Article. Introduction. Faculdade de Farmácia, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro-RJ, Brazil

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1 Article J. Brz. Chem. Soc., Vol. 29, No. 1, , Printed in Brzil Sociedde Brsileir de Químic End Functionliztion by Ring Opening Polymeriztion: Influence of Rection Conditions on the Synthesis of End Functionlized Poly(lctic Acid) Luis P. Icrt, Edson Fernndes, b Lissette Agüero, c Meli Z. Cuest, d Dionisio Z. Silv, d Dniel E. Rodríguez-Fernández, Fernndo G. Souz Jr., Luis Murício T. R. Lim nd Mrcos L. Dis*,e Fculdde de Frmáci, Centro de Ciêncis d Súde, Universidde Federl do Rio de Jneiro, Rio de Jneiro-RJ, Brzil b Centro de Ciênci e Tecnologi, Centro Universitário Serr dos Órgãos, Teresópolis-RJ, Brzil c Centro de Biomteriles nd d Fcultd de Químic, Universidd de l Hbn, L Hbn, Cub e Instituto de Mcromoléculs Professor Elois Mno, Centro de Tecnologi, Universidde Federl do Rio de Jneiro, Rio de Jneiro-RJ, Brzil In this pper, chemicl functionliztion of poly(lctic cid) (PLA) ws crried out by using of slicyl ldehyde (SAl) nd slicylic cid (SAc) s co-inititors of ring opening polymeriztion (ROP). Two fctoril designs (2 2 ) were performed to evlute the effects of the lctide/ctlyst nd co-inititor/ctlyst molr rtios on the content of ldehyde or crboxylic cid end groups, therml properties nd moleculr weight (Mw) of PLA. Tin(II) 2-ethylhexnote ws used s ctlyst. The co-inititor/ctlyst molr rtio hs sttisticlly significnt influence on the polymer functionliztion. The highest co-inititor/ctlyst molr rtio of 12/1 llows the best ldehyde or crboxylic cid functionliztion, independent on the lctide/ctlyst molr rtio. On the other hnd, the used lctide/ctlyst nd co-inititor/ctlyst molr rtios did not show sttisticlly significnt influence on the polymer therml properties. Besides, co-inititor/ctlyst molr rtio hs sttisticlly significnt influence on the polymer moleculr weight. So, the highest co-inititor/ ctlyst molr rtio used (12/1) in combintion with the highest lctide/ctlyst rtio (125/1) produced functionlized PLA with higher moleculr weights. Keywords: poly(lctic cid), ring opening polymeriztion, end group functionlized PLA, experimentl design Introduction Bioresorbble polymers re those cpble of being completely degrded in n queous environment in their corresponding monomers, which, in turn, undergo metbolic ction of living orgnisms. 1-8 Among these polymers, poly(lctic cid) (PLA), poly(glycolic cid) nd their copolymers hve been widely used in biomedicl pplictions, especilly in orthopedics nd controlled drug relese due to chrcteristics such s, biodegrdtion nd biocomptibility PLA cn be synthesized in wide rnge of moleculr weights using two procedures: (i) direct polycondenstion *e-mil: mldis@im.ufrj.br rection of lctic cid tht leds to the formtion of products of low moleculr weight; nd (ii) polyddition rection by ring opening of lctides, in the presence of metl ctlyst nd/or co-inititor gent, producing high moleculr weight polymers s well s generting functionl end groups in the structure of PLA, which re required to the design of new biomcromolecules. 13,14 Ring opening polymeriztion (ROP) llows the synthesis of end functionlized polylctones nd polylctides of high moleculr weight. 6 These polyesters re formed when cyclic ester monomers re rected with ctlyst nd co-inititor. ROP cn be performed s bulk polymeriztion or in solution nd the ctlyst (lso clled inititor) is necessry to strt the rection. 5,7,15 Besides, depending on the type of inititor, ROP proceeds ccording to three

