Controlled Synthesis of Block Copolymers containing N-isopropylacrylamide by Reversible Addition-Fragmentation Chain-Transfer (RAFT) Polymerization

Transcription

1 J. Mex. Chem. Soc. 2011, 55(1), Controlled Article Synthesis of Block Copolymers contining N-isopropylcrylmide by RAFT Polymeriztion 2011, Sociedd Químic de México 21 ISSN X Controlled Synthesis of Block Copolymers contining N-isopropylcrylmide by Reversible Addition-Frgmenttion Chin-Trnsfer (RAFT) Polymeriztion Alejndro Veg-Rios nd Angel Lice-Clveríe * Centro de Grdudos e Investigción, Instituto Tecnológico de Tijun, A.P. 1166, Tijun, B.C., México. e-mil: licec@tectijun.mx. Received June 14, 2010; ccepted November 8, 2010 Abstrct. Synthesis of diblock copolymers of N-isopropylcrylmide with n-hexyl crylte, styrene, methyl methcrylte nd 2-hydroxyethyl methcrylte, were crried out by using sequentil living polymeriztion method in the presence of chin trnsfer gent (CTA) 4-Cyno-4-(phenylcrbonothioylthio)pentnoic cid. The block copolymer composition nd moleculr weight could be well controlled while mintining nrrow moleculr weight distribution. The block copolymers were chrcterized by 1 H NMR, GPC with MALLS detection nd DSC. The molr rtio CTA/Inititor rther thn the sequence of monomer ddition is the key prmeter for chieving the desired mterils. We report the first synthesis of poly(hema)-bpoly() with polydispersity index (IPD) of 1.20 by RAFT. Keywords: Block Copolymer, RAFT, poly(), poly(mma), poly(hema), poly(st). Resumen. L síntesis de copolímeros en dibloques de N-isopropilcrilmid con crilto de n-hexilo, estireno metcrilto de metilo y metcrilto de 2-hidroxietilo, se llevó cbo medinte polimerizción viviente secuencil en presenci del gente de trnsferenci de cden (CTA) ácido 4-cino-4-[fenilcrbonotioiltio] pentnoico. L composición y peso moleculr de los copolímeros en bloques se pudo controlr mnteniendo un índice de polidispersidd bjo. Los copolímeros en bloque se crcterizron por 1 H RMN, GPC con MALLS y por DSC. L relción CTA/Inicidor resultó ser más relevnte que l secuenci de dición de monómeros pr logrr los mteriles desedos. Se report por primer vez l síntesis de poli(hema)-b-poli() con un índice de polidispersidd de 1.20 por RAFT. Plbrs clve: Copolímeros en bloques, RAFT, poli(), poli(mma), poli(hema), poli(st). Introduction Controlled/living free rdicl polymeriztion hs ttrcted much ttention of polymer chemists in recent yers becuse it is powerful tool to synthesize polymers with well-defined structures, nd wide rnge of monomers cn undergo rdicl polymeriztion under reltively simple conditions [1]. The term living polymeriztion originlly described polymeriztion in which the chin could only propgte nd not undergo chin trnsfer or irreversible termintion [2]. Thus, in n idel living polymeriztion system, ech chin should mintin its bility to further propgte in the presence of the monomer. The lst 15 to 20 yers hs been witness to unprecedented dvnces in controlled polymer synthesis. This hs been due, in prt, to the discovery nd development of controlled/living free rdicl polymeriztion (CRP) techniques [3]. Among ll techniques, reversible ddition frgmenttion chin trnsfer (RAFT) polymeriztion, first reported by the Austrlin CSIRO group in 1998 [4], is verstile method cpble of inducing living behvior for vrious monomers vi rnge of initition methods, solvents nd rection tempertures [5]. The reversible ddition frgmenttion chin trnsfer (RAFT) polymeriztion process hs been shown to be highly verstile nd widely pplicble living rdicl polymeriztion method tht lends itself to complex rchitecturl design [6]. Therefore the use of RAFT polymeriztion in reserch groups worldwide hs grown in the lst yers nd is predicted to grow more rpidly fter world known supplier of chemicls (Aldrich) strted to sell series of different RAFT chin trnsfer gents (CTA s) [7]. The generlly ccepted mechnism of RAFT polymeriztion is shown in Scheme 1. The moleculr weight of the obtined polymer is controlled by the monomer to CTA rtio nd cn be roughly predicted using the following idelized eqution: 0 mon M [M] M n [CTA] 0 + M CTA (1) Where [M] 0 is the initil monomer concentrtion, M mon is the moleculr weight of the monomer, ρ is the conversion, M CTA is the moleculr weight of the CTA, nd [CTA] 0 is the initil concentrtion of the CTA [4, 8]. The polymer product of RAFT polymeriztion contins in very high percentge the CTA-moiety in its structure. Therefore it is lso clled mcro-cta nd cn be ctivted gin for further grow s expected in ny living polymeriztion process. This property of the mcro-cta s obtined by RAFT cn be exploited for chin extension with different monomer opening the door for block copolymer synthesis. However pursuing block copolymers by using ny living polymeriztion method sequentilly requires djustment of polymeriztion conditions in ech step. It is esy to predict tht this will not work for ny desired combintion of monomers; especilly if rective functionl groups re present nd lso if the polymeriztion rte of both monomers is very different. In the cse of the RAFT polymeriztion method, one requirement for forming nrrow polydisperse AB diblock copolymer in sequentil copolymeriztion is tht the first-formed polymeric thiocrbonylthio compound (mcro-cta) should hve high trnsfer constnt in the subsequent polymeriztion

2 22 J. Mex. Chem. Soc. 2011, 55(1) Alejndro Veg-Rios nd Angel Lice-Clveríe step to llow the grow of the B block (Scheme 1, Step III) [9]. In the bsence of chin trnsfer to solvent, inititor, or monomer, the totl number of chins formed will be equl to (or less thn) the moles of dithio compound employed plus the moles of inititor-derived rdicls generted during the course of the polymeriztion. These dditionl inititor-derived chins re source of homopolymer impurity in block copolymer synthesis. The level of impurities cn be controlled by pproprite selection of the rection conditions. For mximum purity, it is desirble to use concentrtion of inititor s low s prcticble nd to choose solvents nd inititors which give miniml chin trnsfer. However this is not enough. The sequence of monomer ddition my hve gret impct in the outcome of block copolymer synthesis by RAFT. The RAFT ddition-frgmenttion equilibrium in block copolymeriztion goes through n intermedite dithio rdicl contining two polymer chins, one of the first monomer (A) nd the second one of the second dded monomer in the sequence (B); see fore lst rection in Scheme 1, Step III. This intermedite rdicl my frgment in two wys; to yield n ctive A-polymer chin nd dormnt B-polymer mcro-cta (desired forwrd frgmenttion), or two yield n ctive B-polymer chin nd dormnt A-polymer mcro-cta (undesired bck frgmenttion). The forwrd frgmenttion would result finlly in the desired product: dormnt block copolymer (lst rection of Scheme 1); while the bck frgmenttion would fvor the formtion of more homopolymer B. In extreme cse mixture of homopolymer A nd homopolymer B could be obtined rther thn the desired block copolymer. To fvor the block copolymer formtion nd to diminish the homopolymer impurity, it hs been suggested to chose s A monomer (the first in the RAFT sequence) one yielding good leving group under the rection conditions used nd s B monomer (the second in the RAFT sequence) one tht yields worse leving group under the sme rection conditions. For instnce the A monomer could be methcrylte while the B monomer could be n crylte. Following this Scheme 1. RAFT mechnism for homopolymeriztion (I) nd (II) nd chin extension of mcro CTA (III). A = ddition, F = Frgmenttion.

