Baylis-Hillman reaction as a versatile platform for the synthesis of diverse functionalized polymers by chain and step polymerization

Article abstract of DOI:10.1021/ma4025416

The Baylis-Hillman reaction, which is a carbon-carbon bond forming reaction between an aldehyde and an activated alkene, was utilized to prepare densely functionalized monomers suitable for chain and step polymerization. By reacting formaldehyde with vari

Full text of DOI:10.1021/ma4025416

Article
pubs.acs.org/Macromolecules
Baylis−Hillman Reaction as a Versatile Platform for the Synthesis of
Diverse Functionalized Polymers by Chain and Step Polymerization
Chao Peng and Abraham Joy*
Department of Polymer Science, The University of Akron, Akron, Ohio 44325, United States
S
* Supporting Information
ABSTRACT: The Baylis−Hillman reaction, which is a
carbon−carbon bond forming reaction between an aldehyde
and an activated alkene, was utilized to prepare densely
functionalized monomers suitable for chain and step polymer-
ization. By reacting formaldehyde with various alkyl acrylates, a
series of alkyl α-hydroxymethyl acrylate monomers were
synthesized. These monomers efficiently underwent RAFT
polymerization to provide α-hydroxymethyl-substituted poly-
acrylates with well controlled molecular weight and low polydispersity. The resulting homopolymers were also efficient macro-
chain transfer agents for further RAFT polymerization. The Baylis−Hillman reaction was also utilized to synthesize alkene
functionalized diols which underwent step-growth polymerization to provide polyesters and poly(ester urethane)s. Furthermore,
it was demonstrated that the alkene group can be quantitatively functionalized by thiol−ene click chemistry to provide a series of
polymers with diverse physical properties.
designed an amphiphilic homopolymer, poly(2-hydroxy-3-
phenoxypropyl acrylate) (PHPPA), which can self-assemble
into a wide range of nanostructures.32,33 Additionally, there has
been a concerted effort in designing biodegradable polyesters
and poly(ester amide)s bearing various functional groups in our
lab and elsewhere.7−9,34,35
A novel method for the generation of functionalized
polymers that has largely been under-explored is the use of
monomers derived from the Baylis−Hillman reaction. The
Baylis−Hillman reaction is a carbon−carbon bond forming
reaction between an aldehyde and an activated alkene in
presence of a tertiary amine such as DABCO (1,4-
diazabicyclo[2.2.2]octane), and provides densely functionalized
molecules in a one-pot process (Figure 1).36−40 Several
activated alkenes such as acrylates,41−43 acrylamides,44 acryl-
onitriles,45 vinyl ketones46 or vinyl phosphonates47 are
substrates for the Baylis−Hillman reaction.
Although the wide substrate diversity of the Baylis−Hillman
reaction provides a route to several classes of functionalized
polymers, the number of studies describing their synthesis from
Baylis−Hillman substrates remains rather limited. Klok has
shown the synthesis of polyesters by the Baylis−Hillman
reaction of diacrylates with dialdehydes. However, the reported
degree of polymerization was rather low (DPn = 4−25; Mn =
630−4200 g/mol).48 Mathias has reported proof of principle
experiments demonstrating the feasibility of Baylis−Hillman
monomers as substrates for radical polymerization. His group
showed that methyl acrylate reacts with formaldehyde to
INTRODUCTION
■
Polymer properties are modulated by the presence of various
functional groups and the design and synthesis of function-
alized polymers is an area of research that is witnessing rapid
advances.1−4 Currently, the assimilation of synthetic organic
methodologies into the design of polymers has provided
remarkable examples of precisely engineered polymers such as
polyacrylates and polynorbornenes,2,5,6 polyesters,7−11 and
polyurethanes12 with various functional groups. Different
designs of functionalized polymers have been reported
including pendant,13,14 chain end functionalized,15−18
graft,19−21 and hyperbranched22−24 polymers. Functionalized
polymers have demonstrated several advantages over their
nonfunctionalized counterparts, such as tailored physical,
mechanical, and biological properties. For example, the
antifouling nature of polyacrylonitrile membranes is improved
by functionalization with hydroxyl or carboxyl functionalities.25
Cell attachment and proliferation onto polymeric substrates are
improved by functionalization with the RGD tripeptide.26,27
Conventional and controlled radical polymerizations have
been the most widely studied methods for synthesis of
functionalized polymers.3,28,29 Several examples have been
reported and a representative example is a functionalized
polymethacrylate reported by Maynard et al. containing a
reactive ketone side chain, which can be used to prepare
polymer−drug conjugates.30 Furthermore, interesting examples
exist wherein each monomer is designed to have multiple
functional groups. Thayumanavan et al. reported a class of
styrene-based amphiphilic homopolymers in which the phenyl
group is substituted with both hydrophilic carboxyl and
hydrophobic benzyl groups, which enables their self-assembly
into spherical micelles in aqueous solution.31 Similarly, Du et al.
Received: December 12, 2013
Revised: January 19, 2014
© XXXX American Chemical Society
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Scheme 2. Synthesis of Alkyl α-Hydroxymethyl Acrylate
Monomers
Scheme 3. Synthesis of Alkene-Functionalized Diols
Figure 1. Baylis−Hillman reaction and its utility for the synthesis of
phenylpropionaldehyde or butyraldehyde with 2-hydroxyethyl
acrylate to provide alkene-functionalized diols (Scheme 3)
which can undergo step growth polymerization to provide
poly(ester urethane)s or polyesters. The alkene group can be
functionalized either pre or postpolymerization using the thiol−
ene reaction. The current work demonstrates the utility of the
Baylis−Hillman reaction as a versatile platform for the synthesis
of multiple classes of functionalized polymers.
densely functionalized molecules. EWG = electron withdrawing group.
