ADMET Synthesis of Polyolefins Targeted for Biological Applications

Article abstract of DOI:10.1021/ma035289u

A series of "N-terminus" amino acid and peptide branched, chiral polyolefins, termed bioolefins, have been prepared using acyclic diene metathesis (ADMET) polycondensation chemistry, using a minimal amount of solvent and Grubbs' second generation catalyst. The carboxylic acid functional groups were protected with methyl, benzyl, and tert-butyl esters to enhance both the polymerizability of the monomers themselves and the solubility of the resulting polymers. A number of these polymers are semicrystalline, exhibiting melt transitions of up to 132 and 74°C for the amino acid and dipeptide branched polymers, respectively. Adding a succinic acid spacer between the amino acid entity and the polymer backbone alters the melting behavior of the polymer, increasing the peak melting point by 27°C when compared to a polymer having the same amino acid directly attached to the polymer backbone.

Full text of DOI:10.1021/ma035289u

1180
Macromolecules 2004, 37, 1180-1189
ADMET Synthesis of Polyolefins Targeted for Biological Applications
Tim oth y E. Hop k in s a n d Ken n eth B. Wa gen er *
The George and J osephine Butler Polymer Laboratory, Department of Chemistry, University of Florida,
P.O. Box 117200, Gainesville Florida 32611-7200
Received September 2, 2003; Revised Manuscript Received November 10, 2003
ABSTRACT: A series of “N-terminus” amino acid and peptide branched, chiral polyolefins, termed bio-
olefins, have been prepared using acyclic diene metathesis (ADMET) polycondensation chemistry, using
a minimal amount of solvent and Grubbs’ second generation catalyst. The carboxylic acid functional groups
were protected with methyl, benzyl, and tert-butyl esters to enhance both the polymerizability of the
monomers themselves and the solubility of the resulting polymers. A number of these polymers are
semicrystalline, exhibiting melt transitions of up to 132 and 74 °C for the amino acid and dipeptide
branched polymers, respectively. Adding a succinic acid spacer between the amino acid entity and the
polymer backbone alters the melting behavior of the polymer, increasing the peak melting point by 27 °C
when compared to a polymer having the same amino acid directly attached to the polymer backbone.
In tr od u ction
bio-olefins,17 where the functionality is attached through
the N-terminus rather than the C-terminus. These
polymers offer the potential of having carboxylic acids
present on the surface of the material. Complete syn-
thetic details and thermal analysis of these polymers
are discussed.
The incorporation of a high degree of amino acid
functionality and chirality in a polymer’s repeat unit
can increase the solubility of the material that results,
in addition to enhancing the potential to form secondary
structures such as R-helices and â-sheets.1,2 Such poly-
mers can be useful as drug-delivery agents, chiral
recognition stationary phases, asymmetric catalysts,
metal ion absorbents, and biocompatible materials.3
Advancements in chiral separation and monomer syn-
thesis have led to a wide availability of inexpensive and
enantiopure protected amino acids; the field is ripe for
exploration.
For example, Endo, Sanda, and co-workers have syn-
thesized a variety of amino acid and peptide branched
acrylamides via radical polymerizations,4,5 North et al.
have prepared polyacrylates where the amino acid is
attached through the alcohol side chain of a serine
moiety leaving the N- and C-termini of the amino acid
available for further chemistry,6,7 and Ayres and co-
workers have prepared elastin-based polyolefins via a
“living” polymerization technique, atom transfer radical
polymerization (ATRP).8 The subject has even evolved
to polymers based on conjugated systems; a variety of
amino acid branched polyacetylenes have been pre-
pared.9,10
Given the breadth of application based on the me-
tathesis reaction, it is not surprising to find that ring-
opening metathesis (ROMP) has been employed to
prepare amino acid and peptide branched polymers,11,12
including the polymerization of norbornene functional-
ized with the biologically active tripeptide RGD (argi-
nine-glycine-aspartic acid).13 Copolymerization with
a norbornene bearing a penta(ethylene oxide) branch
yielded a water-soluble polymer capable of inhibiting
cell binding to fibronectin, a property which could be
useful for a variety of biomedical applications.13
Acyclic diene metathesis (ADMET) chemistry also
proves viable for the preparation of amino acid poly-
mers, and recently we presented our first work in this
area.14,15,16 We now report the synthesis and properties
of amino acid and peptide-branched polyolefins, termed
Exp er im en ta l Section
Ch em ica ls. Reagents and chemicals were purchased and
used as received from the Aldrich chemical company,
unless otherwise noted. Diethyl ether and THF were used as
received from Fisher Scientific unless dry solvents were
required, which were obtained from the Aldrich keg system
and dried over Al2O3. Methylene chloride, methanol, and
chloroform were used as purchased from Fisher. Anhydrous
DMF (99.8%) was used as purchased in an Aldrich sure seal
container equipped with an Aldrich Schlenk cap. The second
generation Grubbs Ru catalyst (tricyclohexylphosphine[1,3-bis-
(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][ben-
zylidene]ruthenium(IV) dichloride) was used exclusively and
was synthesized as described previously by Grubbs et al.18 The
protected amino acids and peptides were used as purchased
from Bachem, except for H-Leu-OMe, which was purchased
from Sigma-Aldrich.
In str u m en ta tion . All 1H NMR (300 MHz) and 13C NMR
(75 MHz) spectra were recorded on a Varian Associates Gemini
300, Varian Associates VXR 300, or a Varian Associates
Mercury 300 spectrometer. All chemical shifts were referenced
to TMS (0.00 ppm) for 1H NMR and to CDCl3 (77.23 ppm) or
DMSO-d6 (39.51 ppm) for 13C NMR.
Gel permeation chromatography (GPC) of the unsaturated
ADMET polymers was performed using a Waters Associates
GPCV2000 liquid chromatography system with an internal
differential refractive index detector (DRI), an internal dif-
ferential viscosity detector (DP), and a Precision 2 angle light
scattering detector (LS). The light scattering signal was
collected at a 15° angle and corrected at a 90° angle. The three
in-line detectors were operated in series in the order LS-DRI-
DP. The chromatography was performed at 45 °C using two
Waters Styragel HR-5E columns (10 µm PD, 7.8 mm i.d., 300
mm length) with HPLC grade THF as the mobile phase at a
flow rate of 1.0 mL/min. Injections were made at 0.05-0.07%
w/v sample concentration using a 322.5 µL injection volume.
The Precision LS was calibrated using a narrow polystyrene
standard having a Mw ) 65 000 g/mol.
Differential scanning calorimetry (DSC) was performed
using a Perkin-Elmer DSC 7 at a heating rate of 10 °C/min
using indium and p-nitrotoluene as calibration standards with
heats of fusion referenced against indium. The samples were
* Corresponding author. E-mail: wagener@chem.ufl.edu.
10.1021/ma035289u CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/21/2004

Macromolecules, Vol. 37, No. 4, 2004
Ta ble 1. Mh w , P DI, Tm , a n d Tg Da ta
ADMET Synthesis of Polyolefins 1181
for premonomer 2, using undecenyl bromide (28.0 g, 112
mmol), NaH (3.22 g, 60% in mineral oil, 134 mmol), and diethyl
malonate (7.16 g, 44.7 mmol). The saponification was ac-
complished as discussed above using ethanol (100 mL) and 6
M NaOH (250 mL) and was worked up by acidification followed
by extraction with diethyl ether. Decarboxylation was ac-
complished as described above using Decalin (25 mL) and
catalytic DMAP in a 190 °C oil bath for 1 h. The crude product
was purified using hexane to remove Decalin and 3:1 hexanes:
ethyl acetate to remove the desired product. The product can
be further purified by recrystallization in pentane yielding a
white powder (10.5 g, 65%). 1H NMR (300 MHz, CDCl3, ppm):
δ 1.22-1.55 (br, 28 H), 1.63 (m, 4H), 2.05 (q, 4H), 2.06 (q, br,
4H), 2.37 (m, 1H), 4.98 (m, 4H), 5.82 (m, 2H). 13C NMR (75
MHz, CDCl3, ppm): δ 27.58, 29.15, 29.34, 29.65, 29.68, 29.75,
29.77, 32.37, 34.03, 45.75, 114.31, 139.44, 183.14.
a
b
b
polymer
Mh w (g/mol)
PDIa
Tm (°C)
Tg (°C)
19
20
21
22
23
24
25
26
27
28
29
30
31
26 000
36 000
73 000
63 000
21 000
25 000
42 000
29 000
44 000
26 000
73 000
21 000
38 000
1.54
1.45
1.55
1.67
1.62
1.91
1.85
1.59
1.80
1.40
1.50
1.40
1.64
e
e
28
18
d
132
e
7
38c
e
-21
5
e
e
-10
3
79
e
106
71c
74
d
69
5
d
d
a
Mh w and PDI values were calculated by GPC using LALLS.
