Synthesis of novel polymer/urea peptoid conjugates using RAFT polymerization

Article abstract of DOI:10.1021/ma902427m

The synthesis of novel urea peptoids and their conjugation to polymers prepared using reversible addition-fragmentation chain transfer (RAFT) polymerization is reported. Statistical copolymers of poly(styrene-co-3- azidopropyl methacrylate) (poly(styrene-co-AzPMA)) and poly(3-O-methacryloyl1, 2: 5, 6-di-O-isopropylidene-D-glucofuranose-co-AzPMA) (poly(MAIpGlc-co-AzPMA)) were synthesized with high molecular weight and narrow molecular weight distributions. The polymer conjugates were formed using copper-catalyzed azide/alkyne cycloaddition chemistry and confirmed by FTIR and ¹H NMR spectroscopy. Following conjugate formation with poly(MAIpGlc-co-AzPMA) and the urea peptoid the isopropylidene groups were removed using dilute trifluoroacetic acid. This yielded a sugar functionalized water-soluble, polymer/urea peptoid conjugate. Reactions with fluorescent compounds demonstrated that the peptoids can be further modified after conjugation to the polymer.

Full text of DOI:10.1021/ma902427m

Macromolecules 2010, 43, 1341–1348 1341
DOI: 10.1021/ma902427m
Synthesis of Novel Polymer/Urea Peptoid Conjugates Using RAFT
Polymerization
Xiaoping Chen and Neil Ayres*
Department of Chemistry, The University of Cincinnati, 301 Clifton Court, PO Box 210172, Cincinnati,
Ohio 45221
Received September 4, 2009; Revised Manuscript Received December 18, 2009
ABSTRACT: The synthesis of novel urea peptoids and their conjugation to polymers prepared using
reversible addition-fragmentation chain transfer (RAFT) polymerization is reported. Statistical copolymers
of poly(styrene-co-3-azidopropyl methacrylate) (poly(styrene-co-AzPMA)) and poly(3-O-methacryloyl-
1,2:5,6-di-O-isopropylidene-D-glucofuranose-co-AzPMA) (poly(MAIpGlc-co-AzPMA)) were synthesized
with high molecular weight and narrow molecular weight distributions. The polymer conjugates were formed
using copper-catalyzed azide/alkyne cycloaddition chemistry and confirmed by FTIR and 1H NMR
spectroscopy. Following conjugate formation with poly(MAIpGlc-co-AzPMA) and the urea peptoid the
isopropylidene groups were removed using dilute trifluoroacetic acid. This yielded a sugar functionalized
water-soluble, polymer/urea peptoid conjugate. Reactions with fluorescent compounds demonstrated that
the peptoids can be further modified after conjugation to the polymer.
Introduction
activated ester functional RAFT CTA to a collagen-like peptide.
The subsequent polymer-peptide conjugate exhibited triple-
While the synthesis of new macromolecules and materials has
advanced dramatically in recent years, the challenge of preparing
“tailor-made materials” continues. In meeting this goal, it has been
recommended that chemistries with increased synthetic precision
and control of multiple functionality using simple, robust proto-
cols need to be developed.1 As part of our approach in synthesizing
polymers using these principles, we have become interested in a
class of peptidomimetics known as urea peptoids.2 Many classes of
peptidomimetics have been developed including N-substituted
glycines (peptoids), oligocarbamates, hydrazinopeptides, oligosul-
fones, and (R-β unsaturated) peptidosulfonamides.3 For compar-
ison, the peptide, peptoid, and urea peptoid structures are shown in
Figure 1. The resistance of peptoids to enzymatic degradation
compared to peptides and the hydrogen-bonding properties of the
urea peptoid backbone open areas of research including folded and
helical structures.4 Fischer and co-workers5 suggested that four
urea units may initiate folding, while Violette and co-workers6
reported seven residues can form a stable helix. Our interest
primarily stems from the fact that urea peptoids are attractive
compounds due to their ease of synthesis and ability to incorporate
a large number of diverse and functional side groups.
helical structure showing that the self-assembly properties of the
peptide remained intact. In an alternative strategy RAFT polymers
with a pyridyl disulfide end-group have been used to conjugate a
hexapeptide.16 Peptides can also be conjugated to the polymer
backbone using reactive pendant groups; for example, Hwang and
co-workers17 have prepared RAFT polymers with nitrophenyl and
protected aldehyde functional monomers for coupling with the
tripeptide sequence RGD. N-Acryloylsuccinimide polymers have
been synthesized by RAFT and used for the conjugation of
peptides for anthrax toxin inhibition.18 Recently, Boyes’ group19
reported conjugation of peptides to RAFT polymers for the
preparation of novel targeting/treatment anticancer agents. Fewer
examples exist of peptoid-polymer conjugates. Recently, an
engineered cationic protein polymer was used as a scaffold for
the conjugation of a peptoid as well as other groups.20 The peptoid
was coupled to the lysine residues of the protein polymer using
1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride
(EDC) with N-hydroxysulfosuccinimide.
Herein we report our first examples of the synthesis of a urea
peptoid trimer and its conjugation to polymers prepared using
RAFT polymerization and show that the urea peptoids can be
further functionalized postconjugation. We have used polystyrene
for proof-of-principle purposes and 3-O-methacryloyl-1,2:5,6-di-
Coupled with the goal of “tailor-made materials” is the increas-
ing interest in complex polymers containing biological groups,
i.e., peptide- and protein-conjugates to make new “chimera”
materials.7-9 While not the only polymerization technique
used for the synthesis of polymer conjugates, reversible addition-
fragmentation chain transfer (RAFT) polymerization has proven
adept for this purpose.10 RAFT polymerization has the benefits of
being highly controlled, tolerant of a large number of functional
groups, and the ability to be conducted in a variety of media.11-13
O-isopropylidene-D-glucofuranose (MAIpGlc) to demonstrate
that this chemistry can easily be coupled with more complex
polymers. This is the first report, to our knowledge, of urea
peptoid-polymer conjugates and offers a route to diverse poly-
mers combining synthetic precision and control of multiple
functional groups with simple, robust modular chemistry.
