Synthesis of an electrophilic polymer by ring-opening metathesis polymerization

Article abstract of DOI:10.1071/CH02067

The use of a ring-opening metathesis polymerization (ROMP), for the synthesis of an electrophilic polymer, was discussed. The electrophilic was prepared using ROMP method and it was shown that amine nucleophiles could be introduced to the polymer. Monomers were required for the formation of the polymer that were equipped with two key features such as a polymerizable component and a site at which substitutions could be performed following polymerization. The results show that the target monomer became the 4,6-dichloro-1,3,5-triazine derivative.

Full text of DOI:10.1071/CH02067

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Rapid Communication
Aust. J. Chem. 2002, 55, 245–248
Synthesis of an Electrophilic Polymer
by Ring-Opening Metathesis Polymerization
Caitlin A. Larsen,A Erin L. Taylor,A John N. LambertA,B and John A. ChiefariC
A School of Chemistry, The University of Melbourne, Parkville, Vic. 3010, Australia.
B Present address: Biota Holdings Limited, Level 4, 616 St Kilda Road, Melbourne, Vic. 3000, Australia.
Author to whom correspondence should be addressed (e-mail: john.lambert@sci.monash.edu.au).
C CSIRO Molecular Science, Private Bag 10, Clayton South 3169, Australia.
A new class of modifiable polymer is described. The electrophilic polymer is readily prepared using ring-opening
metathesis polymerization (ROMP), and it is shown that amine nucleophiles can be introduced to the polymer.
Manuscript received: 3 April 2002.
Final version: 16 May 2002.
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Recent years have witnessed a rapid growth in the
development of new methods for the preparation of
polymeric compounds with novel topological features.
While much work in this area has concerned the formation of
dendritic macromolecules,[1–3] the area has also expanded to
encompass other topologically distinct polymer architectures
that have been referred to as arborescent graft polymers,
monodendron-jacketed chains, and molecular brushes.[4–6]
In a practical sense, these hyperbranched molecular
architectures offer potential in materials science and biology.
In the case of biological applications, the growth of interest
in new polymer architectures has coincided with the
emergence of polyvalency as an important feature of many
key biological interactions. It is now apparent that
multimerization of ligands for biological receptors causes
them to bind to their targets many orders of magnitude more
tightly than in the monomeric form. Given the growing
interest in both multivalency and hyperbranched polymer
synthesis, there is a need to explore new ways in which these
two chemical subdisciplines can interact, and develop new
multimeric frameworks able to exploit the biological
multivalent effect. Our own interest in these areas grew from
a need to develop hypervalent polymers that could be readily
modified with a range of biologically active units. In
particular, we were interested in developing methods for the
synthesis of modifiable monodendron-jacketed chains; those
polymers whose linear backbone is decorated with numerous
dendritic side chains (Fig. 1). Here we report the synthesis of
a reactive polymer into which two pendant groups can be
introduced in a sequential manner. Given that our approach
employs well-established methodology, we are confident that
the polymers we describe may be conjugated to a range of
modifiers of both biological and non-biological interest.
For the formation of the polymer, we required monomers
that were equipped with two key features: a polymerizable
Fig. 1. Schematic representation of monodendron-jacketed chain
polymer architecture.
component, and a site at which substitutions could be
performed
following
polymerization.
For
the
polymerization, we chose to apply ring-opening metathesis
polymerization (ROMP) using ruthenium-based catalysts
such as (1) and (2), as this technology has been shown to be
both chemoselective and produce polymers of relatively
narrow polydispersity.[7,8] To introduce reactive sites into the
polymer, we sought to exploit the well-established
substitution chemistry of cyanuric chloride (3). Since it is
known that the three chlorine atoms of (3) can be
sequentially displaced by amine nucleophiles under
increasingly vigorous conditions, we envisaged that
displacement of the first chlorine could be used to attach the
triazine to a suitable monomer and that the remaining two
chlorines could be sequentially displaced following polymer
synthesis. Related sequential displacements using (3) have
recently been applied to the preparation of dendritic
macromolecules based on 1,3,5-triazines.[9] A diagrammatic
representation of our methodology is presented in Scheme 1.