Syn th esis of 1-Un d ec-10-en yl-d od ec-11-en yla m in e (4).
Synthesis was performed as described in a previous publica-
tion, and the characterization matched that previously re-
ported.16
Data obtained using a Perkin-Elmer DSC 7 at 10 °C/ min. c The
b
Tm reported is that of the solvent crystallized sample; no Tm was
d
observed from the melt crystallized sample. No Tg observed over
the scanned range of -80 to +180 °C. e No Tm observed over the
scanned range of -80 to +180 °C.
Syn th esis of N-(1-Un d ec-10-en yl-d od ec-11-en yl)su cci-
n a m ic a cid (5). To a 100 mL round-bottom flask equipped
with a stir bar under nitrogen were added 4 (2.55 g, 7.61
mmol), succinic anhydride (1.90 g, 19.00 mmol), and a catalytic
amount of DMAP in 20 mL of dry THF. The reaction was
stirred under argon for 12 h. Evaporation of THF yielded a
white solid, which was purified by recrystallization from CH3-
CH2OH/H2O to give the pure product in a 67% yield. 1H NMR
(300 MHz, CDCl3, ppm): δ 1.14-1.66 (br, 32 H), 2.04 (q, 4H),
2.51 (t, 2H), 2.70 (t, 2H), 3.78-3.96 (br, 1H), 4.88-5.06 (m,
4H), 5.54 (d, br, 1H), 5.72-5.90 (m, 2H). 13C NMR (75 MHz,
CDCl3, ppm): δ 26.07, 29.16, 29.35, 29.69, 29.76, 29.77, 29.79,
30.42, 31.20, 34.03, 35.28, 50.05, 114.33, 139.43, 172.15,
176.72.
scanned three times to remove recrystallization differences
between samples and when possible the results reported came
from the third scan. The results are listed in tabular form
(Table 1) as well as within the text as Tm (melting peak) and
Tg (glass transition at 1/2 Cp).
Ch a r a cter iza tion . Strenuous purification was only per-
formed on the final monomers reported herein. Only 1H NMR
and 13C NMR spectra are reported for the premonomers (2-
1
6). All of the monomers were fully characterized by H NMR,
13C NMR, EI/HRMS, and elemental analysis with purity
confirmed by TLC. The polymers were characterized by 1H
NMR, 13C NMR, GPC, and DSC.
Gen er a l Cou p lin g P r oced u r e of th e Am in o Acid /
Dip ep tid es to 2, 3, or 5. The appropriate amino acid/
dipeptide and 1-hydroxybenzotriazole (HOBt) (2.5-5 equiv to
amino acid) were added to a 100 mL round-bottom flask. To
the flask, equipped with a stir bar and under argon, was added
premonomers 2, 3, or 5 (1 equiv), 1,3-diisopropylcarbodiimide
(DIC) (1.2-2 equiv to premonomer acid), amino acid/dipeptide
(1.2 equiv), and dry THF (just enough to dissolve the com-
pounds). Finally, NEt3 (1 equiv to amino acid) was added to
the solution to neutralize the amino acid salt. The reaction
vessel was equipped with a reflux condenser heated at 50-60
°C for 12 h for the amino acids and 48 h for the peptides. The
insoluble urea was removed via gravity filtration, followed by
extraction (1 × H2O, 2 × concentrated NaHCO3, 2 × 1 M HCl).
The product was purified with three successive recrystalliza-
tions using methanol/water (the product was dissolved in hot
methanol, and water was added until the solution became
cloudy) or by column chromatography.
Mon om er Syn th esis. Syn th esis of 2-P en t-4-en yl-h ep t-
6-en oic Acid (2).19 To a 500 mL three neck round-bottom flask
equipped with a stir bar, reflux condenser, and addition funnel
was added diethyl malonate (12.01 g, 75.0 mmol, 11.3 mL)
dropwise to a slurry of NaH (10 g, 60% in mineral oil, 0.250
mol) in THF (30 mL). 5-Bromo-1-pentene (25 g, 167.9 mmol)
in THF (10 mL) was then added dropwise. The reaction was
stirred at room temperature for 1 h and at reflux for an
additional 24 h. The reaction was monitored by TLC using a
3:1 hexanes:ethyl acetate mobile phase. Additional 5-bromo-
1-pentene (1.25 g, 8.4 mmol, 1.0 mL) and NaH (1.0 g, 60 % in
mineral oil, 25.0 mmol) were added, and the reaction was
allowed to stir under reflux. After 5 h, the reaction appeared
to be complete by TLC. The mixture was then cooled in an ice
bath, and water was added slowly to neutralize the remaining
NaH. Then 50 mL of water (total ∼ 100 mL) and ethanol (50
mL) were added along with NaOH (15.0 g, 375.0 mmol) and
the reaction was refluxed for 24 h. The reaction was monitored
for the disappearance of the diester using TLC (3:1 hexanes:
ethyl acetate mobile phase). The solution was neutralized with
concentrated HCl and extracted with diethyl ether. Following
evaporation of diethyl ether, Decalin (30 mL), and a catalytic
amount of N,N-(dimethylamino)pyridine (DMAP) were added
to a 500 mL round-bottom flask equipped with a stir bar and
a reflux condenser. The flask was lowered into a 190 °C oil
bath, and decarboxylation was monitored by the excess froth-
ing caused by the release of CO2. After the frothing decreased,
the reaction was allowed to cool to room temperature. The
crude mixture was flashed through a plug of silica gel using
hexane as the initial eluent to remove Decalin and nonpolar
impuritiessthe Decalin could be observed as a clear ring
moving through the plug. Once all of the Decalin was removed,
the eluent was switched to ethyl acetate to remove the desired
Syn th esis of (S)-2-(2-P en t-4-en yl-h ep t-6-en oyla m in o)-
p r op ion ic Acid Ben zyl Ester (6). The pure product 6 was
obtained using the methodology employed above. Purification
was obtained by three recrystallizations from CH3OH/H2O to
1
yield 44% of the pure white solid (mp ) 71-72 °C). H NMR
(300 MHz, CDCl3, ppm): δ 1.28-1.49 (m, 7H), 1.53-1.69 (br,
4H), 1.95-2.10 (br, 5H), 4.68 (p, 1H), 4.88-5.04 (m, 4H), 5.11-
5.27 (m, 2H), 5.68-5.85 (m, 2H), 5.98 (d, br, 1H) 7.29-7.46
(br, 5H). 13C NMR (75 MHz, CDCl3, ppm): δ 18.90, 26.93,
27.01, 32.59, 32.63, 33.92, 33.94, 47.80, 48.09, 67.38, 114.894,
128.38, 128.68, 128.86, 135.54, 138.71, 138.77, 173.24, 175.39.
Anal. Calcd for C22H31NO3: C 73.91, H 8.74, N 3.92. Found:
C 73.45, H 8.75, N 3.88. EI/HRMS [M + 1]: calcd for C22H31
NO3, 357.2304 g/mol; found, 357.2311 g/mol.