provide methyl α-hydroxymethyl acrylate, which underwent
homo or copolymerization with styrene or methyl methacry-
late.49,50 Huang has utilized the Baylis−Hillman reaction to
synthesize a novel acrylate monomer containing an ATRP
initiating group. This monomer was subsequently polymerized
by sequential RAFT and ATRP methods to provide poly(tert-
butyl acrylate)-g-poly(methyl acrylate) graft copolymers.51
As outlined in Scheme 1, the work reported here describes
the synthesis of Baylis−Hillman based monomers and their
polymerization by chain or step polymerization routes. In the
first part of this article, we present the synthesis of a series of
alkyl α-hydroxymethyl acrylate monomers by the Baylis−
Hillman reaction of formaldehyde with alkyl acrylates (Scheme
2). The corresponding alkyl α-hydroxymethyl acrylates
efficiently undergo reversible addition−fragmentation chain
transfer (RAFT) polymerization to provide functionalized
homopolymers or block copolymers. We also demonstrate
that such functionalized polyacrylates can readily form
nanostructures in aqueous solution due to their amphiphilic
nature. In the second part, we show the reaction of 3-
EXPERIMENTAL SECTION
■
Materials. Tin(II)2-ethylhexanoate (Sn(Oct)2), and 2-hydroxy-4′-
(2-hydroxyethoxy)-2-methylpropiophenone (Irgacure 2959) were
purchased from Sigma-Aldrich. 2-Mercaptoethanol was purchased
from TCI. All other reagents were purchased from Alfa Aesar. Unless
otherwise stated, all reagents were used as received. 2,2′-Azobis-
(isobutyronitrile) (AIBN) was recrystallized multiple times from
methanol before use. 4-(4-Cyanopentanoic acid) dithiobenzoate
(CPDB) and 4-(dimethylamino)pyridinium p-toluenesulfonate
(DPTS) were synthesized according to reported procedures.7,52,53
Analytical Methods. NMR spectra were recorded on a Varian
1
NMRS 300 or 500 MHz instrument. H NMR chemical shifts are
reported in ppm relative to the solvent’s residual H signal. 13C NMR
1
spectra were recorded at 125 MHz. Size exclusion chromatography
(SEC) analysis in DMF was performed on a HLC-8320 GPC from
Scheme 1. Utility of Baylis−Hillman-Based Monomers for Chain and Step-Growth Polymerizations
B
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a
Table 1. Synthesis of α-Hydroxymethyl-Substituted Polyacrylates via RAFT Polymerization
b
b
d
e
entry
polymer
P1a(Et)
[M]0/[CTA]0/[I]0
[M]0 (mol L−1
)
time (h)
Mn,SEC (kg/mol)
PDI
convn (%)
Mn,theory (kg/mol)
1
2
180/3/1
180/3/1
180/3/1
180/3/1
200/1/0.2
220/1/0.2
200/1/0.2
220/1/0.2
180/3/1
180/3/1
2
24
24
24
24
24
24
24
24
24
24
7.6
8.0
1.15
1.16
1.21
1.16
1.18
1.19
1.28
1.17
1.07
1.25
92
80
48
73
62
58
41
63
80
73
7.6
8.0
P1b(nBu)
2
3
P1c(tBu)
2
5.4
5.0
4
P1d(nHex)
P1a(Et)
2
9.6
8.5
5
2
19.8
25.4
11.7
29.6
15.8
20.5
13.2
26.1
8.0
6
P1b(nBu)
2
7
P1c(tBu)
2
8
P1d(nHex)
P1b(nBu)
2
c
c
c
9
2
10.3
c
10
P1b(nBu)-b-P1e(TBS)
1.5
24.1
19.4
a
b
All the experiments (entry 1−10) used AIBN as initiator and 1,4-dioxane as solvent. The reaction temperature was kept at 70 °C. Determined by
c
d
SEC using DMF as the eluent and PMMA as the standard. Determined by SEC using THF as the eluent and PS as the standard. Monomer
conversion determined by H NMR. Calculated based on the monomer conversion.
e
1
TOSOH equipped with RI and UV detectors using PMMA or PS as
the standards. ESI MS was performed on Bruker HTC ultra QIT. Size
exclusion chromatography (SEC) in THF was performed on a Waters
150-C Plus instrument equipped with RI and LS detectors and PS was
used as the standard. The decomposition temperature (Td) of the
polymers was determined by thermal gravimetric analysis (TGA) using
TA Q500 thermal gravimetric analysis instrument. The glass transition
temperature (Tg) of the polymers was determined by differential
scanning calorimetry (DSC) using TA Q2000 differential scanning
calorimetry instrument. The morphology of the nanoparticles was
characterized by scanning electron microscope (SEM) using JEOL-
JSM-7401F with operating voltage as 4 kV. The size and distribution
of the nanoparticles were determined by dynamic light scattering
(DLS) using a Malvern Instruments Zetasizer Nano ZS.
13C NMR (125 MHz, CDCl3), δ (ppm): 5.38 (s), 18.25 (s), 25.79 (s),
61.09 (s), 62.63 (s), 66.00 (s), 125.89 (s), 139.47 (s), 166.19 (s).
MS(ESI): 283.0 ([M + Na]+).
Synthesis of Poly(alkyl α-hydroxymethyl acrylate) by RAFT
Polymerization. In a typical experiment (entry 2 in Table 1),
1b(nBu) (316.4 mg, 2.0 mmol), the RAFT agent CPDB (9.3 mg,
0.033 mmol), AIBN (1.8 mg, 0.011 mmol) and anhydrous 1,4-dioxane
(1.0 mL) were added to a Schlenk flask equipped with a magnetic stir
bar. The Schlenk flask was subjected to three freeze−pump−thaw
cycles. Then the flask was sealed and placed in a heated oil bath at 70
°C for 24 h under magnetic stirring. The polymer was precipitated in
hexane, centrifuged and dried in vacuum oven to give a pink solid. (Mn
= 8.0 kg/mol, PDI = 1.16)
P1a(Et). 1H NMR (500 MHz, acetone-d6), δ (ppm): 1.30 (m, 3H),
1.95 (m, 2H), 3.74−4.13 (m, 4H), 7.48 (m, end group), 7.62 (m, end
group), 7.92 (m, end group).
