Poly(ethylene glycol) with Multiple Aldehyde Functionalities Opens up a Rich and Versatile Post-Polymerization Chemistry

Article abstract of DOI:10.1021/acs.macromol.8b02639

Two novel epoxide monomers 3,3-dimethoxy-propanyl glycidyl ether (DMPGE) and 3,3-dimethoxy-2,2-dimethylpropanyl glycidyl ether (DDPGE) were developed for the introduction of multiple aldehyde functionalities into the poly(ethylene glycol) (PEG) backbone. The acetal protecting group for the aldehyde functionality is stable against the harsh, basic conditions of the anionic ring-opening polymerization. Both monomers could be homopolymerized as well as copolymerized randomly with ethylene oxide (EO) in a controlled fashion. Copolymers with molecular weights (M_n) in the range of 4500-20100 g/mol and low dispersity (M_w/M_n) between 1.06 and 1.14 were obtained. The polymers were characterized by size exclusion chromatography, ¹H NMR spectroscopy, and by differential scanning calorimetry regarding their thermal properties. The controlled character of the copolymerization was verified by MALDI-TOF. To study the distribution of the acetal-protected aldehyde functionalities at the polyether chains, the copolymerization with EO was monitored by in situ ¹H NMR kinetics experiments for both monomers. These measurements revealed almost ideally random distribution of the comonomers with reactivity ratio pairs r_EO = 0.96, r_DMPGE = 1.04 and r_EO = 1.20, r_DDPGE = 0.83. The acetal functionalities of DMPGE polymers were successfully addressed by hydrazone formation. In addition, DDPGE copolymers were successfully deprotected in acidic media, and various transformations yielded aldehyde-, ester-, and nitrile-functionalized PEG while maintaining a dispersity below 1.1. Consequently, these monomers represent promising building blocks for the synthesis of multifunctional PEG for a variety of biomedical purposes.

Full text of DOI:10.1021/acs.macromol.8b02639

Article
pubs.acs.org/Macromolecules
Cite This: Macromolecules XXXX, XXX, XXX−XXX
Poly(ethylene glycol) with Multiple Aldehyde Functionalities Opens
up a Rich and Versatile Post-Polymerization Chemistry
Jan Blankenburg,‡,§ Kamil Maciol,‡ Christoph Hahn,‡ and Holger Frey*,‡
‡Institute of Organic Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128 Mainz, Germany
§Graduate School Materials Science in Mainz, Staudinger Weg 9, 55128 Mainz, Germany
S
* Supporting Information
ABSTRACT: Two novel epoxide monomers 3,3-dimethoxy-propanyl
glycidyl ether (DMPGE) and 3,3-dimethoxy-2,2-dimethylpropanyl
glycidyl ether (DDPGE) were developed for the introduction of
multiple aldehyde functionalities into the poly(ethylene glycol) (PEG)
backbone. The acetal protecting group for the aldehyde functionality is
stable against the harsh, basic conditions of the anionic ring-opening
polymerization. Both monomers could be homopolymerized as well as
copolymerized randomly with ethylene oxide (EO) in a controlled
fashion. Copolymers with molecular weights (Mn) in the range of
4500−20100 g/mol and low dispersity (Mw/Mn) between 1.06 and 1.14 were obtained. The polymers were characterized by
1
size exclusion chromatography, H NMR spectroscopy, and by differential scanning calorimetry regarding their thermal
properties. The controlled character of the copolymerization was verified by MALDI-TOF. To study the distribution of the
1
acetal-protected aldehyde functionalities at the polyether chains, the copolymerization with EO was monitored by in situ H
NMR kinetics experiments for both monomers. These measurements revealed almost ideally random distribution of the
comonomers with reactivity ratio pairs rEO = 0.96, rDMPGE = 1.04 and rEO = 1.20, rDDPGE = 0.83. The acetal functionalities of
DMPGE polymers were successfully addressed by hydrazone formation. In addition, DDPGE copolymers were successfully
deprotected in acidic media, and various transformations yielded aldehyde-, ester-, and nitrile-functionalized PEG while
maintaining a dispersity below 1.1. Consequently, these monomers represent promising building blocks for the synthesis of
multifunctional PEG for a variety of biomedical purposes.
Carlotti and Deffieux.12−14 This greatly expands the scope of
tolerated functionalities. For instance, epicyanohydrin could be
INTRODUCTION
■
The extraordinary properties of polyethylene glycol (PEG)
(co)polymerized and its nitrile functionalities transformed by
such as high biocompatibility and aqueous solubility render it
an ideal material for biomedical applications.1 Furthermore,
postpolymerization reactions into amides, amines, and
carboxylates.15 Drawbacks of the monomer-activated polymer-
the flexible polyether backbone and low glass transition fit the
ization method are the use of cytotoxic aluminum salts, a
broadened molecular weight distribution, and nonuniform end
groups. Therefore, block copolymers are usually not accessible
by the monomer-activated polymerization. Very recently, the
issues of the monomer-activated polymerization have been
addressed by using triethyl borane for activation instead of
aluminum alkyls.16,17 However, the copolymerization behavior
of epoxides employing this method has not been studied to
date. In the case of the classical activated monomer
mechanism, the copolymerization of a glycidyl ether with EO
leads to a strong monomer gradient.18 In contrast, the same
copolymerization via AROP yields an ideally random
distribution of the functionalities.18 For these reasons, the
AROP of EO and other epoxide derivatives is still the best
choice to obtain a well-defined polyether with defined
requirement for the soft segment component in hydrophilic
polyurethanes perfectly, commonly as a copolymer with
propylene oxide.2 However, only the terminal hydroxyl groups
are available for polymer modification reactions. This lack of
functionality can be overcome by copolymerizing ethylene
oxide (EO) with functional epoxide monomers to create
multifunctional PEGs.3,4 In this manner, various functionalities
were introduced into the polyether backbone, and the polymer
properties were customized for the targeted application.
