of processes control (Figs. is 3b not R with persistent radical Y (kc), and termination of 2 2 1=3 1=3 and c) [84]. Y 6ktK I t ; based on the SFRP principle but rather follows a ¼ð twoeq 0 transientÞ radicals to form product P (kt). 1=3 (4) KeqI 0 1=3 degenerative4.3. transfer Re-evaluation mechanism of the persistent (cf. radical below) effect[73–76]. R IntÀ this: case, the rates of formation of the ¼ 6kt persistent radical and of loss of the transient radical SFRP and ATRP systems are characterized by The dependence for the persistent radical Y 4.2.4. Metalunusual mediated non-linear polymerization semilogarithmic kinetic plots that should beare valid given in the by time the interval expressions defined by in Eq. (3) (where the Transitionobey metal a peculiar compounds power law. These that kinetics can were mediate first Eq. (5),term and Eq. 2 (6)kt shouldis used be fulfilled because a single termination step elegantly explained by Fischer [42], who introduced ARTICLE IN PRESS 4pconsumesk K twoI radicals) radical polymerizationthe concept of the include persistent those radical effect based in both on Cot t eq t t 0 , (5) W.A. Braunecker, K. Matyjaszewski / Prog. Polym. Sci. 32 (2007) 93–146 L 1=2 3=2 o o101U 2 ¼ 3 ¼ 48K kt [47],Mo[77]organic, Os reactions[78] and, and macromolecular Fe [79]. systems. Controlled As I 0ffiffiffiffiffikd dR eq 2 mentioned above, stable persistent radicals do not d kdI kcRY 2ktR ; polymerization of methyl acrylate with Co porphyr- t ¼ À À (3) successful moderators of vinyl acetate polymeriza- terminate,cross-couplingThe and hence Persistent their (deactivation) concentration progres- of Radical the transientKeqoI 0kdcY=16 k radicalEffectt. (PRE)dR (6)2 ins is onesively ofTh thee increasesPersis mosttent Ra withdical E successfulff theect reaction time, SFRP shifting systems, the dt Chemkicadl RIeviews,k20c0RY1, Vol. 101, Nod. t12 35923 ktR : tion, although the mechanism of control is not R with persistent radical Y (k ), and termination¼ ofÀ ¼ þ having producedequilibriumrespe well-definedct to intimSchemee and the 3 highintowardsitial c molecularoncen thetrati dormantons, a weightcnd species.they Fischer,should ev anden st laterart fro Fukuda,m the a p derivedriori kno precisewledge based on the SFRP principle but rather follows a two transient radicals to form product P (kThet). two coupled differential equations were polyacrylates.kinetico Recently,f t equationshe rate con tost Co(acac) correlateants enter theing2 amountthderivativese form ofula evolveds. Such were degenerative transfer mechanism (cf. below) [73–76]. • vIdeaerifInicati odevelopedn thiss are em case,erging now the.byThu sH., s ratesev eFischer,ral gro ofups formation solved of analyticallythe by Fischer and independently used to controlpersistentmea thesu radicalred polymerizationthe e withxpecte thed ra overallther larg ofequilibriume co vinylncentrat acetatei andons terminationoandpersistentf the p efurthered ratersist constantsent radicalspecies[41,42][ Yby] andbo t.hT.du ofrFukudaing lossnitrox ofide- the transientby radicalFukuda. Both proposed that the increase in and N-vinylpyrrolidone (Fig. 3a) [80–83]31,49,58,59 . Co- Themed essenceiated pol ofyme therizat PREions a cannd AT beRP more. clearlyVery concentration of deactivator (Y) should be propor- 4.2.4. Metal mediated polymerization porphyrin andexplainedoareft glyoximeen, t forh givene o systemsbserve bydderivativest notime thed complicatedepen expressionsdencie dos o byf l notn propaga-([M]0/ control[M in]) Eq. (3) (where the were not curved as in Figure 3 but linear or ap- tional to t1/3 and the loss of transient radical (R) tionp (termrkopx).im Suchate 2lykli ane system,isar. T usedhis p shownoint becauses to c inonsSchemetant t aran singles 5i,en ist termination step Transition metal compounds that canthe mediate SFRP of methacrylatest but rather lead to very 1/3 simplifiedradical intoconc threeentrati elementaryons that are reactions:expected for dissocia-an extra proportional to tÀ according to rconsumesadical generation two, an ini radicals)tial excess of the persistent radical polymerization include those basedefficient on Co catalytiction (activation) chain transferof the alkoxyamine processesR–Y (Figs.(kd), 3b Scheme 5. species, or its decay. The slopes provide [R]s via eq 34. With [R] , [Y], and the initial concentrations, the 2 2 1=3 1=3 [47],Mo[77], Os [78], and Fe [79]. Controlledand c) [84]. dR s 2 Figure 7. TYime evolu6tikon Kof theIpersistentt radical con- equilibrium conkstaInts of tkhe RYreversible 2rakdicaRl forma- t eq 0 ; dt d c t ; centration durin¼ðg a polymerization oÞf 0.76 M styrene in polymerization of methyl acrylate with Co porphyr- tion can th¼en be extrÀacabted from thÀe data. tert-butylbenz cene at 130 °C initiated by the alkoxyamine dY dR 2 (3) 1=3 (4) Fukudaket Ial.49 ikntrRYoduced a chromat2ogkraRphic 6 of Scheme 30 for differeKneqt aIlk0oxyamine c1o=n3centrations. ins is one of the mostThe successfulPersistent Radical Effec SFRPt 4.3. systems, Re-evaluationdt of thed persistentChemcical Reviews, 2 radical00d1,tVol. 101, N effectot. 12 3:593 The solid linesRconfirm eq 18. tÀ : metho¼d for the diÀrect determina¼tion of rþate constants 6kt for the radical generation step (activation). For ¼ having produced well-definedrespect to hightime an moleculard the initial con weightcentrations, and C they should even start from the a priori knowledge several cases these agree with corresponding values deduTheced from twothe time coupleddependence of t differentialhe polydisper- equations were polyacrylates. Recently,of Co(acac)the rate cons2tanderivativests entering theSFRPfo werermulas. andSuch ATRP systems are characterized by The dependence for the persistent radical Y verifications are emerging now. Thus, several groups ssolvedity index (eq analytically38), and this is also bystrong Fischersupport for and independently used to control the polymerizationmeasured the expec ofted r vinylather lunusualarg acetatee concent non-linearrations the und semilogarithmicerlying theoretical princ kineticiples. Whe plotsn K is that should be valid in the time interval defined by of the persistent species [Y] both during nitroxide- kbynown, Fukuda.the rate consta Bothnt for rad proposedical formation (ac that- the increase in and N-vinylpyrrolidonemedi (aFig.ted polym 3aeriz)atio[80–83]ns and obeyATR.P.3 Co-1 a,49,5 peculiar8,59 Very tiva powertion) provi law.des also Thesethe rate co kineticsnstant for th weree cross- first Eq. (5), and Eq. (6) should be fulfilled reaction (deactivation). All Fig.data 3.es Cobalttablish complexesed for ni employed- in metal-mediated SFRP. often, the observed time dependencies of ln([M]0/[M]) concentration of deactivator (Y) should be propor- elegantly explainedtroxide-m byedia Fischerted polymeri[42]zation,s whoso far49, introduced59,60,61 are porphyrin and glyoximewe derivativesre not curved as i don Fig noture 3 controlbut linear or ap- 1/3 p proximately linear. This points to constant transient ntionalot much dif toferentt fromandrate con thestants lossfor ana oflogou transients radical4 (kRt)Keq I 0 the concept ofrea thections persistentinvolving smal radicall carbon-cen effecttered rad inicals both t t t , (5) the SFRP of methacrylatesradical c butoncent ratherrations tha leadt are exp toected veryfor an extra 1/3 L 1=2 3=2 o o U 2 radical generation, an initial excess of the persistent tproportionalhat have been obtai toned tbÀy specaccordingtroscopic tech- to ¼ 3I k ¼ 48Keqkt efficient catalytic chain transfer processes (organicFigs. 3b reactionsniques and.62,63 Th macromoleculare technique has also been systems.applied to As 0ffiffiffiffiffi d 59 species, or its decay. The slopes provide [R]s via eq ATRP systems.64 34. With [R]s, [Y], and the initiamentionedl concentrations, th above,e stable persistent2 2 1=3 radicals do not and c) [84]. Chem. Rev.Figur 2001e 7. T, im101e e,v o3851-3610.lution of th1e= p3ersistent radical con- Figure 8. Time evolution of the polymerization index ln- equilibrium constants of the reversible radical forma- YAcsenintrdaitcioa6ntekddutreKianrgleqiaerIp,ot0lhyme eurnizutastiuoanl ;otfim0.e76dMepesntydrene- in tion can then be extracted fromterminate,the data. andcies henceand react theirion order concentrations expected in the absen progres-ce of ([M]0/[M]) duKrineqg aopolIym0ekrizca=ti16on ofk0t.7.6 M styrene in tert- (6) tert¼ð-butylbenzene at 130Þ°C initiated by the alkoxyamine butylbenzene at 130 °C initiated by the alkoxyamine 6 of Fukuda et al.49 introduced a chromatographic add6itoifonSachl ermaedi3c0alfogredni1effr=ear3etinotnalokroxoyfaamninienictoinacleenxtrcaetsisons. Scheme 30 for different a(4)lkoxyamine concentrations. The sively increasesof t withhTehepesorlsiids thetleinKnetseqscpI reactionoen0cfierms aerqe 1d8if.1fi=c time,u3lt to obs shiftingerve unless the 4.3. Re-evaluation of theme persistentthod for the direc radicalt determina effecttion of rate constants R tÀ : solid lines confirm eq 22. for the radical generation steequilibriump (activation). For inspecSchemeial ¼precaut6ioknts 3aretowardstaken. Moreov theer, a de dormantcrease several cases these agree with corresponding values of the self-termination rate constant kt with increas- parameters from the same polymerization, and this deduced from the time dependence of the polydisper- ing chain length and conversion diminishes the is possible by simultaneous measurements of the species. Fischer, and later Fukuda, derived17 precise SFRP and ATRP systemssity index (e areq 38), a characterizednd this is also strong s byupport for negaThetive curv dependenceature of ln([M]0/[M]) (e forq 22), theand ma persistenty time depen radicaldence of the pYersistent radical concentra- the underlying theoretical principles. When K is lead to a more linear appearance. This was demon- tion and of the conversion and the combination of eqs kinetic equations to correlate the amount46 of evolved unusual non-linear semilogarithmicknown, the rate co kineticnstant for r plotsadical fo thatrmation (ac- sshouldtrated first beby M validatyjaszews inki. theTo av timeoid such interval18 and 22 defined.59 This was re bycently achieved on the same tivation) provides also the rate copersistentnstant for the cr radicaloss- interfe withrences, theexperim overallents desig equilibriumned to prove the andsample by combining an ESR spectrometer with a obey a peculiar power law.reactio Thesen (deactiva kineticstion). All dat werea establi firstshed for ni- uEq.nusual (5),polym anderizati Eq.on kine (6)tics m shouldust be bas beed on fulfilleddilatometer and using another new alkoxyamine for troxide-mediated polymerizatioterminationns so far49,59,60,61 ar ratee syste constantsms that exhibit[41,42]large radi.cal generation (activa- the polymerization of styrene. In pure monomer, the elegantly explained by Fischernot much dif[42]ferent,fr whoom rate introducedconstants for analogous tion) rates, and the conversions should be kept autopolymerization still provided a constant nitroxide The essencemo ofdest. theThe cl PREeavage ra cante cons betants moreof di-tert- clearlybu- reactions involving small carbon-centered radicals 4pktKeq I 0 level and a linear time dependence of ln([M]0/[M]). the concept of the persistentthat have radicalbeen obtai effectned by sp inectr bothoscopic tech- ttylLnitroxide (DBNO, 1 ion ScthoemteU12) based alkoxy- ,However, with styrene (5)diluted by an inert solvent 62,63 explained for systems1 not2 3 complicated2 by propaga-2 niques. The technique has also been applied to amin¼es are kn=own to= be rather large¼. In 48fact, using and for conversions below 50%, the results of Figures 64 3I k Keqkt organic reactions and macromolecularATRP systems. systems. As a sugar-carry0iffiffiffiffiffing stdyrene that does not readily un- 7 and 8 were obtained, and they conform to eqs 18 tion (kp). Suchderg ao au system,toinitiation a shownnd a benzoy inloxyScheme-styryl-DBNO 5, is As indicated earlier, the unusual time dependen- Figure 8. Time evolution of the polymerization index ln- and 22. Moreover, the resulting polymers were living 23 mentioned above, stable persistent radicals do not init(i[aMto]0r/[,MF]u) kdurdiangeat apol.lyfomuenridzatthioant othf 0e.7p6olMymsteyrrieznaetinontert- (>90%) and had low polydispersities (1.15-1.30). cies and reaction orders expectsimplifieded in the absenc intoe of three elementary reactions:2/3 dissocia- additional radical generation or of an initial excess indbeuxtiynlbcernezaesnees awt i1t3h0t°imC einaitsiattedabnydthdeepaleknodxsyaomninthe e6 of Before closing this section, it must be mentioned terminate, and hence their concentration progres- tKhirSeqdchreomote Io3f00tfkhoercdi=nifi16fteiraetnkotrtac.lkoonxcyeanmtrinaeticoonn.c1e9 nTtrhaitsioinssa. sThe (6) Scheme 5. of the persistent species are diffictionult to obs (activation)erve unless solid oflines theconfirm alkoxyamineeq 22. R–Y (kd),that processes involving the persistent radical effect sively increases with thespe reactioncial precaution time,s are tak shiftingen. Moreover, thea decrease expected from eq 22. Other nitroxides that provide are not the only way to obtain living and controlled of the self-termination rate constant k with increas- large cleavage rate constants are becoming available polymerizations. Any reaction scheme that provides t nowpa(rsaeme ebteelroswf)r,oamndthweistahmaecpoorlryemspeornizdaitnigona,laknoxdyt-his equilibrium in Schemeing 3chaitowardsn length and theconvers dormantion diminishes the is possible by simultaneous measurements of the an equilibrium between the dormant polymer chains 17 amine, Lacroix-Desmazes et al. also obtained a clear and the transient propagating radicals suffices, if the negative curvature of ln([M]0/[M]) (eq 22), and may time dependence of the persistent radical6c0o,6n5 centra- lead to a more linear appearance. This was demon- verification of thabe theoretical predictions. For equilibrium highly favors cthe dormant chains and is species. Fischer, and later Fukuda, derived precise ATRtiPon, andeoxfatmheplceonwvaesrsgioivneanndbythKelcuommpbeinrmataionnnoefteqs 46 59 established rapidly and the rate of external radical strated first by Matyjaszewski. To avoid such 616 8 and 22. This was recently achieved on the same kinetic equations to correlateinterferen theces, e amountxperiments d ofesig evolvedned to prove the al. generation is small. For such other living radical sample by combining an ESR spectrometer with a 67 unusual polymerization kinetics must be based on Tdhielasetommeeatesruraenmdeunstisnpgraonvoidtheetrheneewquailkiborxiyuammcionne-for polymerizations, the RAFT process of Rizzardo et al. persistent radical with thesystem overalls that exhibit equilibriumlarge radical genera andtion (activa- stant K of the reversible dissociation, if kt is known. and the moderation by degenerative iodine atom the polymerization of styrene. In pure monomer, the 68 tion) rates, and the conversions should be kept Of acuotuorpsoel,ymitewrizoautlidonbsetililnpterorvesidtiendga tcoonosbtatanitnnibtrootxhide transfCer are illuminating examples. termination rate constantsmode[41,42]st. The cl.eavage rate constants of di-tert-bu- level and a linear time dependence of ln([M]0/[M]). The essence of thet PREylnitroxid cane (DBNO be, 1 in moreScheme 1 clearly2) based alkoxy- However, with styrene diluted by an inert solvent amines are known to be rather large. In fact, using and for conversions below 50%, the results of Figures explained for systems nota sug complicatedar-carrying styrene bythat propaga-does not readily un- 7 and 8 were obtained, and they conform to eqs 18 dergo autoinitiation and a benzoyloxy-styryl-DBNO and 22. Moreover, the resulting polymers were living initiator, Fukuda et al. found that the polymerization (>90%) and had low polydispersities (1.15-1.30).23 tion (kp). Such a system, shown in Scheme2/3 5, is index increases with time as t and depends on the Before closing this section, it must be mentioned 19 simplified into three elementarythird root of th reactions:e initiator concen dissocia-tration. This is as that processes involving the persistent radical effect expected from eq 22. Other nitroxides that provide are not the only way Fig.to obta 3.in Cobaltliving and complexescontrolled employed in metal-mediated SFRP. tion (activation) of thelarge alkoxyaminecleavage rate constantsRar–e bYecom(ikngda),vailable polymerizations. Any reaction schSchemeeme that p 5.rovides now (see below), and with a corresponding alkoxy- an equilibrium between the dormant polymer chains amine, Lacroix-Desmazes et al. also obtained a clear and the transient propagating radicals suffices, if the 60,65 verification of the theoretical predictions. For equilibrium highly favors the dormant chains and is ATRP, an example was given by Klumpermann et established rapidly and the rate of external radical 66 al. abgeneration is csmall. For such other living radical These measurements provide the equilibrium con- polymerizations, the RAFT process of Rizzardo et al.67 stant K of the reversible dissociation, if kt is known. and the moderation by degenerative iodine atom Of course, it would be interesting to obtain both transfer68 are illuminating examples.

