Hydrophobic, Hydrophilic, and Amphiphilic Polyglycocarbonates with Linear and Macrocyclic Architectures from Bicyclic Glycocarbonates Derived from CO2 and Glucoside

Article abstract of DOI:10.1021/acs.macromol.6b02527

Two bicyclic glycocarbonates were synthesized in five steps from α-methyl-d-glucoside without resorting to phosgene or to its derivatives for the first time. The 4- and 6-positions of glucose were modified to introduce a six-membered carbonate ring, using CO₂ as the carbonylating reagent; the 2- and 3-positions of the same glucoside substrate were first transformed into either methyl or triethylene glycol monomethyl ether groups to protect these positions from undesirable reactions and also to impart hydrophobicity in the first case and hydrophilicity in the second. The polymerization behavior of these bicyclic glycocarbonates was then investigated under different conditions. On the one hand, through ring-opening polymerization of the above monomers, linear polyglycocarbonate homopolymers and diblock copolymers were obtained initiated by p-methylbenzyl alcohol using 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as catalyst; on the other hand, macrocyclic polyglycocarbonate homopolymers and diblock copolymers were grown using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) which served as zwitterionic initiator. The various architectures derived were all thoroughly characterized by NMR, GPC, and MALDI-tof and shown to exhibit the expected structure. Finally, the self-assembly of linear and macrocyclic amphiphilic copolyglycocarbonates in water was investigated and characterized by cryo-TEM.

Full text of DOI:10.1021/acs.macromol.6b02527

Article
pubs.acs.org/Macromolecules
Hydrophobic, Hydrophilic, and Amphiphilic Polyglycocarbonates
with Linear and Macrocyclic Architectures from Bicyclic
Glycocarbonates Derived from CO2 and Glucoside
Debasis Pati,† Xiaoshuang Feng,*,† Nikos Hadjichristidis,‡ and Yves Gnanou*,†
‡
†Physical Sciences and Engineering Division and KAUST Catalysis Center, Physical Sciences and Engineering Division, King
Abdullah University of Science and Technology (KAUST), Thuwal 23955, Saudi Arabia
S
* Supporting Information
ABSTRACT: Two bicyclic glycocarbonates were synthesized in
five steps from α-methyl-D-glucoside without resorting to
phosgene or to its derivatives for the first time. The 4- and 6-
positions of glucose were modified to introduce a six-membered
carbonate ring, using CO2 as the carbonylating reagent; the 2- and
3-positions of the same glucoside substrate were first transformed
into either methyl or triethylene glycol monomethyl ether groups
to protect these positions from undesirable reactions and also to
impart hydrophobicity in the first case and hydrophilicity in the
second. The polymerization behavior of these bicyclic glycocar-
bonates was then investigated under different conditions. On the
one hand, through ring-opening polymerization of the above
monomers, linear polyglycocarbonate homopolymers and diblock
copolymers were obtained initiated by p-methylbenzyl alcohol
using 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as catalyst; on the other hand, macrocyclic polyglycocarbonate homopolymers
and diblock copolymers were grown using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) which served as zwitterionic initiator. The
various architectures derived were all thoroughly characterized by NMR, GPC, and MALDI-tof and shown to exhibit the
expected structure. Finally, the self-assembly of linear and macrocyclic amphiphilic copolyglycocarbonates in water was
investigated and characterized by cryo-TEM.
from the corresponding six-membered cyclic carbonate using
for this purpose zinc or tin catalysts; Wooley and co-
workers27,28 described the synthesis of D-glucose-based six-
membered cyclic carbonate that they successfully polymerized
via an organocatalytic approach. Interestingly, the same sugar
substrate, D-glucose, was modified by Endo and co-workers25,26
into a five-membered cyclic carbonate that they anionically
ring-opened under mild conditions to obtain well-defined D-
glucose-based polycarbonates of different structure from that
prepared by Wooley.27,28 Polycondensation reactions involving
sugar-based diols and phosgene were also tried as a means to
generate sugar-containing linear polycarbonates.18,23,29,30
Whether the monomers were meant for ROP or polyconden-
sation all of the carbonylation reactions used so to date for the
generation of carbonate functions in the above works involved
either phosgene or its derivatives: ethyl chloroformates or
bis(pentafluorophenyl)carbonate.18,23−32
INTRODUCTION
■
Glycopolymers are synthetic polymer scaffolds that carry
dangling sugar moieties.1−6 Such sugar-modified synthetic
polymers find applications as clinical diagnostics, bioassays,
affinity separation, etc.,7,8 wherever different carbohydrates
serving as multivalent ligands on the exterior of the membrane
proteins and lipids can bring about biological activity through
carbohydrate−protein interactions.9,10 Polysaccharides are
another family of polymers that also comprise sugars in their
structure. In contrast to the glycopolymers, sugars in
polysaccharides are part of the main chain and serve as
repeating units or building blocks.11−14 In natural polysacchar-
ides that originate from different sources (plants, bacteria, and
animals), sugars are bound one to another by glycosidic
linkages.15−19 But polysaccharides can also be synthetically
produced, and besides glycosidic linkages other chemical
functions have been contemplated to link sugars one to
another.20,21 Carbonates are one such linkage that have been
used to generate polycarbonates featuring sugar moieties in the
main chain.22−28 Sugar-based polycarbonates are usually
prepared through ring-opening polymerization (ROP) of either
five- or six-membered, sugar-derived carbonate rings. For
instance, Gross and collaborators22,24 reported the synthesis
of D-xylofuranose-based polycarbonates and its copolymers
The lack of studies on glucose-based polycarbonates or
polyglycocarbonates and the limitations related to the use of
phosgene and of its derivatives prompted us to explore new
Received: November 23, 2016
Revised: January 18, 2017
© XXXX American Chemical Society
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Scheme 1. General Scheme for the Synthesis of Six-Membered Bicyclic Glycocarbonate Monomers from α-Methyl D-
a
Glucopyranoside
a
Reagents and conditions: (i) PhCH(OMe)2, PTSA, DMF, 1 h (yield, 69%); (ii) DMF/NaH, CH3I (3a)/TEGM-OTs (3b), 0 °C for 1 h and
overnight at RT (yield, 72%); (iii) NBS, CaCO3, CCl4, 1 h (yield, 58%); (iv) 2% NaOH in MeOH, 2 h (yield, 60%); (v) CO2 (10 bar), DBU, DMF,
RT, 5 h for monomer 6a (yield, 40%) and 22 h for monomer 6b (yield, 40%).
