Poly(α-hydroxy alkanoic acid)s derived from α-amino acids

Article abstract of DOI:10.1002/mabi.201300266

Biodegradable polyesters derived from hydrophobic amino acids are synthesized by various techniques, resulting in a wide range of molecular weights. The polymers are prepared via a) direct condensation with p-toluenesulfonic acid (PTSA) as catalyst, b) ring-opening polymerization (ROP) of O-carboxyanhydrides, and c) ROP of cyclic dilactones. The polymers obtained by the first method reach a molecular weight ranging from 1000 to 3000 Da, whereas those formed by the second and third method yield extended molecular weights of 15 000-30 000 Da. The purity of the monomers as well as their steric bulkiness are key factors affecting the polymerizability of cyclic monomers by ROP. Other parameters such as spatial ring alignment and proximity organization may also play a role. Biodegradable polyesters derived from hydrophobic amino acids are prepared by ring-opening polymerization of O-carboxyanhydrides or of cyclic dilactones. Molecular weights in the range 15 000-30 000 Da are observed. The polymers are characterized by GPC, CD, and DSC.

Full text of DOI:10.1002/mabi.201300266

Full Paper
Poly(a-hydroxy alkanoic acid)s Derived From
a-Amino Acidsa
Naomi Cohen-Arazi, Abraham J. Domb,* Joshua Katzhendler
Biodegradable polyesters derived from hydrophobic amino acids are synthesized by various
techniques, resulting in a wide range of molecular weights. The polymers are prepared via
a) direct condensation with p-toluenesulfonic acid (PTSA) as catalyst, b) ring-opening
polymerization (ROP) of O-carboxyanhydrides, and c) ROP of cyclic dilactones. The polymers
obtained by the first method reach a molecular weight ranging from 1000 to 3000 Da,
whereas those formed by the second and third
method yield extended molecular weights of
15 000–30 000 Da. The purity of the monomers as
well as their steric bulkiness are key factors
affecting the polymerizability of cyclic mono-
mers by ROP. Other parameters such as spatial
ring alignment and proximity organization may
also play a role.
1. Introduction
100 kDa) can be routinely synthesized by ROP of the
dilactone of lactic acid using one of the many catalyst/
initiator systems that have been developed. The advan-
tages of this particular polymerization method include
control over the chain length and low polydispersities. ROP
is ascribed to a variety of cyclic systems that are able to
polymerize under the control of a series of catalysts and
initiators.
Over the years biodegradable synthetic polymers, and
particularly poly(lactic acid) (PLA), have received increasing
attention as matrices for controlled drug delivery and as
scaffolds for tissue engineering. Polymerization can take
place through several methods related either to condensa-
tionbydirectesterificationofthea-hydroxyacid,orester,or
via ring-opening polymerization (ROP). The molecular
weight of the polycondensates is generally limited to
about 3–4 kDa, yet a higher molecular weight (30 kDa) can
only be obtained with an appropriate catalyst.[1–3] The high
molecular weight of polylactide (molecular weight above
ROP systems consist of: a) various lactones such as b-
propiolactone, g-butyrolactone, d-valerolactone, and e-capro-
lactone,[4–8] b) O-carboxyanhydrides (OCAs) such as lactic
O-carboxylic anhydride (L-LacOCA),[9] glutamic O-carboxylic
anhydride (GluOCA),[10] c) trimethylene carbonate (1,3-
propylene carbonate),[11–14] d) lactide and homo/hetero
glycolides (dioxane-2,5-dione) bearing pendant groups,[15–22]
e) homo/hetero-substituted morpholine-2,5-dione,[23,24] f)
diolides,[25] and g) cyclic siloxanes.[26–32]
N. Cohen-Arazi, Prof. A. J. Domb, Prof. J. Katzhendler
Faculty of Medicine, School of Pharmacy, Institute of Drug
Research, The Hebrew University of Jerusalem, Jerusalem, Israel
E-mail: avid@ekmd.huji.ac.il
The assigned symmetric 3,6-disubstituted glycolides
(1,4-dioxane-2,5-dione) (Scheme 1) were prepared either
through self condensation reaction in high dilution
[p-toluenesulfonic acid (PTSA) in toluene], via cyclization
of glycoleoyl employing dipyridyldisulfide/PPh3 and
cyanuric chloride/Et3N,[21] or by cracking the appropriate
oligomersinthepresenceofacatalystfollowingdistillation
aFor ‘‘Functional polymers derived from saccharides and amino and
fatty acids’’ to an upcoming special issue of Macromolecular Biosci-
ence on the occasion of the 533th WE---Heraeus--Seminar ‘‘Advanced
Functional Polymers for Medicine’’ taking place from May 27th to
29th in Bad Honnef, Germany, organized by Prof. Andreas Lendlein.
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DOI: 10.1002/mabi.201300266 1689

N. Cohen-Arazi, A. J. Domb, J. Katzhendler
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catalysts. Cationic ROP was reported to consist of
HOTf and methyltrifluoromethane sulfonate (MeOTf).
Bifunctional organocatalysts seem to be highly efficient
catalysts, since they can operate in several modes
of activation as general acid/base catalysts [1-(3,5-
bistrifluoromethylphenyl)-3-(2-dimethylaminocyclohexyl)-
thiourea] or as combined base/general base catalysts
[1,5,7-triazabicyclo-(4.4.0)-dec-5-ene (TBD)]. The common-
ly used metallic catalysts are tin octanoate [Sn(Oct)2],
aluminum alkoxides Al(OR)3, titanium alkoxide [Ti(OR)4],
and a wide range of metal cations and rare-element
derivatives.[27,41,42]
Scheme 1. a) 1,4-Dioxane-2,5-dione and b) morpholine-2,5-dione.
or precipitation of the product. Asymmetrically 3,6-
disubstituted glycolides were prepared using a two step
reaction first forming the linear hetero dimmer of
alpha halo/hydroxyl glycoleoyl glycolate following ring
closure.[16]
Pendant functionalities incorporated as side chains of a
PLA would be a valuable extension of the present arsenal of
biodegradable polymers and would allow greater control of
its material properties such as hydrophilicity, mechanical
strength, and enhanced compatibility with living cells.