Borner14 prepared a RAFT chain transfer agent (CTA) coupled to
€
Experimental Section
the N-terminus of a GGRGDS peptide sequence. Polymerization
of n-butyl acrylate (nBA) afforded a polymer with one peptide
sequence as an end-group. Wiss and co-workers15 conjugated an
All starting reagents were purchased from Aldrich at the
highest purity available and used as received unless otherwise
stated. N-(2-Nitrobenzenesulfonyl)-2-imidazolidone was prepared
according to the method of Wilson and Nowick.2 The RAFT
agents S,S0-bis(R,R0-dimethyl-R00-acetic acid)trithiocarbonate and
*Corresponding author: e-mail ayresni@ucmail.uc.edu; Ph (513) 556-
9280; Fax (513) 556-9239.
r 2010 American Chemical Society
Published on Web 01/14/2010
pubs.acs.org/Macromolecules

1342 Macromolecules, Vol. 43, No. 3, 2010
Chen and Ayres
afford the crude secondary amine which was purified using
˚
column chromatography on silica gel (silica gel 60 A, 70-230
mesh) with CH2Cl2:MeOH (10:1 v/v) as the mobile phase. The
solvent was removed and the product dried in vacuum to yield
1
1.50 g. Yield: 81%. H NMR (CDCl3): δ (ppm) 1.15 (t, J =
7.2 Hz, 6 H, 2 CH3CH2N), 2.87-2.89 (m, 3 H, CH2CH2NHCO
and NHAr), 3.28 (q, J = 7.2 Hz, 4 H, 2 CH3CH2N), 3.41 (t, J =
5.4 Hz, 2 H, CH2CH2NHCO), 3.88 (s, 2 H, CH2NHBn), 5.28
(s, 1 H, NHCO), 7.30-7.39 (m, 5 H, aromatic H). 13C NMR
(CDCl3, 100 MHz): δ (ppm) 13.85 (2 CH3CH2N), 39.59 (CH2-
CH2NHBn), 41.22 (2 CH3CH2N), 48.59 (CH2CH2NHBn),
52.90 (NCH2C6H5), 127.71, 128.64 (4 C), 137.63 (aromatic CH),
157.73 (CONH). FT-IR (cm-1): ν(NH) = 3330 (b), ν(CH) = 2971,
2930, ν(CO) = 1618, ν(phenyl) = 1532, ν(CdC bend) = 742, 698. MS
(TOF MS ESþ): 250.0874 M þ 1.
Figure 1. Comparison of a generic peptide, peptoid, and urea peptoid
repeat structures.
S-1-dodecyl-S0-(R,R0-dimethyl-R00-acetic
acid)trithiocarbonate
were prepared in accordance to literature procedures.21 The sugar
functionalized monomer 3-O-methacryloyl-1,2:5,6-di-O-isopro-
pylidene-D-glucofuranose (MAIpGlc) was prepared following
the reports of Fukuda’s group.22,23 The azide-containing mono-
mer 3-azidopropyl methacrylate (AzPMA) was synthesized fol-
lowing literature procedures.24 Styrene was passed through basic
alumina immediately before use.
Compound 4. The procedure is similar to that described for 1.
N-(2-Nitrobenzenesulfonyl)-2-imidazolidone (1.95 g, 7.2 mmol)
and DMAP (0.37 g, 3 mmol) were added to a solution of
compound 3 (1.50 g, 6.0 mmol) in 15 mL of dry pyridine. The
reaction was heated at 60 °C overnight. The product was
isolated using the method described for compound 1 to generate
2.70 g of 4. Yield: 87%. 1H NMR (CDCl3): δ (ppm) 1.15 (t, J =
7.2 Hz, 6 H, 2 CH3CH2N), 3.08 (appear dd, J = 5.6, 8.4 Hz,
2 H, CH2NC5H6), 3.23-3.29 (m, 6 H, 2 CH3CH2N and CH2-
CH2NCH2C6H5), 3.34-3.38 (m, 2 H, CH2CH2N-Ns), 3.45
(appear dd, J = 4.8, 9.6 Hz, 2 H, CH2N-Ns), 4.51 (s, 2 H,
NCH2C5H6), 4.70 (s, 1 H, NHCO), 7.04 (s, 1 H, NHCO), 7.16
(s, 1 H, NH-Ns), 7.23-7.27 (m, 3 H, aromatic H from C6H5),
7.30-7.34 (t, J = 7.0 Hz, 2 H, aromatic H from C6H5),
7.71-7.81 (m, 3 H, aromatic H from Ns), 8.15-8.17 (m, 1 H,
aromatic H from Ns). 13C NMR (CDCl3, 100 MHz): δ (ppm)
13.63 (2 CH3CH2N), 39.99 (CH2CH2NHBn), 40.78 (CH2CH2N-
Ns), 41.27 (2 CH3CH2N), 44.37 (CH2CH2NHBn), 46.57 (CH2-
CH2NH-Ns), 51.02 (NCH2C6H5), 124.89, 127.31, 127.78, 128.58,
130.98, 132.48, 133.24, 134.35, 138.81, 148.05 (aromatic CH),
Compound 1. N-(2-Nitrobenzenesulfonyl)-2-imidazolidone
(4.00 g, 14.7 mmol) and (dimethylamino)pyridine (DMAP)
(0.75 g, 6.1 mmol) were added to a solution of diethylamine
(2.90 mL, 29.4 mmol) in 37 mL of pyridine. The reaction flask
was sealed with a rubber septum, purged with N2 for 30 min, and
then immersed in preheated oil bath at 50 °C for 6 h. After this
time the solvent was removed using a rotary evaporator, the
residue dissolved in CH2Cl2, and the resulting solution washed
with 0.5 M aqueous HCl and dried over Na2SO4. The solvent
was removed to afford the crude sulfonamide, which was
purified by column chromatography using silica gel (silica gel
˚
60 A, 70-230 mesh) with ethyl acetate:hexane (3:1 v/v) as the
mobile phase. The product was dried in a vacuum oven to afford
5.00 g of white solid. Yield: 99%. 1H NMR (CDCl3): δ (ppm)
1.13 (t, J = 7.2 Hz, 6 H, 2 CH3CH2N), 3.24-3.28 (m, 6 H, 2
CH3CH2N and CH2CH2NH-Ns), 3.40-3.42 (m, 2H, CH2CH2-
NHCH2), 4.91 (bs, 1 H, NH), 6.14 (bs, 1 H, NHCO), 7.73-7.85
(m, 3 H, aromatic H), 8.11-8.14 (m, 1 H, aromatic H). 13C
NMR (CDCl3, 100 MHz): δ (ppm) 13.77 (2 CH3CH2N), 40.54
(CH2CH2NH-Ns), 41.27 (2 CH3CH2N), 44.43 (CH2CH2NH-
Ns), 125.25, 131.07, 132.75, 133.51, 133.58, 148.12 (aromatic
158.16 (CONEt2), 158.59 (CONH). FT-IR (cm-1): ν(NH)
3307 (s), ν(CH) = 2974, 2932, ν(CO) = 1617, ν(phenyl) = 1535,
=
ν
(CdC bend) = 729. MS (TOF MS ESþ): 521.0078 M þ 1.