2 100 End Functionliztion by Ring Opening Polymeriztion J. Brz. Chem. Soc. different mjor rection mechnisms, ctionic, nionic or coordintion-insertion. By these procedures, functionlized polyesters of high-moleculr weight nd low polydispersity cn be synthesized in short periods of time. 12,16 Some limittions of polycondenstion, such s the need for exct stoichiometry, high rection tempertures nd the removl of wter, re excluded in ROP. 16 Tin(II) 2-ethylhexnote (SnOct 2 ) is commonly used ctlyst in ROP of lctones nd lctides nd is pproved s dditive by the Food nd Drug Administrtion (FDA) for PLA pplied in food pckging. 17 By using this ctlyst, polymeriztion rection tkes plce by coordintion insertion mechnism in which monomer impurities contining hydroxyl groups ct s co-inititors, recting with SnOct 2 to form Sn O lkoxide bond necessry to initite the coordintion-insertion of the monomer. ROP of lctides with SnOct 2 is firly slow nd, for economic nd commercil resons, it is desirble to increse the rte of polymeriztion by ddition of hydroxyl-functionlized compounds s co-inititor. 18,19 Ech mcromolecule of PLA formed by the mechnism of coordintion-insertion of ROP will generlly contin one chin end terminted with functionl group originted from the termintion rection nd nother one distl end functionl group coming from the co-inititor gent. By ltering the co-inititor, the nture of the end functionl groups cn be vried to fit the ppliction of the polymer. The type of co-inititor nd end-group plys n importnt role in the therml stbility, hydrolytic stbility nd moleculr weight of the resulting polyester. 4,20 Thus, from these rections, functionl groups cpble of llowing other PLA modifiction rections cn lso be introduced into the polymer structure. This mkes the polyester ble to form ctive mcromolecules by rection of the end-functionl groups with complementry groups tht could be present in biologiclly ctive molecules or other polymeric system of interest. 21,22 Therefore, pplicbility of PLA-bsed mterils cn be mplified if functionl end groups re incorported t the polymer bckbone. 4 For this reson, nowdys, mny uthors investigte the use of new ROP co-inititors iming to generte wide vriety of functionl groups into the polymer bckbone tht will contribute to the design nd synthesis of new biologiclly ctive mcromolecules for biomedicl pplictions. 23,24 It is our interest to study the functionliztion of PLA by ROP in order to generte enough quntities of end functionl groups in the polymer bckbones vilble to prticipte in further syntheses of PLA bsed mcromolecules of biophrmceuticl interest. Therefore, in this work, we show results tht explin sttisticlly the influence of some vribles of ROP on the ldehyde nd crboxylic cid co inititors for the end functionliztion of PLA. Experimentl Mterils L-Lctide (L) (Purlct L, 99.5 wt.%) ws supplied by Purc. Tin(II) 2-ethylhexnote (Sn(Oct) 2 ), slicyl ldehyde (SAl) nd slicylic cid (SAc) were supplied by Aldrich. Toluene, chloroform, dichlorometne nd ethyl lcohol were supplied by Vetec/Aldrich. All rectnts were used s received, except L-lctide tht ws purified by crystlliztion from toluene. Polymeriztion Functionlized poly(l-lctide) (end-ctivted PLA) were obtined from L-lctide (L) polymeriztion in L glss flsk with mgnetic stirring which could be mintined t the initil prt of the polymeriztion. Lctide (1 g) ws fed into the flsk with the pproprite mount of co-inititor nd Sn(Oct) 2. The choice of co-inititor for ech one of the polymeriztion ws