Radical-Incorporated Poly(acrylic acid/lactide/ - caprolactone)

13 Pages·2001·0.25 MB·English

Synthesis and Chemical Structural Analysis of Nitroxyl-
e
Radical-Incorporated Poly(acrylic acid/lactide/ -
caprolactone) Copolymers
MEIDONG LANG,* CHIH-CHANG CHU
FiberScienceProgram,DepartmentofTextilesandApparel,andBiomedicalEngineeringProgram,CornellUniversity,
Ithaca,NewYork14853-4401
Received22May2001;accepted20August2001
Publishedonline00Month2001
ABSTRACT: The goal of this research is to synthesize biodegradable polymers that
wouldhavenitroxylradicalbiologicalfunctions.Linearaliphaticpolyesterswerecho-
sen as the starting materials. The hydroxyl-terminated polylactide/e-caprolactones
(PBLC-OHs)werefirstsynthesizedbymeltring-openingcopolymerizationinthepres-
enceofbenzylalcoholandstannousoctoate.PBLC-OHswereusedastheprecursorfor
thesynthesisofdoublebond-functionalizedpolylactide/e-caprolactones(PBLC-Mas)by
reactingthehydroxylendgroupsofPBLC-OHwithmaleicanhydrideinmeltat130°C.
Acrylic acid/lactide/e-caprolactone graft copolymers (PBLCAs) were then successfully
carried out by the radical copolymerization of acrylic acid and PBLC-Ma initiated by
azobisisobutyronitrile. Finally, nitroxyl radicals [4-amino-2,2,6,6-tetramethylpiperi-
dine-1-oxy (TAM)] were incorporated into the carboxylic acid sites of the acrylic acid/
lactide/e-caprolactone copolymer (TAM-PBLCA) by reacting TAM with PBLCA in the
presence of N,N9-carbonyl diimidazole. A high content of TAM was incorporated into
the PBLCA copolymer. The polymers synthesized were characterized by 1H and 13C
NMR, Fourier transform infrared spectroscopy, and electron paramagnetic resonance
spectra.©2001JohnWiley&Sons,Inc.JPolymSciPartA:PolymChem39:4214–4226,2001
Keywords: biomaterials;bipoodleygcoranddaebnlsea;tion
INTRODUCTION not “biologically active” and cannot exert biologi-
calactivitydirectly.Theyonlyplayapassiverole
Aliphatic polyesters such as polylactide (PLA), inwoundhealing,tissueregeneration,andtissue
poly(e-caprolactone), polyglycolide (PGA), and engineering. It would be ideal to make these bio-
their copolymers are the group of biomaterials materials biologically “alive” and perform some
that have commercially successful applications critical biological function, such as the ability to
because of their biodegradability1,2 and biocom- modulate inflammatory reactions to facilitate
patibility.3,4 Although these polymers have been wound healing or to enhance host defenses
used extensively as sutures, implant materials, against disease. 5
and drug carriers, they do not have any inherent
One of the most recently discovered biological
biologicalfunctions to actively participate in hu- messengersisnitricoxide(NOz).Nitricoxideisa
man body repair. These aliphatic polyesters are
very small but highly reactive free radical with
expanding known biological functions. This mol-
ecule and its biological functions have recently
*Presentaddress:930NUniversity,AnnArbor,MI48109
Correspondenceto:C.-C.Chu become one of themots studied compounds in
JournalofPolymerScience:PartA:PolymerChemistry,Vol.39,4214–4226(2001) biochemistry and biology and the subject of sev-
©2001JohnWiley&Sons,Inc. eralrecentreviews.NOzactsbothasanessential
DOI10.1002/pola.10030
4214
NITROXYL-RADICAL-INCORPORATED COPOLYMERS 4215
regulatory agent to normal physiological activi- ingupto100°Cuntilthesolidwasdissolved,and
tiesandascytotoxicspeciesindiseasesandtheir thencoolingdowntoroomtemperaturetorecrys-
treatments. For example, it was suggested that tallize;thisprocesswasrepeatedthreetimes.The
NOzcouldbeusedasapotentantiviralcompound recrystallizedlactidewasthenwashedwithdried
against poxvirus and herpes simplex virus type- ethyl ether and dried over P O in vacuum as
2 5
1,6asaheartmedicineagainstlowoxygensupply previously described.14 e-Caprolactone (Aldrich)
(a condition know as myocardial ischemia),7 and waspurifiedbydryingwithCaH anddistilledin
2
as an anti-inflammatory drug.8 However, exces- vacuum at 100 °C. Maleic anhydride (99%), TAM
sive introduction of NO z into the body may have (95%), 2-imidazolidinethione (98%), and 2,29-azo-
adverse side effects like microvascular leakage, bisisobutyronitrile(AIBN,98%)wereallobtained
tissue damage in cystic fibrosis, septic shock, B- from Aldrich and used without further purifica-
cell destruction, and possible mutagenic risk.9–13 tion.Stannousoctoate(95%)waspurchasedfrom
Therefore, it is very important to be able to de- Sigma Chemical Co. (St. Louis, MO,) and used
velop a delivery vehicle to control the NO z con- withoutfurtherpurification.Acrylicacidandben-
centration and its release. zyl alcohol were all purchased from Aldrich and
One reported approach toward the research purifiedbydistillinginvacuumpriortouse.Ethyl
and development of such biologically active bio- ether (anhydrous, Fisher Scientific, Fair Lawn,
materialswastochemicallyincorporatenitricox- NJ), toluene (A. R. Mallinckrodt Baker, Inc.,
ide derivative (NOD) like tempamine nitroxyl Paris, KY), and dioxane (99.8%, anhydrous, Al-
radical (TAM) into the carboxylic chain ends of drich)weredriedbyrefluxingoverbenzophenone-
PGA macromolecules via amide linkage.5 This Nacomplexanddistilledinanatmosphereofdry
TAM-incorporated PGA was able to retard the argon.Chloroform(A.R.MallinckrodtBaker)was
proliferationofsmoothmusclecellsaspurenitric extractedwithwaterthreetimestoremoveresid-
oxide does. Because NOD was chemically incor- ual alcohol, dried with anhydrous MgSO over-
4
porated into the chain ends of PGA or PLA, the night, and distilled in an atmosphere of dry ar-
NODconcentrationwasquitelimited.Itwouldbe gon. Petroleum ether (35–60 °C grade, A. R.