-
Syn th esis of (S)-4-Meth yl-2-(2-pen t-4-en yl-h ept-6-en oyl-
a m in o)p en ta n oic Acid Ben zyl Ester (7). The pure product
7 was obtained in 74% yield after purification by column
chromatography using 5:1 hexanes:ethyl acetate as the eluent.
The product was a wax with a slight yellow tint. 1H NMR (300
MHz, CDCl3, ppm): δ 0.90 (d, br, 6H), 1.19-1.50 (br, 6H),
1.48-1.70 (br, 5H), 1.91-2.14 (br, 5H), 4.64-4.75 (m, 1H),
4.86-5.02 (m, 4H), 5.07-5.19 (m, 2H), 5.65-5.83 (m, 2H), 5.95
(d, br, 1H), 7.27-7.38 (br, 5H). 13C NMR (75 MHz, CDCl3,
1
product (12.3 g, 68% yield). H NMR (300 MHz, CDCl3, ppm):
δ 1.31-1.75 (m, 8H), 2.05 (q, 4H), 2.27-2.43 (br, 1H), 4.89-
5.06 (m, 4H), 5.69-5.87 (m, 2H) 10.06-11.22 (br, 1H). 13C
NMR (75 MHz, CDCl3, ppm): δ 26.75, 31.75, 33.79, 45.52,
114.99, 138.54, 183.24.
Syn th esis of 2-Un d ec-10-en yltr id ec-12-en oic a cid (3).19
Premonomer 3 was synthesized using the methodology applied

1182 Hopkins and Wagener
Macromolecules, Vol. 37, No. 4, 2004
ppm): δ 22.00, 23.07, 25.11, 26.91, 26.98, 32.62, 32.73, 33.85,
33.95, 41.73, 47.79, 50.71, 67.20, 114.83, 114.87, 128.43,
128.59, 128.79, 135.63, 138.65, 138.74, 173.17, 178.74. Anal.
Calcd for C25H37NO3: C 75.15, H 9.33, N 3.51. Found: C 74.73,
H 9.40, N 3.59. EI/HRMS [M + 1]: calcd for C34H64N2O3,
399.2773 g/mol; found, 399.2778 g/mol.
2.49. EI/HRMS [M + 1]: calcd for C37H61NO3, 567.4651 g/mol;
found, 567.4654 g/mol.
Syn th esis of (S)-4-Meth yl-2-(2-u n d ec-10-en yltr id ec-12-
en oyla m in o)p en ta n oic a cid m eth yl ester (13). The pure
product 13 was obtained in 74% yield and purified via column
chromatography using a 5:1 hexanes:THF mobile phase (mp
1
Syn th esis of (S)-4-Meth yl-2-(2-pen t-4-en yl-h ept-6-en oyl-
a m in o)p en ta n oic Acid Meth yl Ester (8). The pure product
8 was obtained in 80% yield after purification by column
chromatography using 5:1 hexanes:THF as the eluent yielding
) 42-44 °C). H NMR (300 MHz, CDCl3, ppm): δ 0.94 (d, br,
6H), 1.10-1.48 (br, 30H), 1.48-1.73 (br, 5H), 1.93-2.14 (br,
5H), 3.72 (s, 3H), 4.61-4.77 (br, 1H), 4.87-5.11 (m, 4H), 5.71-
5.93 (br, 3H). 13C NMR (75 MHz, CDCl3, ppm): δ 22.04, 23.08,
25.12, 27.75, 27.84, 29.15, 29.35, 29.72, 29.76, 29.83, 29.92,
33.25, 33.37, 34.03, 41.92, 48.20, 50.52, 52.40, 114.31, 139.42,
139.44, 173.87, 176.03. Anal. Calcd for C31H57NO3: C 75.71, H
11.68, N 2.85. Found: C 75.62, H 11.75, N 2.84. EI/HRMS [M
+ 1]: calcd for C31H57NO3, 491.4338 g/mol; found, 491.4341
g/mol.
1
an opaque wax. H NMR (300 MHz, CDCl3, ppm): δ 0.95 (d,
br, 6H), 1.27-1.51 (br, 6H), 1.51-1.72 (br, 5H), 1.96-2.17 (br,
5H), 3.73 (s, 3H), 4.62-4.73 (m, 1H), 4.89-5.07 (m, 4H), 5.70-
5.87 (m, 2H), 5.92 (d, br, 1H). 13C NMR (75 MHz, CDCl3,
ppm): δ 22.00, 23.04, 25.10, 26.89, 26.96, 32.62, 32.75, 33.84,
33.94, 41.77, 47.80, 50.56, 52.41, 114.79, 114.82, 138.64,
138.74, 173.79, 175.73. Anal. Calcd for C19H33NO3: C 70.55, H
10.28, N 4.33. Found: C 70.51, H 10.27, N 4.35. EI/HRMS [M
+ 1]: calcd for C19H33NO3, 323.2460 g/mol; found, 323.2455
g/mol.
Syn th esis of (S)-6-ben zyloxyca r bon yla m in o-2-(2-u n -
d ec-10-en yltr id ec-12-en oyl-a m in o)-h exa n oic a cid m eth yl
ester (14). The pure product 14 was obtained in 78% yield
after purification by three recrystallizations from CH3OH/H2O
(mp ) 109-111 °C). 1H NMR (300 MHz, CDCl3, ppm): δ 1.14-
1.45 (br, 32H), 1.47-1.94 (br, 6H), 1.96-2.11 (br, 5H), 3.17
(q, br, 2H), 3.73 (s, 3H), 4.56-4.66 (m, 1H), 4.77-4.88 (br, 1H),
4.89-5.84 (m, 4H), 5.06-5.16 (br, 2H), 5.68-5.86 (m, 2H), 6.03
(d, br, 1H), 7.29-7.41 (br, 5H). 13C NMR (75 MHz, CDCl3,
ppm): δ 22.56, 27.76, 27.91, 29.16, 29.37, 29.57, 29.70, 29.73,
29.78, 29.86, 29.92, 32.38, 33.17, 33.27, 34.04, 40.75, 48.11,
51.76, 52.57, 66.85, 114.33, 128.32, 128.74, 136.79, 139.46,
156.73, 173.25, 176.19. Anal. Calcd for C39H64N2O5: C 73.08,
H 10.06, N 4.37. Found: C 73.01, H 10.07, N 4.32. EI/HRMS
[M + 1]: calcd for C39H64N2O5, 640.4815 g/mol; found, 640.4831
g/mol.
Syn th esis of (S)-6-Ben zyloxyca r bon yla m in o-2-(2-p en t-
4-en yl-h ep t-6-en oyla m in o)h exa n oic Acid Meth yl Ester
(9). The pure product 9 was obtained in 55% yield after
purification by three recrystallizations from CH3OH/H2O (mp
1
) 77-79 °C). H NMR (300 MHz, CDCl3, ppm): δ 1.19-1.94
(br, 14H), 1.95-2.14 (br, 5H), 3.17 (q, br, 2H), 3.74 (s, 3H),
4.54-4.66 (m, 1H), 4.75-4.88 (br, 1H), 4.89-5.84 (m, 4H),
5.06-5.16 (br, 2H), 5.68-5.86 (m, 2H), 6.05 (d, br, 1H), 7.27-
7.42 (br, 5H). 13C NMR (75 MHz, CDCl3, ppm): δ 22.57, 26.92,
27.08, 29.58, 32.20, 32.60, 32.69, 33.87, 33.94, 40.74, 47.80,
51.83, 52.61, 66.87, 114.88, 114.92, 128.34, 128.75, 136.78,
138.71, 138.76, 156.76, 173.20, 175.87. Anal. Calcd for
C
27H40N2O5: C 68.62, H 8.53, N 5.93. Found: C 68.33, H 8.66,
Syn th esis of Ar gin in e-Br a n ch ed Mon om er (15).20 The
pure product 15 was obtained as a yellow tinted oil in 78%
yield after purification by column chromatography using ethyl
acetate as the eluent. 1H NMR (300 MHz, CDCl3, ppm): δ
1.14-1.76 (br, 41H), 1.82-1.97 (m, br, 1H), 1.98-2.17 (br, 8H),
2.54 (s, 3H), 2.60 (s, 3H), 2.97 (s, 2H), 3.13-3.29 (br, 1H), 3.30-
3.46 (br, 1H), 3.76 (s, 3H), 4.52-4.64 (br, 1H), 4.89-5.07 (m,
4H), 5.73-5.92 (m, 2H), 6.13-6.23 (br, 2H), 6.30-6.40 (br, 2H).