dependent on the requested chin end functionl group. Slicyl ldehyde nd slicylic cid were used s co-inititor. The investigted lctide/ctlyst molr rtio (R) nd the co-inititor/ctlyst molr rtio (r) were defined ccording to the proposed experimentl design (see below). All the rections were crried out t 180 ºC for 1 h under nitrogen tmosphere. After this time, the flsk ws rpidly cooled down to room temperture nd its content dissolved in chloroform (10 ml). The solutions were kept under stirring for 2 h prior precipittion in cold ethnol (100 ml). The yields were clculted bsed on weight of monomer t the feed nd precipitted polymer. Experimentl design Two 2 2 fctoril designs with replictes t centrl point were developed to evlute the effects of lctide/ctlyst nd co-inititor/ctlyst molr rtios s independent vribles on the ldehyde or crboxyl cid end functionlized PLA. The levels of ech independent fctor picked out nd the correspondent mtrix of experiments for ech co inititor re shown in Tbles 1-3. In both fctoril designs, experimentl runs were crried out in duplicte nd the centrl points in triplicte. Also, the effect of the lctide/ctlyst nd co-inititor/ ctlyst molr rtio on therml properties nd moleculr weight of the synthesized end functionlized PLA ws nlyzed. For these purposes, ech smple ws chrcterized

3 Vol. 29, No. 1, 2018 Icrt et l. 101 Tble 1. Levels of the independent fctor for the 2 2 fctoril design Independent fctor by thermogrvimetric nlysis (TGA), differentil scnning clorimetry (DSC) nd gel permetion chromtogrphy (GPC) (see Mteril chrcteriztion section). The effects of the independent fctors nd its interction, for both fctoril designs, cn be described through the coefficients of the predicted response eqution s follows: Y = β 0 + β 1 X 1 + β 2 X 2 + β 12 X 1 X 2 (1) where X 1 is the independent fctor lctide/ctlyst molr rtio nd X 2 the co-inititor/ctlyst molr rtio. Experiments were mde t rndom nd 0.05 ws considered s significnce level. Sttisticl nlyses were crried on employing softwre Sttistic 7.0. Mteril chrcteriztion Low level Middle level High level Lctide/ctlyst rtio (X 1 ) Co-inititor/ctlyst molr rtio (X 2 ) Tble Fctoril designs for the ldehyde end functionlized PLA study Experimentl run [L]/[Sn(Oct) 2 ] (X 1 ) [SAl]/[Sn(Oct) 2 ] (X 2 ) b PC 0 0 [L]/[Sn(Oct) 2 ]: lctide/tin octote concentrtion rtio; b [SAc]/[Sn(Oct) 2 ]: slicyl ldehyde/tin octote concentrtion rtio; PC: centrl point. Tble Fctoril designs for the crboxylic cid end functionlized PLA study Experimentl run [L]/[Sn(Oct) 2 ] (X 1 ) [SAc]/[Sn(Oct) 2 ] (X 2 ) b PC 0 0 [L]/[Sn(Oct) 2 ]: lctide/tin octote concentrtion rtio; b [SAc]/[Sn(Oct) 2 ]: slicylic cid/tin octote concentrtion rtio. UV-Vis spectroscopy mesurements of end functionlized PLA were performed in Vrin Cry 100 model UV-Vis spectrometer (concentrtion 0.1 wt./v %) using dichloromethne s solvent nd qurtz cuvette (1 cm). Spectr were recorded from nm with determintion of the mximum bsorbnce of slicyl ldehyde nd slicylic cid t 260 nd 320 nm, respectively. An nlyticl curve ws mde from 1.6 to 25.0 µg ml -1 nd 1.0 to 25.0 µg ml -1 for slicyl ldehyde nd slicylic cid, respectively. Anlyses were crried out in triplicte to quntify them in the smples. In typicl procedure, first solution of ech co-inititor ws prepred t concentrtion of 1 mg ml -1. Subsequently, 100-fold dilution ws performed to obtin second dichloromethne solution with concentrtion of pproximtely 10.0 µg ml -1. Nucler mgnetic resonnce ( 1 H NMR) mesurements were crried out in Vrin Mercury VX-300 NMR spectrometer