morebeneficialifawiderangeofNODconcentra- Mallinckrodt Baker) was used without purifica-
tions could be incorporated into its delivery vehi- tion. Borosilicate (Pyrox) press reaction tubes
cle for meeting a variety of specific biomedical (body 30 mm o.d. 3 3 in long; neck 11 mm o.d. 3
needs. 6 in long) were purchased from Scientific Group
Inthisarticle,weinvestigatethesynthesisand (Vineland, NJ) for melt polymerization.
characterization of the acrylic acid/lactide/e-cap-
rolactone graft copolymer that would have pen-
dantcarboxylicgroupsalongthemacromolecular Synthesis
backbone so that a wide range of NODs can be
Thesynthesisschemesinvolvedfourofthefollow-
attached for achieving different extents of NO z
ing basic tasks: (1) synthesis of polylactide,
biologicalactivity.Ourapproachwastointroduce poly(e-caprolactone), and polylactide-co-e-capro-
unsaturated groups like double bonds into the
lactone having one hydroxyl end group per mac-
chainendsofpolylactide-co-e-caprolactonesbyre-
romolecule, (2) incorporation of unsaturated
actingthemwithmaleicanhydride.Thesedouble
groupsintothehydroxylendofthepolymerssyn-
bond-terminated copolymers were then used as
thesized in (1), (3) copolymerization of the poly-
the precursors to further copolymerize with
mers synthesized in (2) with acrylic acid, and (4)
acrylicacidmonomerviafree-radicalmechanism.
chemical attachment of TAM onto the pendant
The resulting copolymer of acrylic acid, lactide,
carboxylic acid groups of the copolymers synthe-
and e-caprolactone was eventually chemically at-
sized in (3).
tached by TAM at the pendant carboxylic acid
group according to our previously reported
SynthesisofHydroxyl-TerminatedPolylactide-co-e-
method.5
caprolactone(PBLC-OH),Polylactide(PBL-OH),
andPoly(e-caprolactone)(PBC-OH)
MATERIALS AND METHODS
The synthesis of PBLC-OH that had its one end
Materials groupcappedbybenzylalcoholandtheotherend
Lactide (Aldrich Chemical Co., Milwaukee, WI) group remaining as a free OOH group was car-
waspurifiedbyfirstdissolvingitintoluene,heat- riedoutbyring-openingpolymerizationoflactide
4216 LANG AND CHU
TableI. TheInfluencesofFeedRatioontheMolecularWeightofPolylactide/«-CaprolactoneCopolymer(PBLC-OH)
FeedMolarRatio MolecularWeight
Benzyl «-Caproyl a-Oxypropiony M a M b M c Polydispersity
n w p
Alcohol (Cunit) (Lunit) (3103) (3103) (3103) (M /M )
w n
1 3 15 1.76 3.05 2.85 1.73
1 7 35 3.28 4.73 4.80 1.44
aNumber-averagemolecularweights(M ’s) determinedbyGPCwithpolystyrenestandards.
n
bWeight-averagemolecularweights(M ’s) determinedbyGPCwithpolystyrenestandards.
w
cPeakmolecularweight(M ).
p
ande-caprolactone(2.5:1molarratio)inthepres- chloroformsolutioninexcesspetroleumetherand
ence of benzyl alcohol (trace amount) and stan- dried in vacuum at room temperature.