Table 1. ROP of Hydrophobic and Hydrophilic Monomers 6a and 6b under Different Initiating Conditions
b
c
d
time
(h)
yield
(%)
M(theo)
Mn(NMR)
Mn(GPC)
a
entry
polymer
LP1-6a
initiator/Cat.
M
[M]0/[I]0
conv (%)
(103 g/mol)
(103 g/mol)
(103 g/mol)
01
02
03
04
05
06
07
PMBA/TBD
PMBA/DBU
PMBA/TBD
DBU
6a
25
1
45
5
98
90
94
91
90
99
90
75
83
65
60
80
75
6.20
6.82
8.18
6.78
6.14
9.91
8.86
6.08
5.33
7.80
6.5/1.2
4.0/1.3
5.0/1.2
5.0/1.2
3.8/1.2
8.6/1.2
8.1/1.2
LP2-6a
LP-6b
6a
30
6b
17
e
CP-6a
6a
30
45
60
1
ND
e
CP-6b
DBU/TU
6b
12
ND
LP3-6a
LP-6a-b-6b
PEG-OH/TBD
PMBA/TBD
6a
20
9.00
8.61
6a:6b
18:9
11
>99 (6a), >92
(6b)
e
08
CP-6a-b-6b
DBU/TU
6a:6b
15:7
96
>99 (6a), >90
(6b)
75
6.90
ND
4.0/1.2
a
b
Aliquots of the reaction medium were analyzed by 1H NMR to calculate the monomer conversion. Expected molar mass deduced from monomer
c
d
conversion (1H NMR). Molar mass was calculated from end-group analysis (1H NMR) of the isolated polymer. Calculated from GPC calibrated
with narrow distributed polystyrene standard in THF as eluent (1 mL/min). Not determined.
e
synthetic avenues. In this study, we demonstrate that CO2 can
be effectively resorted to for the carbonylation reaction of α-
methyl-D-glucoside instead of toxic phosgene or its derivatives,
opening up the access to two bicyclic six-membered carbonate
monomers (Scheme 1)the first hydrophobic and the second
water-soluble. From these two monomers a wealth of well-
defined polyglycocarbonate architectures could be obtained,
including hydrophobic and hydrophilic homopolymers with
either a linear or a macrocyclic structure as well as linear and
macrocyclic amphiphilic diblock copolymers. The ring-opening
polymerization of these glucoside-based bicyclic carbonates was
triggered by an organocatalyst: the latter gave rise to
macrocyclic architectures, and in the presence of an alcohol
serving as initiator it brought about the formation of linear
chains.
investigation (Scheme 1) that both hydrophobic (6a) and
hydrophilic (6b) bicyclic glycocarbonates can be prepared from
α-methyl-D-glucoside using CO2 as carbonylation reagent. Both
6a and 6b monomers were synthesized in five steps starting
from the commercially available α-methyl-D-glucoside: to the
exception of step 2, all steps were carried out following the
same experimental procedures for the two monomers. In step 1,
the 4- and 6-dihydroxyl groups of α-methyl-D-glucoside were
protected by the benzylidene group so as to obtain α-methyl-
4,6-O-benzylidene D-glucopyranoside (2) (Supporting Informa-
tion Figures S8 and S9), using for this purpose benzaldehyde
dimethyl acetal in the presence of a catalytic amount of p-
toluenesulfonic acid. The protection step of the two 2- and 3-
dihydroxyls groups of α-methyl-4,6-O-benzylidene D-glucopyr-
anoside (2), or step 2, served to eventually generate either a
hydrophobic bicyclic glycocarbonate (6a) or its hydrophilic
equivalent (6b). In the first case, 3a (Figures S10 and S11), two
methyl groups were introduced as protecting groups using
methyl iodide and sodium hydride and in the second, 3b
(Figures S24−S26), two molecules of triethylene glycol
monomethyl ether were grafted at the 2- and 3-positions of
the glucopyranosyl rings using tosylated triethylene glycol
methyl ether and sodium hydride. Step 3 was identical for the
two monomers: α-methyl-6-bromo-4-benzyl ester-2,3-di-O-
methyl-d-glucopyranoside (4a) and α-methyl-6-bromo-4-ben-
zoate-2,3-di-O-TEGM-D-glucopyranoside (4b) were obtained
by bromination of α-methyl-2,3-dimethyl-4,6-O-benzylidene-D-
RESULTS AND DISCUSSION
■
Monomer Synthesis. There are only very few reports on
the synthesis of polymers featuring sugar units in their main
chain linked by carbonate groups. As previously indicated,7,8
such polyglycocarbonates whether obtained either by poly-
condensation of sugar-based diols or by ring-opening polymer-
ization of glycocarbonates required at one step of their
synthesis the use of phosgene or its derivatives. In the course
of this work Buchard and co-workers reported the synthesis of
D-mannose-based six-membered glycocarbonate using CO2 as
carbonylation reagent.33 Along the same line we show in this
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Scheme 2. Organocatalytic Anionic Ring-Opening Polymerization (AROP) of Cyclic Glycocarbonates (6) for the Synthesis of
Linear and Macrocyclic Polyglycocarbonates and Block Copolymers
Figure 1. (A) Plot of monomer conversion (%) (1H NMR analysis) vs Mn and PDI values (GPC traces), (B) GPC profiles of the reaction aliquots
over time, and (C) MALDI-tof of LP2-6a.
glucopyranoside (3a) and of α-methyl-2,3-di-O-TEGM-4,6-O-
benzylidene-D-glucopyranoside (3b), respectively, using NBS/
CCl4 in the presence of CaCO3. The benzyl ester deprotection
of 4a and 4b (Figures S27−S29) was carried out next (step 4)
in 2% sodium hydroxide methanol solution at room temper-
ature; these reactions yielded α-methyl-6-bromo-6-deoxy-2,3-
di-O-methyl-D-glucopyranoside (5a) (Figures S12−S17) and α-
methyl-6-bromo-6-deoxy-2,3-di-O-TEGM-D-glucopyranoside
(5b) (Figures S30−S32), respectively. In the final step 5, 6a
and 6b were obtained by carbonylation and cyclization of 5a
and 5b, respectively, under a 10 bar CO2 pressure at room
temperature in the presence of 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU). The yields for the two monomers 6a and 6b were
equal to 40%, a value comparable to that reported by Wooley
and co-workers, who resorted to the use of bis(pentafluoro-
phenyl)carbonate as carbonylation reagent.27 All NMR (Figures
S18−S23 for 6a and Figures S33−S38 for 6b) and HRMS
(Figures S5 and S7) characterizations confirmed the purity and
the structure of monomers 6a and 6b synthesized and also
those of the intermediate compounds.
Hydrophobic Linear Polyglycocarbonates. The poly-
merization of 6a was subsequently carried out in the presence
of p-methylbenzyl alcohol as initiator and TBD as catalyst in
anhydrous dichloromethane and at room temperature: the
polymerization occurred in a “living” fashion.27 The obtained
polymer (LP1-6a) was thoroughly characterized by NMR,
GPC, and MALDI-tof (Figure 4A and Figures S3, S39, and
S40): the data collected confirmed the expected structure of the
formed polymer (Table 1 and Scheme 2).
In contrast to the previous case which witnessed a rather fast
propagation, with a weak base such as DBU, the polymerization
rate was much slower (LP2-6a): the monomer conversion was
indeed only 14% after 1 h, then 67% after 21 h, and it took 45 h
of reaction to reach 90% of conversion (Figure 1 and Figure
S41). As can be seen from Figure 1, the molar mass of the
samples isolated over time increased linearly with the monomer
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Figure 2. (A) Plot of monomer conversion (%) (1H NMR analysis) vs PDIs and Mn (GPC analysis) of reaction aliquots over time, (B) reaction
kinetics plot: ln([M]0/[M]n) vs time, and (C) GPC profiles of reaction aliquots over same time for LP-6b.
Figure 3. (A) Plots of monomer conversion (%) (1H NMR analysis) vs Mn and PDI (GPC analysis) of the reaction aliquots over time, (B) GPC
profiles of the reaction mixture in same time, and (C) MALDI-tof of CP-6a.
conversion. Besides its characterization by NMR and GPC the
final sample quenched with benzoic acid was also subjected to
MALDI-tof analysis. As shown in Figure 1, MALDI-tof
characterization confirms the incorporation of the initiator, p-
methylbenzyl alcohol, at the chain end: the main population
exactly matches the expected structure with a peak-to-peak
mass difference corresponding to the molar mass of 6a (248.23
g/mol). Another small population without any terminal group
and thus corresponding to macrocyclic polycarbonates can also
be seen; the latter are chains that underwent a ring closure
reaction. In one of the next sections, we will discuss in detail
how to obtain exclusively macrocyclic polyglycocarbonates
from either 6a or 6b.
deduced: as seen from the Table 1, they were in good
agreement with the expected values.
One of our other endeavors was to synthesize an amphiphilic
diblock copolymer containing both hydrophobic and hydro-
philic polyglycocarbonate blocks. We first targeted the synthesis
of a diblock copolymer with a composition prone to afford
regular micelles in water. We thus used a hydrophilic
poly(ethylene oxide) precursor (PEG-OH) as macroinitiator
(Mn = 5.0 × 103 g/mol) and grew a hydrophobic
polyglycocarbonate block of same weight fraction from it by
polymerization of 6a. The reaction was carried out in
anhydrous dichloromethane at room temperature, and the
catalyst used was TBD; the diblock copolymer synthesized was
characterized by GPC and NMR (entry 06, Figures S1B and
S42−S44) which confirmed the incorporation of PEG and the
formation of the expected amphiphilic diblock copolymer.