However, the harsh, basic conditions employed in the anionic
ring-opening polymerization (AROP) must be tolerated by the
functional group without side reactions. Monomers containing
vinyl and allyl ethers, tertiary amines, acetals, and thioethers
have been successfully established in recent years for the
AROP.4−6 Acetals were proven to be a good choice for the
protection of hydroxyl groups during the polymerization. In
this way, monools,7−9 diols,10 and catechols11 can be liberated
in acidic conditions after the polymerization. A strategy to
incorporate other functionalities is the monomer-activated
method carried out under milder conditions according to
Received: December 11, 2018
Revised: January 26, 2019
© XXXX American Chemical Society
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Scheme 1. Synthesis Strategy for Homopolymers and Copolymer with EO of DMPGE and DDPGE
architectures.19,20 Motivated by this fact, this work aimed to
expand the compatible functionalities for AROP.
Differential scanning calorimetry (DSC) measurements were
carried out under a nitrogen atmosphere using a PerkinElmer DSC
8500 in the temperature range of −95 to 95 °C, with heating rates of
20 K/min for the first and 10 K/min for the second heating run. The
cooling rate between the two heating cycles was 10 K/min. The heat
flow of the second heating cycle was used for the analysis.
MALDI-TOF measurements were performed on a Shimadzu
Axima CFR MALDI-TOF or a Bruker Rapiflex. Samples were
prepared with α-cyano-4-hydroxycinnamic acid (CHCA) or trans-2-
[3-(4-tert-butylphenyl)-2-methyl-2-propenylidene]malononitrile
(DCTB) as a matrix and potassium trifluoroacetate as a cationization
agent.
Aldehyde functional polymers are interesting due to their
highly reactive aldehyde moiety, for instance for bioconjuga-
tion. Sokolovskaya et al. used a four-step synthesis to generate
a protected aldehyde epoxide-monomer with a photolabile
acetal group. However, the degree of polymerization was
limited and broad distributions were obtained otherwise.21
PEG with aldehyde terminus has been used for the PEGylation
of drugs via imine formation with the N-terminus of
proteins.3,22 Direct use of aldehydes in the AROP would
lead to side reactions such as aldol condensations or
transacetalization, resulting in ill-defined products.23,24 By
using an acetal protected aldehyde as an initiator in AROP and
subsequent deprotection, a terminal aldehyde functionality
could be introduced.25 Multiple aldehyde functionalities in
polymers are of interest for cross-linkable hydrogels and
further postpolymerization modification.26−28
In this work we present two novel monomers with acetal
protected aldehydes that can be polymerized in a controlled
manner under AROP conditions. Statistical copolymers with
EO and homopolymers were synthesized with narrow
dispersities (Mw/Mn) in the range of 1.06−1.14 (Scheme 1).
The acetal functionality of 3,3-dimethoxy-propanyl glycidyl
ether (DMPGE) polymers could be addressed via hydrazone
formation. However, the deprotection of polymers of DMPGE
leads to undesirable side products, which motivated the
development of a second monomer, i.e. 3,3-dimethoxy-2,2-
dimethylpropanyl glycidyl ether (DDPGE). This improvement
allowed for the aldehyde groups to be liberated under acidic
conditions and permitted oxidation in acidic media to generate
ester functionalities. The released aldehyde moieties were
successfully transformed into nitrile functionalities.
Synthesis Procedures. 3,3-Dimethoxy-propan-1-ol (I). 3,3-Dime-
thoxy-propan-1-ol was synthesized from 3,3-dimethoxy-propionic acid
methyl ester in a slightly modified literature procedure.29 Lithium
aluminum hydride (9.22 g, 0.25 mol, 1.2 equiv) was suspended in 250
mL of diethyl ethyl ether and stirred. The flask was cooled in an ice/
water bath to 0 °C, and a solution of 30 g of 3,3-dimethoxy-propionic
acid methyl (0.2 mol, 1 equiv) in 100 mL diethyl ether was added
dropwise. After complete addition, the mixture was stirred for an hour
and allowed to reach room temperature. The reaction was then
quenched by slow addition of 25 mL of 1 M aqueous sodium
hydroxide solution and stirred for 30 min. The resulting white solid
was separated by filtration and washed several times with diethyl
ether. The organic phase was dried with Na2SO4 and the solvent
removed under reduced pressure to give the product with sufficient
purity in 95% yield. 1H NMR (400 MHz, CDCl3): δ (ppm) 4.55 (t, J
= 5.6 Hz, 1H, −CH(OMe)2), 3.75−3.68 (m, 2H, −CH2−OH), 3.36
(s, 6H, C(OCH3)2), 1.87 (q, J = 5.6 Hz, 2H, −CH2−CH2−
CH(OMe)2).
