Sequence-regulated radical polymerization with a metal-templated monomer: Repetitive ABA sequence by double cyclopolymerization

Article abstract of DOI:10.1002/anie.201103007

Two is better than one: Repetitive ABA sequences in copolymers were obtained by a palladium-templated monomer. Crucial in the polymerization were π-π-stacking interactions between aromatic side groups to array three vinyl groups (see picture). Because of

Full text of DOI:10.1002/anie.201103007

Communications
DOI: 10.1002/anie.201103007
Sequence-Regulated Polymers
Sequence-Regulated Radical Polymerization with a Metal-
Templated Monomer: Repetitive ABA Sequence by Double
Cyclopolymerization**
Yusuke Hibi, Makoto Ouchi,* and Mitsuo Sawamoto*
In nature, macromolecules are generated by elaborate
mechanisms, often involving a template, in which the
sequence of repeating units (i.e., monomers) along a main
chain is perfectly programmed or regulated. In peptides, for
example, the repeat unit sequence is well-defined, although as
many as 20 amino acid comonomers are involved in the
polymerization process. Thanks to these well-defined sequen-
ces, even a single molecule of a biologically formed polypep-
tide (protein) forms a specific structure through hydrogen-
bond-directed folding to efficiently function as, for example,
an enzyme.
From this viewpoint, the “sequence” should be the most
essential structural factor for polymers, but no one thus far
can regulate the sequence of synthetic polymers. An excep-
tion is the solid-phase synthesis of “artificial” peptides;[1]
however, this strategy of circumvention based on repetition
of stepwise reactions of monomers requires complicated
procedures such as protection, deprotection, and purification.
Therefore, manipulation of the polymerization through
templates, as observed for natural polymers, is promising for
regulating the sequences of artificial polymers.
Now that such primary structural factors as, for example,
the chain length, finally can be controlled in recently
discovered living radical polymerizations,[3] the sequence of
polymers is recognized as the next structural factor that can
be controlled precisely in artificial polymerizations to express
advanced functions of polymers as observed in nature.[4]
We have thus focused on template-based sequence
regulation in living polymerization by designing initiators[4g–i]
and monomers.[4j] A recent example which is in line with the
design of monomers is to employ a naphthalene framework as
a template that anchors two monomeric units (e.g., meth-
acrylate and acrylate) spatially close to each other in the peri-
position through a “cleavable” ester linkage (Scheme 1A).[4j]
Such an AB-templated divinyl monomer can be polymerized
by a metal-catalyzed living radical polymerization under
diluted conditions to give soluble polymers without the effect
of gelation. Upon hydrolysis of the ester linkers and
subsequent methylation, the resultant copolymers proved to
possess highly regulated methyl methacrylate–acrylate AB-
alternating sequences. Because the conventional radical
copolymerization of these two monomers gives totally
random sequences, this result is significant, because it
suggests the possibility of template-assisted sequence regu-
lation beyond the inherent reactivity ratio. Though effective
the naphthalene-based design is by definition confined to AB-
alternating sequences alone and, equally serious, would be
cumbersome and laborious to realize regulated sequences of
hydroxyl, amino, and other functional groups, unless far more
versatile and perhaps orthogonal linkers other than ester
groups are designed.
Herein, we provide a strategy for such a template-based
sequence-regulated artificial polymer synthesis by radical
polymerization.
Radical polymerization, a chain-growth polymerization of
vinyl monomers, is important for industrial polymer produc-
tion. The majority of products from radical polymerization is
in fact copolymers in which the composition