Fig. 3. Cobalt complexes employed in metal-mediated SFRP. 3590 Chemical Reviews, 2001, Vol. 101, No. 12 Fischer

proportionation was assumed as a general mechanism for the irreversible termination. The latter restriction is not serious, because termination by coupling would simply double the molecular weight of the dead polymer fraction, which should anyway be small. Since the rate constants, including those of the primary radicals, shall not depend on chain length, the total radical concentrations obey eqs 18, and the equilibrium relation (19) is established if the conditions (20) are fulfilled. The only additional equation is the rate equation for the conversion of the monomer M Consequences of the PRE

Figure 3. Polymerization index ln([M]0/[M]) vs time d[M] during a polymerization in the equilibrium regime for kp )-kp[R][M] (21) -1 -1 8 -1 -1 -1 dt ) 5000 M s , kt ) 10 M s , kd ) 0.0045 s , kc ) 7 -1 -1 • Better control over polymer growth2.2‚10 M s , [M]0 ) 10 M, and [I]0 ) 0.02, 0.04, 0.06, and it does not change the evolution of the concen- 0.08, and 0.1 M as obtained by numerical integrations and trations of R• and Y•. It is easy to show that there eq 22 (circles). wi–ll beFastervery little deactivationconversion before the equilibrium regime is established.17 To obtain the conversion in this regime, one inserts eq 18 for [R] into eq 21 and int–eg rFewerates to radicals K[I] 1/3 -3/2kp 0 2/3 2 [M] ) [M• ]0Slowere terminationt or (Rt ~ [R] ) ( 3kt ) 1/3 • Slower polymerization[M]0 3 K[I]0 (Rp ~ [R]) ln ) k t2/3 (22) 2 p 3k • Better chain[M] end (functionalizationt )

(The index R of ktR is dropped here and in the following because ktY is always assumed to be zero). F–o r Odda conve npolymerizationtional polymerization wit hkineticsa constant rate of initiation rI and constant radical concentration Figure 4. Evolution of the total number-average degree 1/2 2 [R]s ) (rI/kt) , one has 1/3the relation of polymerization XN and the polydispersity index with • Approx. t dependence instead cofon vte rsion during a polymerization in the equilibrium regime for k ) 5000 M-1 s-1, k ) 108 M-1 s-1, k ) 0.0045 [M]0 p t d -kp[R]st s-1, k ) 2.2‚107 M-1 s-1, [M] ) 10 M, and [I] ) 0.1 M as [M] ) [M]0e or ln ) kp[R]st (23) c 0 0 [M] obtained by numerical integrations and eqs 24 and 25 – Can add some extra persistent(c irradicalcles). (e.g. nitroxide) to The difference between eqs 22 and 23 is due to the time dimproveependence of [PDI,R] in eq slow18. rate, better cendonvers igroupon, and th econtrollast term in eq 25 with the error Polymerization in the equilibrium regime does function (erf) reflects the residual influence of the provide the control of the molecular weight and a terminations. At short times one has 60 narrow molecular weight distribution. The integra- Chem. Rev. 2001, 101, 3851-3610. tion of the kinetic equations for the moments of the 1 8 PDI0 ) 1 + + (26) distribution (see section IV) leads to equations for the XN 3kdt number-average degree of polymerization (XN) and the polydispersity index PDI ) MW/MN ) XW/XN. and at infinite time the PDI becomes 3 1/2 [M]0 - [M] [I]0 πkp [I]0 XN ) (24) PDI∞ ) 1 + + (27) -kdt k k k [I] (1 - e ) [M]0 ( d c t ) 0

2 For properly chosen rate parameters it attains values 1 [M]0 PDI ) 1 - e-kdt + + (1 - e-kdt) close to one. Figures 3 and 4 display the behavior of X 2 × the polymerization index (X ) and PDI as computed N ([M]0 - [M]) N and as predicted by eqs 22, 24, and 25. πk 3[I] 1/2 K[I] 1/6 p 0 erf (3k )1/2 0 t1/3 (25) The livingness of the polymer is also easily calcu- k k k p 3k lated because the number of dead chains is practi- ( d c t ) [ ( t ) ] cally equal to the number of the released persistent If the dissociation of the initiator occurs well before species, which is known from eq 18. Further, the the conversion (kdt . 1), all chains start to grow analytical solutions provide conditions for the rate practically together at zero time. Then eq 24 provides constants that should allow a successful living and 17 the desired linear increase of MN with the conversion controlled polymerization. First, we may want the and the control by the initial initiator concentration. concentration fraction of the dead polymer products The PDI decreases with increasing XN, time, and [P]/[I]0 at the large monomer conversion of 90% to Atom Transfer Radical Polymerization

R R n Active propagating CuIBr + or N N N N N II radical Cu Br2 + ligand Metal catalyst (& ligand, L) Oxidized metal catalyst

ka q q+1 Pn-X + Mt /L Pn* + X-Mt /L kd Pm* kp kt q+1 Monomer D + 2 X-Mt /L

Dormant chain with halogen (X) Dead chains Br n H n n n m

J.-S. Wang, K. Matyjaszewski, J. Am. Chem. Soc., 1995, 117, 5614. M. Kato, M. Kamigaito, M. Sawamoto, T. Higashimura, Macromolecules, 1995, 28, 1721. 61 V. Percec, B. Barboiu, Macromolecules, 1995, 28, 7970. AtomTransferRadicalPolymerization ChemicalReviews,2001,Vol.101,No.9 2933

in the polymerization of more reactive monomers in Scheme 9. Various r-Brom oe ste rs Use d in ATRP such as MMA. For example, using CuCl- Ruthenium-Mediated ATRP of MMA (dNbpy)2 as the catalyst, inefficient initiation was observed when 1-phenylethyl chloride was employed as the initiator for the polymerization of MMA.123 PMMAwith much higher molecular weights than the theoretic values and high polydispersities (M w/M n ) AtomTransferRadicalPolymerization1.5-1.8) were obtained. In contrast, a well-controlled ChemicalReviews,2001,Vol.101,No.9 2933 polymerization was realized with benzhydryl chloride R-bromoisobutyrate, likely due to the back strain 54,157,158 in the(Ph polymerization2CHCl) as the initiator of more reactiveunder similar monomers conditions. in Schemeeffect; 9. Variousther release-Brom oe of ste the rs stericUse d in strain of the ATRPIn fact, such the as radical MMA. generation For example, was so using fast that CuCl- slow Ruthenium-Mediateddormant species during ATRP rehybridization of MMA from the sp3 (dNbpy)addition2 as the of benzhydryl catalyst, inefficient chloride was initiation necessary was to to the sp2 configuration leads to a higher equilibrium observedavoid when a significant 1-phenylethyl contribution chloride ofirreversible was employed biradi- constant. The dimeric model has also been used in 123123 115 as thecal initiator termination for earlythe polymerization in the polymerization. of MMA. Im- the ATRP of MMA catalyzed by NiBr 2(PPh 3)2, and PMMAwithprovement much of the higher initiation molecular efficiency weights for than the the ATRP the chloride analogue ofthe dimericmodel compound theoreticof MMA values using and primary high polydispersities and secondary (M benzylicw/M n ) ha- leads to the controlled polymerization of MMA and 1.5-lides1.8) were is possible obtained. by employing In contrast, the awell-controlled halogen exchange styrene mediated by a half-metallocene-type ruthe- polymerizationconcept.155 was realized with benzhydrylInitiators chloride R -bromoisobutyrate,fornium complexes. ATRP159 likely due to the back strain 54,157,158 (Ph 2CHCl)Polyhalogenated as the initiator benzylic under halides similar have conditions. been used effect;Malonatethe derivatives release ofare the less steric efficient strain in Cu-based of the In fact,for the the ATRP radical of generation MMA catalyzed was so by fast RuCl that2(PPh slow3)3/Al- dormantATRP, species perhaps during due rehybridization to the previously from mentioned the sp3 120 addition(OiPr) of3. benzhydrylPMMAwith chloride very low was polydispersities necessary to were to theOSET sp2 configuration process. Slow leads addition to a of higher the catalyst equilibrium to the avoidobtained a significant when2948 contribution PhChemical2CCl Reviews,2 was 2001,ofirreversible used Vol. as 101, the No. initiator.9 biradi- In constant.initiator The solution dimeric in model monomer has improves also Matyjaszewski been control and used Xia in tre- 42 contrast, PhCCl3 led to a bimodal molecular123 weight mendously. 115 cal termination• Best early into the polymerization.copy Im-endthe of ATRP growing of MMA catalyzed by NiBrpolymer2(PPh 3)2, and provementdistribution of theScheme consisting initiation 23. Model of efficiency two Compounds narrowly for Mimicking the distributed ATRP Polymericthe Chains chlorideR-Haloesters and analogue Ligands with Used ofthe various in dimericmodelKinetic functional Studies compound groups at- of MMAfractions, using the primary higher and of which secondary was double benzylic the molec-ha- leadstached to the can controlled easily be prepared polymerization through of a MMA straightfor- and 120 lidesular is possible weight byof the employing other. thePhCHCl halogen2 has exchange been also styreneward mediated esterification by a reaction half-metallocene-type of the appropriate ruthe- acid concept.used155 in Cu-based ATRP ofstyrene and MMA, appar- niumhalides. complexes. Since159 ATRPATRP can tolerateinitiators various functional Polyhalogenatedently providing benzylic two-directional halides growth have been of the used poly- Malonategroups, well-defined derivatives are end-functional less efficient polymers in Cu-based have meric chains.156 Scheme 8 illustrates some examples for the ATRP of MMA catalyzed by RuCl2(PPh 3)3/Al- ATRP,been perhaps conveniently due to prepared the previously without the mentioned need for 120 (OiPr)3. PMMAwith very low polydispersities were OSETadditional process. protecting Slow addition reactions. of the A variety catalyst offunction- to the Scheme 8. Some Halogenated Alkanes and alities, such as hydroxy, epoxy, allyl, vinyl, γ-lactone, obtainedBenzylic when Halides Ph 2CCl Used2 was as used ATRP as Initiators the initiator. In initiator solution in monomer improves control tre- 42 contrast, PhCCl3 led to a bimodal molecular weight mendously.and carboxylic acid have been introduced onto the distribution consisting of two narrowly distributed RR-Haloesters-end of the polymer withATRP various by usepolymers functional of a functional groups initiator at- fractions, the higher of which was double the molec- tachedand can will easily be discussed be prepared in through later sections a straightfor- (Scheme 120 10).99,128,160 ular weight of the other. PhCHCl2 has been also ward esterification reaction of the appropriate acid used in Cu-based ATRP ofstyrene and MMA, appar- halides.Scheme Since 10. ATRP Representative can tolerate Functional various functional Initiators ently providing two-directional growth of the poly- groups, well-defined end-functional polymers have 156Table 3. Activation Rate Constants Measured under Derivedcomposition from ofr-Haloe the 1-( steN ,N rs-(2-methylpropyl-1)(1-dimeric chains. VariousScheme Conditions 8 illustrates at 35 °C some172 examples beenethylphosphono-2,2-dimethyl-propyl-1-)- conveniently prepared without theN -oxyl)-1- need for -1 -1 no. RX complex solvent k act [M s additional] phenylethane protecting (PESG1) reactions. alkoxyamine. A variety offunction- SchemeOther 8. ATRP Some Halogenatedinitiators used Alkanes include: and 1 PEBr CuBr/2dNbpy acetonitrile 0.085 alities,The such following as hydroxy, conclusions epoxy, can allyl, be drawn vinyl, fromγ-lactone, the Benzylic Halides2 Used MBrP as CuBr/2dNbpy ATRP Initiators acetonitrile 0.052 and carboxylic acid have been introduced onto the of halogenated3 EBriB alkanes CuBr/2dNbpy and benzylic acetonitrile halides 0.60used model studies. At 35 °C, 2-bromoisobutyrate is ap- successfully4 in ATRP.BzBr CuBr/2dNbpy acetonitrile 0.043 R-endproximately of the polymer 10 times by more use of reactive a functional than the initiator other 5 PEBr CuBr/PMDETA acetonitrile 0.12 and willalkyl halidesbe discussed and 1-phenylethyl in later bromide sections is 103 (Schemetimes 6 MBrP CuBr/PMDETA acetonitrile 0.11 99,128,160more reactive than the corresponding chloride. This 3. R-Haloesters7 EBriB CuBr/PMDETA acetonitrile 1.7 10). difference dramatically decreases at higher temper- Various 2934R-haloesters8 PEClChemical CuCl/Me Reviews, have6TREN been 2001,acetonitrile successfully Vol. 101, No. 9 1.5 em- Matyjaszewski and Xia 9 PEBr CuBr/2dNbpy ethylacetate 0.016 Schemeatures 10. due Representative to the higher activation Functional energy Initiators for the ployed to initiate10 PECl well-controlled CuCl/2dNbpy ATRP. acetonitrile In general, 0.000056 latter. PMDETA forms more reactive Cu(I) complexes Derived from r-Haloe ste rs 4 R-haloisobutyratesScheme 11.produce Examples initiating of Sulfonyl radicals faster Chlorides usedthan as dNbpy. ATRP Me Initiators6TREN is 10 times more active ∼ Table 4. Deactivation Rate Constant Measured under Polyhalogenatedthan the dNbpy-basedR-haloesters complex. The reaction (e.g., CCl is faster3CO2CH3 than the correspondingVarious ConditionsR-halopropionates at 75 oC172 due to andin CHCl acetonitrile2CO2CH than3) in have ethyl also acetate. been successfully ap- better stabilization of the generated radicals after the-1 -1 no. radical complex solvent k deact [M s ] pliedIn as the initiators deactivation for process, the ATRP the CuBr of2 MMA/dNbpycatalyzed com- halogen abstraction step. Thus, slow initiation will 7 of halogenated1 alkanes PE Cu(II)Br and2 benzylic/2dNbpy acetonitrile halides used 2.5 10 120 × 6 byplex RuCl is2(PPh more3 active)3/Al(O iniPr) ethyl3. acetateMultiarm than starsin acetoni- of PMMA generally occur2 PE if Cu(II)BrR-halopropionates2/PMDETA acetonitrile are used 6.1 to10 62 successfully in ATRP.c × 7 trile. Deactivation is slower with CuCl2 instead of 3 PE Cu(II)Br 2/Me6TREN acetonitrile 1.4 10 are produced when multifunctional dichloroacetates K. Matyjaszewskiinitiate the, J. polymerization Xia, Chem. Rev of. 2001 methacrylates., 101, 2921-2990. In con- × 8 4 PE Cu(II)Br 2/2dNbpy ethyl acetate 2.4 10 CuBr2. The reactivity of the CuBr 2/dNbpy complex161,162 × 6 are used in the ruthenium-catalyzed ATRP. 3. R-Haloesterstrast, R-bromopropionates5 PE Cu(II)Cl2/2dNbpy are good acetonitrile initiators for 4.3 the10 is higher than with either Me6TREN or PMDETA. × Mixed benzyl and ester derivatives such as methyl ATRP of acrylates due to their structural resem- Among the studied ligands, Me6TREN appears to be Variousblance.R-haloesters have been successfully em- R-bromophenylacetatemost attractive since it promotes were successfully very fast activation used in the ployedIn to their initiate searchThe well-controlled structures for better of initiators the ATRP. corresponding In in ruthenium-general, reagents are aqueousbut also polymerization sufficiently fast deactivation. of 2-(dimethylamino)ethyl shown in Scheme 23. The activation rate constants 163 R-haloisobutyrates produce initiating radicals faster methacrylate.More systematic studies were performed with a mediated ATRP,were measured Sawamoto using etHPLC al. or examined GC under the three kinetic than the corresponding R-halopropionates due to 120 Polyhalogenatedseries of N-basedR-haloesters tridentate complexes (e.g., CCl shown3CO2 inCH3 R-bromoestersisolation of different conditions structures achieved by (Scheme trapping the 9). gener- and4. CHClRFigure-Haloketones2CO 7 together2CH3) with have their also reduction been successfully potentials.172,251 ap- betterThe stabilization malonateated radicalwith ofwith the two generated 2,2,6,6-tetramethylpiperidinyl-1-oxy geminal radicals esters after generates the halogen abstraction step. Thus, slow initiation will plied asThe initiators rate constants for the of activation ATRP of and MMA deactivation catalyzed radicals faster(TEMPO) than 2-bromoisobutyrateas shown in Scheme 24 and (broken leads arrows to An R-bromoketone has120 been used to initiate the generallylower polydispersities.occurindicate if R-halopropionates reactions The suppressed dimeric are model in used the presence of to the ofby RuClcontrolledfor2(PPh 1-phenylethyl3) polymerization3/Al(OiPr) bromide3. Multiarm and of the MMA corresponding stars catalyzed of PMMA by excess TEMPO). are producedradical correlate when multifunctional well with the113 reduction dichloroacetates potentials 154 initiatedormant the polymerization chain end (dimethyl of methacrylates. 2-bromo-2,4,4-trimeth- In con- Ni{o,o′-(CH 2NMe2)2C6H 3}Br and Ni(PPh3)4. trast, R-bromopropionates are good initiators for the are usedof the in Cu(II) the ruthenium-catalyzed complexes. The catalytic activity ATRP. of161,162 the ylglutarate) initiates a faster polymerization and Polyhalogenatedcomplexes decreasesR-haloketones in the order (e.g., alkylamine CCl3COCH3 Mixed benzyl and ester derivatives such as methyl≈ ATRPprovides of acrylates PMMAScheme due with 24. to Model lower their Reactions polydispersitiesstructural for the resem- Activation than andpyridine CHCl>2COPh)alkyl imine are. amongaryl imine the> bestarylamine. initiators blance. Rate Constant Measurements R-bromophenylacetateThe correlation between were the successfully activation and used deactiva- in the aqueous polymerization of 2-(dimethylamino)ethyl In their searchfor for the better ATRP initiators of MMA in ruthenium- catalyzed by rutheniumtion rate constantsWhen was approximately sulfonyl chlorides reciprocal, were as used in the polym- methacrylate.163 mediated ATRP,complexes. Sawamoto83,120,159,164,165 et al. examinedWell-controlled three polymersshown with in Figureerization 8.Thus,results of MMA with the catalyzed Me6TREN by RuCl (PPh ) /Al- 120 are quite unique, probably due to very small entropic 2 3 3 R-bromoesterslow of different polydispersities structures (M (Scheme/M < 9).1.20) have been ob- (OiPr) ,S-shapedconversionvstimeprofileswere The malonate with two geminal estersw generatesn 4. R-Haloketonesconstraints in the passage3 from the X-Cu(II) to the tained. The stronger electron-withdrawing powerCu(I) of state. obtained.168 Moreover, experimental molecular weights radicals faster than 2-bromoisobutyrate and leads to An R-bromoketone has been used to initiate the the ketone’s carbonyl induces further polarizationKnowing of thewere values higher of the than rate constants the theoretical of all values, indicating lower polydispersities. The dimeric model of the controlledthe elementary polymerization reactions of involved MMA in catalyzed ATRP will by the carbon-chlorine bond, which is attributed to the a low initiator113 efficiency. The polydispersities154 were dormant chain end (dimethyl 2-bromo-2,4,4-trimeth- Ni{o,o′-(CH 2NMe2)2C6H 3}Br and Ni(PPh3)4. faster initiation observed with the ketones thanenhance with thearound mechanistic 1.2 understanding-1.5. The low of ATRP, initiator efficiency was ylglutarate) initiates a faster polymerization and Polyhalogenatedfacilitate optimizationR-haloketones of the reaction (e.g., conditions CCl COCH for the ester counterparts. explained by the formation3 of sulfonyl3 esters from provides PMMA with lower polydispersities than and CHClvarious2COPh) monomers, are and among help in selecting the best the initiators proper 5. RThe-Halonitriles deactivation rate constants were determined initiator and catalystsulfonyl structures. chlorides Without and this Al(O knowl-iPr)3 during the early by trapping 1-phenylethyl radicals using TEMPO in edge, efficientstages catalysts of the such polymerization. as Me6TREN-based Examples of sulfonyl acompetitiveclockreaction(Scheme25).The1-phe-R-Halonitriles are fast radical generators in ATRP,complexes maychlorides lead to poorly used controlled as ATRP ATRP initiators pro- are shown in nylethyl radical was generated by the thermal de- cesses.28 due to the presence of the strong electron-withdraw- Scheme 11. ing cyano group. Moreover, the radical formed after halogen abstraction is sufficiently reactive, which 7. General Comments on the Initiator Structure in ATRP leads to fast initiation through rapid radical addition Two parameters are important for a successful to monomer. Of the initiators studied for the polym- ATRP initiating system. First, initiation should be erization of acrylonitrile catalyzed by copper com- fast in comparison with propagation. Second, the plexes, 2-bromopropionitrile resulted in polymers probability of side reactions should be minimized. with the lowest polydispersities.131 2-Bromopropioni- Analogous to the “living” carbocationic systems, the trile is also the initiator of choice when a bromine main factors that determine the overall rate con- initiator is desired in the iron-mediated ATRP of stants are the equilibrium constants rather than the MMA.98 However, R-halonitriles were not used in absolute rate constants of addition.169,170 ruthenium-catalyzed ATRP as the cyano group de- There are several general considerations for the activates the catalyst by forming a strong complex initiator choice. (1) The stabilizing group order in the with ruthenium.120 initiator is roughly CN > C(O)R > C(O)OR > Ph > Cl > Me. Multiple functional groups may increase 6. Sulfonyl Halides the activity ofthe alkyl halide, e.g., carbon tetrachlo- As ATRP initiators, sulfonyl chlorides yield a much ride, benzhydryl derivatives, and malonates. Tertiary faster rate of initiation than monomer propagation.55 alkyl halides are better initiators than secondary The apparent rate constants of initiation are about ones, which are better than primary alkyl halides. four (for styrene and methacrylates) and three (for These have been partially confirmed by recent mea- acrylates) orders of magnitude higher than those for surements of activation rate constants.171-173 Sulfonyl propagation. As a result, well-controlled polymeriza- chlorides also provide faster initiation than propaga- tions of a large number of monomers have been tion. (2) The general order of bond strength in the obtained in copper-catalyzed ATRP.19,55 End-func- alkyl halides is R-Cl > R-Br > R-I. Thus, alkyl tional polymers have been prepared using sulfonyl chlorides should be the least efficient initiators and chlorides where functionalities were introduced onto alkyl iodides the most efficient. However, the use of the aromatic ring.166 The phenyl group substituent alkyl iodides requires special precautions. They are has only a small effect on the rate constant of light sensitive, can form metal iodide complexes with initiation because the sulfonyl radical and its phenyl an unusual reactivity (e.g., CuI2 is thermodynami- group are not related through conjugation. cally unstable and cannot be isolated), the R-I bond A unique feature of the sulfonyl halides as initia- may possibly be cleaved heterolytically, and there are tors is that although they are easily generated, they potential complications of the ATRP process by only dimerize slowly to form disulfones and slowly degenerative transfer.174,175 By far, bromine and disproportionate. Thus, they can react with the chlorine are the most frequently used halogens. In monomers and initiate the polymerization effi- general, the same halogen is used in the initiator and ciently.167 the metal salt (e.g., RBr/CuBr);however, the halogen AtomTransferRadicalPolymerization ChemicalReviews,2001,Vol.101,No.9 2929