3,3-Dimethoxy-propanyl Glycidyl Ether (DMPGE). Ten grams of
3,3-dimethoxy-propan-1-ol (I) (83 mmol, 1 equiv) and 13.1 mL of
epichlorohydrin (167 mmol, 2 equiv) were added to 100 mL of 50 wt
% aqueous sodium hydroxide. The reaction mixture was heated to 40
°C and stirred vigorously for 24 h. The reaction mixture was extracted
three times with 50 mL diethyl ether. The organic phase was washed
with brine until neutral and dried with Na2SO4, and the solvent was
removed under reduced pressure. DMPGE was obtained in high
purity by distillation in high vacuum in a yield of 56% and stored over
4 Å molecular sieves. 1H NMR (400 MHz, CDCl3): δ (ppm) 4.53 (t,
J = 5.8 Hz, 1H, −CH(OMe)2), 3.71 (dd, J = 11.5, 3.0 Hz, 1H, ring−
CH2,aO−), 3.55 (qt, J = 9.4, 6.5 Hz, 2H, −OCH2CH2), 3.37 (dd, J =
11.6, 5.9 Hz, 1H, ring−CH2,bO−), 3.33 (d, J = 0.6 Hz, 6H,
C(OCH3)2), 3.14 (ddt, J = 5.8, 4.1, 2.8 Hz, 1H, CHring), 2.79 (dd, J =
5.0, 4.2 Hz, 1H, CH2a,ring), 2.60 (dd, J = 5.1, 2.7 Hz, 1H, CH2b,ring),
1.89 (td, J = 6.4, 5.8 Hz, 2H, −CH2−CH2−CH(OMe)2).
EXPERIMENTAL SECTION
■
Reagents. Solvents and reagents were generally purchased from
Acros Organics, TCI, Sigma-Aldrich, or Fluka and used as received,
unless otherwise stated. Deuterated solvents were received from
Deutero GmbH.
Instrumentation. 1H NMR (400 MHz) and 13C NMR (100
MHz) spectra were recorded on a Bruker Avance II 400 (400 MHz, 5
mm BBFO-SmartProbe with z-gradient and ATM, SampleXPress 60
sample changer) and referenced internally to the proton signal of the
deuterated solvent. Solid K2CO3 was added to CDCl3 when
measuring acetal containing compounds to prevent hydrolysis of the
protective groups by acid traces. For in situ 1H NMR kinetics
experiments, an Avance III HD 400 from Bruker was used, which is
equipped with a 5 mm BBFO-SmartProbe (Z-gradient probe), ATM,
and SampleXPress 60.
3-Hydroxy-2,2-dimethylpropanal (A). 3-Hydroxy-2,2-dimethyl-
propanal was prepared in slightly modified procedure of Acerbis et
al.30 A 37% aqueous formaldehyde solution (81.8 mL, 1.1 mol, 1.1
equiv) and isobutyraldehyde (91.3 mL 1 mol, 1 equiv) were mixed
and cooled in an ice water bath to 0 °C. K2CO3 (69.1 g, 0.5 mol, 0.5
equiv) was carefully added, keeping the temperature below 20 °C.
The reaction was then stirred at room temperature for 2 h. The
solidified mixture was dissolved in chloroform, and the organic layer
was washed with brine. The organic layer was dried with Na2SO4, and
the solvent was removed under reduced pressure. The product was
obtained in 79% yield as a colorless liquid. Note that solidification on
standing is due to dimerization of the product by formation of the
cyclic hemiacetal.31 The reversible dimerization did not interfere with
Size exclusion chromatography (SEC) was performed at 50 °C in
dimethylformamide (DMF) with 1 g/L lithium bromide as an eluent,
using an Agilent 1100 Series equipped with Polymer Standards
Service (PSS) HEMA columns with 300/100/40 Å porosity using a
RI detector. Molecular weights were determined by calibration with
polyethylene glycol standards by PSS.
B
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1
the following steps. H NMR (400 MHz, CDCl3): δ (ppm) 9.52 (s,
1H, CHO), 3.62 (s, 2H, −CH2−), 1.10 (s, 6H, −CH3)
added. Then, 20 equiv of DMPGE (or DDPGE) was introduced into
the NMR tube. The frozen NMR tube was evacuated, and 40 equiv of
EO was distilled in the cold. The NMR tube was sealed and allowed
to reach room temperature. To homogenize the mixture, it was
shaken vigorously before placement in the NMR spectrometer.
Spectra were measured on a Bruker Avance III HD spectrometer
equipped with a 5 mm BBFO SmartProbe and an ATM as well as a
SampleXPress 60 auto sampler. The sample temperature was set to 40
°C, and a spectrum was recorded every 30 s with one scan until
complete disappearance of the epoxide signals.
Homopolymers PDMPGE and PDDPGE. 2-(Benzyloxy)ethanol
(50 mg, 0.33 mmol, 1 equiv) and KOtBu (18.4 mg, 0.16 mmol, 0.5
equiv) was dissolved in 6 mL of a benzene and methanol 5:1 mixture.