Our target monomer thus became the 4,6-dichloro-1,3,5-
triazine derivative (7). The synthesis of monomer (7)
commenced with the reaction of cis-5-norbornene-endo-2,3-
© CSIRO 2002
10.1071/CH02067
0004-9425/02/040245

246
C. A. Larsen et al.
to limit the loading of electrophilic sites in the polymeric
product, we also prepared N-methylsuccinimide derivative
(8) as a spacer monomer.
PCy3
Ru
Cl
Mes
Cl
Cl
N
N
Mes
Ph
Cl
Cl
N
N
Ph
Ru
Polymerization reactions could be performed by treating
a solution containing a 1 : 9 ratio of monomers (8) and (7)
with 0.01 molar equivalents of the appropriate ruthenium
catalyst in 1,2-dichloroethane at 50°C until all starting
monomer had been consumed as judged by analytical thin-
layer chromatography (TLC) (Scheme 3). Both the Grubbs
ruthenium catalyst (1) and the second-generation olefin
metathesis catalyst (2) were investigated. The
polymerization using the first generation Grubbs ruthenium
catalyst (1) required two separate additions of catalyst, 65 h
apart, and a total reaction time of over 110 h to accomplish
complete consumption of the monomers. In comparison, the
polymerization using the second-generation ruthenium
catalyst (2) required only a single addition of catalyst, and
was complete after only 1 h. From these results, it was
concluded that for these polymerizations, the second-
generation ruthenium catalyst was much more efficient than
its first-generation counterpart, a finding consistent with
previously reported investigations of ruthenium-based
catalysts for use in ROMP.[7,10]
PCy3
(1)
Cl
N
Cl
PCy3
(2)
(3)
dicarboxylic anhydride (4) with 4-aminobenzylamine (5) in
toluene to produce imide (6) (Scheme 2). Once isolated, (6)
was reacted with cyanuric chloride at –40°C in
tetrahydrofuran (THF) and, after warming to room
temperature, the monosubstituted triazine monomer (7) was
obtained in 50% yield with respect to anhydride (4). In order
Cl
N
N
NH
N
polymerize
Cl
N
Cl
Cl
N
N
NH2
Cl
H
H
H
H
R1−NH2
O
O
O
O
NH
N
N
Cl
N
NH
Me
N
N
N
N
N
N
R1
R1
(8)
(7)
N
H
N
N
H
N
H
Cl
Cl
N
Cl
(1) or (2)
ROMP
Scheme 1
H
NH2
1
9
O
O
H
H
H
O
H
H
H
H
N
toluene, ∆
O
O
O
O
+
O
N
N
Cl
N
Me
N
N
O
NH2
(5)
N
H
Cl
H2N
(6)
(4)
(9)
Scheme 3
O
H
N
Cl
The copolymer products were isolated by precipitation
from hexane at –40°C and were characterized by 1H nuclear
magnetic resonance (NMR) and gel permeation
chromatography (GPC) (Table 1). The relative
incorporations of monomers (8) and (7) into the final
polymers could be measured by comparison of the
integration of the N-methyl protons of monomer (8) with the
benzylic methylene protons derived from monomer (7), and
H
O
N
N
Cl
N
Cl
NH
N
N
THF, −40°C
Cl
N
(7)
Cl
Scheme 2

Synthesis of an Electrophilic Polymer by ROMP
247
Table 1. ROMP of Monomers (8) and (7) (9 : 1) with
(PCy3)2Cl2Ru(=CHPh) (1) or (PCy3)(IMes)Cl2Ru(=CHPh) (2) in
ClCH2CH2Cl at 50°C
1
9
H
H
H
H
Catalyst [M]/[C]A Time
(h)
Yield
(%)
M
kDa
Mn
PDIC
B
O
O
O
O
N
N
Cl
N
kDa
Me
N
N
(1)
(2)
40 : 1
99 : 1
113
1
> 99
> 99
31.82
12.75
25.2
1.26
(9)
6.87 1.86D
N
H
Cl
A [M] and [C] are the concentrations of the monomer and catalyst,
respectively. B Number-average molar mass. C PDI
= poly-
dispersity. D Similar polydispersities have been observed for related
polymers synthesized using catalyst (2).[10]
H2N
ClCH2CH2Cl,
OMe
poly(vinylpyridine),
∆
this allowed us to confirm that monomers (8) and (7) were
incorporated into the polymer with roughly equal efficiency.