nousoctoate(0.5%byweight)inaPyroxpolymer-
izationtube.Afterrepeatedlyvacuumdryingand SynthesisofPoly(acrylicacid/lactide/e-
argon refilling for several times, the polymeriza- caprolactone)Copolymer(PBLCA)
tiontubewasvacuumsealedandplacedinanoil
bath at 130 °C for 48 h to polymerize the mono- The double bond-terminated polylactide-co-e-cap-
mers. After cooling to room temperature, the re- rolactone (1.98 g), acrylic acid (3.0 g), and AIBN
sulting product was dissolved in chloroform. The (0.0335g)(1.1wt%ofacrylicacid)weredissolved
solution was poured into excess petroleum ether in 20 mL of dioxane at room temperature in a
to precipitate the polymer. The precipitate was three-necked flask under N2. The mixture was
washed with distilled water for four times and thenheatedto60°Cfor5h.Afterremovingmost
dried over P O under vacuum at room tempera- of the solvent by distillation at 120 °C, the reac-
2 5
ture until constant weight. By varying the molar tion mixture was precipitated in cold water to
ratio of lactide to e-caprolactone monomers and remove the acrylic acid homopolymer byproduct.
benzyl alcohol, we could control the molecular Theprecipitate,PBLCA,wasfilteredandwashed
weight of the polymer (Table I). with cold water three times and dried over P2O5
The same method described previously was under vacuum at room temperature.
usedtosynthesizehydroxyl-terminatedpoly(e-ca-
prolactone) homopolymer (PBC-OH) and polylac- SynthesisofNitroxyl-Radical-Incorporated
tide homopolymer (PBL-OH). The purpose of Poly(acrylicacid/lactide/e-caprolactone)
making PBC-OH and PBL-OH homopolymers Copolymer(TAM-PBLCA)
wastoprovidecontrolsforcomparingandanalyz-
The chemical incorporation of TAM into the car-
ing the chemical structure of PBLC-OH.
boxylic acid sites of PBLCA was carried out ac-
cording to our previously published procedure.5
SynthesisofDoubleBond-TerminatedPolylactide-
PBLCA (1.1392 g) was dissolved in 20 mL of di-
co-e-caprolactone(PBLC-Ma)
oxane at 50 °C, and 0.2851 g of N,N9-carbonyl
Maleic anhydride was used to introduce both un- diimidazole were then added. After 15 min,
saturated and carboxylic acid groups into PBLC- 0.3140 g of TAM dissolved in 5 mL of dioxane
OH.Thehydroxyl-terminatedPBLC-OHandma- wereaddedslowlytothereactionmixtureatthis
leic anhydride (1:5 molar ratio) were placed in a temperature. The reaction mixture was vigor-
three-necked flask under N atmosphere at 130 ously stirred for several hours at 50 °C. The re-
2
°C for 24 h. After this reaction, the excessive sultingsolutionmixturewasaddeddropwiseinto
maleic anhydride was distilled at 130 °C under petroleum ether to precipitate the TAM-PBLCA.
vacuum, and the reaction mixture was dissolved This polymer was stirred in 100 mL of water for
in chloroform. The chloroform solution was ex- 3 h at room temperature to remove excess TAM,
tracted with water three times to remove the re- N,N9-carbonyl diimidazole, and imidazole pro-
sidual maleic anhydride and dried with anhy- duced during the reaction, filtered and washed
drous MgSO overnight. The purified PBLC-Ma with water four times, and then dried over P O
4 2 5
wasobtainedbyprecipitatingthewater-extracted in vacuum at room temperature.
NITROXYL-RADICAL-INCORPORATED COPOLYMERS 4217
Scheme1. Synthesisofthepolylactide/e-caprolactonecopolymer(PBLC-OH,4)from
benzyl alcohol (1), L-lactide (2), and e-caprolactone (3) and maleic acid end-capped
poly(L-lactide/e-caprolactone) copolymer (PBLC-Ma, 6) from the reaction of poly(L-
lactide/e-caprolactone)copolymer(PBLC-OH,4)withmaleicanhydride(5).
Characterization RESULTS AND DISCUSSION
1Hand13CNMRspectrawererecordedonaVar-
Polylactide-co-e-caprolactone (PBLC-OH)
ian Unity spectrometer operating at 300 MHz.
Thespectrawererecordedindeuterateddimethyl As shown in Scheme 1, the synthesis of polylac-
sulfoxide (DMSO-d ) (for PBLCA and TAM- tide-co-e-caprolactone(4)wasperformedviaring-
6
PBLCA) or in deuterated chloroform (for PBC- opening polymerization of lactide and e-caprolac-
OH,PBL-OH,andPBLC-OHandPBLC-Ma),and tone in the presence of benzyl alcohol and stan-
tetramethylsilane was used as an internal refer- nous octoate as previously described.14 Although
ence. the structure 4 in Scheme 1 showed a e-caprolac-
The molecular weight and molecular weight tone unit-ending group, the PBLC-OH copolymer
distribution of the synthesized polymers were couldalsohavealactideunitastheendinggroup.