While stirring at room temperature, high vacuum was applied. After
removal of the solvents, the mixture was stirred overnight in high
vacuum at room temperature. Twenty equivalents of DMPGE or
DDPGE were then added, and the polymerization was carried out at
60 °C for 24 h in bulk (no solvent added). The products were slightly
yellow, viscous oils in yields ≥95%.
Acidic Hydrolysis of Acetal Groups to Aldehydes. A slightly
modified procedure adopted from Danishefsky et al. was used to
hydrolyze the acetal groups to aldehydes in the copolymers.33 The
procedure is shown here exemplary for the copolymer P(EO160-co-
DDPGE17). Fifty milligrams (1 equiv) of copolymer (Meq = Mn/
n(DDPGE)) and 100 mg of pyridinium p-toluenesulfonate (5 equiv)
were dissolved in a mixture of 5 mL of acetone and 0.5 mL of water.
The solution was stirred at 50 °C for 20 h. Five milliliters of
concentrated NaHCO3 was added, and the solution was concentrated
with a nitrogen stream. The residue was extracted with 20 mL of
DCM. The organic phase was washed twice with 5 mL of brine and
dried with Na2SO4, and the solvent removed under reduced pressure.
The product was dried in high vacuum, yielding 70% of the
deprotected polymer. 1H NMR confirmed the quantitative conversion
of the acetal groups to aldehydes.
3,3-Dimethoxy-2,2-dimethylpropanol (B). 3,3-Dimethoxy-2,2-di-
methylpropanol was prepared analogously to the procedure of
Johnson et al.32 3-Hydroxy-2,2-dimethylpropanal (A) (50 g, 0.49
mol, 1 equiv), trimethyl orthoformate (107 mL, 0.98 mol, 2 equiv),
and p-toluenesulfonic acid (4.22 g, 24 mmol, 0.05 equiv) were
dissolved in 350 mL of methanol and stirred for 24 h. The mixture
was brought to pH 12 by addition of 20 mL of concentrated aqueous
K2CO3 solution and diluted with 80 mL of brine. Methanol was
removed in vacuo, and the product was extracted with diethyl ether.
The organic phase was washed with brine and dried with Na2SO4, and
the solvent removed under reduced pressure. The crude liquid
product was obtained in 66% yield and could be used without further
1
purification. H NMR (400 MHz, CDCl3): δ (ppm) 4.02 (s, 1H,
−CH(OMe)2), 3.53 (s, 6H, C(OCH3)2), 3.43 (s, 2H, −CH2−), 0.92
(s, 6H, C(CH3)2).
3,3-Dimethoxy-2,2-propanyl glycidyl ether (DDPGE). 3,3-Dime-
thoxy-2,2-dimethylpropan-1-ol (B) (25 g, 0.17 mol, 1 equiv) and 18-
crown-6 (2.23 g, 8 mmol, 0.05 equiv) were dissolved in 50 mL of
benzene. Aqueous KOH solution (50 mL, 50 wt %) and
epichlorohydrin (26.5 mL, 0.34 mol, 2 equiv) were added. The
mixture was then vigorously stirred for 4 h at room temperature. The
product was extracted 3 times with 100 mL of diethyl ether. The
combined extracts were washed with brine until the washings were
neutral. The organic layer was dried with Na2SO4, and the solvents
were removed under reduced pressure. The crude product was
distilled in high vacuum to yield 53% liquid DDPGE in high purity.
1
The product was stored over molecular sieves 4 Å. H NMR (400
MHz, CDCl3): δ (ppm) 4.09 (s, 1H, −CH(OMe)2), 3.67 (dd, J =
11.7, 2.9 Hz, 1H, ring−CH2,aO−), 3.48 (d, J = 1.2 Hz, 6H,
C(OCH3)2), 3.33 (dd, J = 11.7, 5.8 Hz, 1H, ring−CH2,bO−), 3.24 (q,
J = 8.7 Hz, 2H, −CH2−), 3.11 (ddt, J = 5.7, 4.1, 2.8 Hz, 1H, CHring),
2.77 (dd, J = 5.1, 4.2 Hz, 1H, CH2a,ring), 2.58 (dd, J = 5.1, 2.7 Hz, 1H,
CH2b,ring), 0.88 (s, 6H, C(CH3)2).
Oxidation of Acetal Groups to Methyl Ester Groups. The general
procedure for oxidation of aldehydes in acidic conditions was directly
applied to the protected polymers.34,35 The procedure is shown here
exemplary for the copolymer P(EO160-co-DDPGE17). One hundred
milligrams (1 equiv) of the copolymer (Meq = Mn/n(DDPGE)) and
276 mg of oxone (5 equiv) were dissolved in 4 mL of methanol. The
solution was stirred at 50 °C for 20 h. Five milliliters of concentrated
NaHCO3 was added. The residue was extracted with 40 mL of
dichloromethane. The organic phase was washed twice with 10 mL of
brine and dried with Na2SO4, and the solvent was removed under
Preparation of the Initiator Solution. To reduce the number of
steps, one initiator solution was prepared for several copolymeriza-
tions. First, 100 mg of 2-(benzyloxy)ethanol (0.66 mmol, 1 equiv)
was mixed with 6.4 mg of KOtBu (0.59 mmol, 0.9 equiv) and
dissolved in a 6 mL of benzene/methanol 5:1 mixture and dried
overnight at room temperature under reduced pressure while stirring.
