Journal of the American Chemical Society
Article
Ozone was bubbled into the solution under stirring until the solution
turned into blue, and then the solution was purged with oxygen.
Dimethyl sulfide (10.0 mL, 137 mmol, 1.2 equiv) was then added
dropwise to quench the system. After being stirred for 5 h, and
warmed to room temperature, the solvent and the residual dimethyl
sulfide were removed by distillation at 70 °C under argon. A pale
yellow liquid (15.3 g, 52%) was obtained after distillation at 150 °C
(200 mbar) over P2O5. 1H NMR (400 MHz, CDCl3): δ 9.39 (s, 1H),
4.31 (t, J = 6.6 Hz, 2H), 1.68−1.76 (m, 2H), 1.37−1.47 (m, 2H), 0.94
(t, J = 7.4 Hz, 3H). 13C NMR (150 MHz, (CD3)2SO): δ 184.2, 159.7,
65.3, 30.0, 18.6, 13.4. MS calcd for [M + H]+ C6H11O3, 131.07082;
found, 131.07088.
rapid depolymerization than in films of pure PEtG. In contrast,
a control sample of micelles that was not irradiated underwent
less than 10% degradation over 24 h. Overall, this demonstrates
that the preparation of block copolymers of PEtG is also an
effective strategy for tuning the properties while at the same
time retaining stimuli-responsive degradation.
CONCLUSIONS
■
It was demonstrated for the first time that, through the use of
stimuli-responsive end-caps, polyglyoxylates serve as a new class
of self-immolative linear polymer backbones. The use of
chloroformates provides an effective end-capping strategy as
demonstrated by the preparation and study of a control PEtG
as well as a triggerable PEtG 4 with a UV light-cleavable end-
cap. This will allow a variety of end-caps responsive to different
stimuli to be incorporated into polyglyoxylates. It was also
shown that glyoxylates with various side chains can be prepared
by simple two-step synthetic processes starting from fumaric or
maleic acid, and these can be homopolymerized or copoly-
merized with EtG to provide materials with a range of
properties and molar masses. Furthermore, using a multifunc-
tional end-cap, it is possible to prepare glyoxylate-based triblock
copolymers, which provides an additional means of tuning
polymer properties. All of the above materials underwent
depolymerization to the expected products selectively upon
cleavage of the end-cap, while the untriggered polymers were
stable under the studied conditions. These new materials are
particularly attractive as the component monomers can be
derived not only from petroleum-based sources, but also from
renewable resources. In addition, while the toxicity of other
alcohol derivatives remains to be explored, PEtG depolymerizes
to ultimately provide the benign products glyoxylic acid hydrate
and ethanol. This should open many new prospects for the field
of self-immolative polymers. Future work will involve further
studies of the toxicity and properties of various polyglyoxyates
available through this chemistry as well as the development of
polyglyoxylate coatings and aqueous assemblies for controlled
release, sensing, and other applications.
Synthesis of Propargyl Amide 17. Compound 16 (580 mg, 2.9
mmol, 1.0 equiv) was dissolved in solvent (12 mL of 5:1
CH2Cl2:pyridine), and then EDC·HCl (690 mg, 3.5 mmol, 1.2
equiv), propargyl amine (1.1 mL, 17.7 mmol, 6 equiv), and DMAP
(430 mg, 3.5 mmol, 1.2 equiv) were added into the stirring mixture
under argon. After being stirred at room temperature for 6 h, the
reaction was diluted with ethyl acetate (60 mL) and washed with
saturated NaHCO3 solution (1 × 30 mL), 1 M HCl (3 × 30 mL), and
deionized water (1 × 30 mL) successively. The organic phase was
dried with MgSO4, filtered, and the solvent removed under reduced
1
pressure to yield compound 17 (395 mg, 57%) as a brown solid. H
NMR (400 MHz, (CD3)2SO): δ 9.26 (t, J = 5.3 Hz, 1H), 8.53 (d, J =
1.2 Hz, 1H), 8.22 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 7.94 (d, J = 7.6 Hz,
1H), 5.67 (t, J = 5.3 Hz, 1H), 4.87 (d, J = 5.3 Hz, 2H), 4.09 (dd, J =
5.3 Hz, 2.4 Hz, 2H), 3.16 (t, J = 2.4 Hz, 1H). 13C NMR (150 MHz,
(CD3)2SO): δ 163.7, 146.4, 141.6, 133.0, 132.0, 128.4, 123.1, 80.7,
73.0, 59.8, 28.6. MS calcd for [M]+: C11H10O4N2, 234.0641; found,
234.0642.