13C NMR (75 MHz, CDCl3, ppm): δ 12.68, 18.07, 19.46, 25.21,
27.70, 27.83, 28.82, 29.15, 29.36, 29.69, 29.78, 29.84, 29.89,
30.96, 33.06, 33.15, 34.03, 40.84, 43.49, 47.95, 52.82, 86.54,
114.34, 117.64, 124.76, 132.51, 133.35, 138.56, 139.43, 156.33,
158.90, 172.88, 177.31. Anal. Calcd for C44H74N4O6S: C 67.14,
H 9.48, N 7.12. Found: C 67.56, H 9.73, N 6.80. EI/HRMS [M
+ 1]: calcd for C44H74N4O6S, 786.5329 g/mol; found, 786.5360
g/mol.
Syn th esis of (S)-6-Ben zyloxyca r bon yla m in o-2-[3-(1-
u n dec-10-en yl-dodec-11-en ylcar bam oyl)pr opion ylam in o]-
h exa n oic Acid Meth yl Ester (16). The pure product 16 was
obtained in 72% yield as a white solid after purification by
three recrystallizations using CH3CH2OH/H2O (mp ) 131-
133 °C). 1H NMR (300 MHz, CDCl3, ppm): δ 1.10-1.75 (br,
38H), 1.75-1.88 (br, 1H), 1.90-1.96 (br, 1H), 2.02 (q, 4H),
2.36-2.61 (br, 4H), 3.06-3.27 (br, 2H), 3.71 (s, 3H), 3.75-3.90
(br, 1H), 4.46-4.61 (br, 1H), 4.86-5.04 (m, 4H), 5.06-5.22 (br,
3H), 5.58 (d, br, 1H), 5.71-5.91 (m, 2H), 6.68 (d, br, 1H), 7.29-
7.39 (br, 5H). 13C NMR (75 MHz, CDCl3, ppm): δ 22.38, 26.06,
26.09, 29.16, 29.36, 29.71, 29.80, 29.87, 31.82, 31.92, 34.03,
35.30, 35.39, 40.62, 49.69, 52.19, 52.55, 66.77, 114.33, 128.28,
128.73, 136.91, 139.45, 156.83, 171.67, 172.46, 172.96. Anal.
Calcd for C42H69N3O6: C 70.85, H 9.77, N 5.90. Found: C 70.65,
H 9.90, N 5.74. EI/HRMS [M + 1]: calcd for C42H69N3O6,
711.5186 g/mol; found, 711.5252 g/mol.
N 5.88. EI/HRMS [M + 1]: calcd for C27H40N2O5, 472.2937
g/mol; found, 472.2937 g/mol.
Syn th esis of (S)-2-(2-Un d ec-10-en yltr id ec-12-en oyla m i-
n o)p r op ion ic Acid Ben zyl Ester (10). The pure product 10
was obtained in 74% yield and purified by three recrystalli-
zations from CH3OH/H2O (mp ) 87-89 °C). 1H NMR (300
MHz, CDCl3, ppm): 1.19-1.46 (br, 32H), 1.48-1.69 (br, 3H),
1.92-2.10 (br, 5H), 4.68 (p, 1H), 4.85-5.04 (m, 4H), 5.10-5.26
(m, 2H), 5.71-5.89 (m, 2H), 5.99 (d, br, 1H) 7.26-7.40 (br,
5H).13C NMR (75 MHz, CDCl3, ppm): δ 19.13, 27.96, 28.02,
29.38, 29.39, 29.56, 29.57, 29.90, 29.93, 29.97, 30.00, 30.08,
30.12, 33.41, 33.44, 34.25, 48.27, 48.30, 67.52, 114.50, 128.50,
128.83, 129.02, 135.78, 139.63, 139.64, 173.44, 175.88. Anal.
Calcd for C34H55NO3: C 77.66, H 10.54, N 2.66. Found: C 77.46,
H 10.53, N 2.66. EI/HRMS [M + 1]: calcd for C34H55NO3,
525.4182 g/mol; found, 525.4190 g/mol.
Syn th esis of (S)-4-Meth yl-2-(2-u n d ec-10-en yltr id ec-12-
en oyla m in o)p en ta n oic Acid ter t-Bu tyl Ester (11). The
pure product 11 was obtained in 78% yield and purified by
column chromatography using 3:1 hexanes:ethyl acetate as the
eluent.1H NMR (300 MHz, CDCl3, ppm): δ 0.94 (d, br, 6H),
1.13-1.74 (br, 44H), 1.92-2.09 (br, 5H), 4.50-4.61 (m, 1H),
4.88-5.05 (m, 4H), 5.72-5.90 (br, 3H). 13C NMR (75 MHz,
CDCl3, ppm): δ 22.31, 23.05, 25.21, 27.78, 27.85 28.21, 29.16,
29.35, 29.71, 29.74, 29.84, 29.92, 33.24, 33.37, 34.03, 42.42,
48.29, 51.18, 81.92, 114.31, 139.47, 172.66, 175.76. Anal. Calcd
for C34H63NO3: C 76.49, H 11.89, N 2.62. Found: C 76.45, H
12.07, N 2.54. EI/HRMS [M + 1]: calcd for C34H63NO3,
533.4808 g/mol; found, 533.4809 g/mol.
Syn th esis of (S)-4-Meth yl-2-(2-u n d ec-10-en yltr id ec-12-
en oyla m in o)p en ta n oic Acid Ben zyl Ester (12). The pure
product 12 was obtained in 78% yield and purified by column
chromatography using a 5:1 hexanes:THF mobile phase (mp
Syn th esis of (S)-2-[2-(2-Un d ec-10-en yltr id ec-12-en oyl-
a m in o)p r op ion yla m in o]p r op ion ic Acid Met h yl E st er
(17). The pure product 17 was obtained in 72% yield after
purification by three recrystallizations from CH3OH/H2O (mp
) 99-100 °C). 1H NMR (300 MHz, CDCl3, ppm): δ 1.12-1.50
(br, 35H), 1.51-1.67 (br, 3H), 1.94-2.12 (br, 5H), 3.75 (s, 3H),
4.55 (m, 2H), 4.88-5.06 (br, 2H), 5.80 (m, 2H), 5.98 (d, 1H),
6.70 (d, 1H). 13C NMR (75 MHz, CDCl3, ppm): δ 18.26, 18.51,
27.81, 29.15, 19.35, 29.69, 29.76, 29.79, 29.86, 29.93, 33.24,
34.03, 48.00, 48.30, 48.54, 52.67, 114.33, 139.45, 172.15,
1
) 46-48 °C). H NMR (300 MHz, CDCl3, ppm): δ 0.75-1.00
(br, 6H), 1.08-1.47 (br, 30H), 1.47-1.75 (br, 5H), 1.90-2.12
(br, 5H), 4.63-4.79 (br, 1H), 4.85-5.06 (br, 4H), 5.08-5.23 (br,
2H), 5.67-5.94 (m, 2H), 5.95 (d, br, 1H), 7.27-7.46 (br, 5H).
13C NMR (75 MHz, CDCl3, ppm): δ 22.05, 23.08, 25.12, 27.76,
27.85, 29.16, 29.36, 29.71, 29.79, 29.84, 29.92, 33.22, 33.34,
34.04, 41.90, 48.22, 50.65, 67.21, 114.33, 128.41, 128.59,
128.80, 135.63, 139.44, 173.27, 176.02. Anal. Calcd for C37H61
NO3: C 78.25, H 10.83, N 2.47. Found: C 78.12, H 10.91, N
-

Macromolecules, Vol. 37, No. 4, 2004
ADMET Synthesis of Polyolefins 1183
173.21 176.28. Anal. Calcd for C31H56N2O4: C 71.49, H 10.84,
N 5.38. Found: C 71.47, H 10.80, N 5.33. EI/HRMS [M + 1]:
calcd for C31H56N2O4, 520.4240 g/mol; found, 520.4232 g/mol.