measured by size exclusion chromatography and There were many different catalysts used for the
carriedoutwithtetrahydrofuranasaneluent(1.0 ring-opening polymerization of glycolide, lactide,
mL/min)usingaWaters510high-pressureliquid andlactone.Amongthosecatalystsreported,stan-
chromatographic pump, a Waters U6K injector, nous octoate (SnOct ) was the most frequently
2
three PSS SDV columns (linear, 104, and 100 Å) used for two main reasons. First, SnOct is a
2
in a series, and a Milton read-only memory dif- highly efficient catalyst and allowed almost com-
ferential refractomer detector. The columns were plete conversions even at very high monomer/
calibrated with polystyrene standards having a catalystratios(e.g.,104:1).15–18Second,theriskof
narrow molecular weight distribution. racemization was low, and 99% optically pure
Fourier transform infrared (FTIR) spectra poly(L-lactide) could be prepared even at 150 °C
wereobtainedfromaPerkinElmerMagna-IR560 when the reaction time was limited to a few
spectrometer. The film for IR analysis was ob- hours.
tainedbycastingaDMSOsolution(3wt%/vol)of Compounds having free hydroxyl groups, such
the polymer onto a KBr crystal. Omnic software as alcohols, have frequently been used as coiniti-
was used for data acquisition and analysis. atingagentsinaring-openingpolymerization.In
The nitroxyl radical property of TAM-PBLCA thisstudy,benzylalcoholwasselectedasacoini-
was characterized by electron paramagnetic res- tiator because its incorporation as a benzylester
onance (EPR) spectra at the X-band using a endgroupcouldbeeasilydetectedbyboth1Hand
Bruker 200D SRC spectrometer operating at 9.6 13C NMR. Thus, the resulting PBLC-OH macro-
GHz, using 100-KHz modulation. moleculehadoneofitstwoendgroupscappedby
Elemental analysis of nitrogen was conducted benzyl alcohol, and the other end group as a hy-
byAtlanticMicrolabInc.,andtheTAMcontentof droxyl group. The molecular weight of PBLC-OH
TAM-PBLCA was calculated accordingly. couldbevariedbythemolarratioofmonomersto
4218 LANG AND CHU
PBLC-OHremainedintact.Therefore,theresults
of the 1H NMR structure analysis of PBLC-OH
could also be used to describe the structure of
PBLC-Ma and PBLCA. The detailed analysis of
the NMR spectra is given subsequently.
Bycomparisonwiththe1HNMRspectraofthe
PBC-OH and PBL-OH homopolymers, it was not
difficulttoassignpeaksinthe1HNMRspectrum
(300MHzNMR)ofthePBLC-OHcopolymer(Fig.
2). Each group was assigned as the following: d
(ppm) 5 7.409–7.294 (H ), 5.297–5.000 (H ),
1 2,3
4.440–4.306 (H , end group), 4.398–4.225 (H ),
2 4
2.513–2.219 (H ), and 1.933–1.235 (H ). The
5 6,7,8,9
H end group was not found.
4
AmongthosepeaksinFigure2,bothH andH
4 5
showeddiadsensitivity,whereasH ,H ,H ,and
6 7 8
H were insensitive to the sequence effect. H
9 2
showedamultiplet.H appearedtobesensitiveto
5
the a-oxypropionyl (L) unit coupled to the car-
bonyl group of the e-oxycaproyl (C) unit but gave
little response to the a-oxypropionyl (L) unit at-
tached to the e-oxygen atom on the other side of
the e-oxycaproyl unit (C). Peak 5 was assigned to
thea-methyleneprotonthatwasconnectedtothe
Figure 1. FTIR spectra of the copolymers synthe- C unit [C-C sequence or poly(e-caprolactone) ho-
sized: (a) benzyl alcohol end-capped poly(L-lactide/e-
caprolactone) copolymer (PBLC-OH), (b) maleic acid
end-capped poly(L-lactide/e-caprolactone) copolymer
(PBLC-Ma), (c) poly(L-lactide/e-caprolactone/acrylic
acid) copolymer (PBLCA), (d) nitric oxide derivative-
attached poly(L-lactide/e-caprolactone/acrylic acid) co-
polymer(TAM-PBLCA),and(e)nitricoxidederivative,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxy(TAM).
benzyl alcohol as shown in Table I. The gel per-
meation chromatographic trace of PBLC-OH in-
dicatedtheabsenceoflowmolecularweightpoly-
mers and/or byproducts. The purified PBLC-OH
was a very sticky colorless solid.
The FTIR spectrum of PBLC-OH is shown in
Figure1(spectruma).Themainabsorptionbands
ofPBLC-OHwereassignedasthefollowing:3560
cm21fortheOOHabsorption,3000cm21forCH
3
stretching, 2970 and 2920 cm21 for CH stretch-
2
ing,1780cm21forCAOstretching,1470cm21for
the benzene ring, and two bands at 1280–1230
cm21 and 1170–1130 cm21 for the stretching of
COO.