Scheme 4. Various Styrenes Polymerized by ATRP

AtomTransferRadicalPolymerization ChemicalReviews,2001,Vol.101,No.9 2929 In addition to 1-phenylethyl halide and benzylic halides. Typically polymerizations were conducted in Scheme 4. Various Styrenes Polymerized by ATRP halides, a variety of compounds, such as allylic bulk with an alkyl 2-bromopropionate initiator. Well- 99 halides and functional R-haloesters, polyhaloge- defined polyacrylates with M n up to 100 000 and M w/ 18,100 55 nated alkanes, and arenesulfonyl chlorides, M n < 1.1 were prepared. Depending on the catalyst, have been used successfully as the initiators for the a wide range of polymerization temperatures are copper-mediated styrene ATRP. One of the most possible to produce polymers within a reasonable extensively studied systems is the polymerization of time (e.g., M n ) 20 000 in ca. 2 h). For example, using styrene conducted at 110 °C with CuBr(dNbpy)2 as 0.05 mol % of CuBr/Me6TREN (Me6TREN ) tris[2- the catalyst and alkyl bromides as the initiators. A (dimethylamino)ethyl]amine) as the catalyst, poly- In addition to 1-phenylethyl halide and benzylic similarhalides. system Typically for the polymerizations chloride-mediated were polymeri- conducted in (MA) with M n ) 12 600 and M w/M n ) 1.10 was 106 halides, a variety of compounds, such as allylic zationbulk is conducted with an alkyl at 130 2-bromopropionate °C to obtain similar initiator. poly- Well- obtained in1hatambient temperature. 99 merization rates.35 The reaction temperature can be halides and functional R-haloesters, polyhaloge- defined polyacrylates with M n up to 100 000 and M w/ A wide range of acrylates with various side chains 18,100 55 lowered to 80-90 °C to produce well-defined poly- have been polymerized using ATRP (Scheme 5). For nated alkanes, and arenesulfonyl chlorides, AtomTransferRadicalPolymerizationM n < 1.1 were prepared.Monomers Depending on the catalyst, for ATRP ChemicalReviews,2001,Vol.101,No.9 2929 have been used successfully as the initiators for the styrenesa wide in a range reasonable of polymerization time with the temperaturesuse ofa more are copper-mediated styrene ATRP. One of the most efficientSchemepossible catalyst, 4. Various to produce such Styrenes as CuBr/PMDETA polymers Polymerized within (PMDETA by a reasonable ATRP Scheme 5. Representative Acrylates Polymerized ) N,N,N ,N ,N -pentamethyldiethylenetriamine)101 by ATRP extensively studied systems is the polymerization of time′ (e.g.,′′ M′′ n ) 20 000 in ca. 2 h). For example, using or CuOAc/CuBr/dNbpy.60 However, to maintain a styrene conducted at 110 °C with CuBr(dNbpy)2 as 0.05 mol % of CuBr/Me6TREN (Me6TREN ) tris[2- the catalyst and alkyl bromides as the initiators.• AStyrenicssufficiently(dimethylamino)ethyl]amine) large propagation rate, avoid as the vitrification catalyst, poly- at high conversion (for polystyrene T 100 °C), and similar system for the chloride-mediated polymeri- (MA) with M n ) 12 600 and gM≈w/M n ) 1.10 was zation is conducted at 130 °C to obtain similar poly- sometimesobtained increase in1hat theambient solubility temperature. of the catalysts,106 merization rates.35 The reaction temperature can be higherA reaction wide range temperatures of acrylates (>100 with °C) various are preferred side chains lowered to 80-90 °C to produce well-defined poly- for styrenehave been ATRP. polymerized The reaction using may ATRP be carried(Scheme out 5). For styrenes in a reasonable time with the use ofa more inIn bulk addition or using to 1-phenylethyla solvent, but halide the stability and benzylic of the halides. Typically polymerizations were conducted in efficient catalyst, such as CuBr/PMDETA (PMDETA• Acrylateshalidehalides,Scheme end a variety group 5. Representative displays of compounds, a pronounced Acrylates such Polymerized as solvent allylic bulk with an alkyl 2-bromopropionate initiator. Well- 101 dependence as demonstrated by model99 studies using ) N,N,N′,N′′,N′′-pentamethyldiethylenetriamine) halidesby ATRP and functional R-haloesters, polyhaloge- defined polyacrylates with M n up to 100 000 and M w/ or CuOAc/CuBr/dNbpy.60 However, to maintain a 1-phenylethyl bromide.18,100 As a result, nonpolar solvents55 nated alkanes, and arenesulfonyl36 chlorides, M n < 1.1 were prepared. Depending on the catalyst, sufficiently large propagation rate, avoid vitrification arehave recommended been used successfully for styrene as ATRP. the initiators for the a wide range of polymerization temperatures are Polystyrenes with molecular weights (M )ranging at high conversion (for polystyrene T g 100 °C), and copper-mediated styrene ATRP. One ofn the most possible to produce polymers within a reasonable ≈ from 1000 to 100 000 with low polydispersities have sometimes increase the solubility of the catalysts, extensively studied systems is the polymerization of time (e.g., M n ) 20 000 in ca. 2 h). For example, using higher reaction temperatures (>100 °C) are preferred been prepared. Better molecular weight control is styrene conducted2930 Chemical at 110 Reviews, °C with 2001, CuBr(dNbpy) Vol. 101, No. 92 as 0.05 mol % of CuBr/Me6TREN (Me6TREN ) tris[2- Matyjaszewski and Xia for styrene ATRP. The reaction may be carried out obtainedthe catalyst at lower and alkyl temperatures, bromides presumablyas the initiators. due to A (dimethylamino)ethyl]amine) as the catalyst, poly- alowercontributionofthethermalself-initiation.42,58 in bulk or using a solvent, but the stability of the similar systemScheme for the 6. Various chloride-mediated Methacrylates polymeri- Polymerized(MA) by ATRP with M n ) 12 600 and M w/M n ) 1.10 was halide end group displays a pronounced solvent Additionally,zation is conducted a wide range at 130 ofstyrene °C to obtain derivatives similar poly-with obtained in1hatambient temperature.106 different substituents on the aromatic ring have been example, well-defined functional polymers were ob- dependence as demonstrated by model studies using merization rates.35 The reaction temperature can be A wide range of acrylates with various side chains polymerized in a well-controlled fashion.34 Well-de- tained by the ATRP of 2-hydroxyethyl acrylate 1-phenylethyl bromide. As a result, nonpolar solvents lowered to 80-90 °C to produce well-defined poly- have been80,107 polymerized using ATRP108 (Scheme 5). For 36 (HEA) and glycidyl acrylate. Poly(tert-butyl are recommended for styrene ATRP. finedstyrenesp-acetoxystyrene in a reasonable was time prepared, with the and use subsequent ofa more • Methacrylateshydrolysis afforded water-soluble poly(vinylphe- acrylate) was also prepared in a well-controlled Polystyrenes with molecular weights (M n)ranging efficient catalyst, such as CuBr/PMDETA (PMDETA Scheme 5. Representative Acrylates Polymerized nol).102 In general, styrenes with electron-withdraw- fashion.109 Subsequent hydrolysis yields well-defined from 1000 to 100 000 with low polydispersities have ) N,N,N′,N′′,N′′-pentamethyldiethylenetriamine)101 by ATRP poly(acrylic acid). In addition, well-defined homopoly- been prepared. Better molecular weight control is ingor CuOAc/CuBr/dNbpy. substituents polymerize60 However, faster. The to maintain Hammett a correlation for ATRP of styrene provided F)1.5 com- mer and block copolymers with long alkyl chain 142 obtained at lower temperatures, presumably due to sufficiently large propagation rate, avoid vitrification 82,110 alowercontributionofthethermalself-initiation.42,58 pared to F)0.5 for the radical propagation constants. and fluorocarbon side chains have been prepared. at high conversionMMA, typical (for polystyrene radical concentrationsT g 100 °C), for and the bulk and mopropionitrile as the initiator at temperatures from Additionally, a wide range ofstyrene derivatives with This indicates that the atom transfer equilibrium≈ was When allyl acrylate was subjected to ATRP condi- sometimessolution increase controlled the solubility ATRP of of the MMA catalysts, are estimated to 44 to 64 °C. The CuBr(bpy) catalyst was soluble in different substituents on the aromatic ring have• been Othermoreexample, shifted monomers, toward well-defined the active functional such species nitriles, polymers side for weresty- can ob- tionsbe polymerized. with bpy or dNbpy as the ligand, a cross-linking2 higher reactionbe between temperatures 10-7 and (>100 l0- °C)9 M. are preferred the strongly polar polymerization58 medium, and the polymerized in a well-controlled fashion.34 Well-de- renictained monomers by bearing the ATRP electron-withdrawing of 2-hydroxyethyl groups. acrylate reaction occurred, even at 0 °C. for styrene ATRP. The reaction may be carried out system was homogeneous. Well-defined polyacryloni- fined p-acetoxystyrene was prepared, and subsequent• NucleophilicThis(HEA) behavior80,107Most wasand polymerizations explainedfunctionalities glycidyl acrylate. by the of higher MMA108 Poly( (e.g., were ATRPtert carried-butyl amines, out in acids) can cause problems. in bulk or using a solvent, but the stability of the 3. Methacrylatestrile with M /M < 1.05 has been prepared within hydrolysis afforded water-soluble poly(vinylphe-reactivityhalideacrylate) end ofsecondarysolution group was displaysalso at benzylichalides temperatures prepared a pronounced in ranging with a well-controlled electron- solvent from 70 to 90 °C. w n 102 109 103 ATRP ofthe methyl molecular methacrylate weight range (MMA) from has 1000 been to 10 000. In nol). In general, styrenes with electron-withdraw- withdrawingfashion.Solvents groups.Subsequent areScheme necessary hydrolysis 4 shows to solubilize yields some well-definedstyrene the forming poly- 15,104 111,112 113-115 63 dependence as demonstrated by model studies using reported for ruthenium,all polymerizationscopper, there wasnickel, significant curvature ing substituents polymerize faster. The HammettK. Matyjaszewskiderivativespoly(acrylic, J. Xia successfully(MMA), Chem acid). (PMMA),. Rev In polymerized. addition, 2001 which, 101 well-defined, 2921-2990. has by ATRP. a glass homopoly- transition tem-98,116,117 118 119 1-phenylethyl bromide. As a result, nonpolar solvents iron, inpalladium, the first-orderand kinetic rhodium plot ofcatalytic the monomer con- mer andperature block copolymersT g > 100 °C. with In36 long addition, alkyl solution chain 142 polym- correlation for ATRP of styrene provided F)1.5 com- 2.are Acrylates recommended for styrene ATRP. systems. The facile polymerizability1 of MMA and the and fluorocarbonerization helps side chains to keep have the been concentration prepared.82,110 of growing sumption. HNMRspectroscopyandMALDI-TOF pared to F)0.5 for the radical propagation constants. ThePolystyrenes controlled with ATRP molecular of acrylates weights has been (M n)ranging reported large range of available catalysts for the ATRP radicals low. Under comparable conditions, the cop- analysis showed that some halide end groups were This indicates that the atom transfer equilibrium was forfrom copper-,When 1000 to16,18,53 allyl 100 acrylateruthenium-, 000 with was low104 subjected polydispersitiesand iron-based to ATRP have sys- condi- reaction is due to the relative ease of activation of per-mediated ATRP of MMA displays a significantly irreversibly removed during the polymerization. It more shifted toward the active species side for sty- tems.beentions105 prepared.Copper with bpy Better appears or dNbpy molecular to asbe the superior weightligand, over a control cross-linking other is the dormant species and the high values ofthe ATRP renic monomers bearing electron-withdrawing groups. reactionhigher occurred, equilibrium even at 0 constant °C.58 when compared with was proposed that the reduction of the propagating transitionobtained at metals lower temperatures, in producing presumablywell-defined due poly- to equilibrium constants.radical by The the equilibriumcuprous halide constants to form can an anion was This behavior was explained by the higher ATRP styrene and MA. As a result, higher42,58 dilution and a acrylatesalowercontributionofthethermalself-initiation.3. Methacrylates with low polydispersities in a relatively sometimes bethe too major high chain to obtain termination a controlled reaction. ATRP66 Acrylonitrile reactivity ofsecondary benzylichalides with electron- Additionally,lower a wide catalyst range ofstyrene concentration derivatives should with be used for the 28 103 short time.ATRP This of is methyl partially methacrylate due to the fast (MMA) deactiva- has been process, as ishas the also case been for copolymerized the Me6TREN with ligands. styrene in a well- withdrawing groups. Scheme 4 shows some styrene different substituentsMMA polymerization. on the aromatic ring have been example, well-defined functional polymers were ob- tionreported of the growing for ruthenium, acrylic15,104 radicalscopper, by111,112 thenickel, cupric113-115 Using the knowncontrolled rate fashion constant to yield of propagation gradient copolymers for with derivatives successfully polymerized by ATRP. polymerized inInitiation a well-controlled plays an important fashion.34 Well-de- role in the ATRPtained of by the ATRP of 2-hydroxyethyl acrylate iron,98,116,117 palladium,118 and rhodium 119 catalytic molecular weights ranging from 1000 to 15 000.133 fined p-acetoxystyreneMMA. The bestwas prepared, initiators includeand subsequent sulfonyl chlorides(HEA)11180,107 and glycidyl acrylate.108 Poly(tert-butyl 2. Acrylates systems. The facile polymerizability of MMA and the hydrolysisand afforded 2-halopropionitrile water-soluble98 poly(vinylphe-because these initiatorsacrylate) was5. (Meth)acrylamides also prepared in a well-controlled The controlled ATRP of acrylates has been reported large range of available catalysts for the ATRP nol).102 In general,have sufficiently styrenes with large electron-withdraw- apparent rate constantsfashion. of 109 Subsequent hydrolysis yields well-defined for copper-,16,18,53 ruthenium-,104 and iron-based sys- reaction is due to the relative ease of activation of Polymers of acrylamide and its derivatives have ing substituentsinitiation polymerize (high atom faster. transfer The equilibrium Hammett constants).poly(acrylic acid). In addition, well-defined homopoly- tems.105 Copper appears to be superior over other the dormant species and the high values ofthe ATRP found wide use in industry, agriculture, and medicine correlation forWell-defined ATRP of styrene PMMA provided can beF) prepared1.5 com- withinmer the and block copolymers with long alkyl chain 142 transition metals in producing well-defined poly- equilibrium constants. The equilibrium constants can owing to their remarkable properties such as water pared to F)molecular0.5 for the weightradical propagation range from constants. 