Synthesis of Alkyl α-Hydroxymethyl Acrylate Monomers. As
an example, the synthesis of 1b(nBu) is as follows: n-butyl acrylate
(14.0 g, 0.109 mol), formaldehyde aqueous solution (2.7 mL, 0.036
mol), and 1,4-diazabicyclo[2.2.2]octane (DABCO) (4.1 g, 0.036 mol)
were added to a round-bottom flask equipped with a magnetic stir bar.
Then 1,4-dioxane (10.0 mL) and distilled water (7.3 mL) were added,
and the mixture was stirred at room temperature for 12 h. The
compound was extracted by ethyl acetate followed by washing with
brine and subsequent drying over anhydrous Na2SO4. The filtrate was
then concentrated under reduced pressure and purified by column
chromatography (30% ethyl acetate and 70% hexane, Rf = 0.5) to give
a colorless liquid. (2.9 g, 51%)
1
P1b(nBu). H NMR (500 MHz, CDCl3), δ (ppm): 0.97 (m, 3H),
1.42 (m, 2H), 1.64 (m, 2H), 1.92 (m, 2H), 3.59−4.07 (m, 4H), 7.36
(m, end group), 7.52 (m, end group), 7.88 (m, end group).
1
P1c(tBu). H NMR (500 MHz, CDCl3), δ (ppm): 1.53 (m, 9H),
1.95 (m, 2H), 3.67 (m, 2H), 7.36 (m, end group), 7.51 (m, end
group), 7.90 (m, end group).
P1d(nHex). 1H NMR (500 MHz, CDCl3), δ (ppm): 1.53 (m, 9H),
1.95 (m, 2H), 3.67 (m, 2H), 7.36 (m, end group), 7.51 (m, end
group), 7.90 (m, end group).
Synthesis of Block Copolymer, P1b(nBu)-b-P1e(TBS), by
RAFT Polymerization (entry 10 in Table 1). P1b(nBu) (192.2 mg,
2.4 × 10−5 mol), AIBN (1.3 mg, 8.0 × 10−6 mol), 1e(TBS) (374.5 mg,
1.438 × 10−3 mol), and anhydrous 1,4-dioxane (1.0 mL) were added
to a Schlenk flask equipped with a magnetic stir bar. The Schlenk flask
was subjected to three freeze−pump−thaw cycles. The flask was then
sealed and placed in a heated oil bath at 70 °C for 24 h under magnetic
stirring. The polymer was precipitated in cold hexane, centrifuged and
dried in vacuum oven to give a pink solid. (Mn = 24.1 kg/mol, PDI =
1.25)
1a(Et). 1H NMR (300 MHz, CDCl3), δ (ppm): 1.33 (t, J = 7.50 Hz,
3H), 2.23 (t, J = 6.00 Hz, 1H), 4.26 (q, J = 7.00 Hz, 2H), 4.35 (d, J =
3.00 Hz, 2H), 5.83 (s, 1H), 6.27 (s, 1H). 13C NMR (125 MHz,
CDCl3), δ (ppm): 14.09 (s), 60.80 (s), 62.36 (s), 125.37 (s), 139.59
(s), 166.29 (s). MS(ESI): 152.8 ([M + Na]+).
1
1b(nBu). H NMR (300 MHz, CDCl3), δ (ppm): 0.96 (t, J = 7.50
Hz, 3H), 1.36−1.49 (m, 2H), 1.64−1.73 (m, 2H), 2.25 (t, J = 6.00 Hz,
1H), 4.20 (t, J = 7.50 Hz, 2H), 4.35 (d, J = 3.00 Hz, 2H), 5.84 (s, 1H),
6.27 (s, 1H). 13C NMR (125 MHz, CDCl3), δ (ppm): 13.62 (s), 19.13
(s), 30.56 (s), 62.41 (s), 64.69 (s), 125.34 (s), 139.61 (s), 166.36 (s).
MS(ESI): 180.9 ([M + Na]+).
1
P1b(nBu)-b-P1e(TBS). H NMR (500 MHz, CDCl3), δ (ppm):
0.10 (m, 6H), 0.92 (m, 9H), 0.97 (m, 3H), 1.42 (m, 2H), 1.64 (m,
2H), 1.92 (m, 4H), 3.59−4.07 (m, 8H)
1c(tBu). 1H NMR (300 MHz, CDCl3), δ (ppm): 1.52 (s, 9H), 2.32
(t, J = 6.00 Hz, 1H), 4.30 (d, J = 6.00 Hz, 2H), 5.75 (s, 1H), 6.16 (s,
1H). 13C NMR (125 MHz, CDCl3), δ (ppm): 28.03 (s), 62.61 (s),
81.31 (s), 124.62 (s), 140.88 (s), 165.65 (s). MS(ESI): 180.9 ([M +
Na]+).
Preparation of Nanoparticles by Dialysis Method. P1b(nBu)
(entry 2 in Table 1, Mn = 8.0 kg/mol, PDI = 1.16) was dissolved in
DMF at a concentration of 1.0 mg/mL and dialyzed against distilled
water for 24 h. The water was refreshed every 6 h. Morphology and
size of the nanoparticles were investigated by SEM and DLS.
Preparation of Nanoparticles by the Dropping Method.
P1b(nBu) (entry 2 in Table 1, Mn = 8.0 kg/mol, PDI = 1.16) was
dissolved in acetone at a concentration of 1.0 mg/mL, and distilled
water was added dropwise to the polymer solution under vigorous
stirring until the solution became faint blue (∼15 wt% water). The
morphology of the nanoparticles was characterized by SEM.