We then tried to synthesize amphiphilic copolymers totally
made of polyglycocarbonate blocks. Starting from the hydro-
phobic and hydrophilic monomers 6a and 6b, such amphiphilic
copolymer could be generated by sequential polymerization of
6a and 6b in one pot as shown in Scheme 2. The first
polymerization of 6a was monitored by GPC and NMR. Then
the second monomer 6b was added after consumption of 90%
of the first monomer 6a. After 10 h of reaction, the
polymerization of 6b reached 92% conversion and that of 6a
was complete. The diblock copolyglycocarbonates obtained
were purified by dialysis against Milli-Q water. Their GPC
traces all exhibited a single monomodal peak clearly shifting to
the high molar mass region with monomer conversion (Figure
4B and Figure S1C). The characteristic peaks due to the two
Hydrophilic and Amphiphilic Linear Polyglycocar-
bonates. After 6a the water-soluble monomer 6b was also
subjected to polymerization using TBD as organic catalyst and
p-methylbenzyl alcohol as initiator. The progress of the reaction
was monitored by GPC, and aliquots of the reaction medium
withdrawn over time were characterized by NMR. The
monomer conversion was 54% after 30 min of reaction and
94% after 5 h of the reaction (Figure 2). In comparison to 6a,
the polymerization of 6b was slower due to the hindering
presence of the two bulky TEGM moieties. The isolated
samples were lyophilized prior to their characterization by
GPC, 1H NMR, and 13C NMR spectroscopy (Figures S1A, S45,
and S46). The GPC traces showed single monodisperse profiles
with no monomeric residues. From the signal due to the methyl
1
group (at 2.4 ppm) in the H NMR spectra to that of the
initiator taken as reference Mn(NMR) values could be easily
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monomers 6a and 6b O-methyl and O-TEG (3.6−3.3 ppm)
could be well detected by 1H NMR spectroscopy (Figure S47),
the composition of the copolymer formed corresponding
almost perfectly to the feeding ratio of monomers 6a and 6b.
Macrocyclic Polyglycocarbonates. As seen in Figure 1 in
the presence of DBU used as catalyst initiation occurs by both
p-methylbenzyl alcohol and DBU; the latter grows chains by a
zwitterionic mechanism where both end-to-end ring closure
reactions and propagation concomitantly occur (entry 02).26
We thus used DBU alone as initiator to trigger the
polymerization of 6a in anhydrous dimethylformamide
(Scheme 2). The reaction proceeded very slowly, the monomer
conversion calculated from NMR reaching only 5% after the
first hour reaction and 13%, 51%, and 91% after 6, 21, and 45 h
of reaction, respectively (Figure 3). As can be seen from Figures
3A and 3B the molar mass of the growing polymer (CP-6a)
increased linearly with the increasing monomer conversion and
PDIs values revolved around 1.2. The molar mass obtained
from GPC was relatively low with respect to the value
calculated from monomer conversion (1H NMR analysis) and
obtained from MALDI-tof (Figure 3C) likely due to the smaller
hydrodynamic volume of the cyclic polymer formed (Figure
4A). The MALDI-tof spectrum of the sample isolated after 91%
hydroxyl groups from NMR data also supports the formation of
macrocyclic polycarbonates (Figure S49). Next, the polymer-
ization behavior of water-soluble hydrophilic monomer 6b was
also investigated. Because of the hindrance of TEGM groups in
6b, it took 5 days to reach 70% of monomer conversion with
the same DBU organocatalyst. Upon adding in 1:1 molar ratio
to DBU 1-(3,5-bis(trifluoromethyl)phenyl)-3-cyclohexyl-
thiourea (TU), which is well-known for its ability to activate
carbonyl groups in cyclic monomers (entry 05),34−38 the
conversion of 6b reached 90% within 60 h without undesired
back-biting side reactions. The obtained water-soluble macro-
cyclic polyglycocarbonate CP-6b was then subjected for
detailed characterizations by NMR, GPC, and MALDI-tof.
The MALDI-tof spectrum (Figure S4) of the polymer CP-6b
exhibits peaks corresponding exclusively to macrocyclic
polycarbonates without end groups and with a peak-to-peak
mass difference corresponding perfectly to the monomer molar
mass (512.5 g/mol). Further, the absence of DBU moieties or
hydroxyl groups from NMR data also supports the formation of
macrocyclic polycarbonates (Figures S50 and S51). PDI values
obtained from GPC revolved around 1.2. The molar mass
obtained from GPC was relatively low with respect to that
given by MALDI-tof likely due to the smaller hydrodynamic
volume of the cyclic polymer formed (Figure S1A).
Similarly, macrocyclic amphiphilic diblock polyglycocarbon-
ates (CP-6a-b-6b) could also be prepared in a same manner as
in the above case by subjecting sequentially 6a and 6b to ROP
using DBU as initiator and TU as monomer activator. After
consumption of 90% of the first monomer 6a the second
hydrophilic monomer 6b was added to the reaction mixture.
The polymerization was continued for another 3 days until
reaching 90% conversion of 6b. The GPC profile of this sample
showed a monomodal signal, the value corresponding to 2/3 of
the expected molar mass due to the lower apparent molar
masses of macrocyclic structures (Figure 4B and Figure S1D).