3 Controlled Synthesis of Block Copolymers contining N-isopropylcrylmide by RAFT Polymeriztion 23 strtegy it is usully not difficult to chieve block copolymers with no detectble homopolymer impurity (<5) while still chieving n cceptble rte of polymeriztion [10]. The im of this investigtion ws to find n esy to follow strtegy for the well controlled synthesis of temperture sensitive diblock copolymers contining poly(n-isopropylcrylmide) (P) s one of the blocks, well known nd worldwide investigted sensitive polymer [11, 12], nd representtive types of polymers s the second block of different fmilies: styrenics, cryltes nd methcryltes. Well defined blockcopolymers contining poly sequences re gol mterils for severl biotechnology pplictions including drug delivery [12, 13], mong others. One of these block copolymers is reported s prepred by RAFT for the first time, while for the others low polydispersity indices nd wide composition rnge, ws gol. Results nd Discussion RAFT homo-polymeriztions: Preprtion of mcro-cta s The overll conditions for the RAFT polymeriztion of mcro- CTA s s pplied in this pper nd their results re shown in Tble 1. The moleculr weight of the homo-polymers is well controlled by the monomer to CTA concentrtion rtio s predicted by the idelized eqution (1) s cn be seen compring the theoreticl with the moleculr weights mesured by gel permetion chromtogrphy (GPC) with multingle lser light scttering detection (MALLS). The key to the RAFT process nd subsequently control over moleculr weight is the thiocrbonylthio moiety of the CTA. However the CTA to inititor rtio needed to obtin the theoreticl moleculr weight depends on the monomer type nd the desired moleculr weight. The comprison between MMA nd HA is lesson telling. For MMA 1.25 to 1 rtio of CTA to inititor is enough to control the moleculr weight nd PDI, while for HA t lest 12 to 1 rtio of CTA inititor is needed to yield the desired moleculr weight mintining low PDI. This my result from the fct tht MMA is reported to show high trnsfer constnt to CTA s of the dithiobenzote type, while crylic esters do not show high trnsfer constnt [10]. The kinetic constnt of propgtion (k p ) reflects the polymeriztion rte of given monomer under given conditions of concentrtion, solvent nd temperture. The reported vlues for MMA nd n-butyl crylte (BA) under the sme polymeriztion conditions: 833 nd 33,700 Lmol -1 s -1 show tht BA polymerizes 40-times fster thn MMA [14]; it cn be ssumed tht HA polymerizes t similr rte thn BA since dodecyl crylte hs k p vlue very similr to BA (36,400 Lmol -1 s -1 ) [14]. The chin trnsfer constnt (C tr ) is the rtio of the kinetic constnt of chin trnsfer (k tr ) to the kinetic constnt of propgtion (C tr = k tr /k p ), therefore high vlue of propgtion kinetics (k p ) results in lower constnt of chin trnsfer. If high rte of trnsfer to the CTA is needed for controlled RAFT process, then higher concentrtion of CTA Tble 1. RAFT polymeriztions of mcro-cta s. Mcro-CTA Time (h) [CTA] 0 :[I] 0 [M] 0 :[CTA] 0 :[I] 0 Yield b () M n theo c () d () Poly() : : 1 : , , Poly() : : 1 : ,000 21, Poly() : : 1 : ,495 31, Poly() : : 1 : ,000 43, Poly(MMA) : : 1 : ,600 37, Poly(MMA) : : 1 : ,100 43, Poly(MMA) : : 1 : ,900 20, Poly(MMA) : : 1 : ,400 16, Poly(HA) : : 1 : , Poly(HA) : : 1 : ,990 16, Poly(HA) : : 1 : ,700 16, Poly(HA) : : 1 : ,026 20, Poly(HEMA) : : 1 : ,990 13,650 e 1.26 Poly(HEMA) : : 1 : ,680 26,180 e 1.50 Poly(HEMA) : : 1 : ,100 37,800 e 1.55 Poly(St) : : 1 : ,000 69, Poly(St) : : 1 : ,320 36, Poly(St) : : 1 : ,500 32, Inititor AIBN; b As determined grvimetriclly; c Clculted using eqution 1; d GPC in THF; e GPC in DMF; f PDI = M w /M n. PDI f

4 24 J. Mex. Chem. Soc. 2011, 55(1) Alejndro Veg-Rios nd Angel Lice-Clveríe is needed when the k p is lso high. In the cse of the CTA s inititor rtio used to control moleculr weight nd polydispersity is 4 to 1, n intermedite vlue s compred with MMA nd HA. A fst lecture of this result is tht trnsfer bility to the CTA used is intermedite, lso. Unfortuntely there re no relible vlues of k p reported for. The only report we found using pulsed lser polymeriztion in wter t room temperture gve vlues vrying significntly depending on monomer concentrtion, inititor type nd its concentrtion, etc.; the verge vlue is round 20,000 Lmol -1 s -1 [15]. In nother report the kinetics of polymeriztion in dioxne re reported to show vlue for k p /[k t ] 1/2 of 0.58 [16]. Using s n pproximtion the reported termintion constnt for crylmide (no vlue reported for ) in wter/dioxne mixture of Lmol -1 s -1 [17] we clculte n pproximte k p = 8800 Lmol -1 s -1 for. Both vlues of propgtion constnt re lower thn for HA. From results in Tble 1 follows lso tht for given monomer low moleculr weight mcro CTA my be prepred not only by incresing the CTA concentrtion s expected (lowering the monomer to CTA rtio in ccordnce with eqution 1); it is lso importnt to lower the inititor concentrtion in order to mintin monomer to inititor concentrtion rtio ([M] o :[I] o ) resulting in similr polymeriztion rte thn for higher moleculr weight mcro-cta. In the cse of this rtio ws 2600 for 10.8 Kg mol -1 mcro-cta, while for HA this rtio ws 2700 for 9.9 Kg mol -1 mcro-cta. For the RAFT polymeriztion of HEMA the sitution is very different from the prent monomer MMA; even if both monomers re from the sme fmily, their properties (MMA, hydrophobic nd HEMA, hydrophilic) nd polymeriztion behvior re quite different. The kinetic constnt of propgtion (k p ) of HEMA is 3270 Lmol -1 s - 1 [14], 4 times greter thn tht of MMA nd from the results obtined is evident tht the trnsfer bility to the CTA used in this study is not very efficient for HEMA. The result is tht for controlling the moleculr weight nd polydispersity of poly(hema) by RAFT polymeriztion it ws necessry to increse the CTA to inititor rtio to vlues between 25 nd 50, more thn ten times tht needed for controlling MMA homopolymeriztion. More CTA mens higher trnsfer