CH), 157.54 (CONH). FT-IR (cm-1): ν(NH) = 3274, ν(CH)
=
Compound 5. The reaction was performed using the procedure
2930, ν(CO) = 1630, ν(phenyl) = 1544. MS (TOF MS ESþ):
described for compound 2. A 100 mL round-bottomed flask
containing 7 (2.60 g, 5.0 mmol), K2CO3 (2.10 g, 15.2 mmol), and
CH3I (3.60 g, 25.0 mmol) in 13 mL of DMF was used, and the
product was isolated using the procedure described for com-
pound 2 to yield 2.50 g of product. Yield: 94%. 1H NMR
(CDCl3): δ (ppm) 1.11 (t, J = 7.2 Hz, 6 H, 2 CH3CH2N), 2.95
(s, 3 H, CH3N), 3.20-3.27 (m, 6 H, 2 CH3CH2N and CH2 CH2N
C5H6), 3.39 (appear dd, J = 5.6, 10.0 Hz, 4 H, CH2CH2N
C5H6), 3.47 (appear dd, J = 5.4, 11.0 Hz, 2 H, CH2N-Ns), 4.51
(s, 2 H, NCH2 C6H5), 5.13 (bs, 1 H, NHCO), 5.99 (bs, 1 H,
NHCO), 7.25-7.28 (m, 3 H, aromatic H from C6H5), 7.31-7.35
(m, 2 H, aromatic H from C5H6), 7.63-7.70 (m, 3 H, aromatic H
from Ns), 7.96-7.99 (m, 1 H, aromatic H from Ns). 13C NMR
(CDCl3, 100 MHz): δ (ppm) 13.72 (2 CH3CH2N), 34.65
(CH2CH2NBn), 36.44 (CH2CH2N-Ns), 38.39 (CH3CH2N),
39.79 (CH2CH2NBn), 40.93 (CH3CH2N), 46.80 (CH2CH2N-
Ns), 49.82 (CH3N-Ns), 50.84 (NCH2C6H5), 124.06, 127.13,
127.26 (2 C), 128.54 (2 C), 130.48, 131.76, 132.15, 133.63,
138.36, 148.08 (aromatic CH), 157.86 (CONEt2), 158.64
345.1473 M þ 1.
Compound 2. Compound 1 (2.80 g, 8.1 mmol) was dissolved in
12 mL of N,N-dimethylformamide (DMF), and K2CO3 (2.80 g,
20.3 mmol) and benzyl chloride (5.10 g, 40.5 mmol) were added.
The reaction was allowed to proceed at room temperature
overnight. The DMF was removed by vacuum distillation,
and the residue dissolved in CH2Cl2 and passed through Celite.
The solution was concentrated and the product isolated by
˚
column chromatography using silica gel (silica gel 60 A,
70-230 mesh) with ethyl acetate:hexane (3:1 v/v) as the mobile
phase. The product was dried in vacuum to afford 3.30 g of white
solid. Yield: 94% 1H NMR (CDCl3): δ (ppm) 1.13 (t, J = 7.2 Hz,
6 H, 2 CH3CH2N), 3.22 (q, J = 7.2 Hz, 4 H, 2 CH3CH2N), 3.31
(dd, J = 5.6, 11.6 Hz, 2 H, CH2CH2N-Ns), 3.49 (t, J = 5.6 Hz, 2
H, CH2CH2N-Ns), 4.60 (s, 2 H, N CH2Ph), 4.67 (s, NH),
7.24-7.28 (m, 3 H, aromatic H), 7.36-7.41 (m, 2 H, aromatic
H), 7.64-7,71 (m, 3 H, aromatic H), 7.96 (d, J = 7.6 Hz, 1 H,
aromatic H). 13C NMR (CDCl3, 100 MHz): δ (ppm) 13.80
(2 CH3CH2N), 38.33 (CH2CH2NH-Ns), 41.15 (2 CH3CH2N),
47.80 (CH2CH2NH-Ns), 51.71 (NCH2C6H5), 124.18, 128.08,
128.19 (2 C), 128.59, 128.81 (2 C), 130.97, 131.81, 133.57,
135.56, 147.91 (aromatic CH), 157.10 (CONH). FT-IR (cm-1):
(CONH). FT-IR (cm-1): ν(NH) = 3325, ν(CH) = 2931, ν(CO)
=
1624, ν(CdC bend) = 728. MS (TOF MS ESþ): 535.2339 M þ 1.
Compound 6. The reaction was performed using the procedure
described for compound 3 using compound 5 (2.40 g, 4.5 mmol),
K2CO3 (1.90 g, 13.8 mmol), and benzenethiol (0.74 g, 6.8 mmol)
in 9 mL of DMF. The product was isolated using the procedure
described for compound 3 to yield 1.45 g of 5. Yield: 92%. 1H
NMR (CDCl3): δ (ppm) 1.13 (t, J = 7.2 Hz, 6 H, 2 CH3CH2N),
2.50 (s, 3 H, CH3N), 2.88 (t, J = 5.4 Hz, 2 H, CH2NC6H5), 3.24
(dd, J = 7.0, 14.2 Hz, 6 H, 2 CH3CH2N and CH2 CH2NC6H5),
3.38 (t, J = 6.8 Hz, CH2CH2NHCH3), 3.47 (dd, J = 5.2,
10.8 Hz, CH2NHCH3), 3.79 (bs, 1 H, NHCH3), 4.52 (s, 2 H,
ν(NH) = 3349, ν(CH) = 2973, 2931, ν(CO) = 1628, ν(phenyls)