Synthesis of Alkene-Functionalized Diol. As an example, the
synthesis of 2b(Ph) is as follows: 2-hydroxyethyl acrylate (6.0 g, 0.052
1d(nHex). 1H NMR (300 MHz, CDCl3), δ (ppm): 0.90 (t, J = 7.50
Hz, 3H), 1.32−1.43 (m, 6H), 1.65−1.74 (m, 2H), 2.26 (s, 1H), 4.19
(t, J = 6.00 Hz, 2H), 4.34 (s, 2H), 5.84 (s, 1H), 6.27 (s, 1H). 13C
NMR (125 MHz, CDCl3), δ (ppm): 13.90 (s), 22.46 (s), 25.57 (s),
28.48 (s), 31.35 (s), 62.46 (s), 65.01 (s), 125.37 (s), 139.61 (s),
166.34 (s). MS(ESI): 208.9 ([M + Na]+).
1e(TBS). 1H NMR (300 MHz, CDCl3), δ (ppm): 0.08 (s, 6H), 0.90
(s, 9H), 2.39 (t, J = 3.00 Hz, 1H), 3.86 (t, J = 3.00 Hz, 2H), 4.27 (t, J =
3.00 Hz, 2H), 4.34 (d, J = 6.00 Hz, 2H), 5.84 (s, 1H), 6.28 (s, 1H).
C
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mol), 3-phenylpropionaldehyde (2.3 g, 0.017 mol), and 1,4-
diazabicyclo[2.2.2]octane (5.8 g, 0.052 mol) were added to a round-
bottom flask equipped with a magnetic stir bar. Then 1,4-dioxane (8.0
mL) and distilled water (8.0 mL) were added to the flask and the
mixture was stirred at room temperature for 24 h. The compound was
extracted by ethyl acetate followed by washing with brine and
subsequent drying over anhydrous Na2SO4. The filtrate was then
concentrated under reduced pressure and purified by column
chromatography (30% ethyl acetate and 70% hexane, Rf = 0.3) to
give a colorless liquid. (1.8 g, 43%)
Synthesis of Polyesters. In a typical reaction (entry 2 in Table 6),
2b(Ph)-Dodecyl (1.0275 g, 2.27 mmol), succinic acid (0.2681 g, 2.27
mmol), and DPTS (0.2657 g, 0.91 mmol) were added to a Schlenk
flask. The flask was evacuated and backfilled with nitrogen three times.
Anhydrous dichloromethane (4.3 mL) was added followed by
diisopropylcarbodiimide (DIC) (0.8581 g, 6.81 mmol) and the
reaction was stirred at room temperature for 24 h. The polymer was
precipitated in methanol three times to give a viscous liquid. (Mn = 8.3
kg/mol, PDI = 1.34)
PE2a(Pr)-nBu. 1H NMR (300 MHz, CDCl3), δ (ppm): 0.92 (t, J =
7.5 Hz, 6H), 1.29−1.64 (m, 8H), 2.52 (m, 2H), 2.62−2.91 (m, 7H),
4.33 (m, 4H), 5.19 (m, 1H).
2a(Pr). 1H NMR (300 MHz, CDCl3), δ (ppm): 0.96 (t, J = 7.50 Hz,
3H), 1.32−1.54 (m, 2H), 1.62−1.70 (m, 2H), 2.00 (s, 1H), 2.51 (s,
1H), 3.90 (t, J = 4.50 Hz, 2H), 4.34 (t, J = 4.50 Hz, 2H), 4.44 (t, J =
6.00 Hz, 1H), 5.84 (s, 1H), 6.28 (s, 1H). 13C NMR (125 MHz,
CDCl3), δ (ppm): 13.79 (s), 18.97 (s), 38.15 (s), 60.80 (s), 66.27 (s),
71.11 (s), 125.26 (s), 142.60 (s), 166.77 (s). MS(ESI): 210.9 ([M +
Na]+).
1
PE2b(Ph)-Dodecyl. H NMR (300 MHz, CDCl3), δ (ppm): 0.89
(t, J = 6.0 Hz, 3H), 1.20−1.33 (m, 18H), 1.55 (m, 2H), 1.95 (m, 2H),
2.45−2.83 (m, 8H), 2.92 (m, 1H), 4.29 (m, 4H), 5.24 (m, 1H), 7.15−
7.33 (m, 5H).
General Procedure for the Thiol−Ene “Click” Reaction of the
Alkene-Functionalized Polymers. In a typical experiment (entry 4
in Table 4), PEU2b(Ph) (0.1 g) and 3-mercaptopropionic acid (0.25
g, 2.4 mmol), Irgacure 2959 (26.9 mg, 0.12 mmol) and anhydrous
chloroform (1.0 mL) were added to a quartz glass test tube. The
solution was irradiated at 350 nm for 30 min. The product was
precipitated in diethyl ether, centrifuged and dried in a vacuum oven.
1
2b(Ph). H NMR (300 MHz, CDCl3), δ (ppm): 1.96−2.05 (m,
2H), 2.67−2.89 (m, 2H), 3.87 (t, J = 6.00 Hz, 2H), 4.32 (t, J = 4.50
Hz, 2H), 4.66 (t, J = 7.50 Hz, 1H), 5.86 (s, 1H), 6.30 (s, 1H), 7.18−
7.32 (m, 5H); 13C NMR (125 MHz, CDCl3), δ (ppm): 31.95 (s),
37.47 (s), 60.69 (s), 66.25 (s), 70.50 (s), 125.58 (s), 128.83 (s),
128.32 (s), 128.38 (s), 141.53 (s), 142.39 (s), 166.64 (s). MS(ESI):
273.0 ([M + Na]+).
1
PEU2a(Pr)-OH. H NMR (300 MHz, MeOD), δ (ppm): 0.93 (t, J
= 7.5 Hz, 3H), 1.35−1.61 (m, 12H), 2.66 (m, 2H), 2.78−2.90 (m,
3H), 3.10 (m, 4H), 3.68 (t, J = 7.5 Hz, 2H), 4.26−4.31 (m, 4H), 5.01
(m, 1H).