Syn th esis of (S)-4-Meth yl-2-[4-m eth yl-2-(2-u n d ec-10-
en ylt r id ec-12-en oyla m in o)p en t a n oyla m in o]p en t a n oic
Acid Meth yl Ester (18). The pure product 18 was obtained
in 71% yield after purification by three recrystallizations from
CH3OH/H2O (mp ) 57-59 °C). 1H NMR (300 MHz, CDCl3,
ppm): δ 0.85-1.01 (m, 12H), 1.12-1.47 (br, 30H), 1.48-1.72
(br, 8H), 1.94-2.08 (br, 5H), 3.73 (s, 3H), 4.43-4.64 (br, 2H),
29.92, 30.54, 31.94, 32.79, 40.74, 47.58, 51.89, 52.54, 66.74,
128.21, 128.27, 128.56, 128.71, 130.36, 136.85, 156.86, 173.23,
176.13.
Ch a r a cter iza tion of 23. 1H NMR (300 MHz, CDCl3,
ppm): δ 1.07-1.49 (br, 32H), 1.50-1.69 (br, 3H), 1.84-2.13
(br, 5H), 4.58-4.76 (p, 1H), 5.09-5.26 (br, 2H), 5.28-5.49 (br,
2H), 6.01-6.21 (br, 1H), 7.24-7.40 (br, 5H).13C NMR (75 MHz,
CDCl3, ppm): δ 18.85, 27.78, 27.84, 29.44, 29.78, 29.91, 32.86,
33.26, 48.05, 67.29, 128.32, 128.63, 128.84, 130.58, 135.61,
173.25, 175.77.
Ch a r a cter iza tion of 24. 1H NMR (300 MHz, CDCl3,
ppm): δ 0.95 (d, br, 6H), 1.13-1.77 (br, 44H), 1.87-2.11 (br,
5H), 4.50-4.63 (m, 1H), 5.28-5.47 (br, 2H), 5.83 (d, br, 1H).
13C NMR (75 MHz, CDCl3, ppm): δ 22.28, 23.05, 25.18,
27.43, 27.79, 27.86, 28.19, 29.42, 29.54, 29.76, 29.80, 29.89,
32.83, 33.26, 33.39, 42.36, 48.26, 51.16, 81.86, 130.54, 172.63,
175.75.
Ch a r a cter iza tion of 25. 1H NMR (300 MHz, CDCl3,
ppm): δ 0.0.92 (d, br, 6H), 1.09-1.47 (br, 30H), 1.48-1.70 (br,
5H), 1.85-2.11 (br, 5H), 4.72 (m, br, 1H), 5.10-5.21 (br, 2H),
5.29-5.41 (br, 2H), 5.86 (d, br, 1H), 7.29-7.40 (br, 5H). 13C
NMR (75 MHz, CDCl3, ppm): δ 22.04, 23.10, 25.12, 27.80,
27.89, 29.44, 29.77, 29.88, 32.85, 33.27, 33.39, 41.85, 48.22,
50.65, 67.18, 128.40, 128.57, 128.79, 130.56, 135.65, 173.24,
176.02.
4.88-5.06 (m, 4H), 5.72-5.92 (br, 3H), 6.51 (d, br, 1H).13
C
NMR (75 MHz, CDCl3, ppm): δ 22.03, 22.24, 23.03, 23.16,
24.91, 24.96, 27.85, 29.16, 29.35, 29.70, 29.73, 29.83, 29.97,
33.16, 33.34, 34.06, 40.92, 41.67, 48.22, 50.93, 51.40, 52.51,
114.35, 139.46, 171.99, 173.24, 176.49. Anal. Calcd for
C
37H68N2O4: C 73.46, H 11.33, N 4.63. Found: C 73.27, H
11.41, N 4.49. EI/HRMS [M + 1]: calcd for C37H68N2O4,
604.5179 g/mol; found, 604.5178 g/mol.
P olym er Syn th esis. Gen er a l Syn th esis. Polymerization
of the monomers containing amino acid and peptide entities
differs somewhat from a typical ADMET polymerization. These
monomers are solids at or near room temperature, and so a
small amount of solvent is necessary to conduct the chemistry
in the liquid state under mild polymerization conditions. The
procedure is described as follows. Monomer is placed in a 50
or 100 mL Schlenk tube equipped with a stir bar and a septum,
followed by the addition of second generation Grubbs’ Ru
catalyst (1) (100:1/monomer:catalyst); both additions are done
while maintaining a positive Ar flow throughout the system,
followed by flushing with Ar for 30 min after the additions
are complete. A minimal amount of dry THF then is added
via syringe to produce a homogeneous solution, and the
reaction mixture is allowed to stir for 144 h at 50 °C. This
lengthy reaction time is done to ensure complete conversion,
which is necessary during a step polymerization; shorter
reaction times likely are feasible. Dry THF was added periodi-
cally to replace solvent lost to evaporation. The reaction then
Ch a r a cter iza tion of 26. 1H NMR (300 MHz, CDCl3,
ppm): δ 0.94 (d, br, 6H), 1.14-1.47 (br, 30H), 1.49-1.72 (br,
5H), 1.89-2.12 (br, 5H), 3.73 (s, 3H), 4.68 (br, m, 1H), 5.28-
5.46 (br, 2H), 5.78-5.96 (br, 1H). 13C NMR (75 MHz, CDCl3,
ppm): δ 22.03, 23.08, 25.11, 27.43, 27.77, 27.87, 29.42, 29.55,
29.77, 29.82, 29.89, 32.83, 33.28, 33.41, 41.88, 48.20, 50.52,
52.39, 130.56, 173.86, 176.03.
Ch a r a cter iza tion of 27. 1H NMR (300 MHz, CDCl3,
ppm): δ 1.09-1.76 (br, 38H), 1.90-2.16 (br, 5H), 3.02-3.23
(br, 2H), 3.71 (s, 3H), 4.52-4.66 (br, 1H), 4.99-5.25 (br, 3H),
5.28-5.45 (br, 2H), 6.26-6.44 (br, 1H), 7.24-7.40 (br, 5H). 13
C
NMR (75 MHz, CDCl3, ppm): δ 22.59, 25.81, 27.74, 27.89,
29.40, 29.53, 29.76, 29.86, 31.98, 32.82, 33.17, 33.29, 40.65,
47.89, 51.81, 52.43, 66.69, 128.18, 128.22, 128.66, 130.52,
136.85, 156.82, 173.21, 176.29.
1
is sampled and assessed for complete conversion via H NMR,
and if necessary, additional catalyst is added and the solution
is allowed to stir for a longer period of time. Once conversion
is complete, the ruthenium catalyst is removed via complex-
ation by treatment with tris(hydroxymethyl)phosphine (THP).
Doing so is accomplished by dissolving the reaction mixture
in chloroform (∼30 mL), combining this solution with a tris-
(hydroxymethyl) phosphine solution (1 M in 2-propanol, 30
equiv. to catalyst) and then extracting this solution with 1 M
HCl (1 × 20 mL), concentrated NaHCO3 (1 × 20 mL), and
concentrated NaCl (1 × 20 mL). The polymer solution that
remains is dried over MgSO4, followed by rotary evaporation
to yield the pure polymer. These polymers can then be solvent-
cast from chloroform on a Teflon plate to yield a thin film.
Ch a r a cter iza tion of 19. 1H NMR (300 MHz, CDCl3,
ppm): δ 1.07-1.73 (br, 7H), 1.74-2.19 (br, 5H), 4.53-4.74 (p,
1H), 5.04-5.39 (br, 4H), 5.94-6.56 (br, 1H), 7.27-7.41 (br,
5H).13C NMR (75 MHz, CDCl3, ppm): δ 18.82, 26.80, 27.75,
32.55, 32.84, 48.07, 48.42, 67.30, 67.40, 128.33, 128.40, 128.65,
128.85, 130.42, 131.47, 135.59, 173.21, 175.62.