1538. MS (TOF MS ESþ): 435.0002 M þ 1.
=
Compound 3. Compound 2 (3.30 g, 7.6 mmol) was dissolved in
38 mL of DM,F and K2CO3 (3.10 g, 22.8 mmol) and benze-
nethiol (1.70 g, 15.2 mmol) were added. The reaction was
allowed to proceed at room temperature overnight. The DMF
was removed by vacuum distillation, and the residue dissolved in
CH2Cl2 and passed through Celite. The solvent was removed to

Article
Macromolecules, Vol. 43, No. 3, 2010 1343
NCH2Bn), 5.19 (bs, 1 H, NHCO), 6.46 (bs, 1 H, NHCO), 7.24-
7.27 (m, 3 H, aromatic H from C5H6), 7.34 (t, J = 7.2 Hz, 2 H,
aromatic H from C5H6). 13C NMR (CDCl3, 100 MHz): δ (ppm)
13.78 (2 CH3CH2N), 34.89 (CH2CH2NBn), 39.29 (CH2CH2-
NCH3), 39.80 (CH2CH2NBn), 41.16 (2 CH3CH2N), 46.88
(CH2CH2NCH3), 51.05 (CH3NH), 51.16 (NCH2C6H5), 127.30
(2 C), 127.34, 128.67 (2 C), 138.25 (aromatic CH), 157.86
(CONEt2), 159, 15 (CONH). FT-IR (cm-1): ν(NH) = 3310,
ν(CH) = 2971, 2931, ν(CO) = 1616, ν(CdC bend) = 700. MS
(TOF MS ESþ): 350.1647 M þ 1.
(CH2CH2NBn), 40.97 (2 CH3CH2N), 46.46 (CH2CH2NHCH2Ct
CH), 48.33 (NCH2C6H5), 48.39 (CH2NHCH2CtCH), 50.65
(NHCH2CtCH), 71.86 (CtCH), 81.51 (CtCH), 127.24, 127.32,
128.57 (3 C), 138.33 (from 127.24, 6 aromatic CH), 157.97 (CONEt2),
159.03 (CONBn), 159.31 (CONCH3). FT-IR (cm-1): ν(NH) = 3306,
ν(CH) = 2932, ν(CtCH) = 2125, ν(CO) = 1610, ν(phenyl) = 1530,
ν(CdCbend) = 700. MS (TOF MS ESþ): 474.4474 M þ 1.
Synthesis of poly(Sty-co-AzPMA). A 100 mL round-bottom
flask was charged with styrene (6.90 mL, 60.0 mmol), AzPMA
(540.8 mg, 3.2 mmol), S,S0-bis(R,R0-dimethylacetic acid)trithio-
carbonate (89.1 mg, 0.32 mmol), and azobis(isobutyronitrile)
(AIBN) (17.3 mg, 0.11 mmol) in 7 mL of anhydrous anisole. The
reaction flask was sealed with a rubber septum, and the contents
were purged with N2 in an ice bath for 30 min and then heated
for 18 h at 95 °C before being quenched by exposure to air (O2)
and rapid cooling. The polymer was precipitated from hexane
and dried in vacuum to afford 5.3 g of pale yellow powder.
Isolated yield: 78%. 1H NMR (CDCl3): δ (ppm) 1.47-3.68 (m,
230 H, CH2CH2N3, protons from polymer backbone and end
groups), 4.24 (bs, 2 H, CH2O), 6.51-7.13 (m, 328 H, CH of
Compound 7. The reaction was performed using the procedure
described for compound 1 with 6 (1.45 g, 4.3 mmol), N-(2-nitro-
benzenesulfonyl)-2-imidazolidone (1.4 g, 5.1 mmol), and DMAP
(0.26 g, 2.2 mmol) in 10 mL of dry pyridine. The product was
isolated using the procedure described for compound 1 to yield
2.1 g of white solid. Yield: 81%. 1H NMR (CDCl3): δ (ppm) 1.11
(t, J = 7.2 Hz, 6 H, 2 CH3CH2N), 2.89 (s, NCH3), 3.20-3.38
(m, 16 H, 2 CH3CH2N and all CH2 groups in main chain), 4.55
(s, 2 H, NCH2C6H5), 5.00 (bs, 1 H, NHCH3), 6.86 (bs, 1 H,
NHCO), 7.14 (bs, 1 H, NHCO), 7.25-7.28 (m, 3 H, aromatic H
from C6H5) 7.33 (t, J = 6.8 Hz, 2 H, aromatic H from C6H5),
7.67-7.77 (m, 3H, aromatic H from Ns), 8.08(d, J = 9.6 Hz, 1 H,
aromatic H from Ns). 13C NMR (CDCl3, 100 MHz): δ (ppm)
13.75 (2 CH3CH2N), 35.22 (CH3N), 39.36 (CH2CH2NCH3), 39.63
(CH2CH2NBn), 40.68 (CH2CH2NH-Ns), 41.11 (CH2NCH3),
44.41 (2 CH3CH2N), 46.75 (CH2CH2NBn), 48.55 (CH2CH2-
NHNs), 50.79 (NCH2C6H5), 124.82, 127.37, 127.42 (2 C), 128.73
(3 C), 130.96, 132.47, 133.28, 134.05, 148.05 (aromatic CH), 158.00
(CONEt2), 158.60 (CONBn), 159.70 (CONCH3). FT-IR (cm-1):
phenyl rings). FT-IR (cm-1): ν(CH) = 2922, ν(N3) = 2097, ν(CO)
1724, ν(phenyl) = 1601, ν(CHbend) = 538.
=
Synthesis of Poly(MAIpGlc-co-AzPMA). A 100 mL round-
bottom flask was charged with MAIpGlc (4.40 g, 13.5 mmol),
AzPMA (120 mg, 0.71 mmol), S,S0-bis(R,R0-dimethylacetic acid)-
trithiocarbonate(51.7mg, 0.142 mmol), and AIBN (1.1 mg, 0.071
mmol) in 5 mL of anhydrous anisole. The reaction flask was
sealed with a rubber septum and purged with N2 in an ice bath for
30 min; the flask was then heated for 6 h at 70 °C before being
quenched by exposure to air (O2) and rapid cooling. The polymer
was precipitated from hexane and dried in vacuum to afford 3.5 g
ν(NH) = 3326, ν(CH) = 2930, ν(CO) = 1616, ν(CdCbend) = 728. MS
(TOF MS ESþ): 621.1813 M þ 1.
1
Compound 8. The reaction was performed using the procedure
described for compound 2 with 7 (1.80 g, 2.9 mmol), K2CO3
(0.8 g, 5.8 mmol), and 3-bromopropyne (80 wt % in toluene
solution) (2.17 g, 14.5 mmol) in 15 mL of DMF. The product
was isolated using the procedure described for compound 2 to
of pale yellow solid. Isolated yield: 77%. H NMR (CDCl3): δ
(ppm) 1.07-1.94 (m, 334 H, CH2CH2N3, all CH3, protons from
polymer backbone and end group), 3.43 (bs, 2 H, CH2N3),
4.02-4.90 (m, 98H, 96 OCH þ 1 OCH2CH2CH2N3), 5.83-
5.93 (19 H, OCHO). FT-IR (cm-1): ν(CH) = 2987, ν(N3)
2100, ν(CO) = 1731, ν(CObend) = 1370, ν(CHbend) = 512.
=
1
yield 1.75 g of yellow oil. Yield: 92%. H NMR (CDCl3): δ
(ppm) 1.12 (t, J = 7.2 Hz, 6 H, 2 CH3CH2N), 2.20 (t, J = 2.0 Hz,
1 H, CtCH), 2.88 (s, 3 H, N CH3), 3.21-3.27 (m, 6 H,
2 CH3CH2N and CH2 CH2N C5H6), 3.34-3.45 (m, 8 H,
4 CH2 on urea-peptoid main chain), 3.56 (t, J = 5.6 Hz, 2 H,
CH2N-Ns), 4.28 (d, J = 2.4 Hz, 2 H, CH2CtCH), 4.50 (s, 2 H,
N CH2 C5H6), 5.21 (bs, 1 H, NHCO), 5.79 (bs, 1 H, NHCO),
6.26 (bs, 1H, NHCO), 7.23-7.26 (m, 3 H, aromatic H from
C6H5), 7.31 (t, J = 7.4 Hz, 2 H, aromatic H from C6H5),
7.65-7.69 (m, 3 H, aromatic H from Ns), 8.01 (dd, J = 1.4,
7.4 Hz, aromatic H from Ns). 13C NMR (CDCl3, 100 MHz): δ
(ppm) 13.76 (2 CH3CH2N), 35.02 (CH3N), 36.61 (CH2CH2-
NCH3), 37.97 (CH2CH2NBn), 39.72 (CH2CH2NNs), 39.88
(CH2CH2NCH3), 41.01 (2 CH3CH2N), 46.49 (CH2CH2NBn),
46.88 (CH2CH2NHNs), 48.61 (NCH2CtCH), 50.60 (NCH2-
C6H5), 74.16 (CtCH), 76.95 (CtCH), 124.13, 127.23, 128.60,
130.77, 131.84, 132.62, 133.73, 138.21, 148.11 (aromatic CH),
157.93 (CONEt2), 158.60 (CONBn), 159.32 (CONCH3). FT-IR
Synthesis of Urea Peptoid/Polymer Conjugates Using Copper-
Catalyzed Azide/Alkyne Cycloaddition Reaction. Poly(MAIp-
Glc-co-AzPMA) (0.75 g, 0.12 mmol of azide), CuBr (11.3 mg,
0.07 mmol), and 9 (61.4 mg, 0.13 mmol) were mixed in 3 mL of
CH2Cl2 and purged with dry N2 gas for 30 min. The ligand N,N,
N,N00,N00-pentamethyldiethylenetriamine (PMDETA) (40.8 mg,
0.24 mmol) was added to the solution using a syringe, and the
solution immediately turned blue. The reaction was stirred over-
night at room temperature. After this time the reaction solution
was passed through a short silica column to remove the copper
complex using CH2Cl2/MeOH = 20:1 (v/v) as the mobile phase.
The solvent was removed using a rotary evaporator, and the urea
peptide/polymer conjugate dissolved in a minimum amount of
CH2Cl2, precipitated from heptane, and dried in vacuum for
2 days. 0.70 g of the urea peptoid/polymer conjugate poly-
(MAIpGlc-co-AzPMA)-9 was obtained. Isolated yield: 87%. 1H
NMR (CD2Cl2): δ (ppm) 0.84-2.50 (m, 302 H, CH2CH2N3, all
CH3, protons from polymer backbone and end group), 2.75-4.83
(m, 109H, OCH, OCH2, NCH2CH2CH2N3, CH2N and NCH3 in
urea peptoid,) 5.77-5.91 (m, 17 H, 16 OCHO þ 1 NHCO), 6.63
(s, NHCO), 6.90 (s, NHCO), 7.24-7.51 (5 H from phenyl ring þ1
H from triazole ring). FT-IR (cm-1): ν(CH) = 2987, ν(CO) = 1732,
(cm-1): ν(NH) = 3303, ν(CH) = 2932, ν(CtCH) = 2234, ν(CO)
=
1623, ν(phenyl) = 1539, ν(CdC bend) = 714. MS (TOF MS ESþ):
659.1726 M þ 1.
Compound 9. The reaction was performed using the procedure
described for compound 3 with 8 (0.85 g, 1.3 mmol) and
benzenethiol (0.21 g, 6.8 mmol) in 9 mL of DMF. The product
was isolated using the procedure described for compound 3 to
ν(CObend) = 1373, ν(CHbend) = 512.
Cleavage of Isopropylidenyl Groups from Poly(MAIpGlc-co-
1
yield 0.51 g of yellow oil. Yield: 82%. H NMR (CDCl3): δ
AzPMA)-9. A solution of 0.10 g of poly(MAIpGlc-co-AzPMA)-9
was stirred for 30 min in 3 mL of trifluoroacetic acid (TFA)/
H2O = 9:1 (v/v). The solution was removed using a stream
of dry N2 gas for 1 h, dried in air for 2 days, and finally dried
in vacuum to afford 0.080 g of pale yellow solid. Isolated yield:
(ppm) 1.05 (t, J = 7.2 Hz, 6 H, 2 CH3CH2N), 2.16 (t, J = 2.4 Hz,
1 H, CtCH), 2.16 (t, J = 5.8 Hz, 2 H, CH2CH2NC6H5), 2.86
(s, 3 H, N CH3), 3.12-3.35 (m, 18 H), 4.45 (s, 2 H, N CH2Bn),
5.45 (bs, 1 H, NHCO), 6.12 (bs, 1 H, NHCO), 6.78 (bs, 1H,
NHCO), 7.16-7.21 (m, 3 H, aromatic H from C6H5), 7.21-7.27
(m, 2 H, aromatic H from C6H5). 13C NMR (CDCl3, 100 MHz):
δ (ppm) 13.74 (2 CH3CH2N), 34.96 (CH3N), 37.71 (CH2CH2-
NCH3), 39.69 (CH2CH2NCH3 and CH2CH2NBn), 40.24
99%. FT-IR: (cm-1) ν(OH) = 3388 (b), ν(CH) = 2938, ν(CO)
1784, 1711, ν(CObend) = 1144, ν(CHbend) = 510.