Such polymers can also be used for the formation of
supramolecular structures like polymeric micelles and
hydrogels.[43–45] Moreover, it is to be expected that
degradation time can be tailored and that non-toxic
degradation products will be formed through proper
selection of the monomers.
In our previous work,[46,47] we referred to direct
condensation of chiral glycolic acid substituted by amino
acid side chains, resulting in low-molecular-weight poly-
esters (around 3000 Da). In light of the above, the aim of the
present study is to inspect diverse polymerization methods
to attain higher molecular weight polymers (>10 000 Da).
The methods considered are enzymatic direct condensation
as well as ROP of OCAs and of dilactones. Moreover,
chemicaldirectcondensationwasalsoexaminedinquestof
notableimprovementsinmolecularweightoftheproduced
polyesters.
Several symmetrically substituted glycolides such as
R ¼ R1 ¼ R2 ¼ ethyl (Et), hexyl (Hex), isobutyl (i-Bu), benzyl
(Bzl), phenyl (Ph) or CH2COOBzl,[33–38] and hetero-substi-
tuted glycolides derived from glycolic acid such as: R1 ¼ H,
R2 ¼ methyl (Me), dodecyl, CH2COOBzl or CH2OBzl were
prepared with retention of configuration.[17,39,40]
However, the preparation of the hetero 3,6-substituted
glycolides derived from lactic acid, e.g., R1 ¼ Me, R2 ¼ Hex,
CH2CH2COOBzl (Glu), and (CH2)4COOCbz (Cbz ¼ Benzyloxy-
carbonyl),[16] associated several times with racemization of
one of the chiral centers.
Another attractive approach in the frame of depsi-
biodegradable polymers is related to the cyclic dimmers of
a-hyroxy and a-amino acid building blocks assigned as
morpholine-2,5-dione (Scheme 1).[24,41] Preparation of
morpholine-2,5-dione derivatives was attained by several
methods: a) cyclization of N-(a-haloacyl)-a-amino acids, b)
cyclization of N-(a-hydroxyacyl)-a-amino acids by i) PTSA,
methanesulfonic acid or trifluoromethanesulfonic acid
(HOTf) as ring closure catalysts, or ii) carbonyldiimidazole
as a cyclization mediator, c) cyclization of O-(a-aminoacyl)-
a-hydroxycarboxylic acids. ROP of morpholine-2,5-dione
derivatives is an elegant way to produce a wide spectrum of
poly(ester amide)s. It should be noted that ROP of
morpholine 2,5-dione can also take place in the presence
of various types of lipase.
2. Experimental Section
2.1. Materials
Lactic acid was purchased from J.T. Baker, Deventer, The
Netherlands. The amino acids were purchased from Fluka, Buchs,
Switzerland; Sigma-Aldrich, Milwaukee, WI (98–99% pure); and GL
Biochem, Shangai, China (98%). Sodium nitrite (99.5%), PTSA
monohydrate (98.5%), tin ethylhexanoate (95%), tributyltin meth-
oxide (97%), and titanium isopropoxide (97%) were also purchased
from Sigma-Aldrich, Milwaukee, WI. Lipozyme, immobilized from
Mucor Miehei, and lipase acrylic resin from Candida antartica were
also purchased from Sigma-Aldrich, Milwaukee, WI. DMAP was
purchasedfromNovabiochem,LaJolla,CA. Neopentylalcohol(99%)
was purchased from Acros Organics, Geel, Belgium. Triethylamine
(99%) was purchased from Abcr, Karlsruhe, Germany. The 20%
phosgene in toluene solution was purchased from Fluka AG, Buchs,
Switzerland. All solvents were analytical grade from Biolab,
Jerusalem, Israel, Frutarom, Haifa, Israel, or Gadot, Or Akiva, Israel.
They were used without further purification.
The following poly[(lactic acid)-alt-(amino acid)]s were
synthesized by ROP of morpholine-2,5-dione: cyclo[LA-Asp
(OBzl)], cyclo[LA-Glu(OBzl)], cyclo[LA-Tyr(Bzl)], cyclo[LA-Cys
(pNBzl)], cyclo(LA-Val), cyclo(LA-Leu), cyclo(LA-Ile), cyclo
[LA-Cys(pNBzl)] where LA and pNBzl refer to lactic acid and
4-nitrobenzl, respectively.
A broad range of organocatalysts (nucleophilic, cationic,
and bifunctional) and metallic catalysts has been reported
for the ROP.[27,33]
Pyridine, dimethylamino pyridine (DMAP), phosphine,
carbenes such as imidazol-2-ylidenes, and imidazolin-2-
ylidenes or thiazol-2-ylidenes were used as nucleophilic
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toluene or diisopropyl ether. The polymerization was conducted at
55 8C, in presence of molecular sieves for up to 7 d.
The molecular weight was checked by GPC several times during
polymerization.
2.2. Techniques
IR (2000 FTIR, Perkin-Elmer) measurements of polymers film were
performed on NaCl plates using a chloroform solution of the
polymers. The molecular weights of polyesters were estimated
with a gel permeation chromatography (GPC) system consisting of
a Waters 1515 isocratic HPLC pump with a Waters 2410 refractive-
index detector, a Waters 717 plus autosampler, and a Rheodyne
(Coatati, CA) injection valve with a 20 mL-loop (Waters, MA). The
samples were eluted with CHCl3 (HPLC grade) through linear
2.6. Preparation of OCAs
1 g (6.02 mmol) of HOPhe was dissolved in 27 mL of dry
tetrahydrofuran (THF). The solution was stirred under nitrogen
and cooled to 0 8C. 6.8 mL (1.3 equiv.) of 20% phosgene in toluene
was then added in one portion. The reaction was stirred overnight
at room temperature and refluxed for 2 h. The solvents were
evaporatedinvacuo,andthecrudeproductwasrecrystallizedthree
times in chloroform/hexane. The same procedure was employed
for HOIle, HOLeu, and HOVal. In the latter cases the derived
compounds tended not to crystallize. The compounds were
characterized by 1H NMR.
StyragelHR1orHR3columns(Waters)ataflowrateof1 mL ꢀ minꢁ1
.
The molecular weights were determined relative to polystyrene
standards (Polyscience, Warrington, PA) with a molecular-weight
range of 100–30 000 using an Empower computer program.