rte to the CTA nd lower polymeriztion rte. By doing this 75 yield of poly(hema) ws obtined in 16 h, while for the sme 75 yield of poly(mma) 24 h of polymeriztion were needed. Even if the gol moleculr weights in both cses were chieved (compre vlues of theoreticl nd GPC mesured moleculr weights in Tble 1 for poly(mma) nd poly(hema) t 75 yield), the polydispersity is quite different 1.09 for poly(mma) while 1.50 for poly(hema) ws mesured. A further increse in CTA concentrtion in RAFT polymeriztion of HEMA showed tht only up to 8 h of polymeriztion (30 yield) resulted in reltively low PDI of In the cse of HEMA is evident tht controlled rdicl polymeriztion is only chieved t low polymeriztion yield, while t higher yields the polydispersity grows to rech vlues close to non controlled rdicl polymeriztion. This result indictes tht side rections nd possibly polymer chin termintion through polymer to polymer ddition widens the PDI. In summry it is evident tht the CTA chosen for this study works well for the RAFT polymeriztion of MMA, nd HA; while for HEMA nother CTA type is needed. In ny cse limiting the polymeriztion yield of HEMA mcro-cta with good chrcteristics for further use cn be obtined. In the cse of Styrene this monomer is known to redily polymerize but t slow rte. The reported k p is 341 L mol -1 s -1 [14], the smllest of ll monomers used in this study. Styrene trnsfer bility is high since styryl rdicls re stbilized by resonnce. The results in Tble 1 show clerly tht poly(st) cn be prepred by RAFT t high moleculr weight with nrrow polydispersity, however t low polymeriztion rte resulting in lower yields thn for the other monomers t the synthetic conditions chosen in our studies. For fster polymeriztion of styrene by RAFT, higher monomer nd inititor concentrtion nd temperture cn be used while djusting the CTA to inititor rtio. Polymeriztion of styrene in bulk dding certin mount of CTA t high temperture is lso possible [10]. Block copolymers The synthetic procedure to prepre diblock copolymers is presented in Scheme 2, while the RAFT mechnism ws described in Scheme 1. Since from the RAFT methodology it is expected tht certin smll mount of inititor derived polymers (terminted) re included in the mcro-cta used in this step of synthesis, nd becuse the RAFT copolymeriztion mechnism goes through the formtion of homopolymers of the second monomer; it is dvisble to limit the monomer conversion in this second step of block copolymer formtion to vlues between In this wy, the purifiction of the block copolymer product includes in first step the precipittion of the polymer product, eliminting residul monomer (myor contminnt) nd inititor derived subproducts; nd in the second step seprtion of homopolymer(s) (minor contminnts) from the block copolymer. Scheme 2. Outline of generl methodology for the synthesis of block copolymers.

5 Controlled Synthesis of Block Copolymers contining N-isopropylcrylmide by RAFT Polymeriztion 25 Theoreticl moleculr weight of the block copolymers cn be clculted by using the following idelized eqution: M (Block) n [M] M 0 mon mon [mcro CTA] 0 + M n (mcro CTA) (2) where [M] 0 is the initil concentrtion of monomer in the second step, M mon is the moleculr weight of this monomer, ρ mon is the conversion of this monomer, [mcro-cta] 0 is the initil concentrtion of the mcro-cta nd M n (mcro-cta) is the moleculr weight of the mcro-cta (first block). The specific results obtined re discussed below for ech type of block copolymer. Synthesis of nd poly(mma)-b-poly() nd poly()-b-poly(mma) As quoted before, for block copolymeriztion using RAFT it is dvisble to strt with the monomer tht shows higher trnsfer bility for the CTA selected. In this cse is dvisble to strt with MMA in the first step nd follow with monomer. Tble 2 show the results obtined by this suggested strtegy. Since will grow in the second block, CTA to inititor rtios from 3 to 1 to 7 to 1 were tested. A reltively smll second block of poly() ws grown in controlled fshion. By compring the theoreticl moleculr weight with the one mesured by GPC mintining PDI close to 1.1 demonstrtes the RAFT control. Figure 1, section A) shows GPC trces from mcro-cta of poly(mma) s compred with the resulting chin extended block copolymer; the GPC trces show similr shpe with no shoulders indicting tht the grow ws the sme for ll mcro-cta chins. The reverse strtegy of strting with poly() mcro-cta nd growing poly(mma) second block, ws tested trying to djust the RAFT polymeriztion conditions to those pproprite for the RAFT polymeriztion of the second monomer. Results re presented in Tble 3. As expected the block copolymers were grown to stisfctory moleculr weights (compre clculted with mesured moleculr weights), however the PDI incresed from 1.1 to 1.4 vlues. This is cler indiction of loss of RAFT control. Even if the CTA to inititor rtio ws incresed from 1.25 to 1, used for homopolymeriztion of MMA, to 1.7 to 1 rtio, no substntil improvement in PDI ws obtined. However the GPC trces, s shown in Figure 1 section B), shows tht the GPC chromthogrms hve similr shpe with no shoulders indicting no termintion nd no homopolymer suggesting tht the chin extension ws effective nd reltively ordered. Another fct tht needs to be highlighted is tht the clculted moleculr weight of the second block is reltively lrge, up to the sme size of the strting mcro-cta. Growing smll block is expected to impct less the polydispersity of polymer thn growing big block. The reltive size of ech Tble 2. Preprtion of poly(mma)-b-poly() strting with polymma mcro-cta. Mcro-CTA M n PDI [PMMA] 0 :[I] 0 [] 0 :[PMMA] 0 M n theo Poly(MMA) 43, : : 1 54,500 47, Poly(MMA) 37, : : 1 52,200 50, Poly(MMA) 50, : : 1 64,200 58, Using the idelized eqution 2; b PDI = M w /M n; c By 1 H-NMR; d by mss of recovered polymer. Fig. 1. GPC chromtogrms of the sequentil synthesis of poly()-b-poly(mma) block copolymers: A) Strting with poly(mma) mcro-cta; B) Strting with poly() mcro-cta.