operting t 300 MHz, temperture of cquisitions t 40 C, number of cquisitions of 20, repetition time of pulses of 20 s nd pulse-length of 9.40 (clibrtion for 45 o ). Smples (15 mg) were dissolved in chloroform-d1 (0.8 ml) in 5 mm NMR tubes t room temperture. GPC nlysis of ech end functionlized PLA ws determined using n Agilent 1200 series HPLC with Phenomenex liner Phenogel column. Chloroform ws used s solvent with flow rte of 1.0 ml min -1. Monodisperse polystyrene stndrds were used s clibrtion nd the moleculr weights re expressed reltively to polystyrene moleculr weights. DSC nlyses of end functionlized PLA were crried out in TA Q1000 V9.9 Build 303 Clorimeter. Briefly, 5 mg of the smples were heted nd cooled t rte of 10 ºC min -1 from 80 to 200 ºC under nitrogen flow. Vlues of glss trnsition (T g ), melting temperture (T m ) nd the crystlliztion temperture on cooling (T cc ) were tken from the second heting run followed by cooling run. TGA nlyses of the end functionlized PLA were performed using TA Instruments TGA Q500 Thermonlyser. Mesurements were crried out in nitrogen t heting rte of 20 C min -1 up to 700 C with gs flow rte of 20 ml min -1. Results nd Discussion The use of two co-inititors, slicylic cid nd slicyl ldehyde, for the synthesis of the ldehyde or crboxylic cid end functionlized PLA by ROP in the presence of Sn(Oct) 2 s ctlyst ws reported in previous work of our group t specific rection condition. 22 Coordintioninsertion is the mechnism by which these co-inititors enble the end functionliztion of PLA (Figure 1). Considering the usefulness of these co-inititors for the end functionliztion of PLA, nd its subsequent

4 102 End Functionliztion by Ring Opening Polymeriztion J. Brz. Chem. Soc. Figure 1. Synthesis of ldehyde nd crboxylic cid end functionlized PLA by ring opening polymeriztion (ROP). ppliction for the design nd synthesis of biologiclly ctive mcromolecules, 21,22 it ws of our interest to study the reltion between the co-inititor/ctlyst nd lctide/ ctlyst molr rtio on the degree of end functionliztion of PLA. The effect of these vribles on the therml properties nd moleculr weight of the end functionlized PLA ws lso investigted. Two fctoril experimentl designs (2 2 ) with replictes t centrl point for ech co-inititor were employed for those purposes. Both designs were duplicte t fctoril points nd the centrl points were triplicte. Experimentl results re shown in Tbles 4 nd 5. As cn be observed from the experimentl dt reported in Tbles 4 nd 5, the nlysed independent fctors (lctide/ctlyst nd co-inititor/ctlyst molr rtio) influence the degree of end functionliztion for both co-inititors (ldehyde or crboxylic cid), s well s, the therml properties nd the moleculr weight of the synthesized PLA. Tble 4. Experimentl results of the 2 2 fctoril designs for the SAl end functionlized PLA study Run [L]/Sn(Oct) 2 [Sl]/Sn(Oct) 2 [Sl] / ppm T d / C T g / C T m / C X c / % Mn / (g mol -1 ) , , , , , , , , , , ,500 Sl: slicyl ldehyde; T d : temperture of mximum weigh lost rte; T g : glss trnsition temperture; T m : melting temperture; X c : degree of crystllinity; M n : number verge moleculr weight. Degree of crystllinity X c determined using the eqution: X c = H m / H mo ; H m : melting enthlpy; H mo : stndrd melting enthlpy for 100% crystlline PLA (106 J g -1 ). 25 Tble 5. Experimentl results of the 2 2 fctoril designs for the SAc end functionlized PLA study Run No. 2 [L]/Sn(Oct) 2 [SAc]/Sn(Oct) 2 [SAc] / ppm T d / C T g / C T m / C X c / % Mn / (g mol -1 ) 1b ,900 2b ,900 3b ,600 4b ,800 5b ,500 6b ,100 7b ,100 8b ,800 9b ,100 10b ,900 11b ,900 SAc: slicylic cid; T d : temperture of mximum weigh lost rte; T g : glss trnsition temperture; T m : melting temperture, X c : degree of crystllinity; M n : number verge moleculr weight. Degree of crystllinity X c determined using the eqution: X c = H m / H mo ; H m : melting enthlpy; H mo : stndrd melting enthlpy for 100% crystlline PLA (106 J g -1 ). 25