Attachment of 5-Carboxyfluorescein to Poly(styrene-co-
=
AzPMA)-9. A mixture of 50.0 mg of poly(styrene-co-AzPMA)-9

1344 Macromolecules, Vol. 43, No. 3, 2010
Chen and Ayres
Figure 2. Synthesis of a urea peptoid using an iterative route. Compound1 is transformed through additions of an alkyl halide (benzyl chloride, methyl
iodide, and propargyl bromide), removal of the 2-nitrobenzenesulfonyl (Ns) group with thiophenol, and reactivation with N-(2-nitrobenzenesulfonyl)-
2-imidazolidone.
(0.014 mmol of NH), 5.8 mg of 5-carboxyfluorescein (0.015
mmol), and 5.8 mg of N,N0-dicyclohexylcarbodiimide (DCC)
(0.028 mmol) in 3 mL of CH2Cl2 was stirred under N2 overnight
in a 10 mL round-bottom flask. The reaction was quenched by
adding 20 μL of water. The mixture was passed through a short
silica gel column to remove unreacted 5-carboxyfluorescein using
CH2Cl2/MeOH = 20:1 (v/v) as the eluent. The solvent was
removed using a rotary evaporator, and the fluorescein attached
polymer conjugate dissolved in minimum amount of CH2Cl2 and
precipitated from heptane to afford 41.7 mg of the final product.
Isolated yield: 74%.
polymer-urea peptoid conjugate activated with the Ns group,
4.6 mg of K2CO3 (0.034 mmol), and 4.3 mg of 3-[4-(bromo-
methyl)phenyl]-7-(diethylamino)coumarin (0.011 mmol) in
3 mL of solvent (DMF/THF = 1:2 (v/v)) was stirred at room
temperature overnight. The solvent was removed using a va-
cuum distillation, and the residue dissolved in minimum amount
of CH2Cl2 and purified by column chromatography on silica gel
˚
(silica gel 60 A, 70-230 mesh) using CH2Cl2:MeOH (20:1 v/v) as
the mobile phase. The polymer solution was dried using a rotary
evaporator, and the resulting conjugate dissolved in the mini-
mum amount of CH2Cl2 and precipitated from heptane to
afford 30.8 mg of product. Isolated yield: 34%.
Attachment of 3-[4-(Bromomethyl)phenyl]-7-(diethylamino)-
coumarin to Poly(styrene-co-AzPMA)-9. A mixture of 80.0 mg
of poly(styrene-co-AzPMA)-9 (0.022 mmol of NH), 6.7 mg of
N-(2-nitrobenzenesulfonyl)-2-imidazolidone (0.024 mmol), and
1.4 mg of (dimethylamino)pyridine (DMAP) (0.011 mmol) in 3
mL of pyridine was stirred at 50 °C under N2 overnight in a
10 mL round-bottom flask. The solvent was removed using a
rotary evaporator, and the residue dissolved in CH2Cl2, washed
with 0.5 M aqueous HCl, and dried over Na2SO4. The solvent
was removed to afford the crude poly(styrene-co-AzPMA)-
tetraurea peptoid conjugate, which was purified by column
Characterization. 1H and 13C NMR measurements were
recorded in CDCl3 and DMSO-d6 with Si(CH3)4 as internal
standard using a Bruker Ultrashield 400 MHz (100 MHz for
13C). 1H NMR spectra were processed by UXNMR version 2.5
and MestRe-C. Fourier transform infrared (FT-IR) spectra
were collected on a Nicolet 6700 spectrometer and analyzed
with OMNIC 32 software. Fluorescence and absorbance spectra
were performed on CaryEclipse fluorescence and Cary 50 UV-vis
absorbance spectrophotometers. Molecular weights of the statis-
tical copolymers were determined by gel permeation chromato-
graphy (GPC) with an Agilent 1100 Series HPLC equipped with a
Varian PL gel (5 μm) guard column and two Varian PL gel (5 μm)
mixed-C columns (linear rane of MW = 200-2 ꢀ 106 g/mol) with
a filtered tetrahydrofuran (THF) mobile phase at a flow rate of
1.0 mL/min at ambient temperature and miniDAWN TREOS
˚
chromatography on silica gel (silica gel 60 A, 70-230 mesh)
using CH2Cl2:MeOH (20:1 v/v) as the mobile phase. The poly-
mer solution was dried using a rotary evaporator, dissolved in a
minimum amount of CH2Cl2, and precipitated from heptane to
afford 56.0 mg of intermediate. Next, a mixture of 40.0 mg of the

Article
Macromolecules, Vol. 43, No. 3, 2010 1345
light scattering (60 mW GaAs linearly polarized laser, 658 nm)
calibrated against a 30 000 g/mol polystyrene standard (Wyatt
Technology Corp.), Optilab rEX differential refractometer (light
source = 658 nm), and Viscostar II viscometer (Wyatt Techno-
logy Corp.) detectors. The polymers (∼5.0 mg/mL) were dissolved
in THF and filtered through 0.2 μm membrane filters. ASTRA
software v. 5.4.14 was used to determine molecular weight and
polydispersity values. The dn/dc values were determined using the
Optilab rEX differential refractometer in offline mode and calcu-
lated using Astra software (Wyatt Technology Corp.). Mass
spectrometry was performed using a Micromass Q-TOF-2 spec-
trometer.
2.16 ppm, in conjunction with mass spectrometry that showed a
molecular ion peak at m/z 474.45 (calculated m/z = 474.31 M þ 1).