Ch a r a cter iza tion of 28. 1H NMR (300 MHz, DMSO-d6,
70 °C, ppm): δ 0.96-1.81 (br, 42H), 1.84-2.29 (br, 8H), 2.39-
2.66 (br, 6H overlapping with DMSO-d6 resonance), 2.89-3.19
(br, 4H), 3.61 (s, br, 3H), 4.14-4.33 (br, 1H), 4.23-4.46 (br,
2H), 6.48-7.33 (br, 3H), 8.12-8.32 (br, 1H). 13C NMR (75 MHz,
DMSO-d6, 70 °C, ppm): δ 12.70, 18.03, 19.36, 26.26, 27.30,
27.49, 28.89, 29.14, 29.61, 31.18, 32.54, 32.98, 33.16, (note some
peaks under DMSO-d6 resonance) 43.36, 46.06, 52.01, 52.25,
86.75, 116.84, 124.87, 130.65, 132.15, 137.84, 156.93, 158.20,
173.06, 175.87.
Ch a r a cter iza tion of 29. 1H NMR (300 MHz, CDCl3,
ppm): δ 1.09-1.77 (br, 36H), 1.77-2.06 (br, 6H), 2.40-2.63
(br, 4H), 3.06-326 (br, 2H), 3.72 (br, s, 3H), 3.79-3.90 (br,
1H), 4.47-4.61 (br, 1H), 5.04-5.17 (br, 2H), 5.22-5.47 (br, 3H),
5.69-6.13 (br, 1H), 6.69-7.02 (br, 1H) 7.20-7.40 (br, 5H).
13C NMR (75 MHz, CDCl3, ppm): δ 22.69, 26.37, 29.62,
29.97, 30.09, 32.05, 33.04, 35.64, 40.86, 49.90, 52.44, 52.69,
66.94, 128.43, 128.88, 130.76, 137.14, 157.00, 171.86, 172.66,
173.10.
Ch a r a cter iza tion of 30. 1H NMR (300 MHz, CDCl3,
ppm): δ 1.10-1.46 (br, 35H), 1.47-1.68 (br, 3H), 1.89-2.13
(br, 5H), 3.74 (s, 3H), 4.52 (br, m, 1H), 4.59-4.76 (br, 1H), 5.07
(m, 4H), 5.72-5.91 (m, 2H), 5.98 (d, br, 1H), 6.70 (d, br, 2H).
13C NMR (75 MHz, CDCl3, ppm): δ 17.97, 18.79, 25.82, 27.39,
27.80, 29.35, 29.75, 29.86, 32.80, 33.24, 47.83, 48.29, 48.49,
52.57, 130.56, 172.54, 173.22, 176.26.
Ch a r a cter iza tion of 31. 1H NMR (300 MHz, CDCl3,
ppm): δ 0.92 (m, 12H), 1.10-1.47 (br, 30H), 1.47-1.73 (br,
8H), 1.86-2.13 (br, 5H), 3.73 (s, 3H), 4.47-4.66 (br, 2H), 5.28-
5.47 (br, 2H), 6.02-6.39 (br, 1H), 6.79-7.09 (br, 1H).13C NMR
(75 MHz, CDCl3, ppm): δ 22.06, 22.38, 22.99, 23.12, 24.88,
24.96, 27.83, 29.39, 29.74, 29.86, 32.80, 33.16, 33.34, 41.10,
41.41, 48.04, 50.94, 51.44, 52.37, 130.08, 130.54, 172.25,
173.18, 176.39.
Ch a r a cter iza tion of 20. 1H NMR (300 MHz, CDCl3,
ppm): δ 0.77-0.97 (br, 6H), 1.10-1.45 (br, 6H), 1.45-1.74 (br,
5H), 1.78-2.18 (br, 5H), 4.59-4.77 (br, 1H), 5.03-5.20 (br, 2H),
5.20-5.39 (br, 2H), 5.80-6.05 (br, 1H), 7.27-7.41 (br, 5H). 13
C
NMR (75 MHz, CDCl3, ppm): δ 22.06, 23.09, 25.10, 27.74,
32.74, 41.73, 47.89, 50.71, 67.19, 128.41, 128.60, 128.81,
130.34, 135.63, 173.28, 175.90.
Ch a r a cter iza tion of 21. 1H NMR (300 MHz, CDCl3,
ppm): δ 0.94 (d, br, 6H), 1.18-1.49 (br, 6H), 1.50-1.78 (br,
5H), 1.82-2.27 (br, 5H), 3.72 (s, 3H), 4.58-4.73 (br, 1H), 5.26-
5.50 (br, 2H), 5.94-6.18 (br, 1H). 13C NMR (75 MHz, CDCl3-
d6, ppm): δ 22.01, 23.08, 25.09, 27.58, 27.67, 30.52, 32.70,
41.69, 47.80, 50.56, 52.39, 130.40, 130.70, 173.78, 175.85.
Ch a r a cter iza tion of 22. 1H NMR (300 MHz, CDCl3,
ppm): δ 1.08-1.74 (br, 13H), 1.74-2.20 (br, 6H), 3.00-3.22
(br, 2H), 3.67 (s, br, 3H), 4.46-4.66 (m, 1H), 4.95-5.16 (br,
2H), 5.16-5.43 (m, 3H), 6.11-6.67 (br, 1H), 7.23-7.40 (br, 5H).
13C NMR (75 MHz, CDCl3, ppm): δ 22.68, 27.64, 29.54,

1184 Hopkins and Wagener
Macromolecules, Vol. 37, No. 4, 2004
F igu r e 1. General synthetic scheme for the preparation of
premonomers 2 and 3.
F igu r e 2. The synthesis of the succinic acid branched
premonomer 5.
Resu lts a n d Discu ssion
method with THF as the solvent (Figure 3). Triethyl-
amine (1 equiv) was added to neutralize the amino acid
salt, and the reactions were stirred at 50-60 °C for 12
to 48 h; the dipeptides were given more time to react,
as previously determined to be necessary.16 Once fin-
ished, the triethylamine hydrochloride and urea salts
were removed by gravity filtration, and the THF was
removed by rotary evaporation. The crude product was
dissolved in methylene chloride, and washings were
performed to remove excess triethylamine, premonomer,
amino acid/dipeptide, and HOBt. The order of the
washings proved importantsa solid precipitated in the
separatory funnel if HCl was added first, while no
problems were encountered when concentrated NaHCO3
was used for the initial washing. The monomers were
purified either by recrystallization or column chroma-
tography, characterized by elemental analysis, HRMS,
1H NMR, and 13C NMR and assessed for purity by TLC
prior to polymerization.
Mon om er Syn th esis. All of the monomers in this
study were synthesized using routine peptide coupling
chemistry to attach the appropriate amino acid/peptide
to the premonomers 2, 3, or 5.21 The synthesis of
premonomers 2 and 3 was accomplished via two con-
secutive SN2 reactions between the deprotonated diethyl
malonate and the corresponding alkenyl halide to form
the diester (Figure 1). The reaction mixture was allowed
to stir overnight under reflux and was easily monitored
for complete conversion by TLC. In most cases, excess
NaH and alkenyl bromide were added to force the
reaction to completion, and in the case of premonomer
3, undecenyl iodide was used as well. Doing so gave
similar overall yields as the bromide; however, the
initial diester synthesis was completed after only 4 h
as determined by TLC. Neutralization of the NaH with
water, addition of ethanol and NaOH, and refluxing
overnight resulted in successful saponification to the
desired diacid. The crude product was dissolved in a
minimal amount of Decalinsjust enough to dissolve the
diacid when hotsa procedure that led to rapid decar-
boxylation at 190 °C as evidenced by the vigorous
bubbling. The large difference in polarity of the product,
starting material, and Decalin permitted easy purifica-
tion by flash chromatography. Decalin can be removed
using hexane as the eluent, a procedure simplified by
the fact that Decalin is observed as a clear band in the
silica gel. Switching to a more polar eluent, i.e., adding
ethyl acetate, removed the desired product. Further
purification of premonomer 3 is possible via recrystal-
lization in pentane.