The1HNMRspectraofPBL-OH,PBC-OH,and
PBLC-OH are depicted in Figure 2. Because the Figure2. 1HNMRspectraofthecopolymerssynthe-
synthesis of PBLC-Ma and PBLCA from PBLC- sized:(a)poly(e-caprolactone)homopolymer(PBC-OH),
OH involved the reaction limiting to the chain (b) poly(L-lactide) homopolymer (PBL-OH), and (c)
ends of PBLC-OH, the backbone sequence of poly(L-lactide/e-caprolactone)copolymer(PBLC-OH).
NITROXYL-RADICAL-INCORPORATED COPOLYMERS 4219
mopolymer]. Peak 50 was assigned to those cou-
pledwiththeLunitintheC-Lsequence.H was
4
alsosensitivetotheLunitcoupledtothee-oxygen
atom. Peaks 4 and 40 were assigned to the
OOCH O proton in the C-C sequence and the
2
C-L sequence, respectively.
The H end group (CH OOH) from the C unit
4 2
could be found at 3.70–3.50 ppm in the 500-MHz
1H NMR spectra. The molar ratio of the H end
4
groupsCH OOHtoH endgroupOCH(CH) OOH
2 2 3
inPBLC-OHwas1:19.62andmuchlowerthanthe
compositionratioofthecorrespondingcopolymer.
The compositional ratio of the e-oxycaproyl unit
(C) to the a-oxypropionyl unit (L) in PBLC-OH
was1:4.53;however,thefeedmolarratioofC/Lin
polymerization crude was 1:5. This difference be-
tween the actual composition ratio of the copoly-
mer and the feed molar ratio qualitatively dem-
onstratedthatthepolymerizationrateofe-capro-
lactone monomer was higher than the rate of
lactidemonomerinthispolymerizationcondition.
The 13C NMR spectra of PBL-OH, PBC-OH,
andPBLC-OHareshowninFigure3.Bycompar-
ison with the published 13C NMR spectra of lac-
tide homopolymer initiated by 2-propanol19 and
high molecular weight e-caprolactone homopoly-
mer,14 and e-caprolactone homopolymer initiated
by alcohol,20,21 each group of peaks in the 13C Figure3. 13CNMRspectraofthecopolymerssynthe-
sized:(a)poly(e-caprolactone)homopolymer(PBC-OH),
NMRspectraofPBC-OH[Fig.3(a)]andPBL-OH
[Fig. 3(b)] was assigned as follows. For PBC-OH, (b) poly(L-lactide) homopolymer (PBL-OH), and (c)
d 173.516 (C ), 173.338 (C ), 173.079 (C ); poly(L-lactide/e-caprolactone)copolymer(PBLC-OH).
109 10 100
135.958, 128.404, and 128.032 (C ); 65.936 (C );
1 3
63.963 (C ), 62.831 (C ), 62.200 (C ); 34.088
4 40 49
(C ),33.958(C ),32,212(C );28.200(C );25.386 3, and 4 region; and the carbon 5, 6, 7, 8, and 9
50 5 59 6
(C ),25.240(C );24.698(C ),24.431(C ).Inthe region. To simplify the notation, we used * that
9 99 79 7
13C NMR spectra of PBL-OH [Fig. 3(b)], each meantthatthe13CNMRdatacamefromtheunit
group of peaks was assigned as the following: designed by *. For example, C , C-C*-L means
10
175.053, 174.859, and 174.664 (C ); 170.038, that the carbon #10 data came from the C* unit
119
169.964, and 169.877 (C ); 169.715, 169.569, (e-oxycaproyl) in the C-C*-L sequence.
110
and169.456(C );135.359,128.760,128.647,and In the carbonyl region (Fig. 4), each group of
11
128.388(C );69.576and69.462(C );69.155(C ); peaks was assigned as follows. d 175.360,
1 20 2
67.263(C );66.745and66.405(C );20.565(C ); 174.713, 174.503, and 174.325 (C , L*-OH);
3 29 80 11
20.193 (C ); 16.813 (C ). 173.274 (C , C-C*-C); 172.627 (C , C-C*-L);
89 8 10 10
The 13C NMR spectra of PBLC-OH copolymer 172.400 (C , L-C*-L); 173.015 (C , B-C*);
10 10
[Fig. 3(c)] were so complex because of the se- 170.702 and 170.524 (C , C-L*-C); 170.168,
11
quenceeffectsofthea-oxypropionyl(L)ande-oxy- 170.039, 169.941, and 169.764 (C , L-L*-C and
11
caproyl (C) units that it was very difficult to as- B-L*); 169.509, 169.440, 169.311, 169.197, and
sign each peak definitely. Fortunately, by com- 169.084 (C , L-L*-L); 167.920 (residual lactide
11
parisonthe13CNMRspectrumofPBLC-OHwith monomer).
the 13C NMR spectra of PBC-OH and PBL-OH In the B region, d136.087, 135.408, 135.198,
and the NMR peaks of PBLC-OH still could be 128.517, 128.388, 128.129, and 128.016 were as-
assigned region by region as follows. There were signed as carbon in the benzyl ring.
four regions: the benzyloxy region (designated as In the carbon 2, 3, and 4 region (Fig. 5), each
the“B”region);thecarbonylregion;thecarbon2, group of peaks was assigned as follows. d69.317,
4220 LANG AND CHU
Figure4. Carbonylregionofthe13CNMRspectrum Figure 6. Carbon 5, 6, 7, 8, and 9 regions of the 13C
ofpoly(L-lactide/e-caprolactone)copolymer(PBLC-OH). NMRspectrumofpoly(L-lactide/e-caprolactone)copoly-
mer(PBLC-OH).