1000 to 180 000.and fluorocarbon A side chains have been prepared.82,110 acrylates with low polydispersities in a relatively sometimes be too high to obtain a controlled ATRP solubility and potential biocompatibility. There are This indicatesseries that of the initiators, atom transfer including equilibrium chloromethanes, was 28 RWhen-chlo- allyl acrylate was subjected to ATRP condi- short time. This is partially due to the fast deactiva- process, as is the case for the Me6TREN ligands. a few reports on the attempted ATRP of acrylamide. more shiftedroesters, towardR the-chloroketones, active species and sideR-bromoesters, for sty- tions were with bpyUsing or dNbpy CuCl- asbpy the as ligand, the catalyst a cross-linking and surface-bound tion of the growing acrylic radicals by the cupric Using the known rate constant of propagation for 120 58 renic monomersstudied bearing in ruthenium-mediated electron-withdrawing groups.ATRP of MMA.reaction occurred,benzyl evenchloride at 0 as °C. the initiator, Wirth et al. made This behaviorCCl was3COCH explained3,CHCl by2COPh, the higher and dimethyl ATRP 2-bromo-3. Methacrylatespoly(acrylamide) films from a silica surface.134 The reactivity ofsecondary2,4,4-trimethylglutarates benzylichalides were with among electron- the best initia- resulting materials provided good analytical separa- 103 ATRP of methyl methacrylate (MMA) has been withdrawingtors, groups. yieldingScheme PMMA 4 shows with some controlled styrene molecular tions; however,15,104 detailed111,112 proof for113- the115 controlled derivativesweights successfully and low polymerized polydispersities by ATRP. (M /M ) 1.1reported-1.2). for ruthenium, copper, nickel, w n iron,98,116,117characterpalladium, of118 theand polymerization rhodium 119 wascatalytic not provided. Li Similar studies were performed for Cu-based sys- and Brittain also attempted the controlled polymer- 2. Acrylates 121,122 systems. The facile polymerizability of MMA and the tems. It should be noted that some of these ization of acrylamide by ATRP but did not obtain any The controlledinitiators ATRP are of too acrylates active has for the been copper-based reported systemslarge range of available catalysts for the ATRP for copper-,16,18,53 ruthenium-,104 and iron-based sys- reaction ispolymers due to the using relative CuBr(bpy) ease of3 as activation the catalyst of and 1-(bro- 105 and lead to excessive termination or other side moethyl)benzene as the initiator at various temper- tems. Copper appears123 to be superior over other the dormant species and the high values ofthe ATRP reactions. 135 transition metals in producing well-defined poly- equilibriumatures. constants.It The was equilibrium shown using constants model compounds can and acrylates withOther low methacrylicpolydispersities esters in have a relatively also been success-sometimes bekinetic too high studies to obtain that the a polymerization controlled ATRP ofacrylamide short time.fully This is polymerized. partially due These to the include fast deactiva-n-butyl methacry-process, asunder is the casetypical for ATRP the Me conditionsTREN ligands. displayed28 a much 55,77,88,124 6 tion of thelate, growing acrylic2-(dimethylamino)ethyl radicals by the cupric methacrylateUsing the knownlower ATRP rate constant equilibrium ofpropagation constant than for the acrylates (DMAEMA),125 2-hydroxyethyl methacrylate (HE- or styrene.136 The inactivation of the catalyst by MA)104,126 and silyl-protected HEMA,127 methacrylic complexation of copper by the forming polymer and acid in its alkyl protected form 128 or as its sodium displacement of the terminal halogen atom by the salt,129 methacrylates with an oligo(ethylene oxide) amide group are two potential side reactions. Inter- substituent,39 and fluorinated methacrylic es- estingly, using 1,4,8,11-tetramethyl-1,4,8,11-tetraaza- 82,110,130 ters. Scheme 6 illustrates examples of meth- cyclotetradecane (Me4Cyclam) as a ligand provided acrylates polymerized by ATRP. polymers in high yields in a short time. Unfortu- nately, the polymerization was not controlled and 4. Acrylonitrile displayed slow deactivation characteristics. Loss of Metal mediated controlled radical polymerization the chain-end halogen was considered previously137 of acrylonitrile has so far only been reported for and recently confirmed by end-group analysis through copper-mediated ATRP.66,131,132 It is necessary to use the use of mass spectrometry.138 The conclusion is a solvent because polyacrylonitrile is not soluble in that the presence of the metal as a Lewis acid in its monomer. DMF is a good solvent for polyacryloni- ATRP and its complexation to the amide functionality trile; however, it may also complex with copper and slows deactivation and makes the process an uncon- deactivate the catalyst. Successful polymerizations trolled polymerization. Nevertheless, by using the have been carried out in ethylene carbonate in the Me4Cyclam-based catalytic system and well-defined presence of the CuBr(bpy)2 complex using R-bro- macroinitiators prepared by ATRP, block copolymers NATURE CHEMISTRY DOI: 10.1038/NCHEM.257 REVIEW ARTICLE

8 II polymerization , and degenerative transfer polymerization such as the higher-oxidation-state deactivating complex (XCu Lm); the reversible addition-fragmentation chain transfer (RAFT) polymeri- resulting accumulation of deactivator follows a peculiar kinetic zation9. Tis review focuses on the application of ATRP in the syn- power low — according to the ‘persistent radical efect’11. Tus if thesis of well-defned polymers. the initial concentration of CuI was only 5 mol% relative to polymer chains, the polymerization would stop when 5% of the chains Fundamentals of atom transfer radical polymerization have participated in termination reactions. Tis is because all of I II In ATRP, alkyl halide initiators or dormant species (RX or PnX) the Cu will have been converted to the Cu deactivator, even at z react with activators — low-oxidation-state metal complexes Mt Lm, relatively low monomer conversion. (Mtz represents the metal species in oxidation state z, L is a ligand; To overcome this problem, the fact that the rate of ATRP does the charges of ionic species are omitted for simplicity) to reversibly not depend on the absolute catalyst concentration, but on the ratio form both propagating radicals (R./Pn.), and deactivators — higher- of activator and deactivator concentrations, was exploited (Fig. 1b). oxidation-state metal complexes with coordinated halide ligands Eforts were made to develop ATRP techniques that operated at z+1 XMt Lm. Te dormant species in this ATRP equilibrium can be extremely low catalyst concentrations — ofen single-digit ppm — polymer chains able to grow in one or many directions, or polymers but steps were taken to keep the activator/deactivator ratio constant. attached to functional colloidal particles, surfaces, biomolecules Novel initiation systems were developed12 in which a very small and so on (Fig. 1). amount of active catalyst was used, and the deactivator formed ATRP is a catalytic process and can be mediated by numer- due to radical termination was constantly converted to activator ous redox-active transition metal complexes (Cu has been the through a redox process (see Fig. 1a). Simple reducing agents such most ofen used transition metal but other studied metals include as ascorbic acid, sugars, tin(ii) octanoate, or amines are used in Ru, Fe, Mo, Os). One limitation of ‘classical’ ATRP was the rela- ARGET (activators regenerated by electron transfer) ATRP13,14, or tively large amount of catalyst used — typically of the order of radical initiators in ICAR (initiators for continuous activator regen- 0.1–1 mol%, relative to the monomer — thus the fnal products eration) ATRP12. ATRP can now be successfully conducted with ofen contained a signifcant amount of residual metal. Various very low amounts of catalyst. Tis approach has now been extended strategies were introduced to either remove the catalyst from the to organic synthesis and radical addition and cyclization reactions fnal product7,10 or to carry out the reactions at lower catalyst con- based on ARGET and ICAR procedures15. Similarly, the advances in centration. However, the amount of catalyst cannot be decreased ring-opening metathesis polymerization (ROMP) have been widely to desired low concentrations because of inevitable termination applied in the synthesis of numerous bioactive molecules16. reactions. In ATRP, as in any radical process, bimolecular control- Te new ATRP initiation techniques allow synthesis of well- led radical termination typically involves 1% to 10% of chains. defned high-MW polymers (markedly higher than in traditional Each termination step leads to irreversible transformationCatalysts of two ATRP) for because ATRP catalyst-related side reactions that limited the poly- I equivalents of the activator (Cu Lm in copper-mediated ATRP) into mer MW are minimized at lower catalyst concentrations. For many a c Mt = Cu, Fe, Ru, Rh, Ni, Pd, Co, Os, Re, Mo, Ti • Ru, Ni, Fe & Cu For Cu, L = Common ligands used with Cu M kp k – Cu mostact used z z+1 Pn–X + Mt Lm Pn + X–Mt Lm kdeact kt

z+1 Pn–Pk + X–Mt Lm ATRP catalysts based on other metals I-X I Red. or Ox. ∆ Radical initiator ICAR ATRP ARGET ATRP b z z kact [M][RX][Mt Lm] [M][RX][Mt Lm] Rp = kp = KATRP kp kdeact z+1 z+1 [XMt Lm] [XMt Lm] M w kp[RX]0 2 = 1 + – 1 z+1 Mn kdeact[XMt Lm] conv

Figure 1 | Illustration of ATRP. a, The reaction scheme for ATRP including the activator regeneration methods ICAR (initiators for continuous activator 64 regeneration) — where the activator is regenerated using a radical initiator and ARGET (activators regenerated by electron transfer) — where reducing K. Matyjaszewski, J. Xia, Chem. Rev. 2001, 101, 2921-2990. z K. Matyjaszewski, N.V. Tsarevsky, Nat. Chem. 2009, 1, 276-288. agents are used. Pn represents the polymer (with degree of polymerization n), Mt is the metal species in oxidation state z, L is a ligand and X is a halogen atom. Changes in oxidation state are represented by changes in colour. The kinetic parameters kact, kdeact, kp and kt represent the rate constants of activation, deactivation, propagation and termination respectively. b, The equations show the dependence of polymerization rate (Rp) and polydispersity index

(Mw/Mn) on kinetic parameters and reagent concentrations. Rp depends on kp, and the ratio of the kact and kdeact, that is, the ATRP equilibrium constant

(KATRP = kact / kdeact), as well as on the concentrations of all reagents involved. Polydispersity is lower for polymerizations with faster deactivation (that is, for catalysts with a higher value of kdeact and/or at higher deactivator concentrations). The polydispersity decreases with the monomer conversion (designated as conv) and is lower for higher MW (lower initiator concentration, [RX]0). c, Examples of metals used in ATRP and the general structures of ligands for Cu- mediated ATRP where R represents the various organic substituents that can be used.

NATURE CHEMISTRY | VOL 1 | JULY 2009 | www.nature.com/naturechemistry 277 NATURE CHEMISTRY DOI: 10.1038/NCHEM.257 REVIEW ARTICLE

a Functional alkyl halide initiators

b Functional monomers Functional Polymers by ATRP

End-group functionalization easy to perform with various alkyl halide reactions

c End-groupClick modiﬁcations chemistries Epoxy

Amine Hydroxy Vinyl Phosphines Figure 4 | Examples of functional polymers prepared by ATRP. a, Examples ofMacromers functional alkyl halide initiators. b, Examples of functional monomers successfully used in ATRP (including ones with nucleobase or peptide groups, as shown by the boxed structures). c, Examples of the numerous transformations that the alkyl halide end-groups (green X) in polymers prepared by ATRP can participate in.