1H NMR spectra (CDCl3 for the polymers and DMSO-d6 for the
hydroxy acids) wereobtained on a Varian300 MHz spectrometer in
5 mm tubes. Tetramethylsilane was used as a reference. The optical
activity of the monomers and polymers was determined using a PE
343polarimeter(Perkin-Elmer).Thermalpropertiesofthepolymers
were determined on a Mettler TA 4000-DSC differential scanning
calorimeter(Mettler-Toledo,Schwerzenbach,Switzerland)calibrat-
ed with an in standard heated at a rate of 10 8C ꢀ minꢁ1 under
2.6.1. HOPhe-OCA
1H NMR: d ¼ 7.36–7.20 (5H, aromatic, m), 5.30 (1H, COCH, dd), 3.42–
3.21 (2H, CH2, dq). 13C NMR: d ¼ 166.59 (1C, CHCOO), 148.08 (1C,
OCOO), 131.79 (1C, aromatic), 129.90 (2CH, aromatic), 129.40 (2CH,
aromatic), 128.64 (1CH, aromatic), 80.15 (1CH), 36.64 (CH2). Mp:
110–115 8C. IR: n ¼ 1883, 1782, 1731 cmꢁ1. Yield: 85%.
ꢀ
nitrogen atmosphere. Contact angles were measured with a Rame-
Hart model 100 contact angle goniometer on polymer covered
microscope slides. The polymers were dissolved in chloroform,
dropped on the slides, and evaporated. These measurements were
repeated three times for each sample; the average values are
reported circular dichroism (CD) measurements recorded using a J-
810 spectropolarimeter (Jasco) in acetonitrile/chloroform 3:1 and
using a 1.0-cm quartz cell. Far-UV CD spectra were collected in a
spectral range of 190–300 nm.
2.6.2. HOLeu-OCA
1H NMR: d ¼ 5.06 (1H, COCH, dd), 1.97–1.83 (3H, CH and CH2, m),
1.02–0.99 (6H, CH3, m).
2.6.3. HOIle-OCA
1H NMR: d ¼ 4.97 (1H, COCH, dd), 1.60–1.47 (3H, CH and CH2, m),
2.3. Synthesis of a-Hydroxy Acids by Diazotization of
a-Amino Acids
1.12–1.03 (6H, CH3, m).
The hydroxy acids derived from L-isoleucine, L- and D-leucine, L- and
D-phenylalanine, and L- and D-valine were prepared by a chemical
diazotization method described in the previously published
work.[46,48] The hydroxy acids were characterized by 1H NMR
(DMSO-d6), melting point, elemental analysis, and optical
activity.[46]
2.6.4. HOVal-OCA
1H NMR: d ¼ 4.90 (1H, COCH, d), 2.38 (1H, CH, m), 1.14 (3H, CH3, d),
1.10 (3H, CH3, d).
2.7. Polymerization of OCA
L-HOPheOCA (1 g, 5.2 mmol) was dissolved in dry dichloromethane
(6.2 mL). Subsequently, a dichloromethane solution (0.19 M) of
neopentyl alcohol (2.3 mg, 1/200 equiv.) and DMAP (3.2 mg, 1/200
equiv.) was added. The reaction mixture was stirred at room
temperature until CO2 no longer evolved. The reaction mixture was
diluted with dichloromethane (4 mL), and the solution was then
washed with cold 2 N HCl (2 ꢂ 25 mL) and brine (25 mL), then dried
over sodium sulfate. The solvent was removed by evaporation to
render the polymer as a white solid. The resulting polymer was
characterized by means of GPC.
2.4. Polymerization of the a-Hydroxy Acids by Direct
Condensation
Direct condensation of hydroxy acids was carried out in bulk as
previously described.[34,49,50] The derived polymers were charac-
terizedby 1H NMR, IR, GPC, optical activity, and solubilityin several
solvents.[46,48]
2.5. Polymerization of the a-Hydroxy Acids by
Enzymatic Condensation
2.8. Preparation of 1,4-Dioxane-2,5-dione
EthylesterofHOLeuwaspreparedandpolymerizedwithtwokinds
of lipases, Candida antartica-fixed and Mucor miehei.[51,52] 200 mg
of HOLeu ethyl ester and 20 mg enzyme were dissolved in 5 mL of
HOPhe (5 g, 30.1 mmol) and PTSA (270 mg) were dissolved in
toluene (820 mL). The solution was refluxed for 8 d, removing the
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ꢃ
water by a Dean Stark trap filled with 4 A molecular sieves. After
washing the toluene three times with saturated aqueous NaHCO3,
the solvent was removed, and the crude crystals were washed with
ether to afford the cyclic dilactone (2.32 g, 52%) as white crystals.
The dilactone of HOIle, however, was washed with ethanol. The
synthesized dilactones were characterized by 1H NMR, 13C NMR, IR,
optical activity, and melting point.
identical to the L-dilactones, except the optical activity which is
opposite.
d-HOPhe dilactone: [a]d (c ¼ 0.5): þ151.98; d-HOLeu dilactone:
[a]d (c ¼ 0.5): þ190.88; d-HOVal dilactone: [a]d (c ¼ 0.5): þ236.18.
2.9. Polymerization of 1,4-Dioxane-2,5-dione
The preparation of 1,4-dioxane-2,5-dione was optimized by
tuning the amount of the catalyst (PTSA).
The method selected for the polymerization of the dilactones was a
solvent-free polymerization. A solution of benzyl alcohol and Sn
(Oct)2 in toluene was added to the monomer. The molar ration
between the monomer and the initiator or catalyst is 1:100. The
solvent was removed in vacuo and the tube was sealed and
immersed in an oil bath at 190 8C. At the end of the polymerization,
the tube was cooled and opened, and the polymer was dissolved in
toluene. A sample of the dissolved polymer was evaporated to
dryness and analyzed by NMR for conversion. The remaining
polymer was precipitated into methanol to remove residual
catalyst.
2.8.1. L-3,6-Dibenzyl-[1,4]dioxane-2,5-dione (HOPhe
dilactone)
1H NMR: d ¼ 7.29 (10H, m), 5.03 (2H, dd), 3.39–2.96 (4H, dq).