69.220, 69.042, 68.896, and 68.718 (C2, L*-L); In contrast with the proton data, all carbon
68.411,68.282,and68.088(C2,L*-C);66.988and NMR data were sensitive to the sequence effect.
66.745 (C3, B*-L); 65.936 (C3, B*-C); 66.616 and Whenthea-oxycaproylunitwasconsideredasthe
66.502(C2,L*-OH);65.111and64.885(C4,C*-L); * unit (C*), the carbonyl carbon C10 showed a
63.963 (C4, C*-C). triad (Fig. 4). The peak at 173.247 ppm could be
In the carbon 5, 6, 7, 8, and 9 region (Fig. 6), assigned to the signals of C in the C-C*-C se-
each group of peaks was assigned as follows. d quence by comparison with10the corresponding
33.878 (C5, C*-C); 33.457 (C5, C*-L); 28.216 (C6, carbonyl carbon signals in the PBC-OH ho-
C*-C); 28.055 (C6, C*-L); 25.418, 25.272, and mopolymer [Fig. 3(a)]. The PBLC-OH copolymer
25.208 (C9, C*-C); 25.078 (C9, C*-L); 24.464 and that had a high molar fraction of a-oxypropionyl
24.382 (C7, C*-C); 24.221 (C7, C*-L); 20.339 (C8, unit (XL 5 0.82) showed a strong signal at
L*-B); 20.023 and 19.977 (C8, L*-OH); 16.570 172.627ppmforC10intheL-C*-Csequenceanda
(C8); 15.535 (residual lactide monomer). weak signal at 172.400 ppm for the L-C*-L se-
Similar to the 1H NMR spectra, the CH(CH3)O quence. This observation indicated that only a
Hendgroupfromthea-oxypropionylunit(L)was small fraction of C unit appeared in the C-C*-C
detectableat66.502ppminthe13CNMRspectra sequence; most of the C unit existed in the C*-L
besides the benzyl ester end group. However, the sequence.
CH2OOH end group from the e-oxycaproyl unit When the a-oxypropionyl unit was considered
(C) was too little to be detected. asthe*unit(L*),amorecomplicatedbutsimilar
phenomenon was observed. The carbonyl carbon
C revealedatetrad(Fig.4).Bycomparisonwith
11
the corresponding carbonyl carbon signals in
PBL-OHhomopolymer[Fig.3(b)],thepeaksfrom
175.360 to 174.325 ppm in the PBLC-OH copoly-
mer were assigned to C of the end a-oxypropio-
11
nyl unit L*-OH, and the peaks from 169.569 to
169.084 ppm were assigned to the L-L*-L se-
quence. Other carbonyl carbon signals, 170.702–
170.524 ppm were assigned to the C-L*-C se-
quence,and170.168–169.764ppmwereassigned
to the L-L*-C sequence. The strongest peaks ap-
peared at 169.440–169.197 ppm, demonstrating
that most L units preferred to connect to the L
unitwhenPBLC-OHcopolymerhadahighmolar
Figure5. Carbon2,3,and4regionsofthe13CNMR fraction of the a-oxypropionyl unit (XL 5 0.82).
spectrum of poly(L-lactide/e-caprolactone) copolymer The more complicated but more informative
(PBLC-OH). signals appeared at the region from 69.317 to
NITROXYL-RADICAL-INCORPORATED COPOLYMERS 4221
TableII. MolecularWeightsaofPolymersSynthesized
Polydispersity
Polymers M (3103) M (3103) M (3103) (M /M )
n w p w n
PBLC-OH 3.28 4.73 4.80 1.44
PBLC-Ma 2.93 7.05 6.53 2.41
PBLCA 4.61 7.17 9.21 1.56
TAM-PBLCA 1.61 4.55 4.05 2.83
aDeterminedbygelpermeationchromatography(GPC).
PBLC-OH:benzylalcoholend-cappedpoly(L-lactide/«-caprolactone)copolymer.
PBLC-Ma:maleicacidend-cappedpoly(L-lactide/«-caprolactone)copolymer.
PBLCA:poly(L-lactide/«-caprolactone/acrylicacid)copolymer.
TAM-PBLCA:nitricoxidederivativeattachedpoly(L-lactide/«-caprolactone/acrylicacid)copolymer,whereTAMisnitricoxide
derivative,4-amino-2,2,6,6-tetramethylpiperidine-1-oxy.
63.963ppm(Fig.5).Inthisarea,therewerethree hydrideinthemeltfor24hat130°C(Scheme1).
kinds of carbons—methine carbon C of the As a result, the hydroxyl functionality in PBLC-
2
a-oxypropionylunit,e-methylenecarbonC ofthe OH was converted to a maleic monoester acid. It
4
e-oxycapronyl unit, and methylene carbon C of appeared that slight chain fragmentation on
3
the benzyloxy unit. By comparing the 13C NMR PBLC-OH also occurred as evidence in a wider
dataofPBLC-OHcopolymerinFigure5withthe molecular weight distribution D (D from 1.44 of
corresponding 13C NMR spectra of PBC-OH ho- PBLC-OHto2.41ofPBLC-Ma)andthereduction
mopolymer and PBL-OH homopolymers [Figs. in number-average molecular weight (M , 11%
n
3(a,b)],thepeaksat69.317–68.411ppminFigure reduction) (Table II). The weight-average molec-
5 were assigned to C in the L*-L sequence (in- ularweight(M ),however,showed49%increase.
2 w
cluding the B-L*-L and L-L*-L sequences). d It is unclear why M and M showed opposite
n w
66.988and66.745ppmwereassignedtoC inthe dependence on the maleic anhydride reaction.
3
B*-L sequence, d 65.936 ppm to C in the B*-C The 1H NMR spectra of PBLC-Ma are illus-
3
sequence, and 63.963 ppm to C in the C-C*-C se- trated in Figure 7. These 1H NMR data showed
4
quence. The other peaks, d 68.411–68.088 ppm several distinctive peaks at 6.546–6.312 ppm
were assigned to C in the L-L*-C and B-L*-C se- that were the characteristics of double bonds in
2
quences.d66.616and66.936ppmwereassignedto the maleic acid, which were absent in PBLC-OH,
C of the end L unit (L*-OH), d65.111 and 64.885 an indication that the maleic acid segment had
2
ppmtoC intheC-C*-LandL-C*-Lsequences. been successfully attached onto the PBLC-OH
4
Both the benzyl ester end group and the chain ends. However, there were some unex-
OCH(CH) OOH end group of the L unit were pectedpeaksatthed7.052–7.031ppmand6.947–
3
found in both the 1H NMR and 13C NMR spectra 6.883 ppm regions. These unexpected peaks of
ofPBLC-OH.Thisobservationsuggestedthatthe PBLC-Ma at 6.947–7.052 ppm could be assigned
polymerization mechanism was consistent with
the one Kricheldorf et al.19 suggested. The coor-
dination between SnOct and benzyl alcohol and
2
the subsequent binding of this complex alcohol
withlactonemonomerwouldcatalyzethenucleo-
philic addition reaction between the complex al-
cohol and the lactone monomer. It was the char-
acteristicofthismechanismthatthepropagation
steps involved exclusively the free orbital of the
catalyst, and neither covalent nor ionic bonds
were involved.
Double Bond-Terminated Polylactide-co-e-
caprolactone (PBLC-Ma)
PBLC-Ma was synthesized by reacting hydroxyl- Figure7. 1HNMRspectrumofmaleicacidend-capped
terminated PBLC-OH copolymer with maleic an- poly(L-lactide/e-caprolactone)copolymer(PBLC-Ma).
4222 LANG AND CHU
to the double bond segments existing in the fu- 134.195–134.065,and129.342–129.116ppm.The
maric monoester acid resulting from the rear- peaks for the carbonyl C and C were at
12 15
rangement reaction of maleic monoester acid 165.541 and 165.072 ppm, respectively. As ex-
(Scheme4).Itiswellknownthatmaleicacidcan pected, the signals at 66.502–66.616 ppm for the
be converted in part into fumaric acid by a rear- methineC oftheLunitadjacenttotheterminal
29
rangement reaction when heated to a tempera- hydroxylfunctionalitywerereducedsignificantly,
ture slightly above its melting point.22 Further- butthesepeaksdidnotdisappearcompletely.The
more,thed’softheseunexpectedpeaksinPBLC- peaksat70.077–69.705ppmwereassignedtothe
OHwerewithinthe1HNMRsignalsofthedouble terminal methine carbon 20 in the C unit (e-oxy-
bond region of the fumaric monoester acid (be- caproyl unit) adjacent to the maleic monoester
tween 7.1 and 6.6 ppm).23 The ratio of the peak acid.