General Procedure of the Thiol−Ene “Click” Reaction of the
Alkene-Functionalized Diols. As an example, the synthesis of
2b(Ph)-Dodecyl is as follows: 2b(Ph) (1.0 g, 4 mmol), 1-
dodecanethiol (8.1 g, 40 mmol), Irgacure 2959 (448.6 mg, 2 mmol),
and anhydrous DMF (3.6 mL) were added to a quartz glass test tube.
The solution was irradiated at 350 nm for 30 min. The product was
purified by column chromatography (50% ethyl acetate and 50%
hexane, Rf = 0.3) to give a colorless liquid. (1.5 g, 83%)
PEU2a(Pr)-COOH. 1H NMR (300 MHz, DMSO-d6), δ (ppm): 0.85
(t, J = 6.0 Hz, 3H), 1.22−1.50 (m, 12 H), 2.63−2.84 (m, 7H), 2.95
(m, 4H), 4.13−4.21 (m, 4H), 4.89 (m, 1H), 6.99−7.11 (m, 2H), 12.24
(s, 1H).
1
PEU2b(Ph)-OH. H NMR (300 MHz, MeOD), δ (ppm): 1.34−
1.50 (m, 8H), 1.93 (m, 2H), 2.65 (m, 4H), 2.76−2.96 (m, 3H), 3.09
(m, 4H), 3.65 (t, J = 7.5 Hz, 2H), 4.23−4.28 (m, 4H), 5.02 (m, 1H),
7.16−7.28 (m, 5H).
1
2a(Pr)-nBu. H NMR (300 MHz, MeOD), δ (ppm): 0.93 (t, J =
7.5 Hz, 6H), 1.31−1.61 (m, 8H), 2.54 (t, J = 7.5 Hz, 2H), 2.66−2.95
(m, 3H), 3.71−3.80 (m, 3H), 4.18 (m, 2H). 13C NMR (125 MHz,
Acetone-d6), δ (ppm): 13.99 (s), 14.32 (s), 19.69 (s), 22.57 (s), 31.12
(s), 32.51 (s), 37.85 (s), 38.15 (s), 54.59 (s), 60.85 (s), 66.71 (s),
72.33 (s), 173.86 (s). MS(ESI): 301.0 ([M + Na]+).
1
PEU2b(Ph)-COOH. H NMR (300 MHz, DMSO-d6), δ (ppm):
1.23−1.38 (m, 8H), 1.83 (m, 2H), 2.44−2.67 (m, 9H), 2.94 (m, 4H),
4.12−4.19 (m, 4H), 4.89 (m, 1H), 7.08 (m, 2H), 7.17−7.26 (m, 5H),
12.23 (s, 1H).
2b(Ph)-Dodecyl. 1H NMR (300 MHz, MeOD), δ (ppm): 0.90 (t, J
= 7.5 Hz, 3H), 1.29−1.37 (m, 18H), 1.55 (m, 2H), 1.70−1.90 (m,
2H), 2.51 (t, J = 7.5 Hz, 2H), 2.63−2.90 (m, 5H), 3.71−3.81 (m, 3H),
4.18 (m, 2H), 7.21 (m, 5H). 13C NMR (125 MHz, CDCl3), δ (ppm):
22.68 (s), 28.84 (s), 29.20 (s), 29.34 (s), 29.46 (s), 29.51 (s), 29.59
(s), 29.64 (s), 31.61 (s), 31.91 (s), 32.03 (s), 32.12 (s), 32.65 (s),
36.08 (s), 37.38 (s), 51.28 (s), 60.84 (s), 66.27 (s), 71.50 (s), 126.03
(s), 128.44 (s), 128.49 (s), 143.89 (s), 173.81 (s). MS(ESI): 475.2
([M + Na]+).
RESULTS AND DISCUSSION
■
Monomer Synthesis. The two types of monomers used for
the polymerizations were synthesized using a one-step Baylis−
Hillman reaction as outlined in Schemes 2 and Scheme 3. The
Baylis−Hillman reaction of formaldehyde with alkyl acrylate in
Synthesis of Poly(ester urethane)s. In a typical reaction (entry
2 in Table 3), 2b(Ph) (0.6554 g, 2.62 mmol) and hexamethylene
diisocyanate (0.4407 g, 2.62 mmol) were added to a Schlenk flask. The
flask was evacuated and backfilled with nitrogen three times. Then
anhydrous dichloromethane (3.0 mL) was added. After that, one drop
of Sn(Oct)2 was added under N2 and the solution was stirred at room
temperature for 48 h. The product was precipitated in diethyl ether,
centrifuged and dried in vacuum oven. (Mn = 9.4 kg/mol, PDI = 1.47)
PEU2a(Pr). 1H NMR (300 MHz, CDCl3), δ (ppm): 0.92 (t, J = 7.5
Hz, 3H), 1.35−1.65 (m, 12H), 3.17 (m, 5H), 4.30 (m, 4H), 4.93 (br,
2H), 5.51 (s, 1H), 5.78 (s, 1H), 6.29 (s, 1H).
PEU2b(Ph). 1H NMR (300 MHz, CDCl3), δ (ppm): 1.33−1.64 (m,
8H), 1.98−2.10 (m, 2H), 2.67 (m, 2H), 3.14 (m, 4H), 4.28 (m, 4H),
4.84 (br, 2H), 5.56 (s, 1H), 5.81 (s, 1H), 6.32 (s, 1H), 7.18 (m, 3H),
7.25 (m, 2H).
1
PEU2a(Pr)-nBu. H NMR (300 MHz, CDCl3), δ (ppm): 0.91 (m,
6H), 1.28−1.65 (m, 16H), 2.51 (m, 2H), 2.69 (m, 1H), 2.85 (m, 2H),
3.16 (s, 4H), 4.23−4.32 (m, 4H), 5.02 (s, 1H).