The flask was then flushed with argon, and the solid was dissolved in
30 mL of dry dimethyl sulfoxide stored over molecular sieve.
Statistical Copolymerization: P(EO-co-DMPGE) and P(EO-co-
DDPGE) Copolymers. In the following, an exemplary synthesis
protocol for the P(EO39-co-DDPGE43) copolymers is described. Ten
milliliters of the previously prepared initiator solution (corresponding
to 33 mg 2-(benzyloxy)ethanol (0.22 mmol, 1 equiv)) was added
under argon flow to a dry Schlenk flask. Then, 1.8 g of DDPGE (8.7
mmol, 40 equiv) (or DMPGE, respectively) was added via syringe,
and the solution was immediately frozen in a cooling bath of liquid
nitrogen and ethanol to −100 °C. Subsequently, the flask was
evacuated. Ethylene oxide (0.4 mL, 8.7 mmol, 40 equiv) was distilled
under vacuum into a graduated ampule, cooled to −100 °C, and
subsequently transferred via distillation into the reaction flask. The
valved flask was closed and heated to 40 °C. The copolymerization
was carried out under stirring for 24 h at 40 °C to ensure complete
conversion of the comonomers. Then, 10 mL of brine and 30 mL of
dichloromethane were added to the reaction mixture. The aqueous
phase was separated and washed four more times with brine. The
organic phase was dried with K2CO3, and the solvent was removed
under reduced pressure. The last traces of DMSO were removed by
stirring at 60 °C in high vacuum for 24 h. Typical yields of the liquid
to solid products after isolation were >90%.
1
reduced pressure. The product was dried in high vacuum. H NMR
spectroscopy evidenced quantitative oxidation of the acetal group, and
the yield was ≥80%.
Transformation of Acetal Groups into Hydrazone Function-
alities. Brady’s test36 was directly performed with the acetal protected
polymers.37 Four hundred milligrams of 2,4-dinitrophenylhydrazine
was dissolved in concentrated sulfuric acid. While stirring, 3 mL of
water was added slowly, and the solution diluted with 10 mL of
absolute ethanol. One hundred milligrams of polymer was dissolved in
1 mL of absolute ethanol and added to the solution. The precipitated
solid was separated by filtration and washed several times with cold
absolute ethanol. After drying in vacuum, orange-red powder could be
recovered typically in yields around 30%.
Oxidation of Aldehyde Groups to Nitrile Groups. The direct
transformation of aldehydes into nitriles was applied to aldehyde-
functionalized PEG, which was obtained from the procedure
described above.38 Twenty milligrams of deprotected P(EO160-co-
DDPGE17) was dissolved in a mixture of 0.4 mL of ammonia solution
(28%) and 0.05 mL of tetrahydrofuran. Twelve milligrams of iodine
was added, and the mixture was stirred until the brownish color
almost completely disappeared (1 h). Then, a solution of 10 mg of
Na2S2O3 in 0.2 mL of water was added, and the mixture was
thoroughly mixed. Ten milliliters of dichloromethane and 2 mL of
brine were added. The organic phase was separated, dried with
Na2SO4 and the solvent removed to yield the nitrile product in
quantitative yield.
1H NMR Copolymerization Kinetics Experiments. A solution of 30
mg of partially deprotonated 2-(benzyloxy)ethanol in 1 mL of
DMSO-d6 was prepared, following the protocol described above.
Then, 0.1 mL of this solution was transferred via syringe into a dried
Norell S-500-VT-7 NMR tube (equipped with a Teflon stopcock).
The solution was frozen in liquid nitrogen, and 0.5 mL DMSO-d6 was
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Angeli−Rimini Test for Aldehydes.39 Twenty milligrams of
deprotected P(EO160-co-DDPGE17) was dissolved in 1 mL of
methanol. Twelve milligrams of benzenesulfohydroxamic acid and
0.07 mL of 2 N sodium hydroxide solution were added while stirring.
The solution was stirred for 15 min, and then 0.1 mL of 2 N
hydrochloric acid was added. Addition of aqueous FeCl3 solution
produced a deeply red colored solution, which confirmed the
conversion of the aldehyde functionalities into hydroxamic acid
groups.
modified version of the DMPGE monomer bearing two methyl
groups at the α-position of the aldehyde.
Because DDPGE does not possess acidic α-protons, cross-
linking via aldol condensation in its deprotected state is not
possible. Furthermore, a reverse oxa-Michael addition is also
prevented.41 The synthesis strategy is outlined in Scheme 3. It
commences with the aldol condensation of formaldehyde and
isobutyraldehyde. The synthesized aldol adduct A is trans-
formed into the dimethoxy acetal by trimethyl orthoformate.