65 initiatorsK. with Matyjaszewski either azide, N.V. Tsarevskyor alkyne, Nat. group Chem to. 2009 biomolecules, 1, 276-288. or to successfully used (Fig. 4). Water-soluble monomers (both neutral inorganic particles. Te discussed functionalities can be used as and ionic) can be polymerized in a controlled fashion by ATRP reactive sites to tether polymers or initiators to the selected mate- directly in protic (aqueous) media, provided that some basic rules rial, as shown later in Fig. 6. for catalyst selection are obeyed7. In some cases polar monomers — especially those that are Functional groups in polymers prepared by ATRP strongly coordinating (basic, nucleophilic or acidic) — can react Functional groups can be incorporated into ATRP polymers in with either the ATRP catalyst, the alkyl halide-type initiator or the three diferent ways: (1) direct polymerization of functional mono- polymeric dormant species. In these cases, monomers with ‘pro- mers provides functional groups along the backbone (density and tected’ groups should be used. Tey can be transformed into the distribution can be regulated by monomer feeding, for example, in desired polar functionalities afer the polymerization. Examples of gradient copolymers); (2) monofunctional ATRP initiators intro- protective groups include t-butyl, benzyl (deprotection by hydrogen- duce functionality at the chain end; difunctional initiators generate olysis), tetrahydropyranyl, 4-nitrophenyl, and 1-ethoxyethyl (ther- functionality at the chain centre; it is also possible to place function- mal deprotection)54,55. Carboxylic acid functional groups can also ality in any specifc part of the chain; (3) chemical transformation be incorporated by reacting succinic anhydride with polymers of the alkyl halide chain end, using nucleophilic substitution, radi- containing hydroxy groups56. Monomers with sulfonic acids were cal or electrophilic addition20. It is also possible to use initiators or polymerized as protected alkyl esters, salts at high pH or neutralized monomers with a ‘protected’ functionality (for example, protected by alkyl amines. Glycidyl groups can be ring-opened by many dif- acids or amines). Te various synthetic approaches are discussed in ferent nucleophiles and thus poly(glycidyl (meth)acrylate) can serve this section and are illustrated in Fig. 4. as a precursor to many functional polymers43. Tetrazoles are both acidic and coordinating compounds, and the Polymerization of functional monomers. Te simplest approach direct ATRP of vinyltetrazoles has not been reported. However, the to a functional polymer is the direct polymerization of a mono- preparation of well-defned tetrazole-containing polymers has been mer containing the desired functionality. ATRP is generally toler- achieved by ATRP of acrylonitrile, followed by a click-type chemical ant to many polar functional groups and this route has ofen been modifcation with sodium azide57. With the development of the very

NATURE CHEMISTRY | VOL 1 | JULY 2009 | www.nature.com/naturechemistry 281 Some Mechanistic Details

Kexch • Halogen exchange RBr + CuCl/L RCl + CBr/L

Cl Br

K. Matyjaszewski et al. Macromolecules 1998, 31, 6836-6840. 66 How to Utilize Halogen Exchange

• Better control of homopolymerizations

K. Matyjaszewski et al. Macromolecules 1998, 31, 6836-6840. 67 Utilizing Halogen Exchange…2 • Better block copolymers

D.A. Shipp, J.-L. Wang, K. Matyjaszewski 68 Macromolecules 1998, 31, 8005-8008. Atom Transfer Radical Polymerization 147

result, there are numerous reported strategies for the removal or reuse of the ATRP catalyst. These include using fluorous biphasic systems,101 performing the polymerization in ionic liquids,102–104 using “precipiton” based ligand systems,105 or using a solid support in the polymerization.106–108 The use of solid supports have included polymeric resins,109–114 silica beads,115–117 ion-exchange resins,118 as well as recoverable polymers.119 Hong and Matyjaszewski107 and Hong et al.112 used a mixed catalyst system comprising of resin- supported catalyst with a small amount of soluble catalyst. The reason for using such a mixed system was that a major factor controlling an ATRP with an immobilized catalyst is the deactivation step. The deactivation step is influenced by both the diffusion of polymer chains in the system, and the mobility of the resin particles. It was argued that an immobilized catalyst attached to a bulky carrier will hinder diffusion of the growing chain end to the catalytic site. This diffusion to the surface thus becomes the rate-determining step. When a small amount of soluble CuBr2/Me6TREN catalyst was added to the immobilized catalyst the level of control attained in the polymerization of MMA was improved. The choice of soluble catalyst (CuBr2/Me6TREN) was made based on its high deactivation rate constant and high reducing power with respect to the immobilized catalyst. The results of the polymerization indicated that the soluble catalyst could deliver a halogen atom from the immobilized catalyst to the propagating polymeric radicals. This process overcame any diffusion barrier and provided an effective deactivation process. An alternative strategy to maximizing the purification and work-up of ATRP polymers to remove the large amounts of catalyst used in the polymerization is to design an ATRP system where the amount of catalyst required to control the polymerization is vanishingly small. One example of this strategy has been coined “initiators for continuous activator regeneration ATRP” or ICAR ATRP.120 It is possible to use very low amounts of catalyst under normal ATRP conditions without affecting the rate of polymerization, which is governed by the ratio of Cu(I) to Cu(II) species, if small amounts of free radical initiators are used to reduce accumulated Cu(II); the “persistent species” in ATRP (Fig. 6).121 While ICAR ATRP clearly shares some similarities with RATRP122–129 it is differen- tiated due to the concentrations of catalyst and free radical initiator employed. Indeed, the small concentrations of catalystReverse and initiator used ATRP in ICAR ATRP lead to some interesting observations in the polymerizations.121 The rate of polymerization in ICAR ATRP is dictated by the rate of free radical initiator decomposition, not the identity of the catalyst Downloaded By: [Ayres, Neil] At: 13:45 23 May 2011 • (i.e.,whichAdd regular ligand is initiator used). However, (e.g. control AIBN), over thewith molecular oxidized weight andmetal molecular weight distribution is very dependent upon the catalyst, or more formally, the value of II K(e.g.ATRP and Cu rateBr of2 deactivation) & ligand of a given catalyst. The limitations of ICAR ATRP are in– the Less synthesis trouble of block handling copolymers, Cu becauseII (c.f. Cu theI free) radical initiator will also generate homopolymer chains. An improved system to reduce the amount of copper catalyst uses – Uses common initiator – Still provides good control, etc.

• FigureRelated 6. Proposed to “ICAR” ICAR process ATRP where a low concentration of a free-radical thermal initiator (e.g. azobisisobutyronitrile) continuously regenerates the ATRP catalyst. Figure adapted from Matyjaszewski– Initiators et al. for121 continuous activator regeneration – Allows for lower Cu concentrations

J.-S. Wang, K. Matyjaszewski Macromolecules, 1995, 28, 7572-7573. 69 K. Matyjaszewski et al. Proc. Natl. Acad. Sci. U.S.A., 2006, 103, 15309-15314. Activator (Re)Generated by Electron Transfer (AGET & ARGET) ATRP

• Problem: use of Cu metal salts contaminates polymer – Usually ends up being green – Adds expense to polymerization • Overcome this by regenerating Cu(I) by using a reducing agent such as amines, glucose, ascorbic acid, etc., as well as Cu(0) wire – Much lower [Cu]

70 K. Matyjaszewski et al. Angew. Chem. Int. Ed. 2010, 49, 541-544. Chem. Rev. 2007, 107, 2270-2299 SARA ATRP vs. SET LRP

• Controversy over ARGET-type approach

• SARA = supplementalView Article Onlineregeneration of activators View Article Online Polymer Chemistry MinireviewMinireview Polymer Chemistry soluble Cu species, simple removal and reuse of unreacted solid Cu0 and control of the polymerization rate by the amount of ligand and the surface area of Cu0.21,38,48–60 Nevertheless, it is important to characterize the reaction mechanism, and determine the effect of different reaction conditions on the resulting Scheme 2 Key differences between the SARA ATRP mechanism and polymer to optimize the reaction conditions for targeted poly- the SET-LRP mechanism. The SET-LRP mechanism assumes that Cu0 mer structures. is the major activator of alkyl halides (green dashed line) and that In the case of RDRP reactions in the presence of Cu0, there disproportionation (blue dashed line) is the dominant fate for CuI I are two models proposed in the literature. One model, called complexes. SARA ATRP (red solid lines) assumes that Cu is the major I the supplemental activator and reducing agent (SARA ATRP), activator of alkyl halides and that Cu species predominantly activate I alkyl halides rather than disproportionate (reprinted with permission has the traditional ATRP reactions of activation by Cu and from ref. 72. Copyright 2014 the American Chemical Society). deactivation by CuII at the core of the process, with Cu0 acting primarily as a supplemental activator of alkyl halides and a II 29,38 reducing agent for the Cu through comproportionation. In This labeling of the reactions as following either the SARA SARA ATRP there is minimal kinetic contribution of dispro- ATRP or SET-LRP mechanisms can be seen in the light of portionation, since CuI primarily activates alkyl halides, and traditional organic chemistry reactions, such as SN1 or SN2 (ref. Scheme 1 (Top) The mechanism of SARA ATRP, (bottom) the mech- activation of all alkyl halides occurs by inner sphere electron 88). Although both the SN1 and SN2 reactions give the same transfer (ISET).38,61–63 The second model for the polymerization anism of SET-LRP. Bold arrows indicate major reactions, whereas solidatomic transformations, the product is predominantly formed71 arrows indicate supplemental or contributing reactions and dashed is called single-electron transfer living radical polymerization by one mechanism. This predominant pathway may be affected 20,64 0 arrowsSARA-ATRP: indicate minor Polym reactions. Chem. that 2014 can, 5 be, 4396-4417. neglected from the SET-LRP: Chem. Rev. 2009, 109, 5069-5119. (SET-LRP). In this model, Cu is the exclusive activator of 0 I II 0 I IIby structure of the reagents and the reaction medium. Similarly, mechanism. Cu , Cu X/L and Cu X2/L represent a Cu , Cu and Cu alkyl halides, which occurs by outer sphere electron transfer species without particular speciation. For clarity, radical products arealthough both SARA ATRP and SET-LRP use the same compo- (OSET), CuII is the major deactivator, CuI does not participate in omitted in activation reactions, alkyl halide products are omitted innents to give the same product, one mechanism should the activation of alkyl halides, instead it undergoes instanta- deactivation reactions, and stoichiometric balance is neglected incorrectly describe the process (if it is a mixed mechanism their neous disproportionation to Cu0 and CuII, and there is minimal comproportionation/disproportionation processes. Finally all radicalscontributions should be determined). In this review article, we can propagate with monomer or terminate. comproportionation.20,21,65,66 The reactions of these models are present evidence, showing that the mechanism of the poly- highlighted in Scheme 1. merization in the presence of Cu0 is consistent with SARA ATRP 0 I II II 68 Scheme 3 Chemical structures of ligands, initiators and monomers. In Scheme 1, the notations Cu , Cu X/L, and Cu X2/L are radicals, and Cu /L species, which have no halide attached,in organic media, and that the polymerization is also consistent used to represent all of the Cu0 species, all Cu species in the and do not deactivate radicals.68 In the systems studied, thewith SARA ATRP in water. Thus, SET-LRP terminology should II oxidation state +1, and all Cu species in the oxidation state +2, Cu X2/L complex, with two bound halides, is expected tonot be used. respectively. In the case of CuI species, the notation CuIX/L dissociate into the CuIIX/L cation and a halide anion, depend- Chemical structures of ligands, monomers and initiators are The complexity of this system means that the thermodynamic includes the CuI/L species, which are the predominant activa- ing on medium polarity. reported in Scheme 3; for simplicity, throughout the paper the position of the reactions that comprises the system is not ffi tors of alkyl halides,67 and CuIX/L complexes, which have a As can be seen in Scheme 1, the SARA ATRP and SET-LRPcharge of complexes is omitted. su cient to characterize the system. Instead, it is important to I consider the rates (not only rate constants) and contributions of halide binding the free site in Cu , and may not activate alkyl mechanisms use the same components and are comprised of 67 II II II ff the underlying reaction in discriminating between mecha- halides. Similarly, for Cu species, Cu X2/L, includes Cu X/L exactly the same reactions, but with vastly di erent contribu-Published on 15 May 2014. Downloaded by Clarkson University 04/03/2015 10:25:55. Describing the complex system II nisms. Recent work indicated that careful measurement of the Published on 15 May 2014. Downloaded by Clarkson University 04/03/2015 10:25:55. species with one halide ion bound to Cu , which deactivates tions to the overall polymerization. The main similarities are in It is broadly agreed that RDRP in the presence of Cu0 is a key kinetic parameters in isolated model reactions gives an the deactivation processes, namely, CuII acting as the major complex system with several potential reactions (cf. Scheme 1). accurate description of the entire process.61–63 This has been deactivator of alkyl radicals, and negligible deactivation by CuI. Krzysztof Matyjaszewski is a The major differences between SARA ATRP and SET-LRP can be J. C. Warner University Professor summarized within the following questions: (1) whether CuI Table 1 Differences and similarities of SARA ATRP and SET-LRP of Natural Sciences and the (ref. 38, 62 and 69) or Cu0 (ref. 70 and 71) is the major activator I director of Center for Macromo- of alkyl halides? (2) Whether the kinetics dictate that Cu Process In SARA ATRP In SET-LRP lecular Engineering at Carnegie primarily activates alkyl halides38,62,63,72 or undergoes dispro- I I Mellon University. His main portionation?20,73 (3) Whether Cu0 is a supplemental activatorActivation by Cu Major activation pathway of alkyl halides Does not occur due to instantaneous loss of Cu 38,62,63,72 by disproportionation research interests include and reducing agent or the major activator of alkylActivation by Cu0 Supplemental activation pathway of alkyl Exclusive activation pathway of alkyl halides – controlled radical polymeriza- halides?70,71 (4) Whether disproportionation20,21,65,66,73 75 or halides, compensating for termination tion, catalysis, environmental comproportionation38,61,72 dominates during polymerization?Activation mechanism Inner sphere electron transfer (ISET) Outer sphere electron transfer (OSET) Deactivation by CuII Major deactivation pathway of alkyl radicals Major deactivation pathway of alkyl radicals chemistry, and synthesis of (5) Whether alkyl halide activation occurs by inner sphere I 76,77 20,78 Deactivation by Cu Negligible Negligible advanced materials for optoelec- electron transfer or outer sphere electron transfer ? (6)Disproportionation of CuI Minimal contribution, since CuI participates Instantaneous, leading to the (re)generation of 63,79 tronic and biomedical applica- Whether there is a limited extent of radical termination, or primarily in alkyl halide activation the Cu0 activator and CuII deactivator tions. He has developed Cu-based there is no termination74,80,81? These differences are summa-Comproportionation Occurs under certain conditions to compensate Does not occur II 0 atom transfer radical polymerization (ATRP) licensed 16 times in rized in Scheme 2 and Table 1. between Cu and Cu for termination Radical termination Minimal extent of termination build up of Proceeds in the absence of termination, giving US, Europe and Japan. Matyjaszewski coauthored over 800 peer- As a result of these vastly different assumptions regarding II Cu Br2 species is directly correlated with loss of ultrafast polymerization and ultrahigh reviewed publications, cited 60 000 times, 46 US and 130 inter- the kinetics of the polymerization, there has been a vigorous end-group functionality molecular weight. (Complete preservation of national patents. Matyjaszewski has received the AkzoNobel North mechanistic debate, with several papers published arguing for chain end functionality at 100% monomer America Science Award in 2013, Wolf Prize in Chemistry in 2011, one or the other mechanism.20,28,29,38,52,61–63,65,66,69,70,75,81–87 Addi- conversion) the Presidential Green Chemistry Challenge Award in 2009 and 7 tionally, there have been various papers claiming to have honorary degrees. prepared polymeric materials by either SET-LRP or SARA ATRP. This journal is © The Royal Society of Chemistry 2014 Polym. Chem.,2014,5,4396–4417 | 4399