integral at 6.947–7.052 ppm (for fumaric mo- When compared with the reaction of oilgo(e-
noesteracid)to6.546–6.312ppm(formaleicmo- caprolactone)s with maleic anhydride,24 PBLC-
noester acid) was used to calculate the content of OH copolymer was found to be more difficult to
fumaric monoester acid, and the calculation indi- react with maleic anhydride. Under the same re-
cated that 13% of the double bond in PBLC-Ma actioncondition,thehydroxylfunctionalityofthe
had been rearranged from maleic monoester acid oilgo(e-caprolactone)s was completely converted
to fumaric monoester acid. to double bond functionality. On the contrary,
Itwasalsoobservedthatnotallofthehydroxyl only54%hydroxylfunctionalityofPBLC-OHhad
endgroupsofPBLC-OHhadbeenesterifiedbyma- been reacted. Because 95% of PBLC-OH copoly-
leicanhydride.Inthe1HNMRspectrumofPBLC- merhadthea-oxypropionylendgroup(Lunit),it
Ma, the intensity of the methine group adjacent to could be considered that the a-oxypropionyl unit
the terminal hydroxyl group H29 was reduced sig- end group [OCOCH(CH3)OOH] was more diffi-
nificantly when compared with the corresponding cult than the e-oxycaproyl unit end group
NMR spectrum of PBLC-OH [Fig. 2(c)], but these [OCO(CH ) CH OOH] to react with maleic an-
2 4 2
peaksdidnotdisappearcompletely.Only54%ofthe hydride. In other words, the hydroxyl functional-
hydroxyl end groups in the PBLC-OH copolymer ityadjacenttotheLunithadamuchlowerchem-
reacted with maleic anhydride and converted to ical reactivity than that adjacent to the C unit.
doublebondfunctionality. Thisdifferenceinreactivitymaybemainlyattrib-
The13CNMRspectraofPBLC-Maaregivenin uted to the different reactivity between primary
Figure 8. The characteristic peaks for the double and second alcohols with maleic anhydride. In
bondcarbons(C andC )appearedatd136.395, addition,theOOCOOgroupthatwasadjacentto
13 14
thea-oxypropionylendgroupwasastrongerelec-
tron-withdrawing group, whereas the OOCOO
group in the C unit was four methylene groups
away, and hence, its electron-withdrawing effect
was significantly smaller as a result of the dis-
tance. The OCH group in the L unit, however,
3
was a weak electron donor and could counteract
somehow this electron-withdrawing effect.
Poly(acrylic acid/lactide/e-caprolactone)
Copolymer (PBLCA)
PBLCA copolymer was synthesized by free-radi-
calpolymerizationofacrylicacid(Aa)withdouble
bond-functionalized PBLC-Ma (Scheme 2). Be-
cause PBLC-Ma has only one double bond func-
tionality to take part in the polymerization, the
resulting PBLCA could be considered as a graft
copolymer with poly(acrylic acid) as the main
Figure 8. 13C NMR spectrum of maleic acid end- backbone and PBLC as the graft segment. The
capped poly(L-lactide/e-caprolactone) copolymer variation of molecular weight from PBLC-Ma to
(PBLC-Ma). PBLCA is found in Table II. M increased after
n
NITROXYL-RADICAL-INCORPORATED COPOLYMERS 4223
Scheme2. Synthesisofpoly(L-lactide/e-caprolactone/acrylicacid)copolymer(PBLCA,
8) by radical polymerization of the maleic acid end-capped polylactide/e-caprolactone
copolymer(PBLC-Ma,6)andacrylicacid(7).
the copolymerization of PBLC-Ma with acrylic carboxyl hydrogen H . The signals for the me-
18
acid, but the increment of M was less than one thine hydrogen of the acrylic acid segment H
n 17
time; thus, the average graft number of PBLC were overlapped with the peaks of a-methylene
was no more than two. It should be possible to hydrogen of the e-oxycaproyl unit at 2.513–2.219
controlthecontentofcarboxylgroupandthemo- ppm.Thepeaksat3.401and2.486ppmwerethe
lecular weight of PBLCA by varying the reaction solvent signals of the residual hydrogen of
condition. DMSO-d .
6
The1HNMRspectrumofPBLCAinDMSO-d The13CNMRspectrumofPBLCA(Fig.10)was
6
is shown in Figure 9. By comparison these NMR more informative with respect to the chemical
data(Fig.9)withthe1HNMRspectrumofPBLC- structureofPBLCA.Thecharacteristicpeaksofthe
Ma(Fig.7),thecharacteristicsignalsforthedou- double bond carbons at 136.395, 134.195–134.065,
ble bond group at 7.052–7.031 and 6.546–6.312 and 129.342–129.116 ppm disappeared com-
ppm that were originally existed in PBLC-Ma pletely in PBLCA (Fig. 10 vs Fig. 8). The corre-
disappeared in PBLCA, and new signals for the sponding signals at 165.541 and 165.072 ppm for
acrylic acid segments appeared. The peak at
1.745 ppm was assigned to the methylene hydro-
gen H , and 12.245 ppm was assigned to the
16
Figure 9. 1H NMR spectrum of poly(L-lactide/e-cap- Figure10. 13CNMRspectrumofpoly(L-lactide/e-ca-
rolactone/acrylicacid)copolymer(PBLCA). prolactone/acrylicacid)copolymer(PBLCA).