5 Vol. 29, No. 1, 2018 Icrt et l. 103 Figure 2. Clibrtion curves used to quntify () slicyl ldehyde nd (b) slicylic cid. Tble 4 resumes the results for slicylic cid employed s co-inititor. It is possible to observe tht the highest functionliztion of PLA ws reched t condition number five, in which the lctide/ctlyst molr rtio ws used t low level nd the co-inititor/ctlyst molr rtio ws t high level. On the other hnd, when co-inititor ws not present in the medium, it ws not detectble end functionliztion of PLA (experiments 1-4). Results for slicyl ldehyde showed similr tendency to tht of slicylic cid (Tble 5). However, the end crboxylic functionliztion of PLA is twice tht shown in Tble 4 t the sme condition. The clibrtion curve used to quntify slicyl ldehyde nd slicylic cid ws obtined with correltion coefficient (R 2 ) of nd for ech co-inititor, respectively (Figures 2 nd 2b). Quntifiction of slicyl ldehyde nd slicylic cid in the smples of PLA showed the success of PLA functionliztion with crboxylic or ldehyde groups fter ROP. Considering the mechnism of ROP, hydroxyl functionl group present in co-inititor molecule rects with Sn(Oct) 2, forming the inititing tin lkoxide linkge necessry to propgte monomer ddition. After termintion, frgment of the co-inititor remins t the end of the chin. These results re in greement with those previously reported in the literture by the use of some liphtic nd romtic lcohols s co inititors of ROP H NMR spectr of both ldehyde nd crboxylic cid end functionlized PLA re shown in Figure 3. These spectr llow the identifiction of the structure of the co inititors linked to the polymer bckbone. 1 H NMR spectr of ldehyde (Figures 3 nd 31) nd crboxylic cid (Figure 3b) end functionlized PLA showed signls t d 1.58 nd 5.19 ppm due to CH 3 nd CH protons of PLA, respectively. In turn, the pek t d 4.2 ppm probbly corresponds to the CH 2 of Sn(Oct) 2 still linked t the end of the chin. Exmintion of the microstructure of both end functionlized PLA by 1 H NMR reveled resonnce signls between d 7.0 nd 8.0 ppm ttributed to romtic protons of slicyl ldehyde nd slicylic cid, respectively (Figures 3 nd 3b). The spectrum of ldehyde end functionlized PLA lso showed pek t d 10.0 ppm (Figure 31) ttributed to the ldehyde proton of slicyl ldehyde covlently linked. Due to the lower molr rtio of these end functionl groups in the polymer, they hve poor contribution in protons, resulting minly in peks of smll intensity in the spectr. Figure 3. 1 H NMR spectr of () nd (1) crboxylic cid nd (b) ldehyde end functionlized PLA. In order to better understnd the influence of the independent fctors on the end functionliztion of PLA, nlyses of vrince (ANOVA) were developed for ech co-inititor, s shown in Tbles 6 nd 7. In the fctoril design, in which slicylic cid ws employed s co-inititor (Tble 6), the co-inititor/ ctlyst molr rtio (X 2 ) ws the independent fctor with significnt influence on the finl ldehyde functionliztion of PLA, while the independent fctor lctide/ctlyst molr rtio (X 1 ) does not hve ny significnt influence on the