The dimethoxy alcohol B is then used to synthesize the
corresponding glycidyl ether DDPGE under basic conditions
with the phase transfer catalyst 18-crown-6. In contrast to the
DMPGE glycidyl ether synthesis, phase transfer catalysis is
required due to the nonpolar nature of the alcohol. As
described above, phase transfer catalysis may lead to an
elimination side reaction of epichlorohydrin. The side reaction
could be suppressed by using crown ether instead of tributyl
ammonium bromide.40 The product could be isolated in high
RESULTS AND DISCUSSION
■
Monomer Synthesis. Acetal groups are well established in
the AROP of epoxides to protect hydroxyl groups during
polymerization. Ethoxyethyl glycidyl ether (EEGE) and 1,2-
isopropylidene glyceryl glycidyl ether (IGG) are prominent
epoxide monomers that can be polymerized in a controlled
manner, releasing hydroxyl groups upon acidic treatment.7,10
Both monomers release a low molecular weight carbonyl
compound as a side product during acidic hydrolysis. The
previously demonstrated stability and facile cleavage inspired
the development of an acetal containing epoxide that can
liberate an aldehyde group. An acetal protected aldehyde
alcohol was introduced for the initiation of the polymerization
of EO long ago.25 In the current work, the DMPGE monomer
represents the first design of an epoxy monomer with an acetal
protected aldehyde group. The monomer was synthesized
according to Scheme 2. In the first step the dimethoxy ester
1
purity by distillation, as confirmed by H, 13C, and 2D NMR
(Figures S5−S8). The deprotection issues experienced in the
case of DMPGE containing polymers was successfully
prevented with the development of DDPGE, as is shown by
a narrow molecular weight distribution after deprotection
(Figure 5).
Anionic Ring-Opening (Co)polymerization. To synthe-
size multifunctional PEGs with acetal functionalities randomly
distributed along the polyether chains, copolymerization with
ethylene oxide (EO) was performed according to Scheme 1.
Partly deprotonated 2-(benzyloxy)ethanol with potassium as a
counterion was chosen as an initiator to enable molecular
Scheme 2. Synthetic Route for DMPGE
1
weight determination via end group analysis in H NMR.
DMSO was used as a solvent for the statistical copolymeriza-
tion. The copolymerization was performed with both
monomers in various ratios from 5−57 mol %, resulting in
molecular weights between 9800 and 20100 g/mol with
dispersities below 1.1 (Table 1). Additionally, both monomers
could be homopolymerized without a solvent to yield polymers
with molecular weights of 5700 and 4500 g/mol and
dispersities below 1.2. The molecular weights determined by
1H NMR characterization are in very good agreement with the
targeted theoretical values (Table 1). These results confirm
that both monomers can be polymerized in a controlled
fashion. The characterization data of these polymers is
summarized in Table 1, and the corresponding SEC traces
was reduced to the corresponding alcohol I. The alcohol was
treated with epichlorohydrin under basic conditions to afford
the monomer DMPGE. The reaction with a phase transfer
catalyst produced a side product due to an elimination reaction
of epichlorohydrin, which was difficult to separate due to
similar boiling points of product and side product.40 When
refraining from using phase transfer catalyst, no side product
1
due to elimination reactions was formed. H, 13C, and 2D
1
are shown in Figure 1. Exemplary H NMR spectra of the
NMR spectra of the monomer purified by distillation are
shown in Figures S1−S4.
copolymers are shown in Figures S9 and S10. The molecular
weights determined by SEC are underestimated in comparison
to the molecular weights obtained from end group analysis in
1H NMR. These deviations can be explained by the different
elution behavior of PDMGPE and PDDPGE in comparison to
the PEG standards used for the SEC calibration.
The thermal properties of the synthesized polymers were
studied by DSC measurements. The determined glass
transition temperatures Tg and melting points Tm of the
DMPGE was successfully employed in homo- and
copolymerization with EO under AROP conditions. However,
attempts to hydrolyze the acetal group in the polymer directly
led to side reactions, as described in detail below. These side
reactions are linked to the tendency of the deprotected
aldehyde to tautomerize into the enol form and can be
prevented for aldehydes without acidic α-protons. This was the
motivation for the development of DDPGE, which is a slightly
Scheme 3. Synthetic Route Employed for DDPGE
D
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Table 1. Characterization Data of Synthesized P(EO-co-DMPGE) and P(EO-co-DDPGE) Copolymers as well as PDMPGE and
PDDPGE Homopolymers
b
b
c
c
polymer sample
ratio/mol %
Mnth/g mol−1
Mn /g mol−1
Mn /g mol−1
Mw/Mn
Tg/°C
Tm/°C
P(EO173-co-DMPGE11)
P(EO179-co-DMPGE20)
P(EO214-co-DMPGE60)
P(EO42-co-DMPGE56)
PDMPGE17
P(EO193-co-DDPGE11)
P(EO160-co-DDPGE17)
P(EO39-co-DDPGE43)
6
10
22
57
100
5
10
52
100
10 300
11 600
15 600
11 600
3700
10 600
9 400
10 100
4300
9800
11 600
20 100
11 900
3200
10 900
10 700
10 600
4500
6400
6100
8500
6900
1300
4700
4600
3700
2200
1.06
1.06
1.09
1.10
1.12
1.08
1.08
1.08
1.13
−62
−62
−63
−64
−68
−52
−54
−45
−46
14
24
36
20
PDDPGE21
a
b
c
1
th: theoretical value. Determined by H NMR (400 MHz, CDCl3, or DMSO-d6). Determined by SEC (eluent: DMF, calibration: PEG).