The relative amounts of E- and Z-isomers with respect to the
polymer backbone olefins could also be determined by
1
9
H
O
H
O
H
O
H
1
examination of the H NMR and these were found to be
O
consistent with previously reported cases of related
N
N
HN
polymers[11] (Fig. 2a).
Me
N
N
OMe
To study the incorporation of amine nucleophiles into
polymer (9), we chose to use the model compound 4-
methoxybenzylamine as this compound bears groups
allowing its ready detection by 1H NMR signatures. Reaction
of polymer (9) with 6 molar equivalents of 4-methoxy-
benzylamine in the presence of insoluble poly(vinylpyridine)
at 90°C for 2 days, followed by filtration and precipitation
N
H
N
NH
(10)
OMe
Scheme 4
afforded a quantitative recovery of modified polymer (10)
(Scheme 4). Integration of the 1H NMR signals attributable
to the aromatic methoxyl protons and those of the olefinic
polymer backbone confirmed incorporation of the 4-
methoxybenzylamine units (Fig. 2b).
In conclusion, we have shown that polymer (9) can be
readily prepared and subsequently modified with amine
nucleophiles. We are now examining the sequential addition
of differing nucleophiles to this polymer, as well as the
introduction of other nucleophiles into this potentially useful
and novel polymer framework.
Experimental
General Experimental
4-Aminobenzylamine (5), 25% cross-linked poly(4-vinylpyridine),
cyanuric chloride (3), 4-methoxybenzylamine and cis-5-norbornene-
endo-2,3-dicarboxylic anhydride (4) were obtained from Aldrich
Chemical Company and used without further purification. Benzyl-
idene (tricyclohexylphosphine) (1,3-dimesitylimidazol-2-ylidene) di-
chlororuthenium (2) was prepared from the commercially available
benzylidenebis(tricyclohexylphosphine)dichlororuthenium (1) (Flu-
ka) according to a published procedure.[12] Toluene, THF and 1,2-
dichloroethane were dried and distilled (toluene from sodium, THF
from sodium/benzophenone ketyl, and 1,2-dichloroethane from
calcium hydride) under N2 prior to use.
NMR spectra were recorded using Varian Unity 300 MHz or Varian
Unity 400 MHz spectrometers. Melting point (m.p.) data were recorded
on an electrothermal melting point apparatus and are uncorrected. GPC
analysis of the polymers was performed on a Shimadzu SCL-10A VP
system Controller connected with a series of four columns (StyroGel
HT1, HT2, HT3, HT4) in addition to a small guard column. The column
Fig. 2. (a) 1H NMR spectrum of polymer (9). (b) 1H NMR
spectrum of polymer (10).

248
C. A. Larsen et al.
oven temperature was 80°C. The solvent was dimethylformamide (LiBr
0.05 M) with flow rate of 1.0 mL/min. The detector set up was a Dawn
EOS light scattering detector and Optilab DSP refractometer both set at
a laser 690 nm wavelength.
Polymerization Procedure to give (9)
Two solutions were prepared. The first contained a mixture of (7) (0.396
g, 2.23 mmol) and (8) (0.106 g, 0.25 mmol) dissolved in 1,2-
dichloroethane (10.0 mL). The second solution contained benzyl-
idene(tricyclohexylphosphine)(1,3-dimesitylimidazol-2-ylidene)di-
chlororuthenium (2) (0.021 g, 0.025 mmol) dissolved in 1,2-
dichloroethane (2 mL). Both solutions were degassed (freeze–pump–
thaw, × 3), and the initiator solution added to the solution of the two
monomers under an atmosphere of nitrogen. The solution was stirred for
1 h at 50°C, then ethylvinyl ether (1 mL) was added and the solution was
allowed to stir at 50°C for a further 30 min. The solution was then added
dropwise to vigorously stirred n-hexane at –40°C. The resulting
precipitate was collected by vacuum filtration to give a pale-brown solid
(0.500 g, 100%). 1H NMR (400 MHz, CDCl3) δ 7.22–7.66, br m, ArH;
5.71, br s, E-CH=CH; 5.67, br s, Z-CH=CH; 4.60, br s, NCH2; 3.19, br
s, CH; 2.95, br s, CH and NCH3; 1.86, br s, CHa; 1.30, br s, CHb.