6 104 End Functionliztion by Ring Opening Polymeriztion J. Brz. Chem. Soc. Tble 6. Fctor coefficient discrimintion nd lck of fit of the model djusted corresponding to the fctoril design 2 2 employing slicylic cid (SAc) s co-inititor. Influence on the PLA functionliztion Regression coefficient Vlue p-vlue β 0 (block effect) β 1 (X 1 ) β 2 (X 2 ) β 12 (X 1 X 2 ) Lck of fit Significnt coefficients. Tble 7. Fctor coefficient discrimintion nd lck of fit of the model djusted corresponding to the fctoril design 2 2 employing SAl s co inititor. Influence on the PLA functionliztion Regression coefficient Vlue p-vlue β 0 (block effect) β 1 (X 1 ) β 2 (X 2 ) β 12 (X 1 X 2 ) Lck of fit Significnt coefficients. ldehyde functionliztion of PLA. First order model obtined in this fctoril design is described in eqution 2: Y = X 2 (2) For the fctoril design employing slicyl ldehyde s co-inititor (Tble 7), ll independent fctors nd its interction generted in this design hve significnt influence on crboxylic functionliztion of PLA. The obtined mthemticl first order model ws represented by eqution 3: Y = X X X 1 X 2 (3) The obtined model generted response surfce in the intervl of ech considered independent fctor. Results of lctide/ctlyst nd co-inititor/ctlyst molr rtio surfce nd contour of predicted functionliztion rtio re shown in Figure 4. As cn be observed from Figures 4 nd 4b, ldehyde nd crboxylic cid functionliztions of PLA were found to increse with the increment of the co-inititor/ ctlyst molr rtio. Hence, ldehyde nd crboxylic cid functionliztions were mximum t the highest level of co-inititor/ctlyst molr rtio (12/1). However, ldehyde or crboxylic cid functionliztion ws not found to be influenced by chnging the [L]/[Sn] molr rtio from 75/1 to 125/1, which ws lso confirmed by the ANOVA nlysis (Tbles 6 nd 7). Considering the mechnism of ROP described bove, higher levels of co inititor/ctlyst molr rtio increse the probbility of rection between the ctlyst nd the co-inititor, stge necessry for the polymeriztion initition. It is importnt to mention tht other hydroxyl impurities, such s lctic cid nd wter could eventully begin the process of chin growth without ny effect on the kinetic of ROP. This fct suggests tht these impurities did not inhibit the syntheses of end functionlized PLA. 29 Therefore, in ROP by coordintion insertion mechnism, higher levels of co-inititor/ctlyst molr rtio ssure the presence of the co-inititor functionl group in the polymer. The results re in greement with those reported for the use of some different co-inititors in ROP. 7,30-33 On the other hnd, the model hs significnt lck of fit for ech co inititor, indicting tht is possible to be in n re where there is n optiml point. In order to show the sttisticl influence of this dependent vribles nd its combintion on the level of ldehyde or crboxylic cid functionliztion of PLA, Preto chrt ws plotted s shown in Figures 5 nd 5b for SAl nd SAc, respectively. As cn be seen from Figure 5 nd previously confirmed by the ANOVA nlysis (Tbles 6 nd 7), only the [SAl]/[Sn] molr rtio vrible showed sttisticlly significnt influence on the functionliztion of PLA. On the other hnd, from Figure 5b, different sitution is observed since both dependent vribles ([SAc]/[Sn] nd [L]/[Sn] molr rtios) showed sttisticlly significnt influence on the functionliztion of PLA. However, the [SAc]/[Sn] molr rtio showed more influence thn [SAl]/[Sn] molr rtio Figure 4. Lctide/ctlyst nd co-inititor/ctlyst molr rtio surfce nd contour of predicted functionliztion rtio for () ldehyde nd (b) crboxylic cid s co-inititors.