Figure 4. GPC profiles of (A) LP1-6a (linear) and CP-6a
(macrocyclic) as well as (B) LP-6a-b-6b (linear) and CP-6a-b-6b
(macrocyclic).
1
The H NMR characterization confirmed the absence of any
end group and the cyclic structure of the copolymer formed
(Figures S52 and S53).
The mechanism (Scheme 3) involves first the ring-opening
of the carbonate bond of monomer 6a or 6b by DBU, followed
by repeated monomer addition by the zwitterionic species thus
formed (zwitterionic intermediate). End-to-end ring closure
reactions also occur but obviously at a much slower rate than
propagation. The growing chains can thus undergo at any time
a ring closure reaction and generate a macrocyclic poly-
conversion contained indeed only one series of peaks
corresponding exclusively to macrocyclic polycarbonates with-
out end groups with a peak-to-peak mass difference
corresponding perfectly to the monomer molar mass (248.5
g/mol). In addition, the average molar mass drawn from
MALDI-tof (6700 g/mol) was in excellent agreement with the
expected values. Further, the absence of DBU moieties or
Scheme 3. Proposed Zwitterionic Mechanism Occurring with DBU as Catalyst in the Synthesis of Macrocyclic Polycarbonates
CP-6a/b
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Figure 5. Cryo-TEM images of the nanostructures of the self-assemblies obtained from the amphiphilic polycarbonates (A) LP3-6a, (B) LP-6a-b-6b,
and (C) CP-6a-b-6b in water.
glycocarbonate, allowing the freed DBU to ring-open further
monomers. Scheme 3 also features monomer activation by TU.
A similar mechanism was proposed by Endo and co-workers in
their work on the ROP of five-membered cyclic carbonates, but
in their study they observed a mixture of macrocyclic species
and linear chains.26
Both linear and macrocyclic amphiphilic diblock copolymers
were then subjected to self-assembling in water. The aggregates
formed were then deposited on a carbon-coated copper-grid
and analyzed by cryo-TEM.
All the amphiphilic samples exhibit micellar aggregation with
an overall size varying from 20 to 40 nm depending upon the
hydrophobic/hydrophilic balance and the overall macro-
structure of the initial copolymers (Figure 5). Those with a
macrocyclic architecture tended to self-assemble into micelles
of bigger size due to entropic constrains. A paper focusing on
the manipulation of the morphology of these self-assemblies as
a function of the content in 6a and 6b and of the overall
architecture is in preparation.
polycarbonates were characterized by cryo-TEM which all
showed micellar aggregation.
EXPERIMENTAL SECTION
■
Materials and Method. 1,8-Diazabicyclo[5.4.0]undec-7-ene
(DBU), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), and p-methylben-
zyl alcohol (PMBA) were purchased from Sigma-Aldrich. DBU was
dried with CaH2 and stored in a glovebox after distillation. 1-(3,5-
Bis(trifluoromethyl)phenyl)-3-cyclohexylthiourea (TU) was prepared
following previously reported literature.39 TBD was stirred in
tetrahydrofuran with calcium hydride and filtered, and solvent was
removed under vacuum and kept in a glovebox. Dichloromethane and
dimethylformamide were dried with CaH2 and stored on activated
molecular sieves (4 Å) after distillation. CO2 (99.995%) cylinder
purchased from Abdullah Hashim Industrial & Gas Co. was further
purified by flowing through the purifier of the VICI Co., USA. The
synthesis and characterization of 5a and 5b are detailed in the
Supporting Information.
FT-IR spectra were recorded on PerkinElmer FT-IR spectrum GX
instrument. 1H and 13C NMR spectra were recorded on Bruker
spectrometers (400, 500, 600, and 950 MHz). Gel permeation
chromatography (GPC) was performed on a VISKOTEK TDA 305-
040 triple detector equipped with two columns (T6000M, GENERAL
MIXED ORG 300X7.8 MM) using THF (1 mL/mL) as the eluent at
35 °C. MALDI-tof MS experiments were carried out by using trans-2-
[3-(4-tert-butylphenyl)-2-methyl-2-propenylidene]malononitrile
(DCTB) as the matrix in THF at a loading of 1:5 with Na-TFA as
ionizing agent. The self-assembled morphology of amphiphilic
polycarbonates in water was characterized by the transmission electron
microscopy (cryo-TEM model Titan 80-300 Krios from FEI Company
(Hillsboro, OR)) by operating it at the accelerating voltage of 300
keV. The specimens for cryo-TEM were prepared by using an
automatic plunge-freezing system of model VitrobotTM from FEI
Company (Hillsboro, OR). A small amount of sample (4 μL) was
placed on a holey-carbon coated hydrophilic copper grid and followed
by blotting of the solution, and its plunge freezing into liquid ethane
cryogen was done. Then, grids were loaded into the VitrobotTM. In
this way, several specimens were prepared for each sample in order to
realize a high quality data sets from superior specimens. Further, this
microscope was equipped with the low-dose option to keep the sample
free of electron beam damage and a charge coupled devices (CCD) of
model US4000 from Gatan, Inc. to record the images in digital format.