6 26 J. Mex. Chem. Soc. 2011, 55(1) Alejndro Veg-Rios nd Angel Lice-Clveríe Tble 3. Preprtion of poly()-b-poly(mma) strting with poly mcro-cta. Mcro-CTA Mn PDI [P] 0 :[I] 0 [MMA] 0 :[P] 0 M n theo Poly() 40, : : 1 69,200 66, Poly() 33, : : 1 71,500 77, Poly() 30, : : 1 72,000 75, Poly() 45, : : 1 89,200 83, Using the idelized eqution 2; b PDI = M w /M n; c By 1 H-NMR; d by mss of recovered polymer. block in the block copolymer cn be estimted by ssuming tht ll mcro-cta chins re ctive nd therefore clculting the number of units dividing the moleculr weight (M n ) by the monomer moleculr weight before chin extension (first block) nd fter chin extension, tking the by GPC mesured M n, substrcting the mcro-cta M n vlue nd clculting the number of units of this second block. Another form is by determining the molr rtio of ech type of units in good solvent for both blocks using 1 H-NMR. Figure 2 shows 1 H-NMR spectr of poly(mma)-b-poly() in deuterted chloroform (200 MHz). Selecting the res of the signls t 4 ppm (for methine proton of ) in reltion to the re of the signl t 3.8 ppm (for methyl protons (3) of MMA), the content of in the block copolymer ws clculted to be 20. On the other side the rtio s clculted bsed on mesured moleculr weight by GPC (M n ) is 24.6 for giving the generl formul poly(mma) 370 -b-poly() 121. The difference by both methods my reflect the inccurcy in determining the true moleculr weight, since the dn/dc vlue used ws clculted nd perhps lso 200 MHz spectrum is not enough for n ccurte content determintion by NMR. In conclusion for block copolymer formtion for which the two monomers show very different polymeriztion bility for selected CTA, it is importnt to follow the strtegy of strting with the methcrylte type monomer nd chin extending with the crylmide type of monomer. The increse of PDI by not observing this suggestion my be reduced by djusting the CTA to inititor rtio for the second monomer; however the loss of control cnnot be neglected. In the literture there is only one report on the preprtion of /MMA block copolymers by RAFT [18]. A totl of three block copolymers were prepred using S-methoxycrbonylphenylmethyl dithiobenzote s CTA. Only one of the block copolymers prepred hs polydispersity lower thn 1.4. Tht copolymer contins only 8 mol of MMA nd ws tested with success for temperture sensitive micelliztion. In tht report the uthors do not py ttention to the sequence of monomer ddition nd use similr mcro-cta to inititor rtio for both types of monomers. Synthesis of poly()-b-poly(ha) nd poly(ha)-b-poly() Strting with the fct tht CTA to inititor rtio for well controlled RAFT polymeriztion ws third of tht required for HA under our experimentl conditions, we concluded tht could be better trnsferring monomer to the CTA used thn HA. Therefore we decide to test first the synthesis of block copolymers of poly()-b-poly(ha), strting with poly() mcro-cta s. Tble 4 summrize the results of this strtegy. As cn be seen, when using rtio of [CTA] 0 /[I] 0 of 2.5 to 2.85 block copolymers with high polydispersity were obtined, no mtter if the size of the second block, reltive to the first block, ws smll or big PDI vlues from 1.53 (smll) to 1.99 (big) were obtined. When the CTA to inititor rtio ws rised to 12.5 to 1, vlue for which HA homopoly- Fig H-NMR Spectrum of poly(mma) 370 -b-poly() 121, M n = 50,690.

7 Controlled Synthesis of Block Copolymers contining N-isopropylcrylmide by RAFT Polymeriztion 27 Tble 4. Preprtion of poly()-b-poly(ha) strting with poly mcro-cta. Mcro-CTA Mn PDI [P] 0 :[I] 0 [HA] 0 :[P] 0 M n theo Poly() 17, : : 1 35,300 27, Poly() 15, : : 1 34,000 29, Poly() 24, : : 1 49,000 30, Poly() 10, : : 1 24,600 31, Using the idelized eqution 2; b PDI = M w /M n ; c By 1 H-NMR; d by mss of recovered polymer. Tble 5. Preprtion of poly(ha)-b-poly() strting with polyha mcro-cta. Mcro-CTA Mn PDI [PHA] 0 :[I] 0 [] 0 :[PHA] 0 M n theo Poly(HA) 16, : : 1 30,000 29, Poly(HA) 9, : : 1 34,900 40, Using the idelized eqution 2; b PDI = M w /M n ; c By 1 H-NMR; d by mss of recovered polymer. merizes by RAFT in controlled wy, the result is drmticlly better (lst row in tble 4): the PDI droped to 1.23 no mtter tht the size of the grown second block is higher thn the first block. This result demonstrted tht not only the sequence of monomer ddition but lso the CTA to inititor rtio re importnt for the success of RAFT block copolymeriztion. The reverse strtegy, strting with poly(ha) mcro-cta s nd growing poly() second block, showed unexpectedly very good results. Meeting the CTA to inititor conditions for RAFT of homopolymeriztion ( 6.5 to 1 rtio) resulted in essentilly the sme PDI for the first block nd for the resulting block copolymer (Tble 5), even if the size of the second block ws very similr to tht of the first block. The lst row of Tble 5 shows n experiment for which we djusted the CTA to inititor rtio for growing 3 times longer second blocks thn the first block. Using 12.5 to 1 rtio we succeded in mintining the sme PDI while growing 3 times lrger second block, even if it ws dvisble to grow n crylic second block rther thn block. Either we re wrong with the ssumption tht hs n intermedite growing bility in RAFT processes between methcryltes nd cryltes; or the CTA to inititor rtio hs n even more profound impct thn the monomer ddition sequence in the outcome of RAFT block copolymeriztion. Figure 3 compres GPC chromtogrms for exmples of the two strtegies used bsed on mcro-cta s with similr moleculr weights nd the sme rtio of [Mcro-CTA] 0 :[I] 0, one strting with poly() mcro-cta (section A) nd the second one strting with poly(ha) mcro-cta (section B). The results show essentilly the sme polydispersity index. The differences Fig. 3. GPC chromtogrms of the sequentil synthesis of poly()-b-poly(ha) block copolymers: A) Strting with poly() mcro-cta; B) Strting with poly(ha) mcro- CTA.