PEU2b(Ph)-Dodecyl. 1H NMR (300 MHz, CDCl3), δ (ppm): 0.89
(m, 3H), 1.26−1.63 (m, 28H), 1.92 (m, 2H), 2.48 (m, 2H), 2.67 (m,
3H), 2.86 (m, 2H), 3.14 (m, 4H), 4.22−4.31 (m, 4H), 5.08 (m, 1H),
7.19−7.30 (m, 5H).
1
Figure 2. H NMR spectra of 1b(nBu) (top) and 2b(Ph) (bottom).
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Scheme 4. Synthesis of Poly(alkyl α-hydroxymethyl acrylate) via RAFT Polymerization
1
Figure 3. H NMR spectra of P1b(nBu) synthesized via RAFT polymerization.
Table 2. Thermal Properties of the Polymers
T
T
T
T
g b
5%a
d1a
d2a
polymer
comment
(°C)
(°C)
(°C)
(°C)
P1a(Et)
entry 5 in
Table 1
165
153
284
86
P1b(nBu)
P1c(tBu)
entry 6 in
Table 1
170
162
168
166
164
165
292
283
293
56
88
28
entry 7 in
Table 1
P1d(nHex) entry 8 in
Table 1
a
Temperature of 5% mass loss (T5%) and decomposition temperature
b
(Td) were determined by thermal gravimetric analysis (TGA). Glass
transition temperature (Tg) was determined by differential scanning
calorimetry (DSC).
Figure 5. SEC traces of P1b(nBu) (entry 9 in Table 1) and
P1b(nBu)-b-P1e(TBS) (entry 10 in Table 1).
the presence of DABCO generated alkyl α-hydroxymethyl
acrylate (1a−1e) and the reaction of aldehyde with 2-
hydroxyethyl acrylate in the presence of DABCO provided
the unsaturated diol (2a(Pr) and 2b(Ph)) in approximately
50% yield for both reactions.
The Baylis−Hillman reaction to give 1(a−e) and 2(a,b) was
carried out in a 1,4-dioxane/water (1/1, v/v) medium as it has
been reported to accelerate the progress of the reaction.54 As
representative examples, the 300 MHz H NMR spectrum of
1b(nBu) and 2b(Ph) is shown in Figure 2.
1
1
Figure 4. H NMR spectra of P1b(nBu)-b-P1e(TBS) synthesized via RAFT polymerization.
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8.0 ppm, the signals of the RAFT end group were detected
around 7.38, 7.54, and 7.98 ppm, which confirmed the retained
RAFT end group. In order to calculate the monomer
conversion, aliquots of the reaction mixture were withdrawn
by syringe at the end of the reaction and analyzed by 1H NMR
spectroscopy. The conversion was determined by integration of
the backbone methylene proton resonances I(−CH2)p relative
to the monomer olefinic proton resonances I(CH2)m by eq 1.
Theoretical number-average molecular weights were calculated
based on eq 2, where MWCTA and MWm are the molecular
weights of RAFT agent and monomer, respectively. [M]0 and
[CTA]0 are the initial concentrations of monomer and RAFT
agent, respectively. The theoretical molecular weight shows
good agreement with the experimental molecular weight.
I(−CH2)p
conversion (%) =
× 100%
I(−CH2)p + I( = CH2)m
Figure 6. SEM image (without sputtering) of P1b(nBu) nanoparticles
prepared by dialysis method. scale bar = 1 μm.
(1)
(2)
[M]0 × MW × conversion
m
Mncalc
=
+ MW
CTA
[CTA]0
Table 1 summarizes the results for the polymers prepared by
RAFT polymerization as obtained from the SEC and 1H NMR
data. It is shown that high [M]0/[CTA]0 molar ratio such as
200:1 or 220:1 afforded a molecular weight between 11.7 and
29.6 kg/mol. With a low [M]0/[CTA]0 molar ratio 60:1,
relatively low molecular weight between 5.4 and 9.6 kg/mol
was obtained. SEC analysis indicated unimodal molecular
weight distributions and the Mw/Mn was around 1.2. It is worth
noting that slightly broader polydispersity was observed for the
polymer with a tert-butyl pendant group, which may be due to
the steric hindrance of the monomer or potential side reactions
that may occur with tert-butyl moieties via thermal pathways.
The thermal properties (decomposition temperature (Td)
and glass transition temperature (Tg)) of the homopolymers
were determined by TGA and DSC. The polymers from entry
5−8 (Table 1) were selected for thermal analysis and the
results are summarized in Table 2. TGA experiments revealed
that the polymers began decomposition at around 152−165 °C
and they showed two stages of weight loss (Supporting
Information). On the basis of DSC experiments, the Tg
decreases with increasing length of the alkyl side chain.
P1b(nBu) (Mn = 25.4 kg/mol, Tg = 56 °C) and P1d(nHex)
(Mn = 29.6 kg/mol, Tg = 28 °C) showed lower glass transition
temperatures (Tg) than P1a(Et) (Mn = 19.8 kg/mol, Tg = 85
°C), which was consistent with the higher flexibility of n-butyl
and n-hexyl side groups in P1b(nBu) and P1d(nHex). The
polymers with t-butyl and ethyl groups provided similar Tg
values; Tg of P1a(Et) (Mn = 19.8 kg/mol) and P1c(tBu) (Mn =
11.7 kg/mol) are 86 and 88 °C, respectively.
Figure 7. Size distribution of P1b(nBu) nanoparticles prepared by
dialysis method.
Figure 8. SEM image (with sputtering) of P1b(nBu) nanoparticles
prepared by the dropping method. Scale bar = 1 μm.