Synthesis of Chloroformate 18. Caution: Phosgene is a highly
toxic gas and must be handled with great care; refer to the MSDS
before using. Compound 17 (390 mg, 1.6 mmol, 1.0 equiv) was
dissolved in THF (7 mL). The resulting solution was then added
dropwise into a phosgene solution (15 wt % in toluene, 3.5 mL, 4.8
mmol, 3.0 equiv) under an argon atmosphere at room temperature
and was stirred for 40 h. The residual phosgene and solvent were then
removed by high vacuum to yield compound 18 (482 mg 98%) as a
brown solid. Phosgene collected in the liquid nitrogen-cooled trap was
then quenched with methanol (10 mL) and saturated sodium
1
hydroxide solution (10 mL). H NMR (400 MHz, CDCl3): δ 8.59
(d, J = 2.0 Hz, 1H), 8.17 (dd, J = 8.2 Hz, 2.0 Hz, 1H), 7.79 (d, J = 8.2
Hz, 1H), 6.36 (s, 1H), 5.81 (s, 2H), 4.31 (dd, J = 5.1 Hz, 2.3 Hz, 2H)
2.35 (t, J = 2.3 Hz, 1H). 13C NMR (150 MHz, CDCl3): δ 164.1, 150.6,
135.49, 133.4, 132.8, 132.3, 129.5, 124.1, 78.8, 72.8, 69.1, 30.4. MS
calcd for [M]+: C12H9O5N2Cl, 296.0200; found, 296.0201.
EXPERIMENTAL SECTION
■
Synthesis of PEtG 4 (Representative Polyglyoxylate Syn-
thesis). EtG in toluene solution (20 mL) was fractionally distilled
under vacuum (55 °C, 125 mbar) over P2O5 to remove toluene and
trace water in the first, discarded fraction. The residue was then
distilled twice successively over P2O5 at atmospheric pressure under
argon at 130 °C to obtain the highly pure monomer. The resulting
pale yellow liquid (5.0 mL, 50 mmol, 1.0 equiv) was dissolved in
CH2Cl2 (5.0 mL) and Et3N (3.5 μL, 25 μmol, 0.0005 equiv). The
solution was stirred for 1 h at −20 °C. NVOC-Cl (0.2 g, 730 μmol,
0.014 equiv) and Et3N (100 μL, 730 μmol, 0.014 equiv) were added at
0 °C to end-cap the polymer. The solution was then allowed to come
to room temperature and stirred for 24 h at room temperature and a
further 16 h at 40 °C. Purification was achieved by precipitation of the
crude reaction mixture into methanol. After decanting the excess
methanol, the residue was dried in vacuo for 48 h to provide 3.2 g of a
Study of PEtG 4 Degradation in Solution (General
Procedure for the Study of Polymer Degradation). PEtG 4
(15 mg) was dissolved into a 9:1 mixture of CD3CN:D2O (1.2 mL) at
ambient temperature (21 °C). The solution was then transferred into
two NMR tubes, and the tubes were promptly sealed. One tube was
exposed to UV light (wavelength: 300−350 nm, 5.3 mW cm−2) to
initiate the removal of the photolabile end-cap, and the absorbance at
340 nm was monitored by UV−vis spectroscopy to ensure the
complete deprotection of the polymer (approximately 80 min).
Another NMR tube was stored in a light-impermeable box over this
time, and was prepared as a control for any background polymer
1
degradation. H NMR spectra then were recorded at defined intervals
to monitor the depolymerization of the materials. At the same time,
polymer 3 also underwent the same irradiation and NMR study,
serving as a nontriggerable control. This same protocol was also
applied to study the degradation of polymers 11−15 and 21.
Mass Loss and SEC Degradation Study of PEtG 4 Films. PEtG
4 (3.0 g) was dissolved in CH2Cl2 (15 mL) and drop-cast onto 60
individual glass slides to provide films. After the solvent was
evaporated in vacuo for 48 h in a desiccator, the mass of each film
was recorded. Thirty films were placed into a UV box as described
above for 17 h to remove the end-cap. During this time, the remaining
slides were stored in the dark. Next, all of the slides were placed into a
phosphate buffer solution (100 mM, pH = 7.4) at ambient
1
white, sticky polymer in 62% yield. H NMR (400 MHz, CDCl3): δ
7.75 (s, 0.04H), 7.01 (s, 0.02H), 5.48−5.75 (m, 312H), 4.06−4.34 (m,
642H), 4.05 (s, 6H), 3.97 (s, 6H), 1.17−1.45 (m, 963H). 13C NMR
(150 MHz, CDCl3): δ 164.8−166.4, 148.1, 107.9, 90.1−94.0, 86.9,
66.7, 61.9, 56.5, 55.1, 13.7. FT-IR (KBr, thin film): 2985, 1757, 1448,
1377, 1022 cm−1. SEC: Mn = 53 kg/mol, Mw = 91 kg/mol, Đ = 1.7, Tg
= −9 °C.
Synthesis of n-BuG 9 (Representative Glyoxylate Synthesis).
Diester 6 (26.0 g, 114 mmol, 1.0 equiv) was dissolved in CH2Cl2 (300
mL), and the solution was cooled to −78 °C in a dry ice/acetone bath.
G
dx.doi.org/10.1021/ja504727u | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX