Poly(carbonate-amide)s derived from bio-based resources: Poly(ferulic acid-co-tyrosine)

Article abstract of DOI:10.1021/ma500454f

Ferulic acid (FA), a bio-based resource found in fruits and vegetables, was coupled with a hydroxyl-amino acid to generate a new class of monomers to afford poly(carbonate-amide)s with potential to degrade into natural products. L-Serine was first selected as the hydroxyl-amino partner for FA, from which the activated p-nitrophenyl carbonate monomer was synthesized. Unfortunately, polymerizations were unsuccessful, and the elimination product was systematically obtained. To avoid elimination, we revised our strategy and used L-tyrosine ethyl ester, which lacks an acidic proton on the α position of the ethyl ester. Four new monomers were synthesized and converted into the corresponding poly(carbonate-amide)s with specific regioselectivities. The polymers were fully characterized through thermal and spectroscopic analyses. Preliminary fluorescent studies revealed interesting photophysical properties for the monomers and their corresponding poly(carbonate-amide)s, beyond the fluorescence characteristics of L-tyrosine and FA, making these materials potentially viable for sensing and/or imaging applications, in addition to their attractiveness as engineering materials derived from renewable resources.

Full text of DOI:10.1021/ma500454f

Article
pubs.acs.org/Macromolecules
Poly(carbonate−amide)s Derived from Bio-Based Resources:
Poly(ferulic acid-co-tyrosine)
Amandine Noel, Yannick P. Borguet, Jeffery E. Raymond, and Karen L. Wooley*
Departments of Chemistry and Chemical Engineering and the Laboratory for Synthetic-Biologic Interactions, Texas A&M University,
College Station, Texas 77842-3012, United States
S
* Supporting Information
ABSTRACT: Ferulic acid (FA), a bio-based resource found in
fruits and vegetables, was coupled with a hydroxyl-amino acid
to generate a new class of monomers to afford poly-
(carbonate−amide)s with potential to degrade into natural
products. L-Serine was first selected as the hydroxyl-amino
partner for FA, from which the activated p-nitrophenyl
carbonate monomer was synthesized. Unfortunately, polymer-
izations were unsuccessful, and the elimination product was
systematically obtained. To avoid elimination, we revised our
strategy and used L-tyrosine ethyl ester, which lacks an acidic
proton on the α position of the ethyl ester. Four new monomers were synthesized and converted into the corresponding
poly(carbonate−amide)s with specific regioselectivities. The polymers were fully characterized through thermal and
spectroscopic analyses. Preliminary fluorescent studies revealed interesting photophysical properties for the monomers and
their corresponding poly(carbonate−amide)s, beyond the fluorescence characteristics of L-tyrosine and FA, making these
materials potentially viable for sensing and/or imaging applications, in addition to their attractiveness as engineering materials
derived from renewable resources.
tion of cereal-based products such as 1,4:3,6-isosorbide,11 and
INTRODUCTION
■
natural phenols to afford copolymers.12 Noteworthy, biorenew-
Polymers are pervasive throughout all aspects of the modern
age and, as described by Rolf Mulhaupt, “without polymers,
able-based polycarbonates have found applications as powder
̈
coating agents13 and as drug delivery vehicles.14,15 Previous
efforts from our lab have led to the synthesis of polycarbonates
derived from both carbohydrates16 and quinic acid.17 In an
effort to broaden the scope to natural products with biological
activities, the present paper describes the synthesis and
characterization of high value poly(carbonate−amide)s derived
from rather inexpensive ferulic acid and a hydroxyl-amino acid.
It was hypothesized that bio-based poly(carbonate−amide)s
derived from FA and a hydroxyl-containing amino acid would
possess interesting mechanical properties arising from the rigid
conjugated cinnamic acid core of FA and the H-bonding
potential of the amino acid component, while also having the
potential to undergo hydrolytic breakdown and lead to
biologically beneficial byproducts and carbon dioxide. Ferulic
acid (4-hydroxy-3-methoxycinnamic acid, FA) is a secondary
metabolite of the biosynthesis of lignin, derived from
phenylalanine and tyrosine via Shikimate pathway.18 It is
found in cereals (ca. 0.3 wt % in wheat bran), fruits, vegetables,
and plant tissues. FA can be naturally found in its free form, as
monomers, dimers, or polymers but also as esters formed by
condensation with hydroxyl acids, alcohols, or saccharides or as
modern life would be impossible because polymers secure the
high quality of life and serve as pacemakers for modern
technologies”.1 Consequently, the urge to find renewable
resources to reduce consumption of fossil fuel feedstocks,
decrease the use of energy intensive products, and solve
recycling and/or degradation issues has led to the investigation
of biopolymers. Additionally, the increase in fuel costs observed
over the past 30 years2 dictates a transition to polymeric
precursors that do not rely expressly on fossil fuels. However,
the full life cycle assessment of most bio-based polymers is not
well reported, and a focus on the environmental impacts of
biopolymers will be necessary.3 As unrecycled polymers end up
in the oceans (estimated 5 billion kg per year),4 water-
degradable polymers such as polycarbonates that degrade into
carbon dioxide and diols5 represent a reasonable class of
materials to investigate further.
Polycarbonates are mainly used where toughness, high
optical transparency, and solvent resistance are required.
Although more stable toward hydrolysis than their polyester
counterparts, polycarbonates are able to degrade in water and
are, thus, considered as aqueous degradable materials.6
Strategies for the use of renewables in polycarbonates include
polycondensation of feedstock products such as aliphatic diols,7
ring-opening polymerization of 6-membered cyclic carbonates,8
epoxides and carbon dioxide-based systems,9,10 polycondensa-
Received: February 28, 2014
Revised: April 9, 2014
Published: April 16, 2014
© 2014 American Chemical Society
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chromatography 0% to 100% of AcOEt in hexane over 40 min (80 g
silica cartridge). The solvent was removed to give the desired product
as a white foam (1.65 g, 4.28 mmol, 67%). FTIR (ATR) υmax (cm−1):
3600−3150, 1726, 1667, 1514. 1H NMR spectrum (500 MHz, CDCl3)
δ: 7.54 (d, J = 15.5 Hz, 1 H), 7.28 (d, J = 0.9 Hz, 1 H), 7.04−6.93 (m,
4 H), 6.89 (dd, J = 8.1, 0.9 Hz, 1 H), 6.78−6.73 (m, 2 H), 6.29−6.24
(m, 2 H), 6.07 (br s, 1 H), 4.99 (dtd, J = 6.7, 5.7, 1.0 Hz, 1 H), 4.21 (q,
J = 7.2, 2 H), 3.88 (s, 3 H), 3.16 (dd, J = 14.1, 5.7 Hz, 1 H), 3.08 (dd, J
= 14.1, 5.7 Hz, 1 H), 1.29 (t, J = 7.2, 3 H) ppm. 13C NMR spectrum
(125 MHz, CDCl3) δ: 172.0 (C), 166.0 (C), 155.3 (C), 147.6 (C),
146.7 (C), 142.1 (CH), 130.4 (2 CH), 127.3 (C), 127.0 (C), 122.5
(CH), 117.2 (CH), 115.5 (2 CH), 114.7 (CH), 109.6 (CH), 61.7
(CH2), 55.9 (CH3), 53.5 (CH), 37.2 (CH2), 14.2 (CH3) ppm. MS
(ESI+) m/z (%) 386.2 (100, [M + H]+). ESIHRMS calcd for
C21H24NO6 (M+H) 386.1604; found 386.1609; mp = 70 °C.
amides formed by condensation with amines. Because of its
antioxidant properties, FA exhibits a wide range of therapeutic
effects such as anticancer, antidiabetic, cardio-protective, neuro-
protective, and anti-inflammatory activities. It has also found
use as a food preservative18 and has shown antibacterial activity
against Gram-negative and -positive bacteria, including the
anthrax agent B. subtilis.20 Moreover, FA has been incorporated
into a biodegradable polymer as a pendant group to enhance
antioxidant properties, specifically for tissue engineering
applications.21,22 Reports of polymers containing FA in the
main chain include (co)polyesters,4,23,24 poly(anhydride−
ester),25 poly(ether ester)s,26,27 a methacrylic−FA copolymer,28
and a polyamide.29 To the best of our knowledge, no FA-based
polycarbonates have been reported to date.
S y n t h e s i s o f E t h y l ( S ) - 2 - A m i n o - 3 - ( 4 - ( ( t e r t -
butyldimethylsilyl)oxy)phenyl)propanoate (10). To a solution
of L-tyrosine ethyl ester chlorohydrate (5.4 g, 22.0 mmol) in THF
(110 mL) were added DMAP (536.8 mg, 4.4 mmol), Et3N (9.2 mL,
65.9 mmol), and TBDMSCl (8.3 g, 54.9 mmol). The reaction was
stirred at reflux for 3 h. After cooling down at room temperature, the
mixture was filtered and the filtrate was purified by flash
chromatography 0% to 100% of AcOEt in hexane over 40 min (80
g silica cartridge). The solvent was removed to give the desired
product as a colorless oil (5.8 g, 17.9 mmol, 81%). FTIR (ATR) υmax
(cm−1) 1732, 1510. 1H NMR spectrum (500 MHz, CDCl3) δ: 7.04 (d,
J = 8.4 Hz, 2 H), 6.76 (d, J = 8.4 Hz, 2 H), 4.15 (q, J = 7.1 Hz, 2 H),
3.66 (dd, J = 7.7, 5.5 Hz, 1 H), 3.00 (dd, J = 13.7, 5.5 Hz, 1 H), 2.81
(dd, J = 13.7, 7.7 Hz, 1 H), 1.24 (t, J = 7.1 Hz, 3 H), 0.97 (s, 9 H),
0.18 (s, 6 H) ppm. 13C NMR spectrum (125 MHz, CDCl3) δ: 175.1
(C), 154.5 (C), 130.2 (2 CH), 129.8 (C), 120.1 (2 CH), 60.9 (CH2),
55.9 (CH), 40.4 (CH2), 25.7 (3 CH3), 18.2 (C), 14.2 (CH3), −4.4 (2
CH3) ppm. MS (ESI+) m/z (%) 324.2 (100, [M + H]+). ESIHRMS
calcd for C17H30NO3Si (M+H) 324.1995; found 324.2004.
Synthesis of Ethyl (S,E)-3-(4-((tert-Butyldimethylsilyl)oxy)-
phenyl)-2-(3-(4-hydroxy-3-methoxyphenyl)acrylamido)-
propanoate (11). To a solution of 10 (5 g, 15.5 mmol) in CH2Cl2
(77 mL) were added ferulic acid (5 g, 15.5 mmol) and HOBt (2.1 g,
15.5 mmol). The reaction was cooled down at 0 °C and Et3N (4.3 mL,
31.0 mmol) and EDCI (2.4 g, 15.5 mmol). The reaction was stirred at
room temperature overnight. To the mixture was added a saturated
aqueous solution of NaHCO3 and the crude product was extracted
with CH2Cl2, dried over Na2SO4, and filtered. The solvent was
removed under vacuum, and the crude product was purified by flash
chromatography 0% to 50% of AcOEt in hexane over 50 min (120 g
silica cartridge). The solvent was removed to give the desired product
as a yellow foam with 10% of 10 (6.39 g, 12.8 mmol, 83%). FTIR
(ATR) υmax (cm−1) 3500−3150, 1732, 1657, 1593. 1H NMR spectrum
(500 MHz, CDCl3) 1H δ: 7.53 (d, J = 15.6 Hz, 1 H), 7.05−6.94 (m, 5
H), 6.88 (d, J = 8.4 Hz, 1 H), 6.74 (d, J = 8.4 Hz, 2 H), 6.25 (d, J =
15.6 Hz, 1 H), 6.19 (d, J = 7.8 Hz, 1 H), 4.96 (dt, J = 7.8, 5.7 Hz, 1 H),
4.17 (qd, J = 7.0, 1.8 Hz, 2 H), 3.88 (s, 3 H), 3.16−3.08 (m, 2 H), 1.25
(t, J = 7.1 Hz, 3 H), 0.96 (s, 9 H), 0.17 (s, 6 H) ppm. 13C NMR
spectrum (125 MHz, CDCl3) δ: 171.8 (C), 165.6 (C), 154.6 (C),
147.6 (C), 146.8 (C), 141.7 (CH), 130.3 (2 CH), 128.5 (C), 127.0
(C), 122.4 (CH), 120.0 (2 CH), 117.4 (CH), 114.8 (CH), 109.5
(CH), 61.5 (CH2), 55.8 (CH3), 53.4 (CH), 37.1 (CH2), 25.6 (3
CH3), 18.1 (C), 14.1 (CH3), −4.5 (2 CH3) ppm. MS (ESI+) m/z (%)
500.2 (100, [M + H]+); ESIHRMS calcd for C27H38NO6Si (M+H)
500.2468; found 500.2453; mp = 47 °C.
EXPERIMENTAL SECTION
■
Materials. All chemicals and reagents were used as received from
Sigma-Aldrich Co or VWR International. Caution: special precautions
should be taken when working with phosgene precursors, including
diphosgene and triphosgene. They are highly toxic by inhalation and
ingestion; use of personal protective equipment, including a
respiratory mask, is recommended. Tetrahydrofuran (THF) and
dichloromethane were purified by passage through solvent purification
system (JC Meyer Solvent Systems) and used as dried solvents.
Column chromatography was performed on a CombiFlash Rf4x
(Teledyne ISCO) with RediSep Rf Column (Teledyne ISCO).
1
Characterization. H and 13C NMR spectra were recorded on a
Varian Inova 500 spectrometer. Chemical shifts were referenced to the
solvent resonance signals. IR spectra were recorded on a Shimadzu IR
Prestige attenuated total reflectance Fourier-transform infrared
spectrometer (ATR-FTIR) and analyzed using IRsolution v. 1.40
software. Size exclusion chromatography (SEC) measurements were
performed on a Waters Chromatography Inc. (Milford, MA) system
equipped with an isocratic pump model 1515, a differential
refractometer model 2414, and a four-column set of 5 μm Guard
(50 × 7.5 mm), Styragel HR 4 5 μm DMF (300 × 7.5 mm), Styragel
HR 4E 5 μm DMF (300 × 7.5 mm), and Styragel HR 2 5 μm DMF
(300 × 7.5 mm) using DMF (0.05 M LiBr) as the eluent (1.00 mL/
min) at 70 °C. Polymer solutions were prepared at a concentration of
about 5 mg/mL and an injection volume of 200 μL was used. Data
collection and analysis were performed with Empower 2 v. 6.10.01.00
software (Waters, Inc.). The system was calibrated with poly(ethylene
oxide) standards (Polymer Laboratories, Amherst, MA) ranging from
106 to 174 000 Da, and an additional internal calibration based on the
oligomeric fraction was also realized (Supporting Information,
Methods to Monitor the Polymerizations). Glass transition temper-
atures (Tg) and melting points (mp) were measured by differential
scanning calorimetry (DSC) on a Mettler-Toledo DSC822 (Mettler-
Toledo, Inc., Columbus, OH) under N2. Measurements of Tg were
recorded with a heating rate of 15 °C/min, and those for mp were
recorded with a heating rate of 10 °C/min. The measurements were
analyzed using Mettler-Toledo Stare v.10.00 software. Thermogravi-
metric analysis (TGA) was performed under an Ar atmosphere using a
Mettler-Toledo model TGA/DSC 1, with a heating rate of 10 °C/min.
UV/vis measurements were acquired on a Shimadzu UV-2550
spectrophotometer. All steady-state emission, excitation, and 3 D
spectra were obtained with a Horiba FluoroMax4 with automatic
polarizers. Measurements were performed in DMF in matched quartz
cuvettes with path lenghts of 1 cm.
Synthesis of Ethyl (S,E)-3-(4-((tert-Butyldimethylsilyl)oxy)-
phenyl)-2-(3-(3-methoxy-4-(((4-nitrophenoxy)carbonyl)oxy)-
phenyl)acrylamido)propanoate (12). A solution of 11 (2.07 g,
4.14 mmol) and pyridine (3.1 mL, 6.2 mmol) in CH2Cl2 (12.5 mL)
was added dropwise to a solution of p-nitrophenyl chloroformate (1.69
g, 8.28 mmol) in CH2Cl2 (25.1 mL). The reaction was stirred at room
temperature for 7 h. Water was added, and the crude was extracted
with CH2Cl2, dried over Na2SO4, and filtered. The solvent was
removed under vacuum. The residue was purified by flash
chromatography on a silica cartridge (80 g, hexane/AcOEt 0 to 50%
Synthesis of (E)-N-(Feruloyl)-L-tyrosine (8). To a solution of
tyrosine ethyl ester hydrochloride (1.57 g, 6.39 mmol) in CH2Cl2 (23
mL) were added ferulic acid (1.97 g, 6.39 mmol) and HOBt (863.3
mg, 6.39 mmol). The reaction was cooled down at 0 °C, and Et3N (2.7
mL, 19.17 mmol) and EDCI (992 mg, 6.39 mmol) were added. The
reaction was stirred at room temperature overnight. To the mixture
was added a saturated aqueous solution of NaHCO3, and the crude
product was extracted with CH2Cl2, dried over Na2SO4, and filtered.
The solvent was removed, and the crude product was purified by flash
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Macromolecules
Article
over 30 min). The desired product was obtained as a yellow foam
(1.95 g, 2.93 mmol, 71%). FTIR υmax (cm−1) 1784, 1738, 1624, 1509.
1H NMR spectrum (500 MHz, CDCl3) δ: 8.30 (d, J = 9.2 Hz, 2 H),
warmed slowly to room temperature and reacted overnight. The salts
and activated charcoal were removed by filtration, and the solvent was
removed under vacuum. The product was purified by flash
chromatography (24 g, 0% to 50% of AcOEt in hexane over 20
min) to lead to a white foam (492.8 mg, 0.88 mmol, 82%). FTIR
(ATR) υmax (cm−1): 1790, 1738, 1659, 1632, 1510. 1H NMR spectrum
(500 MHz, CDCl3) δ: 7.57 (d, J = 15.6 Hz, 1 H), 7.15 (d, J = 8.7 Hz, 1
H), 7.13−7.06 (m, 2 H), 6.97 (d, J = 8.4 Hz, 2 H), 6.75 (d, J = 8.4 Hz,
2 H), 6.36 (d, J = 15.6 Hz, 1 H), 6.12 (d, J = 7.7 Hz, 1 H), 4.96 (dt, J =
7.7, 5.6 Hz, 1 H), 4.20 (q, J = 7.2 Hz, 2 H), 3.91 (s, 3 H), 3.14 (dd, J =
5.6, 2.6 Hz, 2 H), 1.28 (t, J = 7.1 Hz, 3 H), 0.97 (s, 9 H), 0.17 (s, 6 H)
ppm. 13C NMR spectrum (125 MHz, CDCl3) δ: 171.6 (C), 164.7 (C),
154.8 (C), 150.7 (C), 148.9 (C), 141.5 (C), 140.4 (C), 135.0 (CH),
130.4 (2 CH), 128.3 (C), 122.1 (CH), 121.3 (CH), 120.7 (CH),
120.1 (2 CH), 111.5 (CH), 61.6 (CH2), 56.1 (CH3), 53.4 (CH), 37.1
(CH2), 25.6 (3 CH3), 18.2 (C), 14.2 (CH3), −4.4 (2 CH3) ppm.
Synthesis of AA′AA′ Polymer from 14. In the glovebox, a
mixture of 14 (198 mg, 0.35 mmol) and AgF (89.4 mg, 0.70 mmol)
was prepared. Then outside of the glovebox, acetonitrile (0.14 mL)
and pyridine (0.56 mL) were added. The mixture was ventilated with a
cartridge containing NaOH to quench fumes of phosgene. The
reaction mixture was stirred at room temperature for 15 min and was
quenched with a saturated solution of NaHCO3. The mixture was
solubilized in DMF, filtered through a pad of Celite, then precipitated
out into MeOH three times, and dried under vacuum to give the
desired product as a white solid which follows A′AAA′, AA′A′A,
AA′AA′ patterns in 5/5/90 proportions (80.9 mg, 0.20 mmol, 57%).
DMF SEC: Mn = 8.3 kg mol−1, Đ = 2.08. FTIR (ATR) υmax (cm−1):
7.57 (d, J = 15.5 Hz, 1 H), 7.48 (d, J = 9.2 Hz, 2 H), 7.21 (d, J = 8.7
Hz, 1 H), 7.15−7.09 (m, 2 H), 6.98 (d, J = 8.4 Hz, 2 H), 6.75 (d, J =
8.4 Hz, 2 H), 6.37 (d, J = 15.5 Hz, 1 H), 6.22 (d, J = 7.8 Hz, 1 H), 4.96
(dt, J = 7.8, 5.6 Hz, 1 H), 4.19 (qd, J = 7.1, 2.6 Hz, 2 H), 3.93 (s, 3 H),
3.21−3.05 (m, 2 H), 1.27 (t, J = 7.1 Hz, 3 H), 0.96 (s, 9 H), 0.17 (s, 6
H) ppm. 13C NMR spectrum (125 MHz, CDCl3) δ: 171.7 (C), 164.8
(C), 155.4 (C), 154.7 (C), 151.0 (C), 150.2 (C), 145.5 (C), 140.55
(C), 140.50 (CH), 134.5 (C), 130.3 (2 CH), 128.4 (C), 125.4 (2
CH), 122.3 (CH), 121.6 (2 CH), 121.0 (CH), 120.8 (CH), 120.1 (2
CH), 111.5 (CH), 61.6 (CH2), 56.1 (CH3), 53.4 (CH), 37.1 (CH2),
25.6 (3 CH3), 18.1 (C), 14.2 (CH3), −4.5 (2 CH3) ppm; MS (ESI+)
m/z (%) 665.3 (100, [M + H]+). ESIHRMS calcd for C34H41N2O10Si
(M + H) 665.2530; found 665.2519; mp = 56 °C.
Synthesis of Ethyl (E)-(3-(3-Methoxy-4-(((4-nitrophenoxy)-
carbonyl)oxy)phenyl)acryloyl)-L-tyrosinate (13). To a solution of
12 (1.74 g, 2.74 mmol) in CH2Cl2 (13.7 mL) was added dropwise
BF3·OEt2 (0.69 mL, 5.48 mmol). The reaction was stirred at room
temperature for 23 h. A saturated solution of NaHCO3 was added, and
the crude was extracted with CH2Cl2, dried over Na2SO4, and filtered.
The solvent was removed under vacuum. The residue was purified by
flash chromatography on a silica cartridge (120 g, hexane/AcOEt 0 to
100% over 40 min). The desired product was obtained as a white foam
(1.28 g, 2.33 mmol, 85%). FTIR (ATR) υmax (cm−1) 3300−3150,
1
1782, 1732, 1661, 1514. H NMR spectrum (500 MHz, CDCl3) δ:
8.27 (d, J = 9.2 Hz, 2 H), 7.52 (d, J = 15.6 Hz, 1 H), 7.45 (d, J = 9.2
Hz, 2 H), 7.15 (d, J = 8.7 Hz, 1 H), 7.11 (br s, 1 H), 7.03−7.02 (m, 2
H), 6.95 (d, J = 8.4 Hz, 2 H), 6.72 (d, J = 8.4 Hz, 2 H), 6.51 (d, J = 7.9
Hz, 1 H), 6.37 (d, J = 15.6 Hz, 1 H), 4.96 (dt, J = 8.0, 5.7 Hz, 1 H),
4.23−4.16 (m, 2 H), 3.86 (s, 3 H), 3.13 (dd, J = 14.1, 5.7 Hz, 1 H),
3.03 (dd, J = 14.1, 6.2 Hz, 1 H), 1.26 (t, J = 7.1 Hz, 3 H) ppm. 13C
NMR spectrum (125 MHz, CDCl3) δ: 171.9 (C), 165.5 (C), 155.5
(C), 155.3 (C), 150.9 (C),150.3 (C), 145.5 (C), 140.9 (C), 140.5
(CH), 134.3 (C), 130.3 (2 CH), 127.0 (C), 125.3 (2 CH), 122.3
(CH), 121.6 (2 CH), 120.74 (CH), 120.67 (CH), 115.5 (2 CH),
111.6 (CH), 61.8 (CH2), 56.0 (CH3), 53.7 (CH), 37.0 (CH2), 14.1
(CH3) ppm. MS (ESI+) m/z (%) 551.2 (100, [M + H]+). ESIHRMS
calcd for C28H27N2O10 (M + H) 551.1666; found 551.1654.
Synthesis of AA′AA′ Polymer from 13. To a solution of 13
(702 mg, 1.27 mmol) in pyridine (0.42 mL) was added dropwise
triethylamine (0.36 mL, 2.55 mmol). The mixture was stirred at room
temperature for 5 h and was quenched with a saturated solution of
NaHCO3. The product was extracted with CH2Cl2 and dried over
Na2SO4, and the solvent was removed. The mixture was solubilized in
CH2Cl2, precipitated into MeOH three times, and dried under vacuum
to give the desired product as a yellowish solid which follows A′AAA′,
AA′A′A, AA′AA′ patterns in 22/15/63 proportions (389.5 mg, 0.94
mmol, 74%). DMF SEC: Mn = 5.8 kg mol−1, Đ = 1.43. FTIR (ATR)
υmax (cm−1) 3400−3200, 1778, 1736, 1661, 1624, 1508. 1H NMR
spectrum (500 MHz, CDCl3) δ: 7.61−7.51 (m, 14 H), 7.23−7.20 (m,
98 H), 6.43−6.23 (m, 28 H), 5.00 (br s, 14 H), 4.23−4.14 (m, 28 H),
3.87 (br s, 42 H), 3.27−3.13 (m, 28 H), 1.32−1.10 (m, 42 H) ppm.
13C NMR spectrum (125 MHz, CDCl3) δ: 171.5 (14 C), 165.1 (14
C), 152.0 (3.1 C(O)A′AAA′), 151.3 (8.8 CAA′AA′), 151.22 (5.2 CAAA′A′),
151.16 (8.8 C(O)AA′AA′), 150.7 (2.1 C(O)AA′A′A), 150.2 (8.8 CAA′AA′),
150.0 (5.2 CAAA′A′) 141.1, 141.0, 140.9 (14 CH + 14 C), 134.2, 134.1,
134.0 (28 C), 130.52, 130.49 (28 CH), 122.6 (8.8 CHAA′AA′), 122.5
(5.2 CHAAA′A′), 120.94, 120.89, 120.8 (28 CH), 120.6 (14 CH), 111.5
(5.2 CHAAA′A′), 111.4 (8.2 CHAA′AA′), 61.7 (14 CH2), 56.1 (14 CH3),
53.3 (14 CH), 37.2 (14 CH2), 14.2 (14 CH3) ppm. Tg = 134 °C; Tp =
350 °C.
Synthesis of Ethyl (S,E)-3-(4-((tert-Butyldimethylsilyl)oxy)-
phenyl)-2-(3-(4-((chlorocarbonyl)oxy)-3-methoxyphenyl)-
acrylamido)propanoate (14). To a solution of 11 (532.5 mg, 1.07
mmol) in CH2Cl2 (12 mL) were added diphosgene (79 μL, 0.66
mmol) and a catalytic amount of activated charcoal. The solution was
cooled to −45 °C, and N,N-dimethylaniline (0.24 mL, 1.92 mmol) was
added dropwise. The reaction was allowed to stir at −45 °C and then
1
3300−3200, 1789, 1737, 1659, 1622, 1510. H NMR spectrum (500
MHz, d6-DMSO) δ: 8.67−8.47 (m, 20 H), 7.57−7.12 (m, 160 H),
6.72 (d, J = 15.9 Hz, 20 H), 4.68−4.54 (m, 20 H), 4.18−3.98 (m, 40
H), 3.89 (br s, 60 H), 3.20−2.86 (m, 40 H), 1.35−0.94 (m, 60 H)
ppm. 13C NMR spectrum (125 MHz, d6-DMSO) δ: 171.5 (20 C),
164.9 (20 C), 151.7 (2 C(O)A′AAA′), 150.94 (16 CAA′AA′), 150.88 (4
C
AAA′A′), 150.8 (16 C(O)AA′AA′), 150.4 (2 CAA′A′A), 149.4 (20 C),
140.1 (20 C), 138.8 (20 CH), 135.5 (16 CAA′AA′), 135.4 (4 CAAA′A′),
134.5 (16 CAA′AA′), 134.4 (4 CAAA′A′), 130.4 (32 CHAA′AA′), 130.3 (8
CHAAA′A′), 122.7 (20 CH), 122.1 (20 CH), 121.0 (8 CHAAA′A′), 120.8
(32 CHAA′AA′), 120.3 (20 CH), 111.8 (20 CH), 60.6 (20 CH2), 56.05
(20 CH3), 53.8 (20 CH), 36.1 (20 CH2), 14.0 (20 CH3) ppm. Tg =
129 °C, Tp = 337 °C.
Synthesis of Diethyl 2,2′-(((2E,2′E)-3,3′-((Carbonylbis(oxy))-
bis(3-methoxy-4,1-phenylene))bis(acryloyl))bis(azanediyl))-
(2S,2′S)-bis(3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-
propanoate) (15). To a solution of 11 (1.1 g, 2.2 mmol) and 4-
nitrophenyl chloroformate (225.2 mg, 1.1 mmol) in CH2Cl2 (2.2 mL),
at room temperature was added Et3N (0.46 mL, 3.3 mmol). The
reaction was stirred at room temperature overnight. The solvent was
removed under vacuum. The residue was purified by flash
chromatography on a silica cartridge (40 g, hexane/AcOEt 0 to 60%
over 30 min). The desired product was obtained as a white foam
(657.8 mg, 0.64 mmol, 58%, brm: 84%). FTIR (ATR) υmax (cm−1):
1
1782, 1732, 1667, 1508. H NMR spectrum (500 MHz, CDCl3) δ:
7.54 (d, J = 15.6 Hz, 2 H), 7.20 (d, J = 8.7 Hz, 2 H), 7.08−7.05 (m, 4
H), 6.99 (d, J = 8.4 Hz, 4 H), 6.75 (d, J = 8.4 Hz, 4 H), 6.37 (d, J = 7.1
Hz, 2 H), 6.36 (d, J = 15.6 Hz, 2 H), 4.95 (dt, J = 7.9, 5.8 Hz, 2 H),
4.18 (qd, J = 7.1, 2.3 Hz, 4 H), 3.90 (s, 6 H), 3.18−3.01 (m, 4 H), 1.26
(t, J = 7.1 Hz, 6 H), 0.96 (s, 18 H), 0.16 (s, 12 H) ppm. 13C NMR
spectrum (125 MHz, CDCl3) δ: 171.4 (2 C), 154.7 (2 C), 151.2 (2
C), 150.7 (C), 141.0 (2 C), 140.7 (2 CH), 134.1 (2 C), 130.3 (4 CH),
128.4 (2 C), 122.5 (2 CH), 120.7 (2 CH), 120.6 (2 CH), 120.0 (4
CH), 111.5 (2 CH), 61.5 (2 CH2), 56.0 (2 CH3), 53.5 (2 CH), 37.0
(2 CH2), 25.6 (6 CH3), 18.1 (2 C), 14.1 (2 CH3), −4.5 (6 CH3) ppm.
MS (ESI+/MALDI) m/z (%) not detected.
Synthesis of Ethyl (S)-3-(4-(λ-Oxidanyl)phenyl)-2-((E)-3-(4-
(((4-((E)-3-(((S)-1-ethoxy-3-(4-hydroxyphenyl)-1-oxopropan-2-
yl)amino)-3-oxoprop-1-en-1-yl)-2-methoxyphenoxy)-
carbonyl)oxy)-3-methoxyphenyl)acrylamido)propanoate (16).
To a solution of 15 (4.76 g, 4.93 mmol) in CH2Cl2 (25 mL) was
added dropwise BF3·OEt2 (2.5 mL, 19.7 mmol). The reaction was
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stirred at room temperature for 23 h. A saturated solution of NaHCO3
was added, and the crude was extracted with CH2Cl2, dried over
Na2SO4, and filtered. The solvent was removed under vacuum. The
residue was purified by flash chromatography on a silica cartridge (4 g,
hexane/AcOEt 0 to 100% over 15 min). The desired product was
obtained as a white foam (2.55 g, 3.2 mmol, 65%). FTIR (ATR) υmax
(cm−1): 3600−3100, 1784, 1738, 1661, 1614, 1512. 1H NMR
spectrum (500 MHz, d8-THF) δ: 8.18 (s, 2 H), 7.53 (d, J = 15.6
Hz, 2 H), 7.46 (d, J = 8.0 Hz, 2 H), 7.26 (d, J = 1.8 Hz, 2 H), 7.17 (d, J
= 8.2 Hz, 2 H), 7.12 (dd, J = 8.2, 1.8 Hz, 2 H), 6.97 (d, J = 8.4 Hz, 4
H), 6.66−6.59 (m, 6 H), 4.83 (dt, J = 8.0, 6.3 Hz, 2 H), 4.11 (q, J = 7.1
Hz, 4 H), 3.88 (s, 6 H), 3.05 (dd, J = 13.9, 6.3 Hz, 2 H), 2.96 (dd, J =
13.9, 6.7 Hz, 2 H), 1.20 (t, J = 7.1 Hz, 6 H) ppm. 13C NMR spectrum
(125 MHz, d8-THF) δ: 172.2 (2 C), 165.3 (2 C), 157.3 (2 C), 152.3
(2 C), 151.1 (C),141.8 (2 C), 140.0 (2 CH), 135.6 (2 C), 130.8 (4
CH), 127.9 (2 C), 123.0 (2 CH), 122.4 (2 CH), 120.7 (2 CH), 115.7
(4 CH), 112.4 (2 CH), 61.3 (2 CH2), 56.01 (2 CH3), 54.5 (2 CH),
7.22−6.93 (m, 238 H), 6.47−6.22 (m, 72 H), 5.04−4.93 (m, 36 H),
4.18 (br q, J = 7.2, 6.5 Hz, 72 H), 3.86 (br s, 108 H), 3.28−3.11 (m, 72
1
H), 1.42- 1.02 (m, 108 H) ppm. H NMR spectrum (500 MHz, d6-
DMSO) δ: 8.60 (br d, J = 7.7 Hz, 36 H), 7.47−7.15 (m, 252 H),
6.76−6.65 (m, 72 H), 4.64−4.57 (m, 36 H), 4.10−4.01 (m,72 H),
3.89 (br s, 108 H), 3.17−2.93 (m, 72 H), 1.11 (br t, J = 7.1 Hz, 108
H) ppm. 13C NMR spectrum (125 MHz, CDCl3) δ: 171.5 (36 C),
165.1 (36 C), 152.0 (8.3 C(O)A′AAA′), 151.3 (14.4 CAA′AA′), 151.1
(21.6 CAAA′A′), 150.7 (14.4 C(O)AA′AA′), 150.2 (13.3 C(O)AA′A′A),
150.0 (36 C), 141.1, 141.0, 140.9 (36 CH + 36 C), 134.1, 134.0 (72
C), 130.52, 130.49 (72 CH), 122.6 (14.4 CHAA′AA′), 122.5 (21.6
CHAAA′A′), 120.94, 120.89, 120.8 (72 CH), 120.6 (36 CH), 111.4
(21.6 CHAAA′A′), 61.8 (36 CH2), 56.1 (21.6 CH3AAA′A′), 56.0 (14.4
CH3AA′AA′), 53.3 (36 CH), 37.2 (36 CH2), 14.2 (36 CH3) ppm. 13C
NMR spectrum (125 MHz, d6-DMSO) δ: 171.4 (34 C), 165.9 (34 C),
151.6 (8.3 C(O)A′AAA′), 150.93 (14.4 CAA′AA′), 150.87 (21.6 CAAA′A′),
150.8 (14.4 C(O)AA′AA′), 150.3 (13.3 C(O)AA′A′A), 149.4 (36 C), 140.1
(36 C), 138.7 (36 C), 135.5 (14.4 CAA′AA′), 135.4 (21.6 CAAA′A′),
134.44 (14.4 CAA′AA′), 134.38 (21.6 CAAA′A′), 130.4 (28.8 CHAA′AA′),
130.3 (43.2 CHAAA′A′), 122.6 (36 CH), 122.1 (36 CH), 121.0 (43.2
CHAAA′A′), 120.8 (28.8 CHAA′AA′), 120.3 (36 CH), 111.9 (21.6
CHAAA′A′), 111.8 (14.4 CHAA′AA′), 60.6 (36 CH2), 56.1 (36 CH3), 53.8
(36 CH), 36.1 (36 CH2), 14.0 (36 CH3) ppm. Tg = 135 °C, Tp = 343
°C.
1
37.7 (2 CH2), 14.3 (2 CH3) ppm. H NMR spectrum (500 MHz, d6-
DMSO) δ: 9.24 (s, 2 H), 8.48 (d, J = 7.7 Hz, 2 H), 7.44−7.37 (m, 4
H), 7.34 (d, J = 8.2 Hz, 2 H), 7.21 (dd, J = 8.4, 1.8 Hz, 2 H), 7.02 (d, J
= 8.5 Hz, 4 H), 6.74 (d, J = 15.8 Hz, 2 H), 6.66 (d, J = 8.5 Hz, 4 H),
4.52 (ddd, J = 8.8, 7.7, 5.8 Hz, 2 H), 4.06 (q, J = 7.1 Hz, 4 H), 3.91 (s,
6 H), 2.95 (dd, J = 13.9, 5.8 Hz, 2 H), 2.86 (dd, J = 13.9, 8.8 Hz, 2 H),
1.13 (t, J = 7.1 Hz, 6 H) ppm. 13C NMR spectrum (125 MHz, d6-
DMSO) δ: 171.7 (2 C), 164.8 (2 C), 156.0 (2 C), 150.9 (2 C), 150.4
(C(O)AA′A′A),140.1 (2 C), 138.6 (2 CH), 134.5 (2 C), 130.0 (4 CH),
127.0 (2 C), 122.7 (2 CH), 122.3 (2 CH), 120.3 (2 CH), 115.1 (4
CH), 111.9 (2 CH), 60.5 (2 CH2), 56.1 (2 CH3), 54.2 (2 CH), 36.2
(2 CH2), 14.0 (2 CH3) ppm. MS (ESI+/APCI/MALDI) m/z not
detected.
RESULTS AND DISCUSSION
■
We envisioned that the poly(carbonate−amide)s could be
synthesized readily either by copolycondensation of a diol with
a phosgene derivative or by homopolycondensation of an AB
monomer obtained by prior conversion of one of the alcohol
groups to an activated carbonate or chloroformate. The
required diol monomer would first be obtained by coupling
FA to a hydroxyl-containing amino acid by means of a peptidic
bond (Scheme 1). This approach would enable degradation to
Synthesis of A′AAA′A′AAA′ Polymer from 16. To a solution of
16 (122.1 mg, 0.15 mmol) in pyridine (0.60 mL) at 0 °C was added
dropwise diphosgene (21 μL, 0.17 mmol). The mixture was ventilated
with a cartridge containing NaOH to quench fumes of phosgene. The
reaction mixture was stirred at room temperature for 2 h and was
quenched with a saturated solution of NaHCO3. The product was an
orange gel which was solubilized in warm DMF/DMSO mixture and
precipitated out into MeOH three times and dried under vacuum to
give the desired product as a white/yellowish solid which follows an
AAA′A′ pattern (91.3 mg, 0.11 mmol, 73%). DMF SEC: Mn = 18.6 kg
mol−1, Đ = 2.06. FTIR (ATR) υmax (cm−1): 3400−3200, 1776, 1736,
1667, 1625, 1601, 1504. 1H NMR spectrum (500 MHz, d6-DMSO) δ:
8.60 (d, J = 7.6 Hz, 45 H), 7.42 (d, J = 15.6 Hz, 45 H), 7.41−7.24 (m,
315 H), 7.24−7.17 (m, 45 H), 6.72 (d, J = 15.8 Hz, 45 H), 4.61 (q, J =
7.8 Hz, 45 H), 4.06 (q, J = 6.8 Hz, 90 H), 3.90 (s, 135 H), 3.14−2.95
(m, 90 H), 1.11 (t, J = 7.1 Hz, 135 H) ppm. 13C NMR spectrum (125
MHz, d6-DMSO) δ: 171.5 (45 C), 164.9 (45 C), 151.7 (23
C(O)A′AAA′), 150.9 (45 C), 150.4 (22 C(O)AA′A′A), 149.4 (45 C),
140.1 (45 C), 138.8 (45 CH), 135.4 (45 C), 134.5 (45 C), 130.3 (90
CH), 122.7 (45 CH), 122.1 (45 CH), 121.0 (90 CH), 120.3 (45 CH),
112.0 (45 CH), 60.6 (45 CH2), 56.08, 56.06 (45 CH3), 53.8 (45 CH),
36.1 (45 CH2), 14.0 (45 CH3) ppm. Tg = 130 °C, Tp = 343 °C.
Synthesis of the Random Polymer from 8. To a solution of 8
(70.3 mg, 0.18 mmol) in pyridine (0.34 mL) at 0 °C was added
dropwise diphosgene (12 μL, 0.10 mmol). The mixture was ventilated
with a cartridge containing NaOH to quench fumes of phosgene. The
reaction mixture was stirred at room temperature for 15 h and was
quenched with a saturated solution of NaHCO3. The product was
extracted with CH2Cl2 and dried over Na2SO4, and the solvent was
removed under vacuum. The brown film formed was solubilized in
CH2Cl2, precipitated into MeOH three times, and dried under vacuum
to give the desired product as a brownish solid which follows AA′A′A,
A′AAA′, AA′AA′ patterns in 37/23/40 proportions (35.4 mg, 0.086
mmol, 48%). During the reaction, a yellow solid part was formed,
insoluble in CH2Cl2, CHCl3, pyridine, DMF, DMSO, acetone, and
H2O even after sonication and heating. This insoluble fraction could
not be analyzed and consequently may explain the lower yield
observed. DMF SEC: Mn = 14.8 kDa, Đ = 2.57. FTIR (ATR) υmax
(cm−1): 3400−3200, 1778, 1732, 1666, 1628, 1504. 1H NMR
spectrum (500 MHz, CDCl3) δ: 7.53 (br d, J = 15.0 Hz, 36 H),
Scheme 1. Peptidic Coupling between FA and Protected
Hydroxyl-Amino Acids
occur via two distinct pathways: aqueous hydrolysis of the
carbonate bond and enzymatic cleavage of the amide bond.30
Among the naturally occurring amino acids, serine, with its
more reactive primary alcohol, was expected to be the most
attractive coupling partner, followed by threonine, which
contains a less reactive secondary alcohol, and finally tyrosine,
which features a phenolic functionality that could lead to
solubility issues for high molecular weight polymers.
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Scheme 2. Synthesis of the Activated AB Monomer 4 and Attempted Polymerization, with Instead the Product from Elimination
Being Formed
First Strategy: FA−Serine Poly(carbonate−amide)
Precursor. An AB monomer activated as a p-nitrophenyl
carbonate 4 was initially designed, as the polymerization of
similar species has been reported in the literature.31 This
monomer was preferred to its more reactive chloroformate
analogue because the synthesis of the latter requires the
manipulation of phosgene derivatives.
proton on the α-carbon of the amino acid residue, favoring the
elimination pathway. Therefore, the choice of the hydroxyl-
amino acid was reconsidered.
Second Strategy: FA−Tyrosine Poly(carbonate−
amide) Precursors. Tyrosine was selected over threonine in
order to avoid any possible side reaction on the α-carbon of the
amino acid residue in the activated monomer. In an attempt to
minimize the toxicity of the products potentially released
during degradation of the polymers, the commercially available
L-tyrosine ethyl ester, which would generate ethanol upon
hydrolysis, was used as a starting building block (rather than
use of a methyl ester that would generate methanol).
Interestingly, the natural amides (E)-N-(feruloyl)-L-tyrosine
methyl ester 6 and tert-butyl ester 7 have already been
synthesized and tested biologically (Figure 1).33 A stronger
The monomer synthesis began from the commercially
available L-serine, which was protected as its ethyl ester. The
esterification resulted in 1 (92%).32 This protection step was
necessary to selectively convert the hydroxyl group to a silyl
ether derivative and also for the later selective amidation with
ferulic acid (Scheme 2). The TBDMS protecting group is
cleavable under mild acidic conditions and was chosen for its
stability under basic conditions used in the following steps. A
peptidic coupling of this intermediate with ferulic acid
generated 2 in two steps (51%). The structure was confirmed
by the presence of a signal attributed to the quaternary carbon
peak of the amide by 13C NMR (165.8 ppm) and by FTIR
(1658 cm−1) spectroscopies. The p-nitrophenyl carbonate 3
was synthesized in 84% yield by reaction of the phenol with p-
nitrophenyl chloroformate in the presence of pyridine.
Subsequent deprotection by boron trifluoride provided the
activated AB monomer 4 (88%). Formation of the carbonate
link in 3 and 4 was confirmed by both 13C NMR (150.3 ppm)
and FTIR (1778, 1784 cm−1) spectroscopies. A doublet of
1
Figure 1. Structures of the known 6, 7, and the new 8.
triplets at 2.49 ppm by H NMR spectroscopy, as well as a
broad band around 3200−3400 cm−1 by FTIR spectroscopy,
confirmed the presence of a free alcohol in 4. Experimental
details are reported in the Supporting Information.
antioxidant effect was revealed for the more sterically hindered
tert-butyl ester when compared with the methyl ester, and both
surpassed ferulic acid in lipid peroxidation assays.33 The
anticipated hydrolytic degradation product of a FA−tyrosine-
based poly(carbonate−amide) system, (E)-N-(feruloyl)-L-tyro-
sine ethyl ester 8 (Figure 1), may, therefore, present a
bioactivity similar to its methyl and tert-butyl counterparts.
Based upon this strategy, a series of four monomers were
synthesized, having functionalities installed that would allow for
condensation polymerization via carbonate formation and
including regiochemistries that would produce either head-to-
tail, tail-to-head-to-head-to-tail, or random sequences in the
resulting poly(carbonate−amide)s.
Unfortunately, rather than undergoing polymerization, 4 led
to an elimination product 5 upon treatment with base. No
reaction occurred during our first attempt at polymerizing
monomer 4 in the presence of pyridine, and the starting
material was recovered unchanged. The use of a stronger base,
triethylamine, did not lead to a polymer either. Instead, the
elimination product 5 was obtained. Further details confirming
the structure of the former compound are presented in the
Supporting Information.
Alternatively, the introduction of the activated p-nitrophenyl
carbonate on the primary alcohol of the serine residue was not
attempted. We reasoned that the presence of such an electron-
withdrawing group would most likely enhance the acidity of the
BA′ Monomers: Targeting an AA′AA′ (Head-to-Tail)
Polymer Regiochemistry. A monoactivated BA′ monomer
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Scheme 3. Synthesis of BA′ Monomers Activated with p-Nitrophenyl Carbonate (13) and Chloroformate (14) Functionalities
was initially designed in order to synthesize a regioregular
AA′AA′ (head-to-tail) polymer, where A is the phenol of FA, A′
is the phenol of tyrosine, and B is an activated carbonate or
chloroformate derivative of the FA phenol. The p-nitrophenyl
carbonate BA′ monomer 13 was targeted first using the same
synthetic pathway as described above for 4. The phenol group
of the tyrosine ethyl ester hydrochloride 9 was protected with
TBDMSCl, resulting in 10 (81%).34 A peptidic coupling
between 10 and FA generated 11 (83%). The free alcohol of 11
was activated to a p-nitrophenyl carbonate 12 in the presence of
pyridine (71%). Finally, the deprotection of 12 under mild
conditions afforded the activated BA′ monomer 13 in high
yield (85%). 13C NMR and FTIR spectroscopies confirmed
both the formation of the carbonate and the deprotection of
the phenol group (Scheme 3).