Urea peptoid 9 serves as a model compound and “proof-of-
principle” to demonstrate the versatility in the synthesis of urea
peptoids. We have also synthesized a urea peptoid dimer, com-
pound 10 (Figure 3). The synthesis of 10 is described in the
Supporting Information.
Our initial strategy was to incorporate the sarcosine group into
a urea peptoid. However, after extension with 3-bromopropyne we
found the product underwent a cyclization reaction. It is known
that these types of compounds will undergo cyclization reactions
under basic conditions.28 We removed the Ns group to give the
final urea peptoid dimer 10. The structure of the final compound
Results and Discussion
1
was confirmed with H NMR spectroscopy which showed the
We prepared urea peptoids in the manner described by Wilson
and Nowick.2 Urea peptoids were chosen as they offer a solution
phase synthesis (as opposed to resin bead based25,26) where the
products can be easily separated and purified using conventional
column chromatography. The synthesis of the urea peptoids is
simple to perform, iterative in nature, and can be conducted with
standard laboratory techniques. The protocol involves three
steps: (1) main chain extension, (2) side group attachment, and
(3) deprotection. The main chain extension uses a ring-opening
reaction of N-(2-nitrobenzenesulfonyl)-2-imidazolidone. The
structure of this group is shown in Figure 2. Fukuyama’s27
procedure was used for the side group attachment, and the
2-nitrobenzenesulfonyl (Ns) protecting group is removed with
thiophenol yielding a secondary amine used in the next iterative
cycle. The process is shown in Figure 2. The advantages of Wilson
and Nowick’s method are that it uses only the imidazolidone and
commercially available alkyl halides. Considering the number of
alkyl halides available, this gives rise to many potential permuta-
tions. This is the basis for our belief that urea peptoids will lead to
the facile synthesis of heterogeneous polymers containing multi-
ple functionalities. Additional benefits are that the imidazolidone
can be prepared in multigram quantities and stored at room
temperature. We selected the side groups used in this study
because they are readily identified using NMR spectroscopy
allowing for accurate characterization and demonstration of
successful coupling to the polymer. We have chosen to couple
our urea peptoids and polymers using the facile copper-catalyzed
azide/alkyne cycloaddition (CuAAC) reaction and hence have
used terminal alkyne moieties in our urea peptoid design.
N-methyl peak at 3.01 ppm and the alkyne proton at 2.23 ppm, in
conjunction with mass spectrometry which showed a molecular
ion peak at m/z 196.14 (calculated m/z = 196.10 M þ 1).
We prepared two statistical copolymers to form the urea
peptoid/polymer conjugates: poly(styrene-co-AzPMA) and poly-
(MAIpGlc-co-AzPMA). We chose polystyrene for proof-of-
principle purposes and poly(3-O-methacryloyl-1,2:5,6-di-O-iso-
propylidene-D-glucofuranose) (poly(MAIpGlc)) to demonstrate
that this chemistry can easily be coupled with more complex
polymers. Furthermore, following deprotection of the isopropy-
lidine protecting groups the polymer is rendered water-soluble.
MAIpGlc is an interesting monomer that has found uses in a
range of areas including modifying poly(vinylidene fluoride)29
and polysulfone membranes,30 for increased hydrophilicity and
nonfouling properties, blood-compatible surfaces,31 synthesis of
core-shell nanoparticles,32 functionalization of carbon nano-
tubes,33 and synthesis of liquid CO2 amphiphiles.34 We employed
an azide-containing monomer as a comonomer for both poly-
mers to take advantage of copper-catalyzed azide/alkyne cy-
cloaddition reaction in our coupling chemistry. Copper-catalyzed
azide/alkyne cycloaddition chemistry has had an enormous
impact on polymer chemistry, reflected in the large numbers of
original reports and review articles published on this topic in a
short space of time.35,36 Because of the high tolerance for
functional groups and conditions, CuAAC chemistry has been
readily adapted to include biological molecules.37 Specific exam-
ples include synthesis of glycopolymer conjugates38,39 and
BSA-polymer conjugates.40 Fewer examples exist of the click
reaction being used with peptoid chemistry. Holub and co-
workers41 have used CuAAC chemistry to conjugate peptoid
oligomers with 17 R-ethynylestradiol, and CuAAC chemistry has
been coupled with N-substitued glycines in the preparation of
protein microarrays.42 The polymerizations were performed
under controlled/“living” radical conditions using RAFT condi-
tions. This resulted in the formation of polymers with narrow
molecular weight distributions and the potential for formation of
block copolymers. For the styrene copolymerization we used the
difunctional trithiocarbonate while for the copolymerization of
MAIpGlc we used a monofunctional trithiocarbonate. We chose
the two different RAFT agents to further show the versatility of
our approach. The properties of the two statistical polymers are
given in Table 1. We determined the ratio of styrene to AzPMA
to be 65:1 and the ratio of MAIpGlc to AzPMA to be 19:1 by
1H NMR spectroscopy. As can be seen from Table 1, the molecular
The synthesis of the urea peptoid trimer 9 is shown in Figure 2.
The precursor urea peptoid 1 was chain extended using benzyl
chloride, methyl iodide, and 3-bromopropyne to yield 9. The
1
structure of the final compound was confirmed with H NMR
spectroscopy which showed the aromatic protons at 7.16-7.21
ppm, the N-methyl peak at 2.86 ppm, and the alkyne proton at
Figure 3. Structure of urea peptoid dimer 10. The synthesis of 10 is
reported in the Supporting Information.
Table 1. Size Exclusion Chromatography Data for Statistical Copolymers
dn/dca Mnb (g/mol) Mwc (g/mol)
Mw/Mn
0.226 20 000 24 200
polymer
Mn,theod (g/mol)
poly(Sty-co-AzPMA)
poly(MAIpGlc-co-AzPMA)
1.21
1.07
21 800
32 200
0.0963 101 100 107 900
a dn/dc values were calculated using a Wyatt Optilab rEX detector in offline mode with Astra software. b Mn = number-average molecular weight.
c Mw = weight-average molecular weight. d Mn,theo = theoretical molecular weight. Theoretical molecular weight = (([M]0/[CTA]0) ꢀ Mr ꢀ p) þ MCTA
where [M]0 = initial monomer concentration, [CTA]0 = initial RAFT agent concentration, Mr = molecular weight of the monomer, p = conversion,
and MCTA = molecular weight of the RAFT agent.