4398 | Polym. Chem.,2014,5,4396–4417 This journal is © The Royal Society of Chemistry 2014 Macromolecules Article

transfer (ARGET)10 and related processes,11 which achieved polymerization parameters, simplified reaction setups, and an parts per million (ppm) catalyst loadings, tolerance to O ,12 extension of this process as an efficient purification and catalyst REPORTS 2 and diminished side reactions,13 while maintaining all the recycling tool. Variable electrochemical methods were explored, macromolecules to be prepared with precisely polymerization behavior (12, 15, 17), application be decreased tremendously without affecting the controlled molecular weights (Mn)andnarrow of an electrochemical stimulus (i.e., electrolysis) polymerization rate, provided that an adequate and polymerization parameters were investigated, including the traditional attributes of ATRP/CRP. InI ARGETII type systems, molecular weight distributions (Mw/Mn). Polym- can be conveniently paired with atom transfer [Cu X/L]/[Cu X2/L] ratio is sustained. erizations with living characteristicsthe grant access activatorradical polymerization complex (ATRP), is owing continuously to the in- This report (re)generated demonstrates the dynamic by mod- a applied potential, catalyst type and loading, galvanostatic to complex polymeric architectures and asso- herent redox-active nature of theII ATRP catalytic ulation of polymerization rates through electro- ciated functionalities traditionally accessiblereducing only system agent (18, 19 (e.g.,). Sn , ascorbicchemical acid, means, free fostering radical precise temporal initiator, control conditions, and electrodeposition/stripping experiments. through ionic mechanisms. Relative to ionic po- ATRP, one of the most powerful CRP tech- over initiation, cessation, and rejuvenation of a lymerizations, radical pathways providecathodic improved niques, current, proceeds through or a light) concerted atom from transfer otherwiseCRP process. Electrochemical accumulated methods offer ad- X− tolerance to functional groups and impurities,CuIIL+ an originatingmechanism via an frominner-sphere unavoidable electron-transfer justable radical parameters termination (e.g., current, potential, events. and ■ RESULTS AND DISCUSSION expanded range of polymerizable monomers, process (20, 21). The versatility of this process total charge passed) to manipulate polymerization and an efficient means of copolymerizingIn addition a va- is exemplified to these by the vast advancements,array of suitable polym- rates the and ATRPselective targe processting of redox-active can cata- be Characterization and Control Studies. All experimenta- riety of monomers (3, 4). Controlled/living radical erization media, encompassing homogenous, het- lytic species. Moreover, advantages of ARGET polymerizations (CRP), once thoughtmanipulated unobtain- erogeneous, by and a variety aqueous systems of stimuli (3, 22–25), including,ATRP such as ppm but concentrations not limited of catalyst to, tion presented in this work was conducted in a two- able (5), have now been realized through many and14 attainable15 complex polymeric architectures (27, 30)andtolerancetolimitedO12c,16 2 (28)aremain- remarkable breakthroughs providingpressure, character- (3, 26light,). ATRP is dictatedand by electrical an active/dormant current.tained and bolstered byApplied elimination of stimuli environ- compartment electrochemical cell equipped with a platinum istics inherent to living polymerizations (6–10). equilibrium, shown in part by Fig. 1A, between mentally less friendly chemical reducing agents Control is established in CRP by dynamicprovide equilib- additionallower oxidation state features activators {i.e., and CuIBr/tris[2- controland catalyst to the removal ATRP through electrodeposition process by disk and platinum mesh working electrode, platinum plate I 14b − 24 ria, either through dormant/active chainenabling ends or (dimethylamino)ethyl]amine the synthesis (Cu ofBr/Me high6TREN)} molecular(31). The proposed weight mechanism polymers, of ATRP medi- counter electrode, and Ag|AgI|I reference electrode main- degenerative transfer, essentially minimizing the and alkyl halides (Pn-Br), and their corresponding ated electrochemically (eATRP) by (re)genera- II concentration of propagating centers and con- higher oxidation state deactivators (i.e., Cu Br2/ tion of activators is shown in Fig. 1A. Air-stable local/temporal catalyst activation, andII “on-demand” catalyst tained under an inert N2 atmosphere. Prior to each polymer- comitantly reducing bimolecular termination re- Me6TREN) and radicals (Pn•), which are capable Cu Br2/Me6TREN deactivator is reduced to 15d,16a I actions occurring at diffusion-controlledmanipulation. reaction of monomer (M) addition (3, 4Electrochemical, 6, 10). Establishing Cu Br/Mely6TREN mediated activator electrochemically ATRP to ization, cyclic voltammetry (CV) was used to verify the rates (5). this dynamic equilibrium (KATRP = ka/kda), which invoke or trigger polymerization. In the absence Real-time dynamic modulation( ofeATRP), polymer- strongly the favors newest the dormant state,member effectively de- ofof the mass transport ATRP limitations, family, the extent utilizes of reduc- existence of the redox active catalyst and to identify appropriate ization processes offers intermittent regulation creases the concentration of propagating species tion is dictated by the applied potential (Eapp), I II of system variables that may include,both but are not theand mediates concept/advantages the polymerization, allowing simul- ofallowing ARGET a predefined ATRP[Cu X/L]/[Cu X via2/L] ratio an potentials to manipulate its oxidation state. Figure 1 represents limited to, alterations of stereoselectivity (11), re- taneous growth of each polymeric chain. and fine-tuning of the polymerization rate. Fur- activity (12), and reaction rates (13–electrochemical16). Variable In recent years, stimulus the ATRP process (Scheme has been ex- ther 1) to this to point, provide electrochemical methodsenhanced allow I polymerization rates have been demonstrated panded via activators generated by electron trans- aloweroxidationstatecatalyst(CuBr/Me6TREN) in only a few accounts using allostericlevels supra- offer polymerization (AGET), a catalytic activation control. technique that to be reverted back to its original higher oxida- molecular catalysis (13), redox controlled cata- reduces air-stable deactivators to their respective tion deactivator state by simply shifting Eapp to lysts (14), and temporal photoirradiation (15, 16). activators in situ by means of reducing agents more positive values, thus providing a means to These strategies require complex catalytic systems (e.g.,eATRP ascorbic acid, tin (II) 2-ethylhexanoate, and deactivate an ongoing polymerization. Scheme 1.0 Electrochemically Mediated ATRPII (eATRP) or are limited in their available tunable param- Cu )(23). AGET ATRP led to further process re- Reduction of the Cu Br2/Me6TREN complex eters. Furthermore, among the stimuli (e.g., light, finements by providing protocols with diminished was accomplished by application of a cathodic II pressure, and pH) available to externally influence Cu X2 catalyst concentrations down to 10 parts current (32). A similar methodology, although per million (ppm) and simplified reaction setups for generation of acutely air-sensitive click chem- in the presence of oxygen through activators re- istry catalysts, was previously implemented for • Electrochemical1Center for Macromolecular Engineering, Department of Chemistry, Carnegie Mellon University, 4400 Fifth Avenue, generated by electron transfer (ARGET) and bioconjugation reactions with an isosahedral Pittsburgh, PA 15213, USA. 2Kavli Nanoscience Institute and initiators for continuous activator regeneration virus, resulting in high-efficiency reactions in ATRPBeckman Institute, and Division of Chemistry and Chemical (ICAR) ATRP (27–29). These systems are con- the presence of ambient O without chemical re- 2 Engineering, 210 Noyes Laboratory 127-72, California Insti- 3 ducted in the presence of excess reducing agent ducing agents (33). Before our electrolysis exper- tute of Technology, Pasadena, CA 91125, USA. Department I of Chemical Sciences, University of Padova, via Marzolo 1, where Cu X activators are continuously regen- iments, cyclic voltammograms (CVs) of methyl – Reduces Cu(II) II 35131 Padova, Italy. erated from the Cu X2 deactivators, a by-product acrylate (MA) and acetonitrile (MeCN) over a po- *To whom correspondence should be addressed. E-mail: of unavoidable termination events. Notably, the tential range of 1.5 volts, from 0.0 to –1.5 V ver- [email protected] absolute concentration of copper catalyst can sus Ag+/Ag were acquired to ensure the absence REPORTS Fig. 1. (A)Mechanismof AB electrochemically mediated AB 22. W. A. Braunecker, K. Matyjaszewski, Prog. Polym. Sci. 32, ATRP (eATRP) under a cath- 93 (2007). odic current to (re)gener- 23. K. Min, H. Gao, K. Matyjaszewski, J. Am. Chem. Soc. 127, I ate the Cu Br2/Me6TREN 3825 (2005). complex and optional an- Electrochemical methods and reagents24. M. F. Cunningham, areProg. emerging Polym. Sci. 33,365(2008). as an odic current to revert to 25. K. Min, K. Matyjaszewski, Cent. Eur. J. Chem. 7,657 II + II ever more powerful tool in polymer science in regard to catalyst Figure 1. CV of 1.17 mM Br−Cu TPMA in 56% (v/v) BA/DMF the Cu Br2/Me6TREN com- (2009). plex for cessation of po- 8a,17 26. K. Matyjaszewski,18 N. V. Tsarevsky, Nat. Chem. 1,276 ([BA] = 3.9 M) containing 0.2 M TBAClO recorded at a scan rate lymerization. (B)Electrolysis characterization, catalyst (re)generation,(2009). redox responsive 0 4 17b,19 27. K.12c,18a,20 Matyjaszewski et al., Proc. Natl. Acad. Sci. U.S.A. 103, cell configured with plat- (v) of 50 mV/s in the absence (dashed black) and presence (solid materials, and surface chemistries.15309 (2006). In ATRP alone, inum mesh working and 28. K. Matyjaszewski, H. Dong, W. Jakubowski, J. Pietrasik, counter electrodes. The black) of 12.9 mM EBiB. LSV (solid red) using an identical electrochemistry has been critical as aA. Kusumo,characterizationLangmuir 23,4528(2007). method two-compartment cell with 8a 29. W. Jakubowski,21 K. Matyjaszewski, Angew. Chem. 118, formulation to those in CV containing EBiB under convection. afrit-separatedcounter to determine equilibrium, ligand binding,4594 (2006). and activation rate electrode was maintained 7,22 30. T. Pintauer, K. Matyjaszewski, Chem. Soc. Rev. 37,1087 Hollow black dots correspond to applied potential values (Eapp), under an N atmosphere at 25°C. Redox reactionsffi of CuII/CuI couple were performed with applied potentials varied between –0.72 and –0.40 V versus an Ag+/Ag Fig. 4. (A) Conversion2 (solid circles) andcoe applied potentialcients. (dashed line)In with other respect to time polymerization and (2008). systems, catalyst reference electrode. 31. M. Nasser-Eddine, C. Delaite, P. Dumas, R. Vataj, expressed as overpotential (η) values, used in subsequent eATRP (B) Mn and Mw/Mn with respect to conversion. Toggling between active and dormant states is rep- A. Louati, Macromol. Mater. Eng. 289,204(2004). activity was manipulated+ by utilization of redox-sensitive resented by changes of the Eapp values between –0.69V and –0.40 V versus Ag /Ag, respectively. 32. Materials and23 methods are available as supporting72 experiments. E1/2 values of 0.322 and −0.166 V were determined using Reaction82 conditions are identical to those statedcatalysts1APRIL2011 in Fig. 2. in the VOL332 polymerizationSCIENCE www.sciencemag.org of lactide.material on ScienceFromOnline. a materials − K. Matyjaszewski et33. al. V. Science Hong, A. K. Udit, 2011 R. A., Evans,332 M., 81-84. G. Finn, Ag|AgI|I and SCE, respectively. perspective, redox-sensitive polymerChemBioChem materials9,1481(2008). have been References and Notes 11. L. H. Peeck, S. Leuthausser, H. Plenio, Organometallics 34. A. A. Isse, A. Gennaro, J. Phys. Chem. A 108,4180 1. M. Szwarc, Nature 178,1168(1956). developed29,4339(2010). including well-defined ferrocene(2004). containing (meth)- 2. A. H. E. Müller, K. Matyjaszewski, Controlled and 12. M. Benaglia et al., J.19a Am. Chem. Soc. 131,6914(2009). 35. We acknowledge the U.S. National Science Foundation12c Living Polymerizations: Methods and Materials acrylate13. H. polymers J. Yoon, J. Kuwabara, J.-H.and Kim, C. electropatternedA. Mirkin, Science (grants DMR surface 09-69301 and brushes. CHE 10-26060) and theIn a summary of two CVs and one linear sweep voltammogram (Wiley-VCH, Weinheim, Germany, 2009). 330, 66 (2010). members of the CRP Consortium at Carnegie Mellon 3. K. Matyjaszewski, J. Xia, Chem. Rev. 101,2921(2001).regard14. to C. K. A. catalyst Gregson et al., J. Am. generation Chem. Soc. 128,7410 and electropolymerUniversity for financial support. N.C.S. synthesis, acknowledges the (LSV) conducted in a polymerization mixture prior to 4. M. Kamigaito, T. Ando, M. Sawamoto, Chem. Rev. 101, (2006). U.S. National Science Foundation for an American 3689 (2001). eATRP15. Y. Kwak,was K. Matyjaszewski, recentlyMacromolecules developed43,5180(2010). asCompetitiveness a tool in Chemistry to postdoctoral effectively fellowship electrolysis/polymerization. The polymerization medium was 5. K. Matyjaszewski, T. P. Davis, Handbook of Radical 16. M. Tanabe et al., Nat. Mater. 5,467(2006). (CHE-1042006). A.J.D.M. and K.M. filed a U.S. provisional Polymerization. (Wiley-Interscience, Hoboken, NJ, 2002). 17. J. Rzayev, J. Penelle, Angew.fi Chem. Int. Ed. 43,1691 patent application (61/459,724) related to this work. 6. T. E. Patten, J. Xia, T. Abernathy, K. Matyjaszewski,synthesize(2004). well-de ned polymers by mediating ATRP through composed of a solution of monomer, n-butyl acrylate (BA), in Science 272,866(1996). 18. V. Bonometti, E. Labbé, O. Buriez, P. Mussini, C. Amatore, Supporting Online Material 7. M. K. Georges, R. P. N. Veregin, P. M. Kazmaier,passageJ. of Electroanal. current. Chem. 633,99(2009). Enhanced levels of polymerization control solvent, dimethylformamide (DMF), containing a supporting www.sciencemag.org/cgi/content/full/332/6025/81/DC1 G. K. Hamer, Macromolecules 26,2987(1993). 19. J. Qiu, K. Matyjaszewski, L. Thouin, C. Amatore, Materials and Methods 8. M. Kato, M. Kamigaito, M. Sawamoto, T. Higashimura,were realizedMacromol. Chem. via Phys. 201 electrochemical,1625(2000). means by generating the electrolyte, tetrabutylammonium perchlorate (TBAClO4). Figs. S1 to S5 Macromolecules 28,1721(1995). 20. C. Y. Lin, M. L. Coote, A. Gennaro, K. Matyjaszewski, II References 9. J. Chiefari et al., Macromolecules 31,5559(1998).active catalystJ. Am. Chem. Soc.in130,12762(2008). situ through electrolysis. Control of the Initial eATRP experiments utilized a catalytic system of Cu / 10. J.-S. Wang, K. Matyjaszewski, J. Am. Chem. Soc. 117, 21. A. A. Isse et al., J. Am. Chem. Soc.,ASAP(2011); 30 December 2010; accepted 2 March 2011 II + 5614 (1995). polymerizationdoi: 10.1021/ja110538b. rate and ability to10.1126/science.1202357 intermittently switch a tris(2-pyridylmethyl)amine (Br−Cu TPMA ) and later involv- polymerization between “on” and “off” states were demon- ing different ligands to including tris[2-(dimethylamino)ethyl]- 16a strated. The utility of eATRPSuch was constraints further are difficult extended to obtain, however, to amine (Me6TREN) and N,N,N′,N″,N″-pentamethyldiethylene- Thermochronometry Revealsff because erosion itself effaces evidence of past aqueous/bu ered media, typicallytopography. challenging in ATRP, to triamine (PMDETA). In all cases, equimolar concentrations of Headward Propagationproduce well-de of Erosionfined polymers in byWe tuning used the isotopic relative legacy of evolving catalyst crust- copper(II) and bromide were utilized by adding copper(II) al temperature conditions to constrain16b the history fl II concentrations via the appliedof potential relief development (E inapp a mountain). landscape.Most tri uoromethanesulfonate (Cu OTf2) and tetrabutylammo- an Alpine Landscape We collected low-temperature thermochronomet- recently, the eATRP process hasric been measurements extended of 33 bedrock to samples surface- from nium bromide (TBABr), respectively. For clarity, the David L. Shuster,1,2*‡ Kurt M. Cuffey,3,2initiated‡ Johnny W. Sanders, polymerizations2 Greg Balco1 providingalong controlled valley axes and up and valley tailorable walls in high- [TBABr] has been omitted from figures and captions. Specific relief drainage networks near Milford Sound in fi Glacial erosion of mountain ranges producesgrowth spectacular of alpine polymer landscapes and, brushes by linking underFiordland, ambient New Zealand conditions, (8). In this setting, while pat- formulation details are supplied in the gure footnotes and climate with tectonics, influences a broad array of geophysical phenomena. Although the resultant terns of topographic evolution over the past ~2 My landforms are easily identified, the timingenabling and spatial pattern multiple of topographic surface adjustment to functionalizationsare clearly decipherable by because recycling/ of a fortuitous Supporting Information. As expected, a typical copper redox 12c II + Pleistocene glaciations remain poorly known.reusing We investigated the reaction topographic evolution medium. in the correspondence between the temperature sen- couple of Br−Cu TPMA was observed having quasi-reversible archetypal glacial landscape of Fiordland, New Zealand, using (U-Th)/He thermochronometry. sitivity of He isotopic techniques and the overall We find that erosion during the past 2 millionTo years promote removed the entire widespread pre-Pleistocene landscape applicationmagnitude of of PleistoceneeATRP, exhumation. this All work sam- behavior with a half-wave potential (E1/2) value of 0.322 V vs and fundamentally reshaped the topography. Erosion focused on steep valley segments and ples were taken from a ~21-km–by–38-km region | | − propagated from trunk valleys toward theserves heads of drainage to provide basins, a an behavior in-depth expected if investigation(Fig. 1). The valleys and exhibit extension classic glacial of forms, our Ag AgI I . For further reference, CVs were recorded against the fi including U-shaped cross sections, concave lon- subglacial erosion rate depends on ice slidingrst velocity. report, The Fiordland disseminating landscape illustrates practical insight into fundamental saturated calomel electrode (SCE) which gave an E1/2 of complex effects of climate on Earth’ssurfacemorphology. gitudinal profiles dominated by low slopes, and deeply incised valley-head cirques with exception- 4347 dx.doi.org/10.1021/ma400869e | Macromolecules 2013, 46, 4346−4353 he characteristic landforms and large relief change, topography, and tectonic processes. Most 1Berkeley Geochronology Center, 2455 Ridge Road, Berkeley, of many alpine landscapes indicate that quantitative studies of glacial landscape evolution CA 94709, USA. 2Department of Earth and Planetary Science, 3 the effect of glacial erosion over the past rely on model simulations that calculate glacial University of California, Berkeley, CA 94720, USA. Depart- T ment of Geography, University of California, Berkeley, CA ~2.5 million years (My) has been profound (1, 2). erosion from poorly validated parameterizations 94720, USA. Understanding how this erosion progressed at the [e.g., (3, 4)]. Alternatively, direct observational *To whom correspondence should be addressed. E-mail: landscape scale over millions of years is essential constraints could reveal the evolution of topogra- [email protected] for analyzing the connections between climate phy and so guide model development [e.g., (5–7)]. ‡These authors contributed equally to this manuscript.