The amino acid branched dienes 6, 7, 8, and 9, which
possess three methylene units between the olefin and
branch point, were prepared by coupling premonomer
2
with H-Ala-OBz‚HCl, H-Leu-OBz‚p-tosylate,
H-Leu-OMe‚HCl, and H-Lys(CBz)-OMe‚HCl, respec-
tively (Figure 3). Monomers 6 and 9 were purified via
three recrystallizations using CH3OH/H2O to give the
pure compounds in 44% and 55% yield. These yields
were low due to the rather high solubility of the
compounds in methanol. Monomers 7 and 8 are waxy
solids and were thus purified by column chromatogra-
phy using 5:1 hexanes:ethyl acetate and 5:1 hexanes:
THF as the eluents, respectively. The compounds were
recovered in 74% yield for 7 and 80% yield for 8, which
also suggests that the recrystallization method used for
monomers 6 and 9 was the cause of the lower yields.
Monomers 10, 11, 12, 13, 14, and 15 were synthe-
sized by coupling premonomer 3 to H-Ala-OBz‚HCl,
H-Leu-OtBu‚HCl, H-Leu-OBz‚HCl, H-Leu-OMe‚
HCl, H-Lys(CBz)-OMe‚HCl, and H-Arg(PBf)-OMe‚
HCl (Figure 3). Monomers 10 and 11 were purified by
recrystallization using the CH3OH/ H2O method in high
yields, 74% and 78%, respectively. Monomer 11 was
purified by flash chromatography using 3:1 hexanes:
ethyl acetate as the eluent giving the pure product as a
yellow-tinted oil in 78% yield. In the case of monomers
Premonomer 5 (Figure 2) was prepared by reacting
amine 4, which was synthesized as reported previ-
ously,16 with succinic anhydride and a catalytic amount
of 4-(dimethylamino)pyridine (DMAP). The reaction
occurred rapidly, and the product was purified by
recrystallization from CH3CH2OH/H2O giving the de-
sired acid in 67% yield. Succinic anhydride was used
without purification, which could have led to a lower
reaction yield do to the presence of unreactive succinic
acid.
The protected monomers were prepared using the 1,3-
diisopropylcarbodiimide (DIC)(1.5-2 equiv)/1-hydroxy-
benzatriazole (HOBt) (2.5-5 equiv) peptide coupling

Macromolecules, Vol. 37, No. 4, 2004
ADMET Synthesis of Polyolefins 1185
F igu r e 3. Synthesis of the protected amino acid branched monomers and polymers.
12 and 13, 5:1 hexanes:THF was employed as the
mobile phase, which gave pure products as opaque
waxes in 78% and 74% yields, respectively. Monomer
15 was recovered in pure form as an oil in 78%
yieldsthe liquid nature of the monomer is probably due
to the PBf protecting groupsafter purification by flash
column chromatography using ethyl acetate as the
eluent.
Monomer 16 was synthesized having a succinic acid
linkage between the polymer backbone and the amino
acid in order to investigate the effect of a “spacer”
between the amino acid functionality and the polymer
backbone (Figure 4). Premonomer 5 was coupled to
H-Lys(CBz)-OMe‚HCl using the same methodology
discussed above, and purification by recrystallization
from CH3OH/H2O gave the desired product as a white
powder in 72% yield.
The dipeptide branched monomers, 17 and 18, were
prepared by coupling premonomer 3 to H-Ala-Ala-
OMe‚HCl and H-Leu-Leu-OMe‚HBr, respectively (Fig-
ure 5). The reactions were allowed to stir 48 h, the time
being previously determined to give high yields for
dipeptide branched monomers.16 These monomers were
obtained as white solids after purification using the
recrystallization method described above, and recovered
in good yields, 72% and 71%, respectively.
P olym er Syn th esis. Acyclic diene metathesis (AD-
MET) is a simple step polymerization that allows for
precise branch and/or functionality placement along the
polymer backbone, where this structural feature is “built
in” prior to polymerization by way of appropriate
monomer design. Thus, ADMET permits the synthesis
of polymers incapable of being prepared by common
polymerization methods.22 Since all of the monomers
described herein are solids or become solids after
minimal couplings, the polymerizations were run in a
minimal amount of solvent (THF) under an Ar purge
to aid in the removal of ethylene.
This methodology produces polymers of approximately
the same molecular weight as those obtained under
typical ADMET conditions using high vacuum (Table
1).14-16 Dry THF was chosen as the solvent since it has
been shown to be best for polymerizing amino acid and
peptide branched monomers. Apparently the solvent
participates in the polymerization mechanism itself by
shifting the dynamic equilibrium complex of monomer
functionality and catalyst toward the free catalyst state;
thus, the catalyst is available for polymerization chem-
istry.
Previously we described the synthesis of polyolefins
containing amino acids attached through the C-termi-
nus, which have interesting thermal and mechanical
properties.16 We also synthesized polymers with a
leucine methyl ester branch attached through the
N-terminus, on every ninth carbon, a polymer which had
good mechanical properties and a high melting temper-
ature. Consequently, we felt it advantageous to inves-
tigate further the synthesis and properties of polymers
with amino acids/dipeptides attached through the N-
terminus on every 9th and 21st carbon of the backbone
and to compare these results with those polymers
prepared previously having amino acid/peptide moieties
attached through the C-terminus.

1186 Hopkins and Wagener
Macromolecules, Vol. 37, No. 4, 2004
F igu r e 4. Synthesis of the lysine branched monomer separated from the diene with a succinic acid spacer.
F igu r e 5. Synthesis of the dipeptide branched monomers and polymers.
Monomer 6 was polymerized to polymer 19 having a
ogy to larger peptides, which tend to lack solubility in
common organic solvents. The resulting polymer 19 was
only slightly soluble in common organic solvents, which
led to easy purification of the polymer by precipitation
in hexanes.
molecular weight (Mw obtained by light scattering) of
26 000 (Table 1 and Figure 3). After only a few hours,
the growing polymer became insoluble resulting in a
gellike mixture; however, the polymerization continues
to occur even in a gellike state, suggesting that a high
degree of polymer/monomer solubility may not be re-
quired for high polymer preparation. This observation
could become important when applying this methodol-
Monomer 7 was converted to polymer 20, but with
1
some difficulty. End groups were detectable in the H
NMR after the first polymerization attempt, a sign of
incomplete conversion, so the polymer was dissolved in

Macromolecules, Vol. 37, No. 4, 2004
ADMET Synthesis of Polyolefins 1187
F igu r e 7. Previously reported lysine branched polymer
attached through the C-terminus.16
F igu r e 6. “C-terminus” amino acid branched monomers
incapable of being polymerized using catalyst 1.
29. In addition, the lysine branched polymers 27 (Figure
3) and 35 (Figure 7), which have lysine branches directly
attached to the polymer backbone, are semicrystalline;
therefore, polymer 29 should give an interesting insight
on the effect of a spacer on the semicrystallinity of the
resulting polymer.
Dipeptide monomers also are amenable to this po-
lymerization methodology, which converts monomers 17
and 18 (Figure 5) into polymers 30 and 31, both high
in molecular weight as well (Table 1). Peptides, of
course, are of interest since the goal of this research is
to generate high strength materials possessing surfaces
designed for biological activity. The fact that highly
polar monomers such as 17 and 18 are capable of
ADMET polymerization speaks well of the utility of the
ruthenium-based metathesis catalysts.
Th er m a l Ch a r a cter iza tion . Generating durable
materials capable of being shaped into useful biologi-
cally active structures usually means working with
polymers that either have a high glass temperature or
a reasonably high degree of crystallization. A consider-
able number of these biopolymers indeed crystallize,
which likely is a result of both the regularity of spacing
of the amino acid group along the hydrocarbon back-
bone, coupled with the strong interactions between
amino acid and peptide groups.