8 28 J. Mex. Chem. Soc. 2011, 55(1) Alejndro Veg-Rios nd Angel Lice-Clveríe in moleculr weights of the block copolymers is due to the different rtio [McroCTA] 0 :[Monomer] 0. The chromtogrms show shift in retention time, s expected for chin extension, nd no shoulders in the chromtogrms indicting bsence of chin termintion nd no unrected mcro-cta. Synthesis of poly(hema)-b-poly() From the RAFT homopolymeriztion experiments we lerned tht HEMA polymerizes fster thn t the sme CTA to inititor rtio of 25 to 1 (Tble 1). On the other side the CTA used for our studies is evidently not very pproprite for controlling HEMA polymeriztion t high polymeriztion yields. Therefore it ws dvisble to try the block copolymer formtion strting with poly() mcro-cta nd growing second block of poly(hema). These experiments were ll unsuccessful; polymer product with PDI of 4.5 nd in some cses gel product ws formed. When we tried the reverse strtegy, using poly(hema) mcro-cta nd growing poly(), block in the second step, we hve success (Tble 6). We were ble to grow reltively smll poly() second block but with n overll PDI of Since the polydispersity of the mcro-cta ws lrger nd the block copolymeriztion yield is 59 it is strong indiction tht in the homopolymeriztion of HEMA n pprecible mount of terminted (non-living) chins re produced through the not well controlled methodology. However the CTA-functionlized poly(hema) chins were ble to ct s very good mcro-cta for polymeriztion yielding well defined block copolymer in cceptble yield. Since the mcro-cta used for the preprtion of the well defined block copolymer hd not so good polydispersity of 1.5, we tested in how fr the composition of the block copolymer s clculted from the GPC moleculr weight determintion, described before for poly(mma)-b-poly(), could be compred to the composition mesured using 1 H-NMR in deuterted methnol, good solvent for both blocks. Figure 4 shows the 1 H-NMR spectrum of the block copolymer (200 MHz). The composition ws clculted using the signls t 3.77 ppm for methylene (two b Protons of HEMA units in the block copolymer) nd the signl t 4 ppm where two proton types re superimposed: the methine ( ) proton of units nd the other methylene (two protons) of HEMA units. The NMR clcultion yielded 30 content on units, while the GPC clcultion results in generl formul of poly(hema) 201 -b-poly() 99, representing 33 content, very good mtch. For some pplictions of block copolymers nd lso for stbility purposes it is desired to remove the thiocrbonylthio group from the polymer product. There re severl methods for performing this [7, 19]. Since poly(hema)-b-poly() is wter soluble, we decided to test simple procedure reported in conference [20]: rdicl exchnge using hydrogen peroxide queous solution. Tble 6. Preprtion of poly(hema)-b-poly(). Mcro-CTA Mn PDI [P] 0 :[I] 0 [HEMA] 0 :[P] 0 M n theo Poly() 21, : : 1 57,000 73, Poly(HEMA) 26, [PHEMA] 0 :[I] 0 3 : 1 [] 0 :[PHEMA] : 1 Using the idelized eqution 2; b PDI = M w /M n ; c By 1 H-NMR; d by mss of recovered polymer. 39,500 37, Fig H-NMR Spectrum poly(hema) 201 -b-poly() 99, M n = 37,400.