1346 Macromolecules, Vol. 43, No. 3, 2010
Chen and Ayres
Figure 4. Conjugation of urea peptoids to RAFT polymers using copper-catalyzed azide/alkyne cycloaddition reaction.
weight of poly(MAIpGlc-co-AzPMA) was higher than the theo-
retical molecular weight. We ascribe this difference to loss of the
RAFT agent controlling the reaction in the early stages of the
polymerization.
We prepared conjugates of urea peptoids 9 and 10 with both
azide-functionalized statistical polymers, creating four poly-
mer-urea peptoid conjugates (Figure 4).
1
The H NMR spectrum of poly(MAIpGlc-co-AzPMA)-9 is
shown in Figure 5a. We have included the NMR spectra for the
conjugation of 10 in the Supporting Information. We further
confirmed the formation of the polymer-peptoid conjugates by
observing the disappearance of the azide peak at 2100 cm-1 in
the FTIR spectra of the polymer before and after CuAAC
functionalization. To determine the degree of functionalization,
we recorded the 1H NMR spectrum of poly(MAIpGlc-co-
AzPMA)-9 in CD2Cl2 (the spectrum is shown in the Supporting
Information). This allowed the integration of peaks originating
from the benzene group in the urea peptoid and one proton from
the triazole ring between 7.2 and 7.5 ppm from the urea peptoid
against the peak due to the proton between the two O atoms on
the fused rings from the repeat units of MAIpGlc at 5.79 ppm
from the polymer without interference from the NMR solvent.
Comparison of the integrals gives a degree of coupling of 16 urea
peptoids per polymer chain, which matches the MAIpGlc:AzP-
MA monomer ratio in the polymer. Therefore, from the NMR
data coupled with the FTIR spectra, we believe that the CuAAC
reaction is quantitative.
Following the conjugate formation with poly(MAIpGlc-co-
AzPMA) and 9, we performed a deprotection reaction to
remove the isopropylidene groups using dilute TFA. This
yields the water-soluble, sugar-functionalized, polymer-urea
peptoid conjugate poly(MAGlc-co-AzPMA)-9. The deprotec-
1
tion reaction was confirmed using H NMR spectroscopy in
D2O. The NMR spectra of the polymer conjugate before
and after deprotection are shown in Figure 5a with the corres-
Figure 5. (a) 1H NMR (400 MHz) spectra of poly(MAIpGlc-co-
AzPMA)-9 before (in CDCl3) and after (in D2O) deprotection of
isopropylidenegroups. (b) FTIR spectra ofpoly(MAIpGlc-co-AzPMA)
before and after conjugation to 9 and following deprotection of the
isopropylidene groups.
ponding FTIR spectra shown in Figure 6b. The loss of the
peaks resulting from the furan ring structure around 6.2 and
4-5 ppm can be seen along with the appearance of a complex
multiplet between 3 and 4 ppm from the pyran sugar structure
in the 1H NMR spectra. The FTIR spectra show the loss of the
peak at 2100 cm-1 due to the azide moieties after the conjuga-
tion reaction and a large peak at ∼3400 cm-1 due to the sugar
hydroxyls appearing in the FTIR spectra after removal of the
isopropylidene protecting groups.

Article
Macromolecules, Vol. 43, No. 3, 2010 1347
Figure 6. Extension of poly(styrene-co-AzPMA)-9 with (a) 5-carboxyfluorescein and (b) 3-[4-(bromomethyl)phenyl]-7-(diethylamino)coumarin. (i) = DCC,
5-carboxyfluorescein; (ii) DMAP, pyridine, N-(2-nitrobenzenesulfonyl)-2-imidazolidone; (iii) 3-[4-(bromomethyl)phenyl]-7-(diethylamino)coumarin, K2CO3.
While not ideal for direct comparison, the change in polarity of
poly(MAGlc-s-AzPMA) after removal of the isopropylidene
protecting groups resulted in the use of D2O as the NMR solvent
rather than performing the NMR characterization in CDCl3 for
both polymers.
We next determined how effective the coupling reaction was to
the polymers. This was achieved using UV spectroscopy and
preparing a standard concentration curve for each dye. We chose
to use UV spectroscopy rather than fluorescence to eliminate
concerns about changes in the quantum yield of the fluorophore
postcoupling to the urea peptoid/polymer and possible self-
quenching effects. Interestingly, both routes appear to give nearly
identical coupling efficiencies, with 88% efficiency for the fluor-
oscein carbodiimide coupling and 89% efficiency for the coumar-
in coupling iteration cycle.
We have shown that the peptoids can be further modified after
conjugation to the polymer using reaction with fluorescent
compounds. The addition of fluorophores is an effective demon-
stration that the urea peptoids can be further modified as the
polymer/urea peptoid conjugatepossesses no innate fluorescence.
We have taken two strategies: First, we coupled 5-carboxyfluor-
escein to poly(styrene-co-AzPMA)-9 directly using DCC cou-
pling chemistry (Figure 6a). Alternatively, we performed an
iterative synthesis step of addition and attachment using an
alkylbromine-functionalized coumarin derivative (Figure 6b).
Following addition of the fluorescent compounds the polymer/
urea peptoid conjugates were strongly fluorescent while the
parent polymer conjugates were not. This demonstrates that
the urea peptoids are able to be further functionalized postcou-
pling with the polymer. The fluorescence spectra are shown in
Figure 7 with the spectra of the dyes shown as comparison.
Conclusions
We have demonstrated the combination of a powerful set of
reaction strategies (RAFT polymerization, urea peptoid synth-
esis, and CuAAC coupling reactions) that are both complemen-
tary in nature and simple to perform. The reactions are high-
yielding, and extension of the urea peptoid sequences can be
performed either pre- or postcoupling to the polymer chain. The
macromolecular constructs reported here serve as a “first step”
toward urea peptoid-containing chimera polymers, and we are

1348 Macromolecules, Vol. 43, No. 3, 2010
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Acknowledgment. Wethank TheUniversityofCincinnatifor
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Supporting Information Available: Synthesis of urea
peptoid 10; Beer-Lambert plots prepared for fluorescein
and coumarin dyes incorporation study; 1H, 13C NMR, and
FT-IR spectra of the urea peptoids and GPC traces of the
polymers prepared in this work. This material is available free
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