The polymer solution was prepared as following: The synthesized
amphiphilic polyglycocarbonate was first dissolved in dimethyl
sulfoxide, to which water was slowly added to get the final sample
concentration of 1 mg/mL. Then the organic solvent was removed by
continuous dialysis with Milli-Q water for 2 days.
CONCLUSION
■
For the first time different types of bicyclic glycocarbonates
both hydrophobic and hydrophilic could be prepared from
synthetically modified glucose and CO2. Phosgene or its
derivatives were purposely avoided in the chemistry described
in this investigation which opens up the possibility to derive
many more synthetically modified natural glycans. We also
demonstrated the synthesis of both hydrophobic and hydro-
philic linear polyglycocarbonates whose molar mass could be
precisely controlled by using an organocatalyst combined with
an initiator that mediated the ring-opening polymerization of
the above-mentioned bicyclic glycocarbonates under “living”
conditions. The chemistry described in this investigation was
also versatile enough to allow the direct synthesis of
macrocyclic polyglycocarbonates. Both linear and macrocyclic
polyglycocarbonates were thoroughly characterized, and their
structures were confirmed by GPC, MALDI-tof, 1H NMR, and
13C NMR experiments. We also synthesized an amphiphilic
diblock copolymer by using hydrophilic poly(ethylene glycol)
(PEG-OH) as macroinitiator and amphiphilic diblock poly-
glycocarbonates by polymerizing first the hydrophobic
monomer 6a followed by the hydrophilic monomer 6b in a
very controlled manner. Both linear and macrocyclic
amphiphilic structures could be obtained. In some instances
TU was used to activate the cyclic glycocarbonate monomers
and thus accelerate their ROP without provoking side reactions.
Further, the self-assembling of the synthesized amphiphilic
Synthesis of α-Methyl-2,3-di-O-methyl-D-glucoside 4−6
Cyclic Carbonate (6a). α-Methyl-6-bromo-6-deoxy-2,3-di-O-meth-
yl-D-glucopyranoside (5a, 0.5 g, 1.75 mmol), DBU (267 mg, 1.75
mmol), and 3 mL of anhydrous DMF were added into a 50 mL of
dried autoclave with magnetic stirring bar inside a glovebox. Then the
sealed autoclave was taken out and charged with CO2 to a pressure of
F
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10 bar. The reactor was kept stirring at room temperature for 5 h.
Then, CO2 was released; the reaction mixture was poured into HCl
solution (1.0 M) and extracted by dichloromethane. The crude
product was purified by silica gel flash chromatography eluted with a
mixture of hexane/ethyl acetate (1:1−1:2) to give 6a as a white solid
(0.2 g 40% yield). FT-IR (dichloromethane) 1755 cm−1 for six-
membrane for 2 days. Then the dialyzed solution was lyophilized to
afford the amphiphilic block copolymer, LP-6a-b-6b as colorless liquid.
(60 mg, yield 75%). FT-IR (dichloromethane) 1750 cm−1 for
1
carbonate (linear νco). H NMR (400 MHz, CDCl3): δ 4.88−4.76
(m, 1H), 4.75−4.49 (m, 1H), 4.46−3.98 (m, 2H), 3.96−3.67 (m, 3H),
3.66−3.45 (m, 10H), 3.45−3.30 (m, 5H), 3.30−3.16 (m, 1H). The
initiator incorporation at the chain end was confirmed (p-
methylbenzyl alcohol) by the presence of 7.28−7.22 (m, 2H), 7.15−
1
membered cyclic carbonate (νco). H NMR (600 MHz, CD2Cl2): δ
4.93 (d, J = 3.6 Hz, 1H), 4.52 (dd, J = 9.8, 5.8 Hz, 1H), 4.28−4.22 (m,
1H), 4.13−4.02 (m, 2H), 3.66 (m, 4H), 3.54 (s, 3H), 3.49 (s, 3H),
3.31 (dd, J = 9.3, 3.6 Hz, 1H). 13C NMR (151 MHz, CD2Cl2): δ
147.27, 98.72, 81.06, 79.48, 79.13, 69.81, 60.92, 59.53, 59.05, 55.81.
HRMS (M + H+) (ESI+) calcd for C10H16O7H+ 249.09 g/mol; found
249.08 g/mol.
7.12 (m, 2H), 5.17−5.05 (m, 2H), 2.32 (s, 3H) ppm and Mn(NMR)
=
8600. 13C NMR (100 MHz, CDCl3): δ 154.02, 154.20, 154.72, 97.98,
97.85, 79.97, 79.26, 78.21, 72.39, 71.85, 71.83, 71.73, 71.008, 70.54,
70.53, 70.48, 70.47, 70.45, 70.42, 70.33, 69.55, 59.42, 59.0, 58.98, 55.94
ppm. Initiator incorporation was confirmed by the presence of the
corresponding peaks (p-methylbenzyl alcohol); 129.19, 128.50
(benzyl), 72.5 (CH2-benzyl) and 20.29 (Me-benzyl) ppm.
Synthesis of α-Methyl-2,3-di-O-TEGM-D-glucoside 4−6 Cy-
clic Carbonate (6b). α-Methyl-6-bromo-6-deoxy-2,3-di-O-TEGM-D-
glucopyranoside (5b, 0.3 g, 546 μmol), DBU (91.44 mg, 600 mmol),
and 4 mL of anhydrous DMF were added into a 50 mL of dried
autoclave with magnetic stirring bar inside a glovebox. Then the sealed
autoclave was taken out and charged with CO2 to a pressure of 10 bar.