7 Vol. 29, No. 1, 2018 Icrt et l. 105 Figure 5. Preto chrt of lctide/ctlyst, co-inititor/ctlyst molr rtio nd stndrdized effect on the PLA functionliztion for () ldehyde (MS pure error = ) nd (b) crboxylic cid (MS pure error = ) s co-inititors. Figure 6. Lctide/ctlyst nd co-inititor/ctlyst molr rtio surfce nd contour of predicted temperture of mximum degrdtion rte (T d ) for () ldehyde nd (b) crboxylic cid end functionlized PLA. on PLA crboxylic cid functionliztion. Probbly due to the fct tht romtic ldehyde hs higher inductive effect thn romtic crboxyl group, mking the phenolic hydroxyl group of SAl less rective thn in SAc. Finlly, it ws observed tht, the interction of both dependent vribles showed sttisticlly significnt influence on the response vrible of crboxylic cid functionliztion. This result ws lso confirmed by the ANOVA study. Therml chrcteriztion of ll functionlized PLA synthesized by ROP showed tht lctide/ctlyst nd co inititor/ctlyst molr rtios hd slight influence on its therml properties. Results of TGA nlyses re shown in Figures 6 nd 6b. As cn be seen from Figure 6, [SAl]/[Sn] nd [L]/[Sn] molr rtios did not show mrked influence on the temperture of mximum degrdtion rte (T d ) of the ldehyde end functionlized PLA. On the contrry, [SAc]/[Sn] nd [L]/[Sn] molr rtio showed to hve n influence on T d of the crboxylic cid end functionlized PLA. Therefore, more chnge of T d ws observed t [SAc]/[Sn] molr rtio of 12/1 nd [L]/[Sn] molr rtio of 75/1 (Figure 6b). These results re probbly due to the presence of interctions estblished by the crboxylic cid end functionl group with polymer chins. These results gree with those reported by literture in end functionliztion of PLA with mleic nhydride. 34 Sttisticlly significnt influence of [SAc]/[Sn] nd [L]/[Sn] molr rtios on T d of crboxylic cid end functionlized PLA ws evluted by the Preto chrt (Figure 7). Figure 7. Preto chrt of the influence of [SAc]/[Sn] nd [L]/[Sn] molr rtios on the temperture of mximum degrdtion rte (T d ) of crboxylic cid end functionlized PLA (MS pure error of ). As cn be seen from Figure 7, [SAc]/[Sn] nd [L]/[Sn] molr rtios showed sttisticlly significnt influence on T d of the crboxylic cid end functionlized PLA. However, the interction of both independent vribles (X 1 X 2 ) did not hve significnt effect on this response vrible. DSC trces of ldehyde nd crboxylic cid end functionlized PLA re shown in Figures 8 nd 8b,

8 106 End Functionliztion by Ring Opening Polymeriztion J. Brz. Chem. Soc. respectively. As shown in the figures, the end functionlized PLA presented slightly lower vlues of T g nd T m thn the unfunctionlized PLA. Consequently, utiliztion of both co inititors hs moderte impct on the therml properties of these PLA. Figures 9 nd 9b show the sttisticl nlyses of these results. Despite of the slight chnges of T g nd T m, Preto chrt shows tht the influence of co-inititor/ctlyst nd lctide/ctlyst molr rtios were not sttisticlly significnt. From Figure 9, we cn lso see tht the co-inititor/ ctlyst molr rtio dependent vrible hs more effect on the therml properties of the ldehyde end functionlized PLA thn the lctide/ctlyst molr rtio vrible. However, for crboxylic cid functionliztion, the interction of both dependent vribles hs more effect on this response vrible. Degree of crystllinity of ldehyde or crboxylic cid end functionlized PLA ws lso ssessed by the influence of the co-inititor/ctlyst nd lctide/ctlyst molr rtios. Results re shown in Figures 10 nd 10b. As shown in Figure 10, [SAl]/[Sn] nd [L]/[Sn] molr rtios showed lmost no influence on the degree of crystllinity (X c ) of the ldehyde end functionlized PLA. However, more chnges of crystllinity were observed t levels of [L]/[Sn] molr rtio of 125/1 nd [SAc]/[Sn] molr rtio of 12/1 (Figure 10b). The presence of crboxylic cid group t the end of polymer bckbone could mke possible the occurrence of different moleculr interctions, Figure 8. DSC trces of () ldehyde nd (b) crboxylic cid end functionlized PLA. Figure 9. Preto chrt of the influence of [SAc]/[Sn] nd [L]/[Sn] molr rtios on the temperture of mximum degrdtion rte (T d ) of the () ldehyde end functionlized PLA (MS pure error = ) nd (b) crboxylic cid end functionlized PLA (MS pure error = ). Figure 10. Lctide/ctlyst nd co-inititor/ctlyst molr rtios surfces nd contour of predicted crystllinity (%): () ldehyde nd (b) crboxylic cid end functionlized PLA.

9 Vol. 29, No. 1, 2018 Icrt et l. 107 which could chnge the crystlliztion behvior of these functionlized PLA. However, [L]/[Sn] rtio ws the dependent vrible with mjor influence on this response vrible. These results re in greement with previous reports on therml chrcteriztion of end functionlized PLA. 35,36 Sttisticlly significnt influence of [SAl]/[Sn], [SAc]/[Sn] nd [L]/[Sn] molr rtios on the degree of crystllinity ws lso evluted by Preto chrt (Figure S1 in the Supplementry Informtion (SI) section). The influence of [SAl]/[Sn] nd [L]/[Sn] on the crystllinity of the ldehyde end functionlized PLA ws sttisticlly non-significnt. On the other hnd, interction of both dependent vribles showed sttisticlly significnt influence on the degree of crystllinity for crboxylic cid end functionlized PLA s well s the dependent vrible of [SAc]/[Sn] molr rtio (Figure S1b in the SI section). The influence of [L]/[Sn], [SAl]/[Sn] nd [SAc]/[Sn] on the moleculr weight of the functionlized PLA ws lso investigted by nlyzing GPC dt in terms of response surfce plots (Figures 11 nd 11b). Figures 11 nd 11b illustrte tht highest vlues of moleculr weight were chieved with the increse in lctide/ctlyst molr rtio. Hence mximum vlue of moleculr weight (Mw) ws chieved for lctide/ ctlyst molr rtio of 125/1 in both experimentl designs. Both co inititors/ctlyst molr rtios ([SAl]/[Sn] nd [SAc]/[Sn]) showed the sme behvior, i.e., they showed no effect on Mw. Considering the mechnism of ROP previously described, higher lctide/ctlyst molr rtio increses the probbility of coordintion between lctide nd ctlyst gent nd the synthesis of polymers with higher moleculr weight. 7,37 However, some impurities such s lctic cid nd other hydroxyl impurities re lso ble to coordinte with the ctlyst nd they hve influence on the finl polymer moleculr weight. 29,38-41 In our study these impurities were not ssessed. Sttisticlly significnt influence of lctide/ctlyst nd co-inititor/ctlyst rtios on the Mw ws evluted by the Preto chrt (Figures S2 nd S2b in the SI section). Results obtined from Preto chrt confirmed tht the effect of lctide/ctlyst molr rtio on Mw ws sttisticlly significnt. On the other hnd, this influence ws independent on the co-inititor/ctlyst molr rtio used in the ROP. Therefore, the co-inititor/ctlyst molr rtio ws sttisticlly non-significnt on Mw. Conclusions Tin initited ring opening polymeriztion ws used to synthesize PLA with ldehyde nd crboxylic cid end groups by using slicyl ldehyde nd slicylic cid s co inititors. Identifiction of the functionl groups linked to the end of PLA bckbones ws elucidted by UV-Vis nd 1 H NMR techniques. The two experimentl designs used in this work mde possible the identifiction of the best ROP condition to ssure mximum ldehyde nd crboxylic cid functionliztion of PLA. Besides both experimentl designs llow to determine the influence of the [lctide]/[sn], [SAl]/[Sn] nd [SAc]/[Sn] molr rtios on the therml properties nd moleculr weights of the functionlized PLA. Although [lctide]/[sn] molr rtio shows the expected behvior regrding to moleculr weight, i.e., the Mw is higher s [lctide]/[sn] increses, co inititors/ctlyst molr rtios ([SAl]/[Sn] nd [SAc]/[Sn]) showed no sttisticlly significnt effect on Mw. The content of functionl end groups in the polymer ws drmticlly influenced by these rtios, tht incresed the ldehyde nd crboxylic cid content in the polymers when they were incresed. We found tht the influence of co-inititors/ctlyst rtios on the degrdtion temperture (T d ) of the polymers hs different behvior, the crboxylic cid end groups influenced much more the T d decrese thn the ldehyde functionlity. Both slicyl ldehyde nd slicylic cid were quite useful for the synthesis of PLA contining ldehyde nd crboxylic cid functionl end groups. These functionlized PLA could be potentilly useful for the synthesis nd design of some different ctive biomteril for medicl pplictions. Figure 11. Response surfce plots of moleculr weight versus lctide/ctlyst nd co-inititor/ctlyst of () ldehyde nd (b) crboxylic cid end functionlized PLA.

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