Figure 1. SEC traces (DMF, PEG-calibration) of statistical (co)polymers of DMPGE (left) and DDPGE (right).
polymers are summarized in Table 1. As it is apparent from the
PDMPGE17 homopolymer, the glass transition temperature of
PDMPGE is very similar to that of PEG. Consequently, all
glass transition temperatures of the DMPGE copolymers are in
the narrow range of −62 to −64 °C. The additional methyl
groups of the DDPGE monomer lead to an increase the glass
transition of the PDDPGE21 homopolymer to −46 °C, well
above the Tg of PEG. This results in glass transitions of the
DDPGE copolymers in the range between −52 and −45 °C.
Only the copolymers with a comonomer content below 10%
were found to exhibit a melting point of the PEG domains. For
higher comonomer ratios, the PEG segments in the
copolymers are too short to pack into ordered crystalline
domains.
To further confirm the controlled character of the AROP of
the two new monomers, mass spectrometry was used. MALDI-
TOF spectra of the homopolymers were fully assigned to the
expected peaks of the 2-(benzyloxy)ethanol-initiated chains by
an approach described in recent work (Figure 2).42 The clear
assignment of the signals to the benzyloxy-initiated homopol-
ymers confirms that controlled polymerization of both
monomers with defined end groups takes place. The same
characterization has been also carried out for P(EO193-co-
DDPGE11) copolymers, as shown in Figure S11, and supports
successful copolymerization. As the molecular weight of
DMPGE is four times that of EO, MALDI-TOF character-
ization could not be carried out for P(EO-co-DMPGE)
copolymers. The determined degree of polymerization by the
assignment of the peaks is slightly smaller compared to the one
Figure 2. MALDI TOF spectra of PDMPGE17 (top) and PDDPGE21
(bottom) homopolymers with peak assignment.
determined by NMR due to mass discrimination effects. On
the other hand, the determined molecular weights are higher
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1
Figure 3. Copolymerization diagrams obtained from H NMR kinetics experiments using EO and DMPGE (left) and EO and DDPGE (right).
Scheme 4. Possible Side Reactions Occurring during the Acidic Deprotection of DMPGE Copolymers
than the molecular weights determined by SEC with PEG
calibration.
alities along the polymer chain shows an almost ideally random
microstructure for both cases (Figure S17).
In Situ 1H NMR Kinetics Investigation of the
Copolymerization. The copolymerization of the two
Postpolymerization Modification Reactions. As men-
tioned before, hydrolysis of the (co)polymers of DMPGE to
well-defined multialdehyde functional polyether was not
successful, despite the use of different deprotection methods.
When using pyridinium p-toluene sulfonate,33 no soluble
product could be recovered from the reaction mixture due to
cross-linking via aldol reactions under acidic conditions
(Scheme 4). A broad molecular weight distribution due to
cross-linking was observed in a deprotection attempt of a block
copolymer (Figure S18). Similar observations for aldol
reactions were made previously for multialdehyde functional
polyoxazolines by Taton and coworkers.26 When a very mild
deprotecting route with iodine in acetone was employed,47 the
1
monomers with EO was investigated by in situ H NMR
kinetics studies to gain a detailed understanding of the
copolymer microstructure. The epoxide signals (highlighted in
Figures S12 and S13) were monitored up to full conversion of
the copolymerization. Reactivity ratios can be evaluated from
these data, as shown in previous works.42,43 As the reactivity
ratios are very close to one, the composition shift is minimal in
the case of the copolymerization of EO and DMPGE.
Therefore, only the nonterminal model could be applied.44
The resulting reactivity ratios of the Jaacks fit are rEO = 0.96
and rDMPGE = 1.04 (Figure S14).45 This implies a random
incorporation of EO and DMPGE in the copolymerization.
The bulkier DDPGE monomer showed a slight deviation from
fully random copolymerization. The reactivity ratios deter-
mined by Jaacks fit are rEO = 1.20 and rDDPGE = 0.83 (Figure
S15).45 In this case, a composition shift was observed, and the
terminal Meyer−Lowry model was fitted to the conversion
data. The determined reactivity ratios from the Meyer−Lowry
fit are rEO = 1.19 and rDDPGE = 0.83 (Figure S16). The values
are in very good agreement with the Jaacks fit.46 The slightly
higher reactivity of DMPGE compared to the bulkier DDPGE
is most probably due to sterically hindrance. Similar reactivity
ratios were observed by Niederer et al. for the bulky catechol
acetonide glycidyl ether (CAGE) in the copolymerization with
EO.11 However, both monomers are very close to an ideal
random copolymerization, as shown in the copolymerization
diagrams (Figure 3). The simulated distribution of function-
1
formation of acrolein was observed in the H NMR spectrum
(Figure S19). This confirms the occurrence of a reverse oxa-
Michael addition, as shown in Scheme 4.41,48 However, under
acidic conditions which form the aldehyde in situ, the acetals in
the PDMPGE homopolymers were successfully transformed by
the reaction with dinitro phenyl hydrazine. The formation of
the polyhydrazone product causes a shift of the molecular
weight distribution in SEC (Figure 4) and was also confirmed
1
in the corresponding H NMR spectrum (Figure S20).
The side reactions observed upon deprotection of DMPGE-
containing polymers motivated a shift of the focus to polymers
of the alternative monomer DDPGE, for which no undesired
side reactions were observed. The sample P(EO160-co-
DDPGE17) was used as an example to demonstrate possible
postpolymerization reactions. These reactions were performed
according to the scheme in Figure 5. 1H NMR spectra
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conditions of the oxone oxidation, the acetal functionality can
be directly transformed to the carboxylic acid methyl ester.