Polymerizations were conducted in the presence of a base to
generate the nucleophilic phenoxide group. Optimization of the
experimental conditions was performed through variation of the
solvents (CH2Cl2 and pyridine), the initial monomer
concentration (1 M, 3 M), the base (Et3N, pyridine, DIPEA,
DMAP or a mixture), the reaction times (5 to 72 h), and
temperatures (rt, 50 °C, 95 °C). The outcomes of the reactions
were evaluated in terms of the final degree of polymerization
(DPn), as determined by SEC. The reliability of the number-
average molecular weights (Mn) determined against PEO
calibration was confirmed by comparison with the Mn obtained
from a relative calibration performed from the oligomeric
fraction contained in the crude polymerization mixture (Table
S1, see details in Supporting Information). Also, chain-end
functionalization of the polymers with reactive capping agents
(allylchloroformate and furfuryl isocyanate) and their sub-
sequent analysis by 1H NMR spectroscopy gave further support
to the DPn values that are reported and also revealed that the
primary component of the system is an acyclic polymer (see
details in Supporting Information). Despite parametrization, all
the reactions resulted in polymers with DPn values limited to a
range of 15−20, according to SEC and 1H NMR spectroscopic
measurements. One of the samples was further characterized by
13C NMR spectroscopy to obtain insight into the regioselec-
tivity of the polymerizations. Surprisingly, the analysis of the
spectrum showed evidence of the formation of all three possible
regioisomers (head-to-tail, head-to-head, tail-to-tail) in the
isolated polymer (vide infra), instead of the expected AA′AA′
(head-to-tail) regiospecificity as implied by monomer design.
The poor regioselectivity and the limited DPn achieved can
plausibly be explained by the release of a p-nitrophenolate,
which may act as an additional nucleophile able to attack the
polymeric carbonyl-based backbone and promote exchange
reactions or by the insufficient difference in the leaving group
ability of p-nitrophenol and the FA phenol.
In an attempt to minimize regiorandomness and achieve
higher DPn, the alcohol 11 was converted to the more reactive
chloroformate 14 by reaction with either diphosgene,35 which
gave the best yield (82%), or triphosgene36 (70%) (Scheme 3).
Despite the lower yield, triphosgene was preferred because of
its ease of use. The presence of a chloroformate functionality in
14 was confirmed by 13C NMR (148.9 ppm) and FTIR (1790
cm−1) spectroscopies. Interestingly, this new BA′ monomer,
designed to generate a polymer with higher regioregularity and
molecular weight, was obtained in only three synthetic steps.
The polymerization was then triggered by the deprotection of
the phenol silyl ether, which generated the propagating
nucleophile in a single sequence.
Several sources of fluoride such as tetrabutylammonium
fluoride, potassium fluoride, cesium fluoride, and silver fluoride
were evaluated for the deprotection of the silyl ether to the
phenolate. Among them, silver fluoride, which drove the
reaction by precipitation of silver chloride, was the most
promising and afforded oligomers. The screening of solvents
(pyridine, pyridine/CH3CN, THF/CH3CN, or CH3CN)
revealed the necessity of both CH3CN (AgF solubility) and
pyridine (polymer solubility) to achieve polymerization. The
use of 2 equiv of AgF proved necessary to obtain high DPn
values, whereas higher loadings complicated the purification
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Scheme 4. Synthesis of the A′AAA′ Monomer as the Dimer 16 from 11
process. Although no effect of the reaction temperature (rt vs
60 °C) was observed, a marked effect of the initial monomer
concentration was noticed. In dilute media (0.1 M) only small
oligomers were formed (Supporting Information, Table S3,
entry 1) while some precipitate was noticeable at 0.5 M (entry
3), and the reaction mixture almost instantaneously crashed out
of solution at even higher concentration (0.75 M, entry 4). A
kinetic study was performed at an intermediate concentration
of 0.5 M (entries 5−8). After 1.5 h, a polymer of Mn = 11.1 kg
mol−1 (Đ = 1.92) was extracted with a low yield (14%) from
the heterogeneous reaction mixture. Reduction of the reaction
time down to 15 min facilitated the work-up and led to a
polymer of Mn = 8.3 kg mol−1 (Đ = 2.08, DPn = 20) with a
decent yield (56%). The corresponding polymers exhibited a
high degree of AA′AA′ (head-to-tail) regioselectivity as inferred
from 13C NMR spectroscopic measurements.
A′AAA′ Monomer: Targeting an A′AAA′A′AAA′ (Tail-to-
Head-to-Head-to-Tail-to-Tail-to-Head-to-Head-to-Tail) Re-
gioregular Polymer, Abbreviated as AAA′A′. With the
AA′AA′ polymer in our hands, we then sought to synthesize
the AAA′A′ polymer with a high regioselectivity by
polycondensation of the dimeric monomer 16. The A′AAA′
monomer 16 was obtained from 11 by dimerization, using p-
nitrophenyl chloroformate as an activating reagent, followed by
deprotection of the phenol groups under mild conditions
(Scheme 4). The initial formation of the carbonate bond
between the two FA subunits in 16 was performed because of
the potentially lower reactivity of the corresponding phenols
during the polymerization process (steric hindrance of the o-
methoxy group). Also, this strategy allowed for ready
attribution of the peak at 150.4 ppm to the carbonate in an
A′AAA′ sequence in the 13C NMR spectrum, which is
necessary to quantify the relative ratio of regioisomers in the
polymers.
Figure 2. 13C NMR attribution of carbonyl carbons corresponding to
the carbonate functionalities of the FA−FA coupling A′AAA′ in
monomer 16 (black), the newly established tyrosine−tyrosine
couplings AA′A′A of the resulting polymer (blue), the predominance
of FA−tyrosine couplings AA′AA′ from the polymerization of 14 and
all three types of carbonate carbonyls from the random couplings of
FA and tyrosine groups during the polymerization of 8.
AA′ Monomer: Straightforward Access to a Regiorandom
Polymer. In order to fully realize a FA-co-tyrosine strategy for
the generation of bio-derived poly(carbonate−amide)s, it was
of interest to develop a shorter monomer synthesis. The so-
called AA′ monomer 8 was obtained in only one step (67%) by
peptidic coupling of commercially available FA and L-tyrosine
ethyl ester hydrochloride (Scheme 5). The formation of the
amide linkage in 8 was confirmed by spectroscopic character-
ization.
Scheme 5. Synthesis of the AA′ Monomer 8
The desired AAA′A′ polymer was obtained by polyconden-
sation of the diphenol 16 with a phosgene derivative. A first set
of experiments performed in pyridine, which acted as a base
and solvent, revealed that neat diphosgene was more effective at
promoting polycondensation than was triphosgene. Optimiza-
tion of the reaction conditions, such as the initial monomer
concentration, the diphosgene feed ratio, and the reaction time,
led to the isolation of a high molecular weight AAA′A′ polymer
of Mn = 18.0 kg mol−1 (Đ = 2.06, DPn = 44) in 2 h with 74%
yield (Supporting Information, Table S4). Detailed 13C NMR
spectroscopic analyses revealed the presence of only two signals
attributed to carbonate groups (150.4 and 151.7 ppm for the
FA−FA carbonate of the monomer A′AAA′ and the newly
established tyrosine−tyrosine carbonate AA′A′A sequences,
respectively) which confirmed the high regioselectivity of the
AAA′A′ polymer (Figure 2).
Polymerization conditions were based on those employed
during the polymerization of monomer 16; modifying the
diphosgene equivalency, the global concentration and the
reaction time, a polymer of Mn = 14 kg mol−1 (Đ: 2.57, DPn =
34) was obtained (47%) (Supporting Information, Table S5).