9 Controlled Synthesis of Block Copolymers contining N-isopropylcrylmide by RAFT Polymeriztion 29 Fig. 5. GPC chromtogrms of poly(hema)-b-poly(): ) s synthesized nd b) fter removl of thiocrbonylthio-group. Figure 5 show GPC chromtogrms of the block copolymer s synthesized (M n = 37,400 ; PDI 1.2), nd fter rection with hydrogen peroxide to remove the thiocrbonylthio group (M n = 40,920 ; PDI 1.5). Even if the desired group removl ws evident by chnge in color from pink to white (dithiobenzotes re red) the process resulted lso in increse of polydispersity. The insert in Figure 5 shows tht higher moleculr weight shoulder is produced; this is n indiction of termintion of chins by polymer to polymer ddition. Using hydrogen peroxide for this removl ws not very successful; we recommend using insted the improved rdicl exchnge method with zo-compounds reported recently [19]. Poly()-b-poly(St) nd poly(st)-b-poly() The first synthesis of poly()-b-poly(st) block copolymers by RAFT ws reported by Nuopponen et l. [21]. The uthors used the sme CTA s we re using in this study, so our results cn be well compred to those. From our results in the homopolymeriztions studies follows tht the best promising strtegy would be to strt with polystyrene mcro-cta s nd to grow poly() block in the second step. Tht ws the strtegy followed in reference [21] with success. Giving the fct tht we showed for other systems tht chnging the CTA to inititor rtio we succeeded in prepring block copolymers in the opposite sequence, we wnted to test here if this ws possible. Tble 7 shows the results on block copolymers synthesized, it ppers tht when poly() mcro-cta is used to grow second block of poly(st), the polydispersity decreses with incresing rtio of [Mcro-CTA] 0 :[I] 0. A rtio of mcro-cta to inititor greter thn 7 is needed to control the block copolymeriztion while for block copolymers prepred strting with poly(st) mcro-cta rtio of 3.5 to 1 is enough to yield good polydispersity, see Tble 8. Figure 6 shows chromtogrms from the two strtegies for the synthesis of poly()-b-poly(st) block copolymers; section A compres chromtogrms of the synthetic strtegy strting with poly() mcro-cta nd section B compres chromtogrms of the synthetic strtegy strting with poly(st) mcro-cta. Note the lrge displcement of block copolymer retention time in section A nd lso note tht no shoulders or dditionl peks re observed demonstrting clen block copolymer product. In the cse of section B smll shift in retention time is observed becuse the difference in moleculr weight between mcro-cta nd block copolymer is not s big s for the other cse (section A). DSC mesurements The glss trnsition temperture (T g ) of selected block copolymers ws determined by clorimetry (DSC) nd re shown in Tble 9. In generl terms, the results show tht different blocks re phse seprted since two seprte Tg s with vlues similr Tble 7. Preprtion of poly()-b-poly(st) strting with poly() mcro-cta. Mcro-CTA Mn PDI [P] 0 :[I] 0 [St] 0 :[P] 0 M n theo Poly() 33, : : 1 135, , Poly() 56, : : 1 81,500 87, Using the idelized eqution 2; b PDI = M w /M n ; c By 1 H-NMR; d by mss of recovered polymer. Tble 8. Preprtion of poly(st)-b-poly() strting with poly(st) mcro-cta. Mcro-CTA Mn PDI [PSt] 0 :[I] 0 [] 0 :[PSt] 0 M n theo Poly(St) 66, : : 1 112,800 91, Poly(St) 32, : : 1 147,000 48, Using the idelized eqution 2; b PDI = M w /M n ; c By 1 H-NMR; d by mss of recovered polymer.

10 30 J. Mex. Chem. Soc. 2011, 55(1) Alejndro Veg-Rios nd Angel Lice-Clveríe Fig. 6. GPC chromtogrms of the sequentil synthesis of poly()-b-poly(st) block copolymers: A) Strting with poly() mcro-cta; B) Strting with poly(st) mcro-cta. Tble 9. Glss trnsition tempertures of blockcopolymers by DSC. Copolymer M n PDI T g 1 st Block ( C) T g Homopolymer T g P Block 1 st Block ( C) ( C) b Poly(MMA)-b-poly() 66, Poly(St)-b-poly() 91, Poly(HEMA)-b-poly() 37, Poly(HA)-b-poly() 40, From reference [22], tctic polymers; b Reported T g of 130 o C [22]. to those reported for the pure homopolymer segments in Polymer Hndbook [22] re found. However, detiled nlysis of these T g -vlues shows tht in ll cses, the mesured vlues re higher thn the reported ones. This finding my result from the method used in the DSC nlysis (temperture modultion of 0.5 K with heting rte of 5 K/min). In the cse of poly block (130 o C reported) nd polyst block (100 o C reported) the mesured T g -vlues re only 5 to 8 o C higher; however in the cse of the polymma block (105 o C reported) nd polyhema block (85 o C reported), the mesured vlues re significntly higher: 125 o C nd 120 o C respectively. One possible explntion for the high T g of polymma block could be n incresed tcticity, since it is reported tht the T g vlue for syndiotctic PMMA is 126 o C [22]. In the cse of the polyhema block, we cn postulte tht hydrogen bonding to the poly block in the blockcopolymer could be responsible for the incresed T g of the polyhema block. This rgument is supported by the fct tht the poly block in the sme blockcopolymer shows lso n bnorml high T g vlue of 145 o C. It is worth to mention tht the T g of the polyha block (-57 o C reported) could not be determined in our experimentl setup working in the temperture rnge from -50 to 220 o C. Conclusions It ws demonstrted tht series of diblock copolymers contining poly() s one of the blocks cn be prepred by sequentil living rdicl polymeriztion by using the RAFT methodology. Only one chin trnsfer gent ws used, however it ws possible to prepre mcro-cta s with controlled moleculr weight nd low polydispersity of different type of monomers: crylics (HA), methcrylics (MMA), crylmides () nd styrenics (St) by djusting the CTA to Inititor rtio. In the synthesis of block copolymers the good choice of the first block (monomer showing best trnsfer bility to the CTA) results in better controlled block copolymer in terms of reltive size of blocks, predicted moleculr weight nd low polydispersity; however the reverse strtegy: strting with the monomer showing worst trnsfer bility, my result lso in block copolymers with controlled moleculr weight nd polydispersity if the CTA to Inititor rtio is djusted ccordingly. The RAFT homopolymeriztion of HEMA using the chosen CTA for this study resulted in non controlled process, however by djusting the CTA to Inititor rtio nd limiting the monomer conversion, good working mcro-cta s cn be prepred tht showed bility to grow poly() second block with controlled moleculr weight nd polydispersity. Experimentl Section Mterils N-isopropylcrylmide (NIPAAM) ws purified by recrystlliztion in hexne. Methyl methcrylte (MMA) nd styrene (St) were distilled dding 1,3,5,trimethyl-2,4,6-tris(3,5-di-tertbutyl-4-hydroxybenzyl)benzene (ETHANOX-330) s polymeriztion inhibitor during distilltion. The monomers n-hexyl

11 Controlled Synthesis of Block Copolymers contining N-isopropylcrylmide by RAFT Polymeriztion 31 crylte (HA) nd 2-hydroxyethyl methcrylte (HEMA) were purified by pssing through column contining n inhibitor remover for methyl ether hydroquinone (MEHQ). The following solvents were used in the RAFT polymeriztion: 1,4 dioxne (99) for RAFT polymeriztion; nd tetrhydrofurne (THF, HPLC Grde, >99) nd N,N -dimethylformmide (DMF, HPLC Grde, >99) for GPC chrcteriztion. All monomers nd solvents were bought from Sigm-Aldrich, Mexico. Synthesis nd polymeriztions Synthesis of CTA nd Polymeriztions The synthesis of 4-Cyno-4-(phenylcrbonothioylthio)pentnoic cid ws conducted ccording to the literture [23, 24]. All polymeriztions were performed in mpoules. In ll cses, 4-Cyno-4-(phenylcrbonothioylthio)pentnoic cid nd 4,4 -zo-bis(4-cynopentnoic cid) (Aldrich) were used s the CTA nd inititor, respectively. One exception ws tht for the synthesis of poly(st) mcro-cta nd its block copolymer with poly(), 4,4 -zobis(isobutironitrile) (AIBN, Aldrich) s inititor ws used. Clculted mounts of monomers, CTA nd inititor were dissolved in 1,4-dioxne (20 ml) under stirring t room temperture. Solutions were degssed by three freeze-pump-thw cycles. After degssing, the mpoules were flme-seled under vcuum nd heted in n oil bth t 70 C while stirring. The polymeriztions were terminted by rpid cooling nd freezing. The homopolymers obtined, lso nmed mcro-cta s since they include the CTA-moiety, were purified by repeted precipittions using pproprite non-solvents: ethyl ether for poly() nd poly(hema), petroleum ether for poly(mma), methnol for poly(st) nd poly(ha). Products were dried in vcuum overnight, chrcterized nd stored in cool dry plce until further use. An exmple of the synthesis of poly() is described in detil: N-isopropylcrylmide (4 g, mol), 4,4 -zobis(4-cynopentnoic cid) (0.012 g, mmol) nd 4-Cyno-4-(phenylcrbonothi oylthio)pentnoic cid ( g, mmol) were dissolved in 1,4 dioxne (30 ml) nd poured in glss mpoule (50 ml) contining mgnetic stir br. Oxygen ws removed using 3 freeze-thw evcution cycles, nd the mpoule ws seled with flme under vcuum. The mpoule contining polymeriztion solution ws submerged in n oil bth with mgnetic stirring t 70 o C. The polymeriztion ws stopped by rpid cooling t given time. The polymeriztion yield ws obtined grvimetriclly by dding 5 fold excess of cold ethyl ether. The polymer product ws purified by dissolution in the minimum mount of cetone followed by dding 5 fold excess of cold ether nd filtering. This procedure ws repeted three times to remove residul monomer followed by drying under vcuum to constnt weight. Block Copolymeriztions Well chrcterized homopolymers synthesized in the first step were used s mcro-cta s. The clculted mount of mcro- CTA ws dissolved in 1,4-dioxne (20 ml) before dding the second monomer in different mounts iming different compositions, nd the inititor. The copolymeriztion procedure ws the sme s for polymeriztion. For mens of purifiction the following combintion of solvent/non-solvent ws estblish for ech type of block copolymer: cetone/ethyl ether followed by cetone/petroleum ether for poly()-b-poly(mma); methnol/ethyl ether for poly()-b-poly(hema), THF/ ethyl ether followed by THF/methnol for poly()-bpoly(st) nd cetone/methnol for poly()-b-poly(ha). As n exmple, the detiled synthesis of poly()- b-poly(mma) block copolymer strting with mcro-cta of poly() is described next: poly() (1.0 g, mmol) M n = 30,890, 4,4 -zobis(4-cynopentnoic cid) (11.1 mg, mmol) nd (2.2 g, 22 mmol) of MMA were dissolved in 1,4 dioxne (40 ml) s solvent, nd poured in glss mpoule (50 ml) contining mgnetic stir br. Oxygen ws removed using 3 freeze-thw evcution cycles, nd the mpoule ws seled with flme under vcuum. The mpoule contining copolymeriztion solution ws submerged in n oil bth with mgnetic stirring t 70 o C. The polymeriztion ws stopped by rpid cooling t given time. The copolymeriztion yield ws obtined grvimetriclly by dding 5 fold excess of ethyl ether, filtering, dissolving the filtrte in cetone, precipitting gin using petroleum ether, nd filtering gin. This procedure ws repeted three times to remove residul monomer nd homopolymers, it ws followed by drying under vcuum to constnt weight. Chrcteriztion Methods Nucler Mgnetic Resonnz Spectroscopy (NMR) 1 H NMR mesurements were crried out on Vrin Mercury (200 MHz) NMR instrument using chloroform-d nd methnold 4 s solvents nd tetrmethylsilne s reference. The min signls of NMR spectr for one exmple of ech mcro-cta re described below. The multiplicity of signl is bbrevited s follows: s = singlet, d = doublet, t = triplet, br = prefix for brod signl. Mcro-CTA of poly(): GPC(THF) M n = 21,500, PDI = H NMR (CDCl 3, 200 MHz) δ 6.45 (1H, brs, NH), 4.05 (1H, brs, CH), 2.06 (1H, brs, CH), 1.69 (2H, brm, CH 2 ), 1.12 (6H, brs, 2(CH 3 )). Mcro-CTA of poly(mma): GPC(THF) M n = 39,120 g/ mol, PDI = H NMR (CDCl 3, 200 MHz) δ 3.60 (3H, brs, OCH 3 ), 2.00 (2H, m, CH 2 ), 0.90 (3H, m, C-CH 3 ). Mcro-CTA of poly(ha): GPC(THF) M n = 20,500, PDI = H NMR (CDCl 3, 200 MHz) δ 4.0 (2H, m, CH 2 ), 2.34 (2H, m, CH 2 ), 1.88 (1H, brs, CH), 1.63 (2H, m, CH 2 ), 1.28 (6H, m, (CH 2 ) 3 ), 0.83 (3H, m, CH 3 ). Mcro-CTA of poly(hema): GPC(DMF) M n =13,650 g/ mol, PDI = H-NMR (CD 3 OD, 200 MHz) δ 4.15 (2H, m, CH 2 ), 3.77 (2H, m, CH 2 ), 1.93 (2H, m, CH 2 ), 1.02 (3H, m, CH 3 ). Mcro-CTA of poly(st): GPC(THF) M n = 69,970, PDI = H-NMR (CDCl 3, 200 MHz) δ 7.37 (3H, m, (Arom. 3CH)), 6.44 (2H, m, (Arom. 2CH)), 1.99 (1H, m, CH), 1.29 (2H, m, CH 2 ).

12 32 J. Mex. Chem. Soc. 2011, 55(1) Alejndro Veg-Rios nd Angel Lice-Clveríe Gel Permetion Chromtogrphy (GPC) with multingle lser light scttering detection (MALLS) The number-verge moleculr weights (M n ) nd polydispersity of the moleculr weight distribution (M w /M n ) of the polymers were determined with two sets of GPC equipment. (1) For ll homopolymers (mcro-cta s) nd block copolymers (excepting polyhema nd its block copolymers), Vrin 9002 chromtogrph equipped with two mixed-bed columns in series (Phenogel 5 liner nd Phenogel 10 liner) nd two detectors: refrctive index (Vrin RI-4) nd tri-ngle light scttering detector (MINI-DAWN, Wytt Technology), ws used. The mesurements were performed in THF t 35 C nd t flow rte of 0.5 ml/min. Reported dn/dc vlues poly(mma) [25], poly(st) [25] nd poly() [26] were used for the moleculr weight evlutions of poly(mma), poly(st) nd poly() mcro-cta s, respectively. The dn/dc of poly(ha) ws determined using differentil refrctometer IR OptiLb DSP (Wytt Technology) t wvelength λ = 633 nm, 40 C, using six solutions with concentrtions of 1.2 mg/ml to 3.5 mg/ml in THF, obtining vlue of ml/g. (2) For poly(hema) mcro CTA s nd its block copolymers, the second, gel permetion chromtogrphy (GPC) equipment is Wters 510 HPLC with three Ashipk columns (Shodex) in series (GF-1G7B, GF-510HQ, GF-310HQ) in column oven (40 C) nd two detectors: refrctive index (Optilb DSP, Wytt Technology) nd multingle light scttering detector (Dwn DSP, Wytt Technology), ws used. The mesurements were performed in DMF t 40 C s the mobile phse t flow rte of 0.4 ml/min. Reported dn/dc vlues in DMF for poly(hema) [25] nd poly() [27] were used for the moleculr weight evlutions of poly(hema) nd poly(), respectively. For the moleculr weight clcultion of block copolymers the verge dn/dc ws clculted from the dn/dc vlues for the corresponding homopolymers in the blocks. Differentil scnning clorimetry The glss trnsition temperture (T g ) of polymers were obtined on TA Instrument modulted DSC Anlyses were crried out under nitrogen. Smples of 5-10 mg were heted in luminum pns t heting rte of 5 K/min in the temperture rnge from -25 o C to 220 o C using temperture modultion of ±0.5 K every 60 sec. Acknowledgements This investigtion ws supported by grnts of CONACYT N o SEP nd DGEST No P. We thnk A. Ocho nd I. Rivero for performing NMR nlysis nd U. Pérez nd F. Soto for some synthetic work. References 1. Sebenik, A. Prog. Polym. Sci. 1998, 23, Szwrc, M. Nture 1956, 178, Lowe, B. A., McCormick, L. C., Prog. Polym. Sci. 2007, 32, Chiefri, J.; Chong, Y. K.; Ercole, F.; Krstin, J.; Jeffery, J.; Le, T.P.T.; Mydunne, R. T. A.; Meijs, G. F.; Mod, C. L.; Mod, G.; Rizzrdo, E.; Thng, S. H. Mcromolecules 1998, 31, Feldermnn, A.; Ah Toy, A.; Phn, H.; Stenzel, H. M.; Dvis, T. P.; Brner-Kowollik, C. Polymer 2004, 45, McLery, B. J.; Tonge, P. M.; Klumpermn, B. Mcromol. Rpid Commun. 2006, 27, Mod, G.; Rizzrdo, E.; Thng, S. H., Mteril Mtters 2010, 5, Mod, G.; Rizzrdo, E.; Thng, S. H., Aust. J. Chem. 2005, 58, Mod, G.; Anderson, A. G.; Ercole, F.; Johnson, C. H. J.; Krstin, J.; Mod, C. L.; Rizzrdo, E.; Spurling, T. H.; Thng, S. H. in Mtyjszewski, K. (Ed.) ACS Symp. Ser. Vol. 685: Controlled Rdicl Polymeriztion. Americn Chemicl Society, Wshington 1998, Chong, Y. K.; Tm, P. T. L.; Mod, G.; Rizzrdo, E.; Thng, H. S. Mcromol. 1999, 32, Schild, H. G. Prog. Polym. Sci. 1992, 17, Rzev, Z. M. O.; Dinçer, S.; Pişkin, E. Prog. Polym. Sci. 2007, 32, York, W. A.; Kirklnd, E. S.; McCormick, L. C. Adv. Drug Delivery Rev., 2008, 60, Mtyjszewski, K.; Dvis, T. P.: Eds. Hndbook of Rdicl Polymeriztion, Wiley-Interscience; Hoboken 2002, Gnchud, F.; Blic, R.; Monteiro, M. J.; Gilbert, R. G. Mcromolecules 2000, 33, Costioli, M. D.; Berdt, D.; Freitg, R.; André, J.; Müller, A. H. E. Mcromolecules 2005, 38, Brndrup, J.; Immergut, E. H.; Grulke, E. A. Eds. Polymer Hndbook Fourth Ed., John Wiley & Sons: New York 1999, p II Tng, T.; Cstelleto, V.; Prrs, P.; Hmley I. W.; King, S. M.; Roy, D.; Perrier, S.; Hoogenboom, R.; Schubert, U. S. Mcromol. Chem. Phys. 2006, 207, Cortez-Lemus, N.; Slgdo-Rodriguez, R.; Lice-Clverie, A. J. Polym. Sci. A: Polym. Chem. 2010, 48, Pfukw, R.; Pound, G.; Klumpermn, B. Polym. Prep. (Amer. Chem. Soc., Div. Polym. Chem.) 2008, 49, Nuopponen, M.; Ojl, J.; Tenhu, H. Polymer 2004, 45, Brndrup, J.; Immergut, E. H.; Grulke, E. A. Eds. Polymer Hndbook Fourth Ed., John Wiley & Sons: New York 1999, Chpter VI. 23. Mitsukmi, Y.; Donovn, S. M.; Lowe, B. A.; McCormick, L. C. Mcromolecules 2001, 34, Thng, H. S.; Chong, B. Y. K.; Mydunne, T. A. R.; Mod, G.; Rizzrdo, E. Tetrhedron Lett. 1999, 40, Brndrup, J.; Immergut, E.H.; Grulke, E.A. Eds. Polymer Hndbook Fourth Ed., John Wiley & Sons: New York 1999, Chpter VII. 26. Slgdo-Rodriguez, R.; Lice-Clverıe, A.; Arndt, K. F. Eur. Polym. J. 2004, 40, Wed, P.; Trzebick, B.; Dwork, A.; Tsvetnov, C. B. Polymer 2008, 49,