Synthesis of the α-Hydroxymethyl-Substituted Poly-
acrylate Library by RAFT Polymerization. A library of α-
hydroxymethyl substituted polyacrylates was synthesized using
RAFT polymerization (Scheme 4). Within this series, the
pendant groups of the polymers were varied, such as ethyl, n-
butyl, tert-butyl, or n-hexyl. The homopolymers were
synthesized by RAFT polymerization at 70 °C using AIBN as
initiator. 4-(4-Cyanopentanoic acid) dithiobenzoate, CPDB,
was selected as the chain transfer agent to control the
polymerization as it was found to be compatible with the α-
hydroxymethyl substituted acrylate monomers. The structures
Copolymerization Studies. In the previous section, we
demonstrated successful RAFT polymerization of the alkyl α-
hydroxymethyl acrylate monomers and confirmed the retained
1
end-group functionality by 500 MHz H NMR spectroscopy.
The homopolymer was subsequently tested as a macro-CTA to
prepare block copolymers. To investigate this, we selected
P1b(nBu) (entry 9 in Table 1, Mn = 10.3 kg/mol, PDI = 1.07)
as the macro-CTA. In order to minimize the signal overlap of
the two blocks in the 1H NMR spectra, the TBS (tert-
butyldimethylsilyl) protected hydroxyl monomer, 1e(TBS),
was selected for block copolymer synthesis as the difference in
chemical shifts of the pendant groups corresponding to each
1
of the polymers were confirmed by H NMR spectroscopy. A
typical example is shown in Figure 3 (entry 2 in Table 1) with
the proton assignments corresponding to the repeating unit. As
shown in the expanded region of the spectrum between 7.2 and
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Scheme 5. Synthesis of Functionalized Poly(ester urethane)s
Table 3. Synthesis of Alkene-Functionalized Poly(ester
urethane)s
Table 4. Post-Polymerization Modification of Poly(ester
urethane)s
a
a
b
entry
polymer
time (h)
Mn,SEC (kg/mol)
PDI
DPn
entry
polymer
thiol
time (min) conversion (%)
1
2
PEU2a(Pr)
PEU2b(Ph)
24
24
6.2
9.4
1.46
1.47
35
45
1
2
3
4
PEU2a(Pr)
PEU2a(Pr)
PEU2b(Ph)
PEU2b(Ph)
HSCH2CH2OH
30
30
30
30
100
100
100
100
HSCH2CH2COOH
HSCH2CH2OH
a
Determined by SEC using DMF as the eluent and PS as the standard.
Number-average degree of polymerization.
b
HSCH2CH2COOH
Figure 9. Postpolymerization modification of poly(ester urethane)s as evidenced by 1H NMR; PEU2b(Ph) (top), PEU2b(Ph)-OH (middle), and
PEU2b(Ph)-COOH (bottom).
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Table 5. Thermal Properties of Post-Functionalized
Poly(ester urethane)s
Table 6. Synthesis of Pre-Functionalized Polyesters and
Poly(ester urethane)s
a
a
b
polymer
PEU2a(Pr)
T5% (°C)
Td (°C)
Tg (°C)
time
(h)
Mn,SEC
a
a
b
entry
polymer
(kg/mol)
PDI
DPn
147
187
206
190
201
205
142
186
207
166
199
210
5
16
21
9
1
2
3
4
PE2a(Pr)-nBu
48
48
24
24
11.8
8.3
1.16
1.34
1.61
1.66
60
29
16
17
PEU2a(Pr)-OH
PEU2a(Pr)-COOH
PEU2b(Ph)
PE2b(Ph)-Dodecyl
PEU2a(Pr)-nBu
PEU2b(Ph)-Dodecyl
3.5
5.2
PEU2b(Ph)-OH
PEU2b(Ph)-COOH
21
22
a
Determined by SEC using DMF as the eluent and PS as the standard.
Number-average degree of polymerization.
b
a
Temperature of 5% mass loss (T5%) and decomposition temperature
b
(Td) were determined by thermal gravimetric analysis (TGA). Glass
transition temperature (Tg) was determined by differential scanning
calorimetry (DSC).
homopolymer forms well-defined spherical nanoparticles with
an average diameter of 283 nm.
The average hydrodynamic diameter determined by DLS is
323 nm with a PDI of 0.18 (Figure 7). The slight difference in
reported size obtained from SEM and DLS analysis is probably
due to nanoparticle swelling in the aqueous medium.
Preparation of Nanoparticles by the Dropping
Method. Self-assembly properties of P1b(nBu) was also
investigated by the dropping method. In this experiment,
P1b(nBu) (Mn = 8.0 kg/mol, PDI = 1.16) was initially
dissolved in acetone at a concentration of 1 mg/mL and then
an appropriate amount of water was added dropwise into the
solution under vigorous stirring. It was observed that the
polymer solution became faint blue after adding 15% water
(weight fraction), which indicated self-assembly of the polymer.
The SEM image (Figure 8) shows the size of the obtained
nanoparticles to be about 200 nm.
The above section described the chain polymerization of
Baylis−Hillman monomers to provide homo and copolymers.
In the next section, the use of Baylis−Hillman based monomers
for the synthesis of poly(ester urethane)s and polyesters is
described.
Synthesis of Functionalized Poly(ester urethane)s.
Step growth polymerization of the alkene-functionalized diol
monomers with diisocyanates provided degradable poly(ester
1
block are easily distinguished in the H NMR spectra. The
structure of the block copolymer, P1b(nBu)-b-P1e(TBS), was
confirmed by 1H NMR spectroscopy (Figure 4) The
characteristic peaks of the second block (TBS group at 0.10
and 0.92 ppm) are observed as well as that of the first block
(methyl group at 0.97 ppm). SEC analysis showed unimodal
distribution for the homopolymer and block copolymer (Figure
5). The first block P1b(nBu) (Mn = 10.3 kg/mol, PDI = 1.07)
was successfully chain extended, as indicated by the distinct
shift in the SEC retention volume. The polydispersity of the
P1b(nBu)-b-P1e(TBS) (Mn = 24.1 kg/mol, PDI = 1.25) block
copolymer increased slightly after chain extension but remained
low, indicating good living character of the polymerization.