13C NMR: d ¼ 165.8 (2COO), 134.9 (2 aromatic C), 130.0 (4 aromatic
CH), 128.9 (4 aromatic CH), 127.7 (2 aromatic CH), 76.8 (2 CH), 36.8
(2CH2). IR: n ¼ 1747–1753 cmꢁ1. Mp:165–167 8C; [a]D (c ¼ 0.5):
ꢁ148.38. Elemental analysis: calcd. C 72.96, H 5.44; found C
72.67, H 5.38. Yield: 52%.
Thepolymerswerecharacterizedby1HNMR, IR, GPC,andoptical
activity.
2.8.2. L-3,6-Diisobutyl-[1,4]dioxane-2,5-dione (HOLeu
dilactone)
3. Results and Discussion
1HNMRd ¼ 4.91(2H, dd), 1.99–1.88(6H, m), 1.00(12H, dd). 13CNMR:
d ¼ 167.6 (2 COO), 74.3 (2 CH), 38.9 (2 CH), 24.0 (2 CH2), 23.3 (2 CH3),
21.5 (2 CH3); IR: n ¼ 1747–1753 cmꢁ1. Mp: 170–173 8C; [a]D (c ¼ 0.5):
ꢁ190.18; Elemental analysis: calcd. C 63.14, H 8.92; found C 62.65, H
8.92. Yield: 45%.
This work is on the synthesis of new functional a-
hydroxypolyesters derived from natural amino acid con-
verted into a-hydroxy alkanoic acid monomers. These
monomers have been polymerized into polyesters using
direct polycondensation and ROP of their corresponding
lactone derivatives. Cyclic reactive monomers suitable for
ROP have been synthesized.
2.8.3. L-3,6-Diisopropyl-[1,4]dioxane-2,5-dione (HOVal
dilactone)
1H NMR: d ¼ 4.71 (2H, d), 2.63 (2H, m), 1.16 (6H, d), 1.10 (6H, d).
13C NMR: d ¼ 166.7 (2 COO), 79.8 (2 CH), 29.6 (2 CH), 18.8 (2 CH3), 16.1
(2 CH3); IR: n ¼ 1747–1753 cmꢁ1. Mp: 147–149 8C; [a]D (c ¼ 0.5):
ꢁ231.68; Elemental analysis: calcd. C 59.98, H 8.05; found C 59.38, H
8.06. Yield: 28%.
3.1. Direct Condensation
The polyesters prepared by direct condensation in bulk
(Scheme 2) with PTSA as a catalyst resulted in a molecular
weight about 2000. The characterization of the derived
polymers was previously described.[46,48]
2.8.4. L-3,6-Di-sec-butyl-[1,4]dioxane-2,5-dione (HOIle
dilactone)
Briefly, the prepared polymers are soluble in chloroform,
even more so than PLA. They are also soluble in THF and
acetonitrile (ACN) but not in water. 1H NMR spectroscopy
confirms the polymerization of the monomers by the
appearance of a CH peak between d ¼ 5.1 and 5.3,
corresponding to the ester group CH—COO—CH, and the
notable disappearance of the CH OH peak of the hydroxy
acid at d ¼ 4.0–4.3. All polymers disclosed an IR major ester
1H NMR: d ¼ 4.72 (2H, d), 2.22 (2H, m), 1.56 (2H, m), 1.39 (2H, m), 1.15
(6H, d), 0.95 (6H, t). 13C NMR: d ¼ 166.7 (2 COO), 79.7 (2 CH), 36.2
(2 CH), 23.7 (2 CH2), 15.3 (2 CH3), 12.0 (2 CH3). IR: n ¼ 1747–
1753cmꢁ1.Mp:80–83 8C.[a]D (c ¼ 0.5):ꢁ177.68;Elementalanalysis:
calcd. C 63.14, H 8.83; found C 62.57, H 8.97. Yield: 24%.
The dilactones of D-HOPhe, D)-OLeu, and D-HOVal were
prepared by the same method. Their characteristics were
Scheme 2. Direct condensation of the a-hydroxy acids.
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peak between 1750 and 1765 cmꢁ1 and a small acid peak at
Table 1. Characterization of poly(L-HOPhe) prepared from OCA.
about 1640 cmꢁ1
.
Molar ratio
monomer/
3.2. Enzymatic Condensation
initiator/catalyst
Mn [Da]
Mw [Da]
Mp [Da]
Theformation ofpolyesterswas alsotestedin an enzymatic
system in non-aqueous solution. In this case lipase is
apparently an appropriate enzyme. The substrate (hydroxy
acid) should be transformed into an ester form to direct the
reaction toward the products.
200:1:1
20 000
22 000
28 000
The polymerization of HOLeu-OCA, HOIle-OCA, and
HOVal-OCA was not successful. These OCAs resulted in
polymersof3000Da. Thelow-molecular-weightobtainedis
probably due to acidic impurities in the OCA, which quench
polymerization. Additional experimental conditions were
conducted to improve the molecular weight of the
polymers. These included different catalysts (triethyl-
amine, TEA) for an additional catalyst as triethylamine
(TEA) and higher catalyst ratios: 1:2 equiv. TEA, or 1:2–1:1
equiv. DMAP. The molecular weight obtained was slightly
higher (Table 2) but not in the expected range.
The ethyl ester of hydroxy leucine (HOLeu) was prepared
and polymerized with two types of lipases, Candida
antarticans-fixed and Mucor miehei. Polymerization was
conducted in toluene or diisopropyl ether at 55 8C, with
molecular sieves. The Mucor miehei lipase resulted in
oligomers of Mn <700 Da, whereas the Candida antartica
polymerization gave two ranges of molecular weights (700
and 1500 Da), even after 4 d of reaction.
3.3. Preparation of OCA
During the reaction course it was noticed that the rate of
HOPhe-OCA polymerization is much slower than otherOCA
polymerization. One indication is the longer time of CO2
release (several hours). In the case of HOLeu-OCA, for
instance, carbon dioxide evolved intensely during the first
minute of the reaction and then ceased. The high reaction
rate was confirmed by 1H NMR measurement. HOLeu-OCA
and DMAP (1 equiv.) dissolved in CDCl3 were introduced
into an NMR tube, and the spectrum was recorded.
Neopentyl alcohol (1/200) was then added, and the
spectrum was again recorded within the first minute.