The crystallinity within these materials is manifested
in terms of tensile strength and toughness, which for
some of the polymers roughly matches that of low-
density polyethylene.16 Our work in understanding the
nature of the crystallinity present in these bio-olefins
remains under investigation and will be published
elsewhere. At this point we report only the thermal data
collected by differential scanning calorimetry. The data
can be found in Table 1.
Roughly half of the bio-olefins made to date crystal-
lize; those which appear to be completely amorphous
exhibit glass transitions in the range of -10 to +69 °C,
while those which are semicrystalline exhibit melting
points between 40 and 130 °C. Both of the dipeptide
bioolefins are semicrystalline. Furthermore, the initial
wide-angle X-ray work on many of these polymers
suggests they possess a high degree of crystallinity. It
appears that the size and polarity of the amino acid and
dipeptide entities influence the nature of the crystal-
lization that we observe.
Only one of the leucine-containing polymers is semi-
crystalline (21, the methyl ester branched polymer); this
polymer exhibits the highest melting point as well. It
is interesting to compare it with polymer 26, which
differs only in the location of the branchspolymer 21
possesses leucine on every ninth carbon of the back-
bone, while 26 places leucine on every 21st carbon.
THF and exposed to additional catalyst (100:1 initial
monomer: catalyst), which yielded high polymer with
a Mw of 36 000 (Table 1). Monomers 8 and 9 were
easily converted to high polymers 21 and 22 having
Mws of 73 000 and 63 000, respectively (Figure 3). In
addition, several “N-terminus” polymers (23-27 in
Figure 3) were prepared possessing an amino acid
branch on every 21st carbon, and all of these polymers
are high in molecular weight (Table 1).
The orientation of the amino acid entity with respect
to the polymer backbone influences the reactivity of the
diene toward ADMET chemistry, regardless of the
frequency of appearance of the amino acid along the
hydrocarbon polymer backbone. For example, “N-
terminus” polymers 19 and 20 (those which have the
amino acid attached via the N-terminus), and which
have the amino acid attached on every ninth carbon,
can be synthesized in high molecular weight, whereas
the previously reported “C-terminus” monomers 32 and
33 (Figure 6) only yield oligomers. This phenomenon is
even observed when the amino acid appears on every
21st carbon; the highly polar arginine-based “C termi-
nus” monomer 34 (Figure 6) does not polymerize to high
molecular weight, whereas the similar “N-terminus”
monomer 15 (Figure 3) does. This observation likely is
a result of the intramolecular complexation, mentioned
above, being more of a factor in the mechanism for “C-
terminus” monomer polymerization than for “N-termi-
nus” polymerization. Furthermore, the arginine moiety
of the biologically active peptide sequence arginine-
glycine-aspartic acid (RGD),11,23 which is a target
molecule for the preparation of a biologically active bio-
olefin, is the most polar entity making the polymeriz-
ability of monomer 15 an important result.
Interesting solubility characteristics were observed for
polymer 28. Although the monomer was soluble in a
variety of solvents, e.g. CHCl3, CH2Cl2, and THF, the
polymer was only slightly soluble in hot THF and
DMSO. During the removal of the catalyst using the
methodology described previously, a white coating of
polymer formed on the glassware, which upon addition
of ethyl acetate formed a tacky aggregate that was
easily isolated. Furthermore, addition of concentrated
NaHCO3 solution broke up the aggregation producing
a granular material that was easily filtered and purified
by washing with DI H2O to yield polymer 28 as a white
fibrous material.
We also investigated the effect of inserting a “spacer”
molecule between the hydrocarbon backbone and lysine.
The monomer synthesis and polymerization are trivial
(Figure 4), yielding a high molecular weight bio-olefin,

1188 Hopkins and Wagener
Macromolecules, Vol. 37, No. 4, 2004
N-terminus of the amino acid polymerize more readily
than monomers with amino acids/peptides attached
through the C-terminus.
Other than the result obtained for polymer 21, the
thermal data support our previous suggestion16 that the
amino acid moiety and not the polymer backbone is
responsible for the semicrystalline nature of the poly-
mer, with the more polar amino acids tending to be
semicrystalline (lysine) and the nonpolar amino acids
(leucine) being amorphous. In addition, results for the
arginine branched polymer 28 and dipeptide branched
polymers 30 and 31 are encouraging when contemplat-
ing the polymerization of ADMET monomers possessing
biologically active peptides such as the RGD sequence.
These bio-olefins described in this paper have proper-
ties uncharacteristic of typical branched polyolefins,
leading to many questions regarding structure property
relationships. At present we are studying the X-ray
scattering, mechanical properties, and surface proper-
ties of these materials.
F igu r e 8. DSC scans of polymer 29, demonstrating cold
crystallization phenomena.
Ack n ow led gm en t. We would like to thank the
National Science Foundation, Division of Materials
Research, and the Army Research Office for financial
support of the research. We would like to thank Mr.
Travis Baughman, Dr. Stephen Lehman, and Mr. J ohn
Sworen for help in the preparation of the acid premono-
mers, and Mrs. Florence Courchay and Mr. Piotr Mat-
loka for synthesizing the catalysts used in this work.
In addition, we acknowledge Mr. Wendell Bob, Mr.
Xavier Guerrero, and Mrs. Stephanie Spence for their
contributions during the course of this work. We also
thank Mr. J ohn Sworen, Dr. Ravi Orugunty, and Dr.
Shane Waybright for helpful discussions and synthetic
advice. We acknowledge Mr. Clay Bohn and Prof.
Anthony Brennan for their help in obtaining initial
material property data on these polymers. We thank Mr.
J ohn Sworen and Mr. Travis Baughman for their help
in the preparation of this manuscript. Finally, we are
grateful to Dr. Richard Pederson of Materia, Inc. for
providing the THP solution required for removal of the
catalyst from the polymers.
One might predict that polymer 26 should be semicrys-
talline as well, but that is not the case. Also interesting
is the comparison of polymers 22 and 27, which again
are identical in structure with the exception of the
distance between points of attachment of the amino
acid. This time the order is reversed: the longer spaced
bio-olefin (amino acid on every 21st carbon) crystallizes
while the other does not.
The lysine branched polymer 29 possessing a succinic
acid “spacer” separating the amino acid from the
backbone is semicrystalline; its DSC curve exhibits what
may be a cold crystallization (Figure 8). The first scan
reveals an isomorphic response, with a “premelt” ap-
pearing at about 60 °C, followed by a higher melting
response at about 105 °C. The cold crystallization
phenomenon, if indeed that is what we observe, is
apparent at around 60 °C followed by a melt at 106 °C
in the second and third scans on the same sample.
Adding the succinic acid “spacer” increases the melting
point of a bio-olefin, an observation evident through
comparison of polymer 29 (Figure 4) with the lysine
branched polymers 27 (Figure 3) and 35 (Figure 7),
which lack the spacer and melt (Tm) 27 and 10 °C lower,
respectively. It may be that the spacer provides ad-
ditional freedom for the amino acid moiety to order.
Although both dipeptide branched polymers 30 and
31 crystallize and possess similar melting points, they
appear to do so at different crystallization rates, with
the alanine-alanine polymer (31) being the slower of
the two. In fact the semicrystalline form of polymer 31
can be generated only by casting from solution, whereas
polymer 30 recrystallized from the melt. Similar re-
sponses were observed for the N-terminus polymer, 23,
and several of the C-terminus polymers as well. At this
point we are unable to offer full explanations for the
thermal behavior that is observed; the X-ray scattering
experiments that are underway should provide us with
a better view.
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Bio-olefins have been prepared using ADMET chem-
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Macromolecules, Vol. 37, No. 4, 2004
ADMET Synthesis of Polyolefins 1189
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(20) Not capable of being named using the AutoNom 2.1 naming
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MA035289U