Preparation of Nanoparticles by Dialysis Method. The
repeating unit of the described α-hydroxymethyl substituted
polyacrylates is amphiphilic due to the presence of a
hydrophilic hydroxyl group and a hydrophobic alkyl group.
As a result, these amphiphilic polymers self-assemble into
nanoparticles when dissolved in DMF and dialyzed against
water. The SEM image (Figure 6) of the nanoparticles prepared
from P1b(nBu) (Mn = 8.0 kg/mol, PDI = 1.16) shows that the
1
Figure 10. H NMR spectra of 2a(Pr)-nBu (top) and 2b(Ph)-Dodecyl (bottom).
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1
Figure 11. H NMR spectra of PE2a(Ph)-Dodecyl (top) and PEU2b(Ph)-Dodecyl (bottom).
Scheme 6. Synthesis of Functionalized Polyesters
urethane)s. Two synthetic routes were explored for the
synthesis of the poly(ester urethane)s (Scheme 5). The first
involved the direct polymerization of the unsaturated diol
followed by postpolymerization modification. The second
involved the conjugate addition of thiols to the unsaturated
diol prior to polymerization.
therefore be used for postpolymerization modification via
thiol−ene click chemistry.
Postpolymerization Functionalization via Thiol−Ene
“Click” Chemistry. The alkene pendant groups in the polymer
can be converted to other functional groups via thiol−ene click
chemistry.55 Functional groups which are potentially incompat-
ible with the polymerization conditions such as hydroxyl or
carboxyl groups can be incorporated into the polymers in high
yields via post polymerization modification using thiol−ene
chemistry. In this work, the reaction was carried out with 10
equiv of functionalized thiol and 0.5 equiv of photoinitiator
(Irgacure 2959) in anhydrous CHCl3. After irradiation at 350
nm for 30 min, the excess thiol was removed by precipitation in
diethyl ether.
Direct Polymerization with Subsequent Postpolymeriza-
tion Functionalization. The polymerization of unsaturated
diols 2a(Pr) and 2b(Ph) with hexamethylene diisocyanate was
achieved by solution polymerization in anhydrous CH2Cl2 at
room temperature using Sn(Oct)2 as a catalyst. As shown in
Table 3, polymerization of 2a(Pr) and 2b(Ph) afforded
polymers with molecular weights of 6.2 and 9.4 kg/mol,
respectively. The low molecular weight is probably a result of
differential reactivity of the primary and secondary hydroxyl
groups of the monomer. Evidence for the existence of the
As a proof-of-concept, the postpolymerization modification
of PEU2b(Ph) with 2-mercaptoethanol and 3-mercaptopro-
pionic acid was investigated. The conjugate addition of the thiol
to the unsaturated polymers was confirmed by 1H NMR
1
alkene group in PEU2b(Ph) is provided from the H NMR
peaks at 5.81 and 6.32 ppm (Figure 9). The alkene group can
I
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spectroscopy. Figure 9 shows the appearance of new signals
consistent with the corresponding functional groups. Addition-
ally, the characteristic peaks of the alkene groups in the H
that alkene functionalized diols synthesized from the Baylis−
Hillman reaction underwent step-growth polymerization to
provide polyesters and poly(ester urethane)s. The alkene group
can be further functionalized (pre- or postpolymerization) to
provide an additional functionality to the polymer.
The current work demonstrates the versatility of the Baylis−
Hillman based monomers for the synthesis of functionalized
polyacrylates, polyesters and poly(ester urethane)s. In addition
to the polymers demonstrated here, several other polymers can
also be synthesized by this strategy, including poly(α-
hydroxymethyl vinylphosphonic acid), poly(α-hydroxymethyl
acrylamide), and poly(α-hydroxymethyl acrylonitrile). Studies
directed toward the synthesis and use of such polymers are
currently underway in our laboratory.
1
NMR spectra have completely disappeared after the thiol−ene
reaction, which indicates quantitative conversion of the alkene
groups (Table 4). The glass transition temperatures (Tg) of the
functionalized polymers were determined by DSC (Table 5).
The addition of polar functional groups such as hydroxyl and
carboxyl groups leads to an increase in the glass transition
temperature. The Tg of PEU2b(Ph)-OH is 21 °C as compared
to 8 °C for the polymer before functionalization. The Tg of
PEU2b(Ph)-COOH is 22 °C.
Prefunctionalization and Subsequent Polymerization of
Functionalized Monomers. An alternative approach to provide
functionalized degradable polymers is the conjugate addition of
thiols to the unsaturated diols prior to polymerization. As a
proof-of-concept, the thiol−ene reactions of 2a(Pr) with 1-
butanethiol and 2b(Ph) with 1-dodecanethiol were inves-
tigated. The conjugate addition of thiols to the unsaturated diol
was carried out by irradiation at 350 nm for 30 min in the
presence of Irgacure 2959. The 1H NMR spectra of the
prefunctionalized diol monomers are shown in Figure 10.
The prefunctionalized diol monomers can be used to
synthesize poly(ester urethane)s by copolymerizing with
hexamethylene diisocyanate using Sn(Oct)2 as catalyst.
However, for the prefunctionalization method, the degree of
polymerization (DPn) of the poly(ester urethane) was much
lower (average of 16) (Table 6) compared to that for the
postfunctionalization method (average of 40). This relatively
low efficiency is probably the result of increased steric
hindrance present in the functionalized diol monomers. The
chemical structure of the poly(ester urethane)s was charac-
ASSOCIATED CONTENT
* Supporting Information
NMR, TGA, and DSC data. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*(A.J.) E-mail: abraham@uakron.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors express their gratitude to The University of Akron
for startup funding.
■
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■
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dx.doi.org/10.1021/ma4025416 | Macromolecules XXXX, XXX, XXX−XXX