The characteristic signal of the OCA at d ¼ 5.06 was
immediately shifted to the corresponding polyester signal
at d ¼ 5.10. No changes were observed in the NMR spectra
during the following hour.
The preparation of the OCA derivative and its polymeriza-
tion is delineated in Scheme 3.
OCAs were prepared from the hydrophobic hydroxy
acids, HOIle, HOLeu, HOPhe, and HOVal, high yields (95%)
were obtained.
HOPhe-OCA was recrystallized three times in chloro-
form/hexane to afford highly pure white crystals. The
same protocol was employed for HOIle, HOLeu, and
HOVal, however at room temperature they turned out to
be liquid and could not be recrystallized nor purified by
other methods (silica or alumina column, HPLC). Their
purity was approximately 95% according to 1H NMR
analysis.
The increase of the DMAP ratio apparently results in
acceleration of the polymerization rate. This may account
for the slight ascent in the molecular weight of the polymer
(Table 2). It is likely that under these conditions the
quenching by impurities is slower than the assemblage
process of polymerization. The role of DMAP in the present
case is probably to mask acidic impurities which trigger
the quenching reaction. In conclusion, it can be presumed
that the purity of OCA plays a major role in attaining
polymerization of high molecular weight.
3.4. Polymerization of OCA
The OCAs were polymerized in solution (dry dichloro-
methane) with neopentyl alcohol as an initiator and DMAP
as a catalyst. During the course of polymerization, CO2
evolvesslowly. Thereactioniscompletedwhennomoregas
evolves. After washing and evaporation, the polymers were
characterized by GPC (Table 1). The molecular weight of
poly(L-HOPhe) obtained was close to the expected value
considering the monomer:initiator ratio.
Scheme 3. OCA preparation and polymerization.
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Table 2. Polymerization of L-HOLeu-OCA.
Molar ratio M/I/C in
polymerization step
Catalyst
Mn [Da]
Mw [Da]
Mp [Da]
200:1:100
200:1:100
200:1:200
TEA
2800
4500
4700
3100
6200
6400
–
DMAP
DMAP
5700
5900
3.5. Preparation of Cyclic Diactones (1,4-Dioxane-2,5-
dione)
solvent of choice for this method are PTSA and toluene,
whereas the water is captured by a Dean-Stark apparatus.
Homolactones are the preferred substance obtained in this
reaction course. The observed yields are 30–50%, while the
main byproducts in this process are the linear oligomers.
The required duration of the reaction is between 8 and
20 days.[34,54]
The preparation of cyclic di-lactone derivative and its
polymerization are depicted in Scheme 4.
Three major routes are employed in the literature for the
preparation of lactones. Route 1 consists of cracking a low-
molecular-weight polymer.[37,53]
Route3consistsoftwostages;firstisadimmerformation
ensued by ring closure to yield the dilactone (Scheme 6).
This method requires a large number of steps. The main
advantage of this route is its potential in the preparation of
heterodilactones. The overall yields of this method are
<40%.[17,21,36,55,56]
In Scheme 5 the method for the preparation of lactide
(from lactic acid) is given. The yields obtained by this
method are usually above 50%, and homodilactones may
conceivably be prepared (the substituents R are identical).
However, the more the bulkiness of the alkyl substituent,
the more severe the cracking conditions (high temperature
and vacuum).
The method of choice implemented in this work for
preparing homolactones from the hydroxy acids was
Route 2.
Route 2 is related to the synthesis of the di-lactone from
the monomer in solution (high dilution). The catalyst and
The preparation of the lactones was optimized by
inspection of the impact of the catalyst (PTSA) ratio on
the yield of the reaction. The optimization was performed
with two hydroxy acids (HOPhe and HOIle), as is presented
in Figure 1.
The optimal percentage of PTSA required for cyclic
dilactone formation derived from HOPhe and HOLeu was
found to be about 5 mol%, whereas in the case of HOVal and
HOIle it is about 10 mol%.
Scheme 4. Polymerization pattern through ROP of dilactones.
3.6. Polymerization of Dilactones
The dilactones were polymerized by a solvent-free ring
openingreaction. Theinitiatorusedisbenzylalcohol, which
was formerly dried on molecular sieves. The catalyst used is
Sn(octanoate)2. For D-HOVal and L-HOIle dilactones, two
Scheme 5. Synthesis of homodilactones by cracking low-
molecular-weight polymers.
Scheme 6. Synthesis of hetero-dilactones by dilactone closure.
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under these reaction conditions with different catalysts.
L-HOIle dilactone was also polymerized in solution but
without success. It is noted that in contrast to the L-HOVal
dilactone, the D-HOVal dilactone is polymerized to a
substantial lower extent.
Ring-opening polymerization of substituted cyclic lac-
tones is slower than lactide itself. It requires solvent-free
reaction, whereas lactide can be polymerized in toluene
(high concentration). In addition it requires a higher
polymerization temperature according to the dilactone
melting point. Namely, the polymerization rate of
glycolide is faster than lactide, probably due to the steric
effect of the methyl groups that hinders nucleophilic attack
on the carbonyl groups of the cyclic dilactone. Thus, it is
expected that increasing the substituents bulkiness should
decrease the polymerization rate. A survey of dilactone
monomers by Hall,[11,57] shows that ring substitution plays
a major role in defining the polymerizability of dilactones.
For example, 3,3,6,6-tetramethyl-1,4-dioxane-2,5-dione,
does not undergo ROP. Presumably, nucleophilic attack
by either the initiator or the growing polylactide chain is
too hindered to lead to a polymer. In the present work the
order of polymerizability of the compounds tested is as
follows:
Figure 1. Effect of %PTSA (molar) on the yield of formed
dilactone.
alternative catalysts were used, titanium isopropoxide and
tributyltin methoxide. The ratio of catalyst/initiator/
monomer is 1:1:100. The reaction vial was heated to the
desired temperature (10 8C above the melting point of the
monomer) until polymerization terminated (demonstrated
by GPC and NMR). The polymers were then dissolved in
toluene, precipitated into methanol to remove residual
HOPhe ¼ HOLeu > HOVal : HOIle. In the case of HOPhe
and HOLeu the b carbon atom of the alkyl side chain is a
secondary carbon (R2CH2), while the b carbon atom of (L)
HOVal and HOIle is a tertiary carbon atom (R3CH). Thus, it
seems conceivable that the cyclic dilactone of HOPhe and
HOLeu is less hindered and accordingly is more reactive. On
the other hand, the considerable discrepancy between the
relativities of L-HOVal compared to L- HOIle cannot be
interpreted solely on the basis of steric bulkiness. Appar-
ently some other parameters as spatial ring alignment and
proximity may play a role.
1
catalyst, and characterized by GPC, H NMR, IR, DSC, and
optical activity.
The optimal molecular weights of polymersderived from
the various lactones are presented in Table 3.
The molecular weight obtained by ROP extremely
depends on polymerization time. Actually, the backward
reaction of depolymerization competes with the forward
reaction along the reaction time scale. Prolongation of time
after the consumption of the dilactone enhances the
backward reaction of depolymerizaton and consequently
decreasesthemolecularweightofthepolymer. Theoptimal
reaction time for L-HOPhe and L-HOLeu dilactones was
found to be about 1.5 h, whereas for L-HOVal dilactone it
was around 4 h. L-HOIle dilactone was resistant to ROP
3.7. NMR
1H NMR spectroscopy confirm the polymerization of the
lactones by the appearance of a CH peak between d ¼ 4.9
and 5.2 corresponding to the ester group CH—COO—CH,
and the significant disappearance of the CH signal of the
dilactone between d ¼ 4.71 and 5.02, Figure 2.
Table 3. Molecular weight of polymers prepared by ROP of
dilactones.
The yield of the polymerization is also evaluated
from the ratio of OCH (polymer backbone signal)/OCH
(lactone signal) in the NMR spectrum of the crude
polymer. Polymerization yields for L- and D-HOPhe dilac-
tone, and L- and D-HOLeu dilactone were close to
100%, whereas for L-HOVal dilactone it was about 80%.
Purification was implemented by recrystallization in
methanol.
Depsi polymers
Mn [Da]
Mw [Da]
Mp [Da]
poly(L-HOPhe)
poly(L-HOLeu)
poly(L-HOVal)
poly(L-HOIle)
poly(D-HOPhe)
poly(D-HOLeu)
poly(D-HOVal)
20 200
14 800
13 000
2700
25 000
19 000
15 000
3000
27 000
16 000
16 000
2300
21 000
13 500
2600
24 000
18 000
2800
26 000
17 000
2700
Regarding L-HOIle dilactone and D-HOVal dilactone, the
polymerization yield after 2 h was <10%. However, after
more than 24 h of reaction, it reached a value of 80%.
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N. Cohen-Arazi, A. J. Domb, J. Katzhendler
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Figure 2. 1H NMR spectrum of poly(L-HOLeu) (19 000 Da) in chloroform.
According to the NMR analysis, 10% of the corresponding
linear hydroxy acid and 10% of the lactone remained
unreacted in the reaction mixture. Since the molecular
weight of these polymers is low (3000 Da) and is not in
accordancewiththeROPresults,itseemslikelythatinthese
cases polymerization proceeds through a direct condensa-
tion mechanism, which is directed through a non-polymer-
izable lactone ring opening.
This assumption is in accordance with the previous
premise that spatial ring alignment and proximity may
play a role in ROP process.
3.8. IR
All polymers show major ester peak around 1760 cmꢁ1
(Figure 3).
Figure 3. IR spectrum of poly(L-HOLeu) (19 000 Da).
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Poly(a-hydroxy alkanoic acid)s Derived From a-Amino Acids
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Table 4. Thermal properties of the a-hydroxy acids polymers
determined by DSC at 10 8C ꢀ minꢁ1 (Tg, Tm, and DH).
Table 5. Optical activity of the polymers. Specific optical rotation
(c ¼ 1–1.2 g per 100 mL of CHCl3 at 25 8C).
Polymers
Tg [8C]
Tm [8C]
DH [J ꢀ gꢁ1
]
Polymer
Optical activity [a]D
poly(L-/D-HOPhe)
poly(L-/D-HOLeu)
poly(L-HOVal)
89.79
28.63
35.37
–
–
–
–
poly(L-HOPhe)
poly(L-HOLeu)
poly(L-HOVal)
ꢁ2.6
ꢁ6.0
ꢁ4.2
202.42
ꢁ30.41
3.9. DSC
The CD spectra of all polymers display a band with a
maximum ranging from 224 to 229 nm (Table 6 and
Figure 4), which is probably attributed to an n–pꢄ transition
of the ester bond. Regarding the polyHOPhe polymers, the
maximum amplitudes (A01 for the L isomer and A02 for the
D isomer) are significantly higher than for other polymers,
42 and –20 mdeg, respectively, compared to 8 and 12 mdeg
for poly(L-HOVal) and poly(L-HOLeu). The increase in
rotational strength of the polyHOPhe can be due to the
structural alignment of the attached phenyl groups. As
expected, the L polymers showed a positive rotation,
whereas the D rotation is negative.
DSCscanswereusedtomeasuretheglasstransitionandthe
melting temperature of the polymers (Table 4).
Poly(L-HOPhe) shows a well-defined Tg at 90 8C but no
evidence of crystallinity. Overall, thermal analysis data
show that the Tg’s of the polymers range from 35 to 90 8C.
Only poly(L-HOVal) showed evidence of crystallinity with a
clear Tm peak.
3.10. Optical Activity
The optical activity of the polymers was measured, and the
results are summarized in Table 5.
Since the polymers are not soluble in acetonitrile, the
spectra were recorded in chloroform/acetonitrile 1:3.
However, chloroform is incompatible with far-UV CD,
inducing a voltage higher than 600 V at wavelengths lower
than 220 nm. Indeed, the spectra recorded down to 220 nm
were not legible, whereas the region ranging from 220 to
230 nmwasslightlydisturbed byacertaindegreeofsolvent
interference. This phenomenon could explain the slight
difference between the spectra of L- and D-polyHOPhe,
which exhibit either one or two maxima.
The polymers show relatively low specific optical
rotation although the lactones were enantiomerically pure,
as shown from their optical rotation.
3.11. Circular Dichroism
The CD data were fitted to one [or two, only for Poly(D-
HOPhe)] term of Equation 1 by a nonlinear regression,
A comparison of the present results with the authors’
previous work[47] (low molecular weights) reveals that poly
(L-HOPhe¼ (3000 Da) exhibits a CD maximum at 220 nm,
which is close to the maximum of polyHOPhe (25 000 Da) at
224 nm. However, concentrations of the polymer samples
were quite different, 0.5 M for the 3000 Da polymer
comparedto0.003forthepolymerof25 000Da.Considering
that the concentration of polyHOPhe (3000 Da) is higher
than that of the 25 000 Da, one can infer that the rotational
strength of the high molecular weight polymer is more
profound than that of the low-molecular-weight polymer.
ꢀ
ꢁ
2 þ A02exp
l1 ꢁ l1;max
Al ¼ A01exp ꢁ
D1
ꢀ
ꢁ
2
l2 ꢁ l2;max
ꢁ
D2
where Al is the CD amplitude at the wavelength l, A01 and
A02 are the maximum amplitudes at l1,max and l2,max
,
respectively, and D1 and D2 are the widths of the curves at
A0/2.71828; the subscripts 1 and 2 denote poly(L-HOPhe)
and poly(D-HOPhe), respectively.
Table 6. Calculated parameters (A01, l1max, and D ) emerged from CD absorbance curve fitting employing Equation 1.
1
Polyesters
Concentration [10ꢁ3 M]
A01 [mdeg]
l1max [nm]
D1 [nm]
poly(L-HOPhe)
poly(D-HOPhe)
poly(L-HOVal)
poly(L-HOLeu)
0.0031
0.002
42
224.7
8.80
5.87c)
6.00
7.15
ꢁ10.744a)
8.412
229.60b)
228.89
228.43
0.0033
0.0026
12.151
a)
A02 ¼ –20.398; b)l2max ¼ 224.30; c)D2 ¼ 2.92.
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N. Cohen-Arazi, A. J. Domb, J. Katzhendler
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Figure 4. CD curves: A) poly(L-HOVal); B) poly(L-HOLeu); C) poly(L-HOPhe) (a and b) and poly(D-HOPhe) (c and d). Red and black lines refer
to the predicted and experimental curves, respectively.
Keywords: a-amino acids; biodegradable polyesters; circular
dichroism; cyclic dilactones; ring-opening polymerization
This may indicate that the spatial alignment of the phenyl
groups in the high-molecular-weight polymer is more
strongly synchronized.
[1] S. H. Hyon, K. Jamshidi, Y. Ikada, Biomaterials 1997, 18,
4. Conclusion
1503.
[2] X. D. Lou, C. Detrembleur, R. Jerome, Macromol. Rapid
Substituted polyglycolides can be readily prepared by
different synthetic procedures. Direct condensation of
a-hydroxy acids leads to polyesters of lowmolecular weight
intherangeof1000–3000Da. OCApolymerizationresultsin
high-molecular-weight polymer only in the case of highly
pure monomer (polyHOPhe). Polymerization of dilactone in
bulk using Sn(Oct)2 as catalyst with benzyl alcohol as an
initiator generally results in high conversions and predict-
able molecular weights (20 000 Da). The polymerizability of
the lactones is probably controlled by the bulkiness of the
substituents on the glycolide ring and their spatial ring
orientation. Substituent effects are also pronounced in Tg
value of the polymers. The polymers show different Tg’s
depending on thelengthandthebranchingof theside chain
on the glycolide ring. Enzymatic polymerization was not
effective for the polymerization of the a-hydroxy acids.
These new polymers broaden the scope of physical
properties ofsubstituted polylactidesthat possiblycouldbe
used for medical applications like stands and drug delivery
carriers.
Commun. 2003, 24, 161.
[3] A. Takasu, Y. Oishi, Y. Iio, Y. Inai, T. Hirabayashi, Macro-
molecules 2003, 36, 1772.
[4] A. P. Dove, Chem. Commun. 2008, 48, 6446.
[5] T. Moore, R. Adhikari, P. Gunatillake, Biomaterials 2005, 26,
3771.
[6] K. M. Schreck, M. A. Hillmyer, Tetrahedron 2004, 60, 7177.
[7] S. Slomkowski, Macromol. Symp. 2007, 253, 47.
[8] C. K. Williams, Chem. Soc. Rev. 2007, 36, 1573.
[9] O. Thillaye du Boullay. E. Marchal, B. Martin-Vaca, F. P. Cossio,
D. Bourissou, J. Am. Chem. Soc. 2006, 128, 16442.
[10] O. Thillaye du Boullay. C. Bonduelle, B. Martin-Vaca, D.
Bourissou, Chem. Commun. 2008, 15, 1786.
[11] M. Helou, O. Miserque, J. M. Brusson, J. F. Carpentier, S. M.
Guillaume, Chem. Eur. J. 2010, 16, 13805.
[12] F. Li, M. Danquah, R. I. Mahato, Biomacromolecules 2010, 11,
2610.
[13] X. L. Wang, R. X. Zhuo, L. J. Liu, F. He, G. Liu, J. Polym. Sci., Part A
2002, 40, 70.
[14] Y. Zhang, R. X. Zhuo, Biomaterials 2005, 26, 2089.
[15] M. Leemhuis, N. Akeroyd, J. A. W. Kruijtzer, C. F. Van Nostrum,
W. E. Hennink, Anglais 2008, 44, 308.
[16] W. W. Gerhardt, D. E. Noga, K. I. Hardcastle, A. J. Garcia, D. M.
Collard, M. Weck, Biomacromolecules 2006, 7, 1735.
[17] M. Leemhuis, C. F. Van Nostrum, J. A. W. Kruijtzer, Z. Y. Zhong,
M. R. Ten Breteler, P. J. Dijkstra, J. Feijen, W. E. Hennink,
Macromolecules 2006, 39, 3500.
Acknowledgements: This study was supported by The Israel
Science Foundation Grant No. 591/08.
[18] K. Nakano, N. Kosaka, T. Hiyama, K. Nozaki, Dalton Trans.
2003, 21, 4039.