This can be seen in the 1H NMR spectra in Figure S21 by the
disappearance of the single proton (labeled d) and the shift of
methyl groups (labeled c) from 0.9 to 1.2 ppm. The IR
spectrum evidenced the presence of a carbonyl group with the
band at 1731 cm−1 (Figure S22). The aldehyde functional PEG
could further be oxidized in a second postpolymerization
reaction to the nitrile in a mixture of ammonia and iodine.38 In
this case, the peak of the single proton d disappears, and the
methyl groups (labeled c) shift from 1.0 to 1.3 ppm (Figure
S20). The IR spectrum shows the presence of the nitrile group
with the vibration at 2237 cm−1 (Figure S22). Herzberger et al.
demonstrated that multinitrile-functional PEG can be synthe-
sized by copolymerization of EO and epicyanohydrin via the
activated monomer mechanism and also demonstrated trans-
formation into amide- and amine-functional PEG.15 The
postpolymerization reactions reported in the respective
publication can generally also be applied to the nitrile
functional PEG synthesized in this work. This would make
the respective functional copolymers accessible via AROP,
resulting in improved molecular weight control. Because
aldehydes are highly reactive, numerous other postpolymeriza-
tion reactions are possible.
A chemical test for the presence of aldehydes is the Angeli−
Rimini reaction, which oxidizes the aldehyde to the
corresponding hydroxamic acid. The hydroxamic acid forms
deep red colored complexes with iron(III).39 The positive test
solution of the aldehyde functionalized PEG is shown in Figure
S23, where some of the formed complexes of iron and
hydroxamic acid-functionalized PEG were transferred to the
organic layer of dichloromethane.
Figure 4. Top: Transformation of acetal functionalities into hydrazine
moieties. Bottom: Shift of SEC traces of transformed PDMPGE
homopolymers.
confirming the respective modification reactions are shown in
Figure S21. The corresponding SEC traces are shown in Figure
5 and confirm that the monomodal distribution of the
copolymers is preserved with a dispersity of 1.1 for all
subsequent modifications. In contrast to the DMPGE-
containing polymers, the acetals at the P(EO-co-DDPGE)
copolymers could be hydrolyzed by treatment with pyridinium
p-toluene sulfonate to release the aldehyde functionalities.33
The 1H NMR spectrum in Figure S21 clearly shows the shift of
the single proton adjacent to the acetal (labeled d) at 4.0 ppm
to 9.5 of the corresponding aldehyde. The release of the
aldehyde moieties shifts the protons at the two methyl groups
in α-position (labeled c) from 0.9 to 1.0 ppm. The IR
spectrum shows the carbonyl band at 1728 cm−1 (Figure S22).
Aldehydes are also known to be easily oxidized to the
corresponding carboxylic acid.34 Capitalizing on the acidic
CONCLUSION
■
In this work, two novel epoxide monomers DMPGE and
DDPGE were developed, aiming at introducing multiple
aldehyde functionalities into a PEG backbone. Both monomers
are based on acetal-protected aldehyde moieties connected to
an epoxide that can be polymerized by conventional AROP in
a highly controlled manner.
Both homo- and copolymerization of both monomers in
various ratios with EO were successful and yielded well-defined
polymers with low dispersity (Mw/Mn < 1.2). The micro-
1
structure of the copolymers was investigated by in situ H
NMR kinetics experiments, revealing an almost ideally random
Figure 5. Left: Reaction scheme of postpolymerization modification reactions for DDPGE-containing copolymers. Right: SEC traces of the
corresponding polymers.
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structures behave different. It became evident that the
deprotection of DMPGE polymers was difficult due to aldol
and reverse oxa-Michael side reactions, leading to cross-linking
and degradation of the polymers. Nevertheless, DMPGE acetal
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discussed. This permitted quantitative deprotection of DDPGE
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and paved the way to a variety of other postpolymerization
reactions, leading to aldehyde, ester, and nitrile functionalities
at the polyether backbone.
The insights regarding the structural features required to
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highly relevant for bioconjugation. The use of aldehyde-
functional PEG in biomedical applications will be part of our
future work. In conclusion, especially the new monomer
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ASSOCIATED CONTENT
■
́
(13) Labbe, A.; Carlotti, S.; Billouard, C.; Desbois, P.; Deffieux, A.
S
* Supporting Information
Controlled High-Speed Anionic Polymerization of Propylene Oxide
Initiated by Onium Salts in the Presence of Triisobutylaluminum.
Macromolecules 2007, 40, 7842−7847.
The Supporting Information is available free of charge on the
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mol.8b02639.
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Additional NMR and IR spectra as well as fits for the
evaluation of reactivity ratios (PDF)
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(16) Zhang, C.-J.; Duan, H.-Y.; Hu, L.-F.; Zhang, C.-H.; Zhang, X.-
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hfrey@uni-mainz.de (H.F.).
ORCID
Holger Frey: 0000-0002-9916-3103
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Elena Berger-Nicoletti and Silvio Natalello for
technical assistance. J.B. thanks the Graduate School “Materials
Science in Mainz (MAINZ)” for financial support.
̈
(19) Staudinger, H.; Schweitzer, O. Uber hochpolymere Verbindun-
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