2-Methyl-3a,4,7,7a-tetrahydro-4,7-methano-1H-isoindole-1,3(2H)-
dione (8)
Methylamine (30% aqueous solution, 0.8 mL, 6.09 mmol) was added
dropwise to a solution of cis-5-norbornene-endo-2,3-dicarboxylic
anhydride (4) (1.00 g, 6.09 mmol) in glacial acetic acid (7 mL). The
solution was heated at reflux for 3 h, and then cooled to room
temperature. The acetic acid was removed under vacuum, and the
resulting pale yellow solid was recrystallized from water to give white
1
needles (1.04 g, 96%, m.p. 106–108°C, lit. [13] 105–106°C). H NMR
(400MHz, CDCl3) δ 6.09, s, CH=CH; 3.38, s, H4/7; 3.26, s, H3a/7a;
2.81, s, NCH3; 1.73, d, J 8.8 Hz, H8a; 1.54, d, J 8.8 Hz, H8b. 13C NMR
(400MHz, CDCl3) δ 178.08, C=O; 134.41, CH=CH; 52.18, C8; 45.92,
C4/7; 44.77, C3a/7a; 24.21, NCH3. Electrospray ionisation (ESI)
mass spectrometry (MS): found [M + H]+, 178.0858. Calc. for
[M + H]+: 178.0868. Found [M + Na]+, 200.0676. Calc. for [M + Na]+:
200.0687.
Modification of Polymer to give (10)
1,2-Dichloroethane (7.5 mL) was added to a mixture of (9) (0.150 g,
equivalent to 0.075 mmol of reactive triazole moiety) and
poly(vinylpyridine) (25% cross-linked, 0.075 g) under an atmosphere of
nitrogen. 4-Methoxybenzylamine (58 µL, 0.45 mmol) was added, and
the mixture was allowed to stir at 90°C for 42 h. The mixture was then
filtered and the filtrate was added dropwise to a vigorously stirred
solution of n-hexane at –40°C. The resulting precipitate was collected
2-(4-Aminobenzyl)-3a,4,7,7a-tetrahydro-4,7-methano-1H-isoindole-
1,3(2H)-dione (6)[14]
A stirred solution of cis-5-norbornene-endo-2,3-dicarboxylic anhydride
(4) (1.00 g, 6.09 mmol) in toluene (60 mL) was heated to 50°C under
an atmosphere of nitrogen and then added to 4-aminobenzylamine (5)
(1.4 mL, 12.8 mmol) in toluene (50 mL) also stirred and maintained at
50°C. The resulting mixture was brought to reflux with azeotropic
removal of water (Dean–Stark apparatus). The mixture was allowed to
heat at reflux for 100 min, after which time the solvent was removed
under vacuum. The resulting pale-yellow solid was added to hot ethanol,
the large clumps broken up, and the suspended white solid was collected
by filtration (1.18 g, 72%, m.p. 234–236°C). 1H NMR (400 MHz,
(CD3)2SO) δ 6.83, d, J 8.4 Hz, ArH; 6.43, d, J 8.4 Hz, ArH; 5.87, s,
CH=CH; 4.99, s, NH2; 4.17, s, NCH2; 3.31, s, H4/7; 3.21, s, H3a/7a;
1.50, m, CH2. 13C NMR (400MHz, (CD3)2SO) δ 177.33, C=O; 147.95,
C4´; 134.23, C5/6; 128.97, C2´/6´; 123.38, C1´; 113.47, C3´/5´; 51.74,
C8; 45.22, C4/7; 44.33, C3a/7a; 40.88, NCH2. ESI MS: Found [M + H]+,
269.1287. Calc. for [M + H]+: 269.1290. Found [M + Na]+, 291.1103.
Calc. for [M + Na]+: 291.1109.