Received: May 30, 2013; Revised: July 1, 2013; Published online:
August 22, 2013; DOI: 10.1002/mabi.201300266
[19] K. Marcincinova Benabdillah, J. Coudane, M. Boustta, R. Engel,
M. Vert, Macromolecules 1999, 32, 8774.
Macromol. Biosci. 2013, 13, 1689–1699
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1698
www.MaterialsViews.com

Poly(a-hydroxy alkanoic acid)s Derived From a-Amino Acids
www.mbs-journal.de
€
[20] M. Trollsas, V. Y. Lee, D. Mecerreyes, P. Lowenhielm, M. Moller,
R. D. Miller, J. L. Hedrick, Macromolecules 2000, 33, 4619.
[21] M. Leemhuis, V. Steenis, H. Jan, V. Uxem, J. Michelle, V.
Nostrum, F. Cornelus, Hennink, E. Wim, Eur. J. Org. Chem.
2003, 17, 3344.
[22] Y. J. Yuan, Y. Jian, P. H. Zhong, G. Z. Wei, C. W. Xiao, F. X. De,
Chin. J. Polym. Sci. 2001, 19, 509.
[23] D. A. Barrera, E. Zylstra, P. T. Lansbury, R. Langer, Macro-
molecules 1995, 28, 425.
[36] T. Trimaille, M. Moller, R. Gurny, J. Polym. Sci., Part A 2004, 42,
4379.
[37] M. Yin, G. L. Baker, Macromolecules 1999, 32, 7711.
[38] T. Ouchi, A. Fujino, Makromol. Chem. 1989, 190, 1523.
[39] Y. Kimura, K. Shirotani, H. Yamane, T. Kitao, Macromolecules
1988, 21, 3338.
[40] M. Leemhuis, J. A. W. Kruijtzer, C. F. V. Nostrum, W. E.
Hennink, Biomacromolecules 2007, 8, 2943.
[41] C. Jerome, P. Lecomte, Adv. Drug Delivery Rev. 2008, 60, 1056.
[42] H. Yasuda, J. Polym. Sci., Part A: Polym. Chem. 2001, 39, 1955.
[43] W. E. Hennink, C. F. V. Nostrum, Adv. Drug Delivery Rev. 2002,
54, 13.
[24] Y. Feng, J. Guo, Int. J. Mol. Sci. 2009, 10, 589.
[25] Y. Oohashi, K. Fukumoto, T. Mukaiyama, Chem. Lett. 2005, 34,
710.
[26] T. C. Kendrick, B. Parbhoo, J. W. White, in The Chemistry of
Silicon Compounds (Eds: S. Patai, Z. Rappoport), Wiley,
Chichester, UK 1989, p 1289.
[44] Y. Kakizawa, K. Kataoka, Adv. Drug Delivery Rev. 2002, 54, 22.
[45] K. Kataoka, A. Harada, Y. Nagasaki, Adv. Drug Delivery Rev.
2001, 47, 31.
[27] S. Penczek, M. Cypryk, A. Duda, P. Kubisa, S. Somkowski, Prog.
Polym. Sci. 2007, 32, 247.
[46] N. Cohen-Arazi, J. Katzhendler, M. olitz, A. J. Domb, Macro-
molecules 2008, 41, 7259.
[28] M. G. Voronkov, V. P. Mileshkevich, Y. A. Yuzhelevskii, The
Siloxane Bond, Consultants Bureau, New York 1978.
[29] J. Chojnowski, M. Cypryk, in Silicon-Containing Polymers–-
The Science and Technology of Their Synthesis and Applica-
tions, (Eds., R. G. Jones, W. Ando, J. Chojnowski), Kluwer
Academic, Dordrecht, The Netherlands 2000.
[47] M. Kolitz, N. Cohen-Arazi, I. Hagag, J. Katzhendler, A. J. Domb,
Macromolecules 2009, 42, 4520.
[48] N. Cohen-Arazi, A. J. Domb, J. Katzhendler, Polymers 2010, 2,
418.
[49] T. Kajiyama, H. Kobayashi, T. Taguchi, K. Kataoka, J. Tanaka,
Biomacromolecules 2004, 5, 169.
[30] J. Chojnowski, in Siloxane Polymers, (Eds., S. J. Clarson, J. A.
Semlyen), Prentice Hall Englewood Cliffs, NJ 1993.
[31] J. Chojnowski, in Silicon Compounds: Silanes and Silicones,
1st ed., B. Arkles, G. Larson, Eds., Gelest, Morrisville 2004,
p 187.
[50] A. C. Albertsson, I. K. Varma, ‘‘Aliphatic polyesters: Synthesis,
properties and applications’’. in Degradable Aliphatic Poly-
esters, Springer, Berlin 2002, Vol. 157.
[51] X. T. Shuai, Z. Jedlinski, M. Kowalczuk, J. Rydz, H. M. Tan, Eur.
Polym. J. 1999, 35, 721.
[32] T. C. Kendrick, B. M. Parbhoo, J. W. White, in Comprehensive
Polymer Science: The Synthesis, Characterization, Reactions
and Applications of Polymers: Chain Polymerization, G.
Eastmond, A. Ledwith, S. Russo, P. Sigwalt, Eds., Pergamon
Press, Oxford 1990, Vol. 4, p 459.
[52] I. K. Varma, A. C. Albertsson, R. Rajkhowa, R. K. Srivastava,
Progr. Polym. Sci. 2005, 30, 949.
[53] M. Noda, H. Okuyama, Chem. Pharm. Bull. 1999, 47, 467.
[54] D. E. Noga, T. A. Petrie, A. Kumar, M. Weck, A. J. Garcia, D. M.
Collard, Biomacromolecules 2008, 9, 2056.
[33] D. Bourissou, S. Moebs-Sanchez, B. Martn-Vaca, Comptes.
Rendus. Chimie. 2007, 10, 775.
[55] D. A. Barrera, E. Zylstra, P. T. Lansbury, R. Langer, J. Am. Chem.
Soc. 1993, 115, 11010.
[34] T. L. Simmons, G. L. Baker, Biomacromolecules 2001, 2, 658.
[56] O. Thillaye du Boullay, N. Saffon, J. P. Diehl, B. Martin-Vaca, D.
Bourissou, Biomacromolecules 2010, 11, 1921.
[57] H. K. Hall, A. K. Schneider, J. Am. Chem. Soc. 1958, 80, 6409.
€
[35] T. Trimaille, R. Gurny, M. Moller, J. Biomed. Mater. Res. A 2007,
80A, 55.
Macromol. Biosci. 2013, 13, 1689–1699
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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www.MaterialsViews.com