The relative ratio of the three types of carbonates, having
tyrosine−tyrosine, FA−FA, and tyrosine−FA couplings,
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Table 1. Characterization of the Polymers Synthesized
a
b
c
d
Mn,PEO
Mn,OLIGO
Tg
Tp
yield
(%)
proportion
AA′A′A:A′AAA′:AA′AA′
b
d
entry
polymer
(kg mol−1
)
(kg mol−1
)
(DPn)SEC
Đ
(°C)
(°C)
1
2
3
4
AA′AA′ from 13
AA′AA′ from 14
AAA′A′
5.5
8.5
5.8
8.3
14
20
44
1.43
2.08
2.06
2.57
134
129
130
135
350
337
343
343
74
57
73
48
22:15:63
5:5:90
17.7
14.6
18.6
14.8
50:50:0
37:23:40
random
34
a
b
Determined by SEC (DMF, 0.05 M LiBr) using PEO standards. Determined by SEC (DMF, 0.05 M LiBr) using oligomer calibration.
c
d
e
Determined by DSC. Determined by TGA. Determined by 13C NMR spectroscopy.
AA′A′A, A′AAA′, and AA′AA′ sequences, respectively, present
in the polymer was found to be 37:23:40, as determined by the
integration of the 13C NMR signals of the carbonate carbonyl
carbon (Figure 2). It is clear that the AA′A′A and AA′AA′
sequences are more prevalent than the A′AAA′ sequence in the
regiorandom polymer sample. This lack of true regiorandom-
ness could be rationalized by a lower reactivity of the phenolic
group from the FA subunit vs the one from the tyrosine residue
during polycondensation because of a higher steric hindrance.
A summary of the properties of this regiorandom polymer is
provided Table 1, entry 4.
Thermal Analysis. The thermal stability of all four
polymers has been assessed by thermogravimetric analysis
(TGA) and differential scanning calorimetry (DSC) (Table 1).
The nominal difference observed in the glass transition
temperature (129 °C < Tg < 135 °C) and the first derivative
TGA peak (337 °C < Tp < 351 °C) for each of the polymers
under investigation reveals that the thermal properties were not
influenced by the regiochemistry. The thermal stability of a
representative polymer sample (AA′AA′ polymer from 13) was
compared to the monomer (8)/multimer (16) and the starting
materials (Figure 3). As expected, the AA′ and A′AAA′
disposition in food.39 A recent study of tyrosine’s three-
dimensional emission spectra provided a way to distinguish
tyrosine from tryptophan, which can find applications in the
analysis of deep sea chemistries.40 Because of these fluorescent
properties in the starting materials (Supporting Information,
Figures S4 and S5), a comparison of absorbance, excitation, and
emission spectra of the AA′ monomer 8 and the random
polymer was obtained, revealing a shift in the maximum
wavelength in the emission spectra from 394 nm (8) to 427 nm
(random polymer from 8) (Figure 4). These initial results
displayed a variation in the fluorescence properties of the
monomer and the polymer. This red-shift to a material that is
suited to 350 nm excitation and 430 nm emission regimes
makes the emissivity of the random polymers viable for their
immediate use as imaging agents, employing one of the most
common imaging modalities in microscopy (DAPI filter set).41
CONCLUSIONS
■
The design and synthesis of a poly(carbonate−amide) based on
FA, a renewable and biocompatible resource present in fruits
and vegetables, has been reported. In order to generate a
poly(carbonate−amide) by polycondensation, FA was coupled
to a hydroxyl-amino acid via an amide link. An activated
monomer based on the FA−L-serine couple was synthesized
but failed to polymerize. Moving to an L-tyrosine partner led to
the generation of an array of new FA−tyrosine monomers and
copolymers. A good overall control of the regioselectivity of the
resulting polymers was achieved by careful design of the
monomers and led to the synthesis of poly(carbonate−amide)s
possessing head-to-head, tail-to-tail, and head-to-tail sequences
in a nearly regiospecific fashion. Additionally, a regiorandom
poly(carbonate−amide) was generated from the easily
synthesized AA′ monomer 8. Although the glass transition
and thermal degradation properties of the FA−tyrosine-based
poly(carbonate-amide)s (Tg and Tp) were not significantly
influenced by the regioselectivity or the chain length,
preliminary results on the fluorescent properties showed a
shift in the maximum of the excitation and emission spectra
between the AA′ monomer 8 and the corresponding random
polymer. Further fluorescence studies are underway to probe
the imaging promise of this new class of bio-derived
poly(carbonate−amide)s. It is envisioned that bio-based
poly(carbonate−amide)s derived from FA and a hydroxyl-
containing amino acid could potentially undergo hydrolytic
breakdown and lead to biologically beneficial byproducts and
carbon dioxide. Moreover, the rigidity of both FA and tyrosine
subunits as well as the polar, hydrogen-bonding amide groups
may lead to materials with enhanced mechanical properties.
Degradation and mechanical properties testing experiments are
underway. Specifically, applications would include engineering
plastics, biomedical components, and other applications where
mechanical strength and degradation are both desired.
Figure 3. Thermogravimetric analysis of AA′AA′ polymer from 13,
AA′ monomer 8, A′AAA′ monomer 16, FA, and tyrosine.
monomers (8 and 16, respectively) were less thermally stable
than the polymer (318 and 328 °C, respectively) and more
stable than the L-tyrosine ethyl ester (224, 276, and 375 °C)
and FA (243 °C). High residual masses were observed at 500
°C for all polymers as well as for monomer 8 and multimer 16.
This stability may plausibly be explained by the formation of
highly conjugated structures.
Fluorescence Properties. Fluorescent properties of FA
and tyrosine have been investigated in the past, and these
compounds have been used as probes for assessing
intermolecular interactions37,38 as well as FA proportion and
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Macromolecules
Article
Figure 4. Absorbance, excitation, and emission spectra for (a) monomer 8 and (b) the corresponding regiorandom polymer.
(11) Fenouillot, F.; Rousseau, A.; Colomines, G.; Saint-Loup, R.;
Pascault, J. P. Prog. Polym. Sci. 2010, 35, 578−622.
ASSOCIATED CONTENT
* Supporting Information
Additional experimental, characterization, and spectroscopic
information. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
(12) Sommerfeld, S. D.; Zhang, Z.; Costache, M. C.; Vega, S. L.;
Kohn, J. Biomacromolecules 2014, 15, 830−836.
(13) Noordover, B. A. J.; Haveman, D.; Duchateau, R.; van Benthem,
R. A. T. M.; Koning, C. E. J. Appl. Polym. Sci. 2011, 121, 1450−1463.
(14) Lee, A. L. Z.; Ng, V. W. L.; Gao, S.; Hedrick, J. L.; Yang, Y. Y.
Adv. Funct. Mater. 2013, DOI: 10.1002/adfm.201301307.
(15) Costache, M. C.; Vaughan, A. D.; Qu, H.; Ducheyne, P.;
Devore, D. I. Acta Biomater. 2013, 9, 6544−6552.
AUTHOR INFORMATION
Corresponding Author
*E-mail: wooley@chem.tamu.edu (K.L.W.).
■
(16) Mikami, K.; Lonnecker, A. T.; Gustafson, T. P.; Zinnel, N. F.;
Pai, P.-J.; Russell, D. H.; Wooley, K. L. J. Am. Chem. Soc. 2013, 135,
6826−6829.
Notes
The authors declare no competing financial interest.
(17) Besset, C. l. J.; Lonnecker, A. T.; Streff, J. M.; Wooley, K. L.
Biomacromolecules 2011, 12, 2512−2517.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the National
Heart Lung and Blood Institute of the National Institutes of
Health as a Program of Excellence in Nanotechnology
(HHSN268601000046C), the National Science Foundation
(CHE-1057441), and the Welch Foundation through the W. T.
Doherty-Welch Chair in Chemistry (A-0001).
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ABBREVIATIONS
(21) Morozowich, N. L.; Nichol, J. L.; Mondschein, R. J.; Allcock, H.
R. Polym. Chem. 2012, 3, 778−786.
■
brsm, based on recovered starting material; DSC, differential
scanning calorimetry; equiv, equivalent; DPn, degree of
polymerization; FA, ferulic acid; Mn, number-average molecular
weights; NMR, nuclear magnetic resonance; PEO, poly-
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