The reactor was kept stirring at room temperature for 22 h. Then, CO2
was released, and the reaction mixture was poured into HCl solution
(1.0 M) and extracted by dichloromethane. The crude product was
purified by silica gel flash chromatography eluted with a mixture of
hexane/acetone (1:0.2−1:1) to give 6b as a colorless liquid (0.1 g,
40% yield). 1H NMR (950 MHz, CDCl3): δ 4.90 (d, J = 3.7 Hz, 1H),
4.46−4.44 m, 1H), 4.20−4.18 (m, 1H), 4.05−4.01 (m, 2H), 3.95−
3.88 (m, 3H), 3.80 (ddd, J = 11.5, 7.6, 3.3 Hz, 1H), 3.75 (t, J = 9.0 Hz,
1H), 3.65−3.63 (m, 3H), 3.63−3.60 (m, 12 H), 3.59 (ddd, J = 10.9,
4.6, 3.4 Hz, 1H), 3.54−3.52 (m, 4H), 3.48 (dd, J = 9.4, 3.7 Hz, 1H),
3.45 (s, 3H), 3.37−3.34 (m, 6H) ppm. 13C NMR (100 MHz, CDCl3):
δ 147.36, 99.33, 79.97, 79.26, 78.21, 72.39, 71.85, 71.83, 71.73, 71.008,
70.54, 70.53, 70.48, 70.47, 70.45, 70.42, 70.33, 69.55, 59.42, 59.0,
58.98, 55.94 ppm. HRMS (M + H+) (ESI+) calcd for C22H40O13H+
513.25 g/mol; found 513.25 g/mol.
Synthesis of Macrocyclic Polyglycocarbonate (CP-6a) by the
Polymerization of 6a. Inside a glovebox, a solution of monomer 6a
(195.06 mg, 786 μmol) in 800 μL of anhydrous DMF was prepared in
a Schlenk tube; DBU (3.98 mg, 26.20 μmol) was dissolved in 100 μL
of deuterated DMF and added to the monomer solution. The
polymerization was kept stirring inside the glovebox for 48 h and then
quenched with benzoic acid. Finally, the reaction mixture was
precipitated in water; the collected crude product was dissolved in
CH2Cl2 and precipitated again in diethyl ether to afford the
macrocyclic polymer CP-6a (126 mg, yield 65%). 1H NMR (400
MHz, CDCl3): δ 4.73−4.61 (m, 1H), 4.61−4.27 (m, 1H), 4.17−3.93
(m, 2H), 3.80−3.62 (m, 1H), 3.50−3.40 (m, 1H), 3.39−3.28 (m, 6H),
3.27−3.18 (m, 3H), 3.16−3.05 (m, 1H) ppm. 13C NMR (151 MHz,
CDCl3): δ 155.1, 154.8, 154.46, 97.92, 81.7, 80.8, 78.1, 75.1, 67.8, 66.6,
61.33, 61.1, 59.1, 55.8 ppm. FT-IR (dichloromethane) 1750 cm−1 for
carbonate (linear νCO).
Synthesis of Macrocyclic Polyglycocarbonate (CP-6b) by the
Polymerization of 6b. Inside a glovebox, a solution of monomer 6b
(87 mg, 169.74 μmol) in 400 μL of anhydrous DMF was prepared in a
Schlenk tube; DBU (2.15 mg, 14.14 μmol) and 1-(3,5-bis(trifluoro-
methyl)phenyl)-3-cyclohexylthiourea (TU; 5.24 mg, 14.14 μmol) were
dissolved in 100 μL of deuterated DMF and added to the monomer
solution. The polymerization was kept stirring inside the glovebox for
60 h and then quenched with benzoic acid. The obtained
polymerization mixture was diluted with deionized water and dialyzed
against water using 1 kDa cutoff cellulose membrane for 2 days. The
dialyzed solution was lyophilized to give the cyclic polyglycocarbonate,
Synthesis of Linear Polyglycocarbonates. Polymerization of
6 Using TBD and p-Methylbenzyl Alcohol. LP-6b is given as an
example. Inside a glovebox, a solution of monomer 6b (71.32 mg,
139.15 μmol) in 300 μL of anhydrous dichloromethane was prepared
in a Schlenk tube;a mixture of p-methyl benzyl alcohol (1 mg, 8.19
μmol) and TBD (0.6 mg, 4.31 μmol) in 100 μL of anhydrous
dichloromethane was then added to the monomer solution. After kept
stirring inside the glovebox for 5 h, the polymerization was quenched
with benzoic acid. The resulting suspension was dialyzed thoroughly
against deionized water using 1 kDa cutoff cellulose membrane for 2
days to remove remaining monomers. The dialyzed solution was
lyophilized, and 50 mg of LP-6b was obtained (yield 83%). FT-IR
1
CP-6b as colorless liquid (52 mg, yield 60%). H NMR (400 MHz,
CDCl3): δ 4.90−4.781 (m, 1H), 4.79−4.50 (m, 1H), 4.50−4.0 (m,
2H), 3.99−3.70 (m, 6H), 3.72−3.50 (m, 20H), 3.51−3.30 (m, 10H).