1
by vacuum filtration to give a pale-brown solid (0.164 g, 100%). H
NMR (300 MHz, CDCl3) δ 7.20–7.48, br m, ArH; 6.86, br m, ArH;
5.66, br s, E-CH=CH; 5.70, br s, Z-CH=CH; 4.54, br s, 2 × NCH2; 3.76,
br s, OCH3; 3.19, br s, CH; 2.94, br s, CH and NCH3; 1.93, br s, CHa;
1.30, br s, CHb.
References
[1] S. Hecht, J. M. J. Frechet, Angew. Chem., Int. Ed. 2001, 40, 74.
[2] G. R. Newkome, C. N. Moorefield, F. Voegtle, Dendritic
Molecules: Concepts, Syntheses, Perspectives 1996 (VCH:
Weinheim).
[3] D. A. Tomalia, S. Uppuluri, D. Swanson, R. J. Li, Pure Appl.
Chem. 2000, 72, 2343.
[4] V. Percec, W.-D. Cho, G. Ungar, D. J. P. Yeardly, Angew. Chem.
Int. Ed. 2000, 39, 1598.
[5] V. Percec, M. N. Holerca, Biomacromolecules 2000, 1, 6.
[6] A. D. Schluter, J. P. Rabe, Angew. Chem. Int. Ed. 2000, 39, 864.
[7] C. W. Bielawski, R. H. Grubbs, Angew. Chem. Int. Ed. 2000,
2000, 16.
[8] S. Kanaoka, R. H. Grubbs, Macromolecules 1995, 28, 4707.
[9] A. Zhang, E. E. Simanek, Org. Lett. 2000, 2, 843.
[10] J. Huang, H.-J. Schanz, E. D. Stevens, S. P. Nolan,
Organometallics 1999, 18, 5375.
[11] S. C. G. Biagini, V. C. Gibson, M. R. Giles, E. L. Marshall, M.
North, Chem. Commun. 1997, 1097.
[12] (a) L. Jafarpour, S. P. Nolan, Organometallics 2000, 19, 2055;
(b) L. Jafarpour, A. C. Hillier, S. P. Nolan, Organometallics
2002, 21, 442.
2-{4-[(4,6-Dichloro-1,3,5-triazin-2-yl)amino]benzyl}-3a,4,7,7a-
tetrahydro-4,7-methano-1H-isoindole-1,3(2H)-dione (7)
Amide (6) (0.500 g, 1.86 mmol) in THF (4.5 mL) was cooled to –40°C
with stirring under an atmosphere of nitrogen. Poly(vinylpyridine)
(25% cross-linked, 0.02 g) was then added, followed by cyanuric
chloride (3) (0.343 g, 1.86 mmol). A further 4 mL of THF was then
added. The mixture was stirred at –40°C for 2.5 h, then filtered and the
filtrate was concentrated under vacuum. The resulting off-white solid
(1.23 g, 75%, m.p. 219–221°C) did not require further purification. 1H
NMR (300 MHz, CDCl3) δ 7.82, s, NH; 7.48, d, J 8.6 Hz, ArH; 7.33, d,
J 8.6 Hz, ArH; 5.92, s, CH=CH; 4.47, s, NCH2; 3.37, s, H4/7; 3.28, s,
H3a/7a; 1.70, d, J 8.8 Hz, H8a; 1.52, d, J 8.8 Hz, H8b. 13C NMR
(400MHz, CDCl3) δ 177.45, C=O; 172.50, CCl; 164.02, C2´´; 135.36,
C4´; 134.36, CH=CH; 133.50, C1´; 129.91, C2´/6´; 121.10, C3´/5´;
52.18, NCH2; 45.80, C4/7; 45.02, C3a/7a; 41.41, C8.
[13] C. F. Culberson, P. Wilder, Jr, J. Chem. Soc. 1960, 25, 1358.
[14] V. C. Gibson, E. L. Marshall, M. North, D. A. Robson, P. J.
Williams, Chem. Commun. 1997, 1095.