84 1APRIL2011 VOL332 SCIENCE www.sciencemag.org Some1844 Ma tyjInterestingaszewski et al. PolymersMacromolecules, Vol. 36 , Nfromo. 6, 2003 ARTICLEATRP IN PRESS Scheme 1. Synthesis of Three- and Four-Arm Star Molecular Brushes W.A. Braunecker, K. Matyjaszewski / Prog. Polym. Sci. 32 (2007) 93–146 129

• Stars

Fig. 16. AFM image of four armed star brushes prepared by ATRP [356]. ARTICLE IN PRESS 130 W.A. Braunecker,Anionic K. Matyjaszewski and/or cationic / Prog. polymerizations Polym. Sci. 32 (2007) are 93–146used to make ABC or ABCBA segments using much better suited to make cyclic polymers than sequential polymerization techniques. ATRP (I) chloride (Cu(I)Cl) (Acros, 99%) were purified by washing SampMMAles were reHEMA-TMSmoved toCRPanaly processesze convers byion usingby GC complimentaryand reagents at macroinitiators can also be used to create difunc- Macromoleculeswith gl a2003cial aceti,c 36acid,, fo1843-1849.llowed by absolute e thanol and analyze molecular weight bveryy GPC lowin d concentrations.ifferent time inte However,rvals cyclization has tional a-alkyne-o-azido-terminated blocks. Click acetone, and then dried under vacuum. Copper(II) bromide during the polymerizaOtion. After 12.5 h, the polymerization O been reported when click chemistry was used in a coupling in a step growth process then affords an (Cu(II)Br2) (Aldrich, 99%) and copper(II) chloride (Cu(II)Cl2) was stopped a+t 51.6%Oconversion by cooling to rt and opening (Aldrich, 99+%) were used as received. 4,4′-Di(5-nonyl)-2,2′- the flaskOto air. The mixturereactionwas then ofdis azido-solved i andnto 5 acetylene-terminated0 mL of Random chains Brush efficient route to multisegmented block copolymers bipyridine (dNbpy) was prepared as described elsewhere.29 All THF and passed through TMSOne[365]utral.alu Thismina; processthe solven wast and t recentlyhe optimized to [365]. other regents and solvents were used as received from Aldrich residual monomer were remprovideoved usin ang h efficientigh vacuum route. to polystyrene macro- Graft copolymers have been synthesized with or Acros Chemicals. ATRP • Gradients & brushes Esterification of Three-ArmcyclesStar p[366]HEM.A-TMS to Three-Arm techniques similar to those applied in the prepara- Measurements. Monomer conversion of HEMA-TMS and pBPEM. The product of the pHEMA-TMS p1.Siteolym eTransformationr was placed nBuA was determined using a Shimadzu GC 14-A gas chro- in a 250 mL round-bottom flask (assum i n g to1 2Macroinitiator.7 mmol of tion of comb polymers (grafting from, onto and matograph equipped with a FID detector using a J&W R-OTMS groups). After KF8.2.(0.74 Compositiong, 12.7 mmol) addition, the through) in addition to methods known for block 2 Grafting From Scientific 30m DB WAX Megabore column. Injector and flask was sealed and flushed with N2, and 120 mL of dry THF copolymerization such as site transformation. The detector temperatures were kept constant at 250 °C with a was added. TetrabutylammoniuThem flu toleranceoride (0.03 that4 g, 0. CRP13 mm processesol) show toward density of the grafts can be varied along the length heating rate of 20 °C/min. (Co)polymer molecular weights were in tetrahydrofuran was added dropwise to the flask, followed determined using a GPC system equipped with a Waters WISP by the slow addition of 2-brofunctionalmopropiony groupsl bromid allowse (4.12 forg, 2 the.0 prolific production of the chain to generate gradients (Scheme 21) 712 autosampler and Polymer Standards Service columns mL, 19.1 mmol) over the ofcou ars vaste of array40 mi ofn. statistical,The reactio segmentedn (blocks and [378,379], and various types of block graft-copoly- (guard, 102 Å, 103 Å, 105 Å); toluene was used as an internal mixture was stirred overnighgraft),t at rt a periodicnd afte1.Siterwa (mostlyrd Transformationprecip alternating),itated and gradient mers have also been created, including core-shell standard for the system. 1H NMR characterization was to Macroinitiator into methanol/ice (80/20 v/v copolymers.%). The separa Inted additionprecipitate towa materialss prepared by cylinders as well as heterografted [380] and double performed in CDCl3 (using CHCl3 δ ) 7.24 ppm as an internal redissolved in 150 mL of CHCl3 and filtered2t hGraftingrough a cFromolumn standard) on a Bruker 300 MHz instrument. Atomic force of activated alumina (basic)one, and specificthe solv CRPent w technique,as removed manyin are prepared by a grafted [351] structures, etc. micrographs were recorded with a Multimode Nanoscope IIIa aContinuousvacuum. T he isolated polycombinationmer was reprec ofipit radicalated from polymerizationTHF and other When comonomers have a similar reactivity, instrument (Veeco Metrology Group, Santa Barbara, CA) iadditionnto hex aofn es threATRPe times atechniques.nd dried under vacuum at 25 °C statistical copolymers are formed. Different como- operating in the tapping mode. The measurements were HEMA-TMS for 24 h. 2.2 g of three-arm staBlockr pBPE copolymerizationM was obtained (65 has.6% been conducted with nomer reactivity ratios result in copolymers with a performed at ambient conditions using Si cantilevers with a yieOld). Complete conversion was determined by 1H NMR Gradient Brush 73 spring constant of ca. 50 N/m and a resonance frequency of (absence of TMS-O- resonan combinationce (δ ) 0.2 ppm of(9 methodsH, bs, (H3 throughC)3- site transforma- spontaneous gradient [381,382]. When monomers O O 1 Macromoleculesabout 300 kH z2002. The sam,p l35es fo,r t3387-3394.apping mode AFM me asure- Si-))). Mn(GPC) ) 90 200; Mtionw/Mn of) 1 the.15. polymerH NMR ( end300 M groups.Hz, ATRP initiators with strong electron donor groups are copolymer- ments were prepared by the Langmuir-Blodgett technique as CDCl , δ in ppm): 4.52 (1H, quart., J ) 6.8 Hz, Br-CH-CH ); 3TMSO O have been successfully converted3 to RAFT and ized with those that have strong electron acceptors, described in ref 27. For every sample, monolayers were 4.36 (2H, bs, -O-CH2-CHNMP2-O-C initiatorsO-CH-Br[367]); 4.15and(2H, vicebs, versa. Polymer end polymerization occurs in alternating fashion to transferred to a mica substrate at the same surface pressure -O-CH2-CH2-O-CO-CH-Br); 1.82 (overlapped, d, J ) 6.8 π ) 1 mN/m. Hz, Br-CH-CH3); 2.21-1.4groups4 (overl originallyapped, m, preparedCH2-C-C byH3) cationic; [368], anionic generate periodic copolymers [383]. Other examples Synthesis of Three-Arm Star Molecular Brushes. All 1.22-0.94 (overlapped, 3 [369,370]bs, CH2-,C ionic-CH3 ring). Scheme opening 21.[371,372], ring opening of alternating copolymerizations occur with kineti- × the polymerizations including the star macroinitiators and Three-Arm Star Moleculametathesisr Brushes. I[373]n a 1,00 coordinationmL Schlenk [342,353,374], and cally reactive but thermodynamically non-homo- corresponding brushes were synthesized via similar proce- flask pBPEM (0.1 g, 0.38 mmstep-growthol of initiatin polymerizationg sites), CuBr2 (2.[375–377]12 have all been polymerizable monomers (e.g., maleic anhydride) dures, unless specified otherwise. Typical procedures of three- mg, 0.0095 mmol), and dNbpy (154.5 mg, 0.38 mmol) were arm star pHEMA-TMS, three-arm star pBPEM and corre- purged three times with ineconvertedrt gas. Deox toyg CRPenated initiatingnBuA (24 sites..3 Multi-segmented [384] and when less reactive monomers are used in sponding three-arm star brushes were as follow. also affectg, monomer0.19 mol) and sequencesanisole (6.8block[386]mL, 25 copolymersandv%) w polymerere ad areded, typicallyand thavehe prepared been converted by poly- tolarge thiols, excess alkoxyamines to reactive monomers in (e.g., olefins with Synthesis of Three-Arm Star pHEMA-TMS. In a 25 mL dried reaction mixture was degascondensationsed by three fre processes.eze-pump- However,thaw ATRP has been acrylates) [385]. The addition of Lewis acids can Schlenk flask 3BriBu (10.3 mg, 0.0137 mmol) and dNbpytacticity(25.3 [103–105]cycles. Aft.er stirring for 1 h at rt, CuBr (27.2 mg, 0.19 mmNMPol) to alkyl chlorides, and the alkyl halides in mg, 0.062 mmol) were purged three times with inert gMolecularas. was hybridsadded, an cand the beflas generatedk was placed byin a covalentlythermostated oil baATRPth to allyl, hydroxy, amino, azido and ammo- Deoxygenated HEMA-TMS (5.0 g, 24.71 mmol) and 1.5 mL of at 70 °C. After 2 min, an initial kinetic sample was taken, and anisole were then added, and the reaction mixtureattachingwas s syntheticamples wer polymerse removed toto a inorganicnalyze conv materialsersion by GC usiniumng or phosphonium groups in excellent yields degassed by three freeze pump thaw cycles. After stirring anisole as internal standard and analyze molecular weight by - - and natural products [313]. Functional groups (NH2 (Scheme 22). The conversion of dormant species in for 1 h at room temperature (rt), Cu(I)Cl (3.06 mg, 0.031 mmol) GPC during the polymerization. The polymerization was was added, and the flask was placed in a thermostated oiorl bat OH)h insto naturalpped at 6. products2% conversi canon aft beer 4 converted2 h by coolin tog to rt alinearnd chains growing in two directions leads to at 75 °C. After 2 min, an initial kinetic sample was tATRPaken. initiatorsopening the (bromoamidesflask to air. The po andlymer bromoester)was purified by distillitelechelicsng and in stars to multifunctional polymers. and polymerization subsequently conducted. Chains Functionalities can be also introduced to specific prepared by CRP containing functionalities (NH2 parts of macromolecules. This includes the func- or OH) can be used to grow polypeptide or DNA tional core of stars, the centers of two-directionally [387]. Biotin-avidin and click chemistry can also be grown chains, and in between periodically repeated used to fuse functionalized natural products to- segments prepared by ATRP or click coupling. gether with organic polymers [316,388–392]. 9. Material applications 8.3. Functionality Although the CRP processes of SFRP, ATRP Propagating radicals are tolerant to many func- and RAFT were realized in just the last decade, tionalities, which allow incorporation of functional these techniques are already finding application in monomers and initiators into a (co)polymer via the commercial production of many new materials. most CRP processes. Additionally, functionality A few examples of such materials already in can be introduced to specific parts of a macro- production are highlighted hereafter, although it is molecule. This includes incorporation of side func- anticipated that many more specialty products will tional groups directly to a polymer backbone [326] become available in the relatively near future [395]. or in a protected form [393]. End groups can be Block copolymers based on acrylates and other incorporated by using either functional initiators or polar monomers may find applications as polar by converting a chain end to another functional thermoplastic elastomers [177] similar to those for group [394]. For example, dithioesters in RAFT Kraton, a landmark material whose production was Degenerate Transfer

• Reversible chain transfer

k tr + Pn• + TG Pm Pn TG Pm• k-tr

kp kp transfer group monomer monomer

• Examples – Iodine-mediated (TG = I atom) – Methacrylic macromonomers – Thiocarbonylthio (RAFT) polymerization

74 Iniferters …1

• Initiator, transfer agent, terminator

Otsu et al. Makromol. Rapid Commun., 1983, 3, 127 & 133 • Disulfides – High amounts of transfer – Examples • Diaryl disulfides • Dithiuram disulfides (most successful) S S X X

• Dithiocarbamyl end groups S S C2H5 C2H5 – Thermally stable N C S S C N – Photochemically labile C2H5 C2H5

75 Iniferters …2

Initiation

S S S C2H5 C2H5 Δ or hν C2H5 N C S S C N 2 N C S C2H5 C2H5 C2H5

Chain Transfer

S S S S C H C2H5 C2H5 C2H5 2 5 N C S S C N N C S S C N C H C2H5 C2H5 C2H5 2 5

Termination / Reinitiation

S h S C2H5 ν C2H5 N C S N C S C2H5 C2H5

76 RAFT Polymerization

• Reversible addition-fragmentation chain transfer

S S R S S S S S S S S Initiation / Chain Transfer CN CO CH CO CH CO CH S 2 3 N 2 3 O 2 3 Z Ph Ph Δ or hν I2 Pn• dithioesters trithiocarbonates dithiocarbamates xanthates monomer

kadd kβ Pn• S S R Pn S • S R Pn S S R• k Z -add Z Z kp kp

monomer monomer

Chain equilibrium kadd kβ Pn• S S Pm Pn S • S Pm Pn S S Pm• k Z -add Z Z

kp kp

monomer monomer G. Moad, E. Rizzardo, et al., Macromolecules, 31, 5559 (1998) G. Moad, E. Rizzardo, et al., Patent WO98/01478 (1998) 77 S. Z. Zard et al. Patent WO98/58974 (1998) Iodine & Methacrylic Macromonomers

• Iodine-mediated polymerizations – Tatemoto (Eur. Patent 489370A1, 1992) – Matyjaszewski (Macromolecules, 1995, 28, pp. 2093 and 8051) k tr + Pn• + I Pm Pn I Pm• k-tr

kp kp

monomer monomer • Polymerization of vinyl acetate – Iovu & Matyjaszewski (Macromolecules, 2003, 35, 9346)

78 Macromonomer Method

• Methacrylate-based macromonomers – Moad et al. (Macromolecules, 1996, 29, 7717)

kadd kβ Pn• Pm Pn • Pm Pn Pm• k k CO CH β CO CH add CO CH k 2 3 2 3 2 3 p kp monomer monomer

79 Macromonomer Mechanism

Moad et al. Macromolecules, 1996, 29, 7717. 80 5056 Chemical Reviews, 2009, Vol. 109, No. 11 Yamago

Figure 1. Correlation of experimental and theoretical Mn of polystyrene in the bulk polymerization of 100 equiv of St using Te-11 as a function of the conversion of St. Reprinted with permission from ref 35. Copyright 2005 John Wiley & Sons, Inc.

Scheme 6. Reduction of Methyltellanyl Polymer End Group with Tributyltin Hydride or Deuteride

22 experiments. First, Mn increased linearly with an increase in the conversion of St (Figure 1). Second, Mn also increased linearly with an increase in the amount of St used. Mono- disperse PSts with an Mn close to the theoretical value calculated from the ratio of St/CTA and a narrow MWD were obtained in all cases (Mn ) 9200-62600, Mw/Mn ) 1.17-1.30). The same linear correlations were also observed 5054 Chemical Reviews, 2009, Vol. 109, No. 11 Yamago under second-generation conditions using AIBN as an Scheme 3. Structures of Organoheteroatom CTAs Scheme 5. Structural Effect of CTA on the Control of LRP additive. 5054 Chemical Reviews, 2009, Vol. 109, No. 11 Yamago Scheme 3. Structures of Organoheteroatom CTAs Scheme 5. Structural Effect of CTA on the Control of LRP The existence of a carbon-tellurium bond in the ω-poly- Table 1. Structural Effect of Organotellurium,22,27,28 Organostibine,30 and Organobismuthine34 Chain-Transfer mer end group was confirmed by labeling experiments. PSt Agents (CTAs) on the Polymerization of Styrene (100 equiv) under Thermal Conditions -1 a 22,27,28 8 prepared using Te-7 and St (30 equiv) was reduced CTATable BDE 1. Structural (kJ mol ) Effectyield of Organotellurium, (%) Mn Mw/Mn 30 34 Te-1 Organostibine,114and Organobismuthine 88 11500Chain-Transfer 1.18 Organoheteroatom-Mediated5054 Chemical Polymerization Reviews, 2009, Vol. 109, No. 11 Agents (CTAs) on the Polymerization of Styrene (100 equiv)Yamago quantitatively using either tributyltin hydride or tributyltin Te-2 99 10300 1.25 Te-3 under Thermal Conditions 88 12200 1.08 Scheme 3. Structures of Organoheteroatom CTAs Scheme 5. Structural Effect-1 a of CTA on the Control of LRP deuteride to yield the end-protonated 9 or deuterated Te-4 CTA BDE (kJ mol ) 90yield (%) 9400Mn 1.09 Mw/Mn Te-5 81 9100 1.06 22,26 Te-1 114 88 11500 1.18 Te-6 88 7800 1.23 polystyrene 9-d1, respectively (Scheme 6). Selective Te-2 99 10300 1.25 • Organotellurium Te-7 120 98 9400 1.15 Te-3 88 12200 1.08 Te-9b 142 70 3100 1.33 incorporation of the deuterium atom in the polymer was Te-4 90 9400 1.09 Te-11 123 91 9100 1.18 – A. Goto et al. JACS, 2003, 125, 8720 TableTe-5 1. Structural Effect of Organotellurium,8122,27,28 9100 1.06 Te-12 142 86 8300 1.34 Organostibine,Te-6 30 and Organobismuthine8834 Chain-Transfer 7800 1.23 confirmed from MALDI-TOF mass spectra of 9 and 9-d1 as Sb-1 99 9300 1.22 AgentsTe-7 (CTAs) on the120 Polymerization of 98 Styrene (100 9400 equiv) 1.15 2 Sb-2 121 99 8700 1.14 Figure• 2.OrganostibineMALDI-TOF mass spectra of (a) end-protonated underTe-9 Thermalb Conditions142 70 3100 1.33 silver adducts (Figure 2). The H NMR spectrum of 9-d1 Sb-4 95 9000 1.17 Te-11 123-1 a 91 9100 1.18 Bi-1 CTA BDE113 (kJ mol ) 99yield (%) 10500Mn 1.07Mw/Mn further supported the selective incorporation of deuterium polystyrene–9 S.and Yamago (b) end-deuterated et al. JACS, polystyrene 2004, 126, 913908-d1. The mo- Te-12 142 86 8300 1.34 + a BondTe-1Sb-1 dissociation114 energy calculated 8899 by the 11500 9300 B3LYP/6- 1.18 1.22 lecular ions were observed as silver ion adducts [m/z ) (M + Ag) ]. 31G*(H,C,N,O)Te-2Sb-2 +LANL2DZ(Te,Sb,Bi).121b Polymerization99 99 10300 was 8700 carried 1.25 1.14 at the benzylic position (δ ) 2.36 ppm, broad singlet). These • Organobismuthin out withTe-3 30Sb-4 equiv of styrene. 8895 12200 9000 1.08 1.17 Reprinted with permission from ref 26. Copyright 2003 American Te-4Bi-1 11390 99 9400 10500 1.09 1.07 results clearly demonstrate the existence of an organotellu- Te-5 81 9100 1.06 Chemical Society.– S. Yamago et al. Angew. Chem. Int. Ed., 2007, 46, 1304 Te-6a Bond dissociation energy88 calculated 7800 by the 1.23 B3LYP/6- basic conditions, many polar functionalb groups are not rium ω-polymer end group in 8. The difference between the Te-731G*(H,C,N,O)+120LANL2DZ(Te,Sb,Bi). 98Polymerization 9400 was 1.15 carried Scheme 4. Synthetic Route to Organoheteroatom-Transfer compatible.Te-9outb with The 30 fourth equiv142 of method styrene. shown 70 in Scheme 3100 4d, which 1.33 Scheme 7. Activation/Deactivation Mechanisms InvolvedAgents in reliesTe-11 on the reaction123 of a radical generated 91 from 9100 an azo- 1.18 main mass peaks was 104 in the MALDI-TOF mass initiatorTe-12 with ditellurides14226 and distibines, 8632 proceeds 8300 under 1.34 spectrum, which corresponds to the molecular mass of St, TERP, SBRP,Two concurrent and BIRP mechanisms: neutralSb-1basic conditions conditions, and is many applicable polar99 functional to the synthesis 9300 groups 1.22 of are not Scheme 4. Synthetic Route to Organoheteroatom-Transfer functionalSb-2compatible. CTAs. The The121 reaction fourth method of an azo-initiator 99 shown in 8700 Scheme with iodine 4d, 1.14 which Sb-4 95 9000 1.17 Agents has beenrelies also on used the for reaction the in ofsitu a synthesis radical generated of organoiodine from an azo- and there were no significant peaks arising from impurities. Bi-1 11326 99 1050032 1.07 chain-transferinitiator agents. with ditellurides56,85,86,89,90 and distibines, proceeds under aneutralBond dissociation conditions energyand is applicablecalculated by to the the synthesis B3LYP/6- of These observations strongly suggest the highly controlled Organotellurium CTAs Te-7 and Te-8b were prepared by 31G*(H,C,N,O)functional CTAs.+LANL2DZ(Te,Sb,Bi). The reaction of anPolymerization azo-initiator was with carried iodine reactingout with AIBN 30 equiv with of styrene. dimethyl- and diphenylditelluride, character of TERP, in which the polymerization is initiated respectively,has been but also in low used yields for the (8% in situ18%). synthesis26 This of route organoiodine has 56,85,86,89,90- the practicalchain-transfer advantage agents. that both AIBN and ditellurides are by a radical generated from Te-7 and proceeds in the absence stablebasic in airOrganotellurium conditions, and can be many handled CTAs polar withoutTe-7 functionaland specialTe-8 groupsprecautions.were prepared are not by Scheme 4. Synthetic Route to Organoheteroatom-Transfer Furthermore,compatible.reacting theThe AIBN air fourth sensitive with method dimethyl-CTAs shown formed and in canScheme diphenylditelluride, be directly 4d, which 26 of unfavorable side reactions. The labeling experiments in Agents usedrelies forrespectively, polymerization on the reaction but withoutin lowof a yields radicalpurification (8% generated- because18%). from theThis only an route azo- has sideinitiator productthe practical withis a dimer ditellurides advantage of AIBN-derived26 thatand both distibines,radicals, AIBN32 andproceeds which ditellurides does under are SBRP and BIRP also confirmed the living character of these not affectneutralstable the conditions in polymerization air and can and be is reaction. handled applicable Despite without to the special simplicity synthesis precautions. of methods. The reaction of an organostibanyl anion, which was of thisfunctionalFurthermore, procedure, CTAs. the the The use air ofreaction sensitive purified of initiatorsCTAsan azo-initiator formed is the can methodwith be iodine directly reductively generated from the diorganostibanyl bromide and of choicehasused been for for also obtaining polymerization used for living the without in polymers situ synthesis purification with of the becauseorganoiodine highest the only nisms. Involvement of the two mechanisms makes thesesodium LRPmetal, with 1-phenylethyl bromide afforded the levelchain-transfer ofside control product of agents.is MWD. a dimer56,85,86,89,90 of AIBN-derived radicals, which does S. Yamago Chem. Rev., 2009, 109, 5051-5068. 31 81 organostibanyl transfer agent Sb-1. However, because of Organotelluriumnot affect the polymerization CTAs Te-7 reaction.and Te-8 Despitewere prepared the simplicity by The reaction of an organostibanyl anion, which was The reaction of azo-initiators with tetramethyldistibine, on methods unique, and it is the origin of three polymerizationthe difficulty to generate the stibanyl anions and their low reactingof this AIBNprocedure, with the dimethyl- use of purified and initiators diphenylditelluride, is the32 method reductively generated from the diorganostibanyl bromide andthe other hand, took place with high coupling efficiencies. 3.4. Mechanism reactivities, the synthetic scope of this route is limited. respectively,of choice but for in obtaining low yields living (8%- polymers18%).26 This with route the highest has sodium metal, with 1-phenylethyl bromide afforded theYields of the CTAs were about 60% when a 1:1 mixture of conditions described in the previous section. RecentOrganostibanyl inves- transfer agents Sb-2 and Sb-3 were thelevel practical of control advantage of MWD. that both AIBN and ditellurides are organostibanyl transfer agent Sb-1.31 However, because ofan azo initiator and the distibine was employed. Since about prepared by the reaction of lithium ester enolate generated 40%stable of theThe in radicals air reaction and generated can of be azo-initiators handled from the without withazo initiators tetramethyldistibine, special dimerizeprecautions. on Studies on the kinetics involved in the activation and tigation of cobalt-mediated LRP revealed that this reactionthe difficulty to generate the stibanyl anions and their low 32 from ethyl 2-methyl-2-propanoate and lithium diisopropyl- Furthermore,the other hand, the air took109 sensitive place with CTAs high formed coupling can efficiencies.be directly 41,43,44reactivities, the synthetic scope of this route is limited. within a solvent cage, the result indicates that almost all amide with dimethylstibanyl bromide as an electrophile theused radicalsYields for polymerization that of the diffused CTAs from were without theabout purification cage 60% were when because captured a 1:1 themixture by only of deactivation of dormant species have revealed the existence also takes place by the RT and DT mechanisms. Organostibanyl31 transfer agents Sb-2 and Sb-3 were (Scheme 4c). The same method was used for the cyano- sidean product azo initiator is a dimer and theof AIBN-derived distibine was employed.radicals, which Since does about prepared by the reaction of lithium ester enolate generatedthe distibine. Organostibine CTAs Sb3-Sb8 were prepared of two mechanisms: reversible termination (RT, Scheme 7a) The first-order rate constant for the activationderivative ofSb-3 thestarting from 2-methyl-2-propionitrile. Or- via thisnot40% affect route of thestarting the polymerization radicals from generated the corresponding reaction. from the Despite azo azo initiators the initiators. simplicity dimerize Thefrom reaction ethyl 2-methyl-2-propanoate of an organostibanyl and anion, lithium which diisopropyl- was 109 27,33,114 ganobismuthine transfer agents Bi-1 and Bi-2 were also Ester,of thiswithin ether, procedure, a terminal solvent the cage, alkene, use ofthe purified and result alcohol initiators indicates groups is that the were method almost all preparedreductivelyamide via this with generated route dimethylstibanyl using from dimethylbismuthanyl the diorganostibanyl bromide as an bromide electrophile and and degenerative chain transfer (DT, Scheme 7b). dormant species via RT (kd) and the second-order rate 31 incorporatedofthe choice radicals into for theobtaining that CTAs. diffused living-Functional from polymers the cage polymers with were the captured were highest by (Scheme 4c).34 The same method was used for the cyano- R as ansodium27,28,114 electrophile. metal, with 1-phenylethyl bromide afforded the levelthe of distibine. control Organostibineof MWD. CTAs Sb3-Sb8 were prepared derivative Sb-3 starting from 2-methyl-2-propionitrile.31 Or-synthesized starting from these functional CTAs (see section Although NMP and ATRP proceed exclusively via the RT constant for the activation via DT (kex) in TERP,Despiteorganostibanyl the high synthetic transfer agent efficienciesSb-1. ofHowever, the routes because shown of Thevia this reaction route of starting azo-initiators from the with corresponding tetramethyldistibine, azo initiators. on ganobismuthine transfer agents Bi-1 and Bi-2 were also3.5.3). 30,33 34 in Schemethe difficulty 4a-c, itto is generate difficult the to introduce stibanyl anions polar functional and their low theEster, other hand, ether, took terminal place with alkene, high and coupling alcohol efficiencies. groups were32 prepared via this route using dimethylbismuthanyl bromide mechanism and RAFT proceeds via the DT mechanism, SBRP, and BIRP are summarized in Table 3.groups Thereactivities, into rate the CTAs. the synthetic As the scopeheteroatom of this functional route is limited. groups Yieldsincorporated of the CTAs into were the CTAs. about 60%R-Functional when a 1:1 polymers mixture ofwere as an electrophile.34 3.1.2. Structural Effect of CTAs on the Control of LRP 115 116 in theOrganostibanyl CTAs are moderately transfer sensitive agents toSb-2 oxygenand andSb-3 alsowere ansynthesized azo initiator starting and the from distibine these was functional employed. CTAs Since (see about section TERP, SBRP, and BIRP proceed through the two mecha- constants of IRP and RAFT are also listed as a reference.Despite the high synthetic efficiencies of the routes shown reactiveprepared under by various the reaction conditions, of lithium post ester modifications enolate generated to Structural40%3.5.3). of the effects radicals of thegenerated CTAs from on MWD the azo are initiators summarized dimerize in Scheme 4a-c, it is difficult to introduce polar functional 22,26,33 introducefrom ethyl functional 2-methyl-2-propanoate groups starting from and the lithium existing diisopropyl- CTAs in Schemewithin 5a andsolvent Table cage, 1. 109 theThe result control indicates is usually that higheralmost all groups into the CTAs. As the heteroatom functional groups are limited.amide with In addition, dimethylstibanyl as synthesis bromide of the asCTAs an requireselectrophile withthe the3.1.2. radicals CTAs Structural from that left diffused Effect to right; fromof cyano- CTAs the andon cage the ester-substituted were Control captured of LRP by in the CTAs31 are moderately sensitive to oxygen and also (Scheme 4c). The same method was used for the cyano- the distibine. Organostibine CTAs Sb3-Sb8 were prepared reactive under various conditions, post modifications to Structural effects of the CTAs on MWD are summarized derivative Sb-3 starting from 2-methyl-2-propionitrile. Or- via this route starting from the corresponding azo initiators. introduce functional groups starting from the existing CTAs in Scheme 5 and Table 1.22,26,33 The control is usually higher ganobismuthine transfer agents Bi-1 and Bi-2 were also Ester, ether, terminal alkene, and alcohol groups were preparedare limited. via this In route addition, using as dimethylbismuthanyl synthesis of the CTAs bromide requires with the CTAs from left to right; cyano- and ester-substituted 34 incorporated into the CTAs. R-Functional polymers were as an electrophile. synthesized starting from these functional CTAs (see section Despite the high synthetic efficiencies of the routes shown 3.5.3). in Scheme 4a-c, it is difficult to introduce polar functional groups into the CTAs. As the heteroatom functional groups 3.1.2. Structural Effect of CTAs on the Control of LRP in the CTAs are moderately sensitive to oxygen and also reactive under various conditions, post modifications to Structural effects of the CTAs on MWD are summarized introduce functional groups starting from the existing CTAs in Scheme 5 and Table 1.22,26,33 The control is usually higher are limited. In addition, as synthesis of the CTAs requires with the CTAs from left to right; cyano- and ester-substituted Cobalt-Mediated Polymerization

• Organometallic mediated polymerization (OMRP) – Various metals can be used (Ti, V, Fe, Os, Mo, Cr) but most successful is Co – Co-mediated polymerization mechanism depends on conditions • Degenerate transfer (DT) if high radical conc. • Reversible-deactivation (RD) if low radical conc. – Largely works for vinyl acetate & acrylates • Ti okay for MMA and derivative