13C NMR (100 MHz, CDCl3): δ 154.02, 154.20, 154.72, 97.98, 97.85,
1
(dichloromethane) 1750 cm−1 for carbonate (linear νco). H NMR
80.42, 79.44, 74.87, 72.39, 71.85, 71.83, 71.73, 71.008, 70.54, 70.53,
70.48, 70.47, 70.45, 70.42, 70.33, 69.55, 59.42, 59.0, 58.98, 55.94 ppm.
FT-IR (dichloromethane) 1750 cm−1 for carbonate (linear νCO).
Synthesis of Macrocyclic Amphiphilic Polyglycocarbonate
(CP-6a-b-6b). Inside a glovebox, a solution of monomer 6a (42.80
mg, 172.80 μmol) in 300 μL of anhydrous DMF was prepared in a
Schlenk tube; DBU (1.75 mg, 11.49 μmol) dissolved in 100 μL of
deuterated dimethylformamide (DMF) was added to the monomer
solution. The reaction was kept stirring inside the glovebox for 28 h;
90% of the monomer was consumed at this time. Then the second
monomer, 6b (41.24 mg, 80.46 μmol), and 1-(3,5-bis(trifluoro-
methyl)phenyl)-3-cyclohexylthiourea (TU; 4.26 mg, 11.49 μmol) were
added to the reaction mixture. The polymerization continued for
another 3 days before being quenched by a few drops of HCl (1 N).
The obtained polymerization mixture was diluted with deionized water
and dialyzed against water using 1 kDa cutoff cellulose membrane for 2
days. The dialyzed solution was lyophilized to give the amphiphilic
cyclic block copolymer CP-6a-b-6b as colorless liquid (60 mg, yield
75%). 1H NMR (400 MHz, CDCl3): δ 4.90−4.78 (m, 1H), 4.77−4.51
(m, 1H), 4.50−4.09 (m, 2H), 4.01−3.67 (m, 2.18 H), 3.66−3.47 (m,
10H), 3.46−3.32 (m, 5H), 3.32−3.15 (m, 1H) ppm. 13C NMR (100
MHz, CDCl3): δ 154.02, 154.20, 154.72, 97.98, 97.85, 79.97, 79.26,
78.21, 72.39, 71.85, 71.83, 71.73, 71.008, 70.54, 70.53, 70.48, 70.47,
(400 MHz, CDCl3): δ 4.90−4.81 (m, 1H), 4.79−4.52 (m, 1H), 4.50−
4.02 (m, 2H), 3.99−3.73 (m, 6H), 3.72−3.52 (m, 20H), 3.51−3.33
(m, 10H). Initiator incorporation was confirmed by the presence of
7.32−7.27 (m, 2H), 7.23−7.17 (m, 2H), 5.22−5.10 (m, 2H), 2.38 (s,
3H) ppm, Mn(NMR) = 8300. 13C NMR (100 MHz, CDCl3): δ 154.02,
154.20, 154.72, 97.98, 97.85, 79.97, 79.26, 78.21, 72.39, 71.85, 71.83,
71.73, 71.008, 70.54, 70.53, 70.48, 70.47, 70.45, 70.42, 70.33, 69.55,
59.42, 59.0, 58.98, 55.94 ppm. The incorporation of the initiator on
the chain end was confirmed by the presence of the corresponding
peaks; 128.50 (benzyl), 72.5 (CH2-benzyl) and 20.29 (Me-benzyl)
ppm.
Synthesis of Linear Amphiphilic Block Polyglycocarbonate
LP-6a-b-6b. Inside a glovebox, a solution of monomer 6a (36.57 mg,
147.34 μmol) in 300 μL of anhydrous dichloromethane was prepared
in a Schlenk tube; a mixture of p-methylbenzyl alcohol (1 mg, 8.19
μmol) and TBD (1.14 mg, 8.19 μmol) in 100 μL of anhydrous
dichloromethane was then added to the monomer solution. The
reaction was kept stirring inside the glovebox for 10 min; 90% of the
monomer was consumed at this time. The second monomer, 6b
(37.76 mg, 73.67 μmol), was added to the reaction mixture. The
polymerization continued for another 11 h and quenched by the
addition of benzoic acid. The resulting suspension was dialyzed
thoroughly against deionized water using 1 kDa cutoff cellulose
G
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.macro-
mol.6b02527.
Synthesis details of the precursors 5a and 5b for bicyclic
monomers 6, the characterizations of 2−5, linear and
cyclic polyglycocarbonates, Figures S1−S53 (PDF)
(18) Kricheldorf, H. R.; Sun, S.-J.; Chen, C.-P.; Chang, T.-C.
Polymers of carbonic acid. XXIV. Photoreactive, nematic or cholesteric
polycarbonates derived from hydroquinone-4-hydroxybenzoate 4,4′-
dihydroxychalcone and isosorbide. J. Polym. Sci., Part A: Polym. Chem.
1997, 35, 1611−1619.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: fxs101@gmail.com (X.F.).
*E-mail: yves.gnanou@kaust.edu.sa (Y.G.).
(19) Scheible, W.-R.; Pauly, M. Glycosyltransferases and cell wall
biosynthesis: novel players and insights. Curr. Opin. Plant Biol. 2004, 7,
285−295.
ORCID
Nikos Hadjichristidis: 0000-0003-1442-1714
Yves Gnanou: 0000-0001-6253-7856
Notes
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Polymerization of Methyl 4,6-O-Benzylidene-2,3-O- carbonyl-α-d-
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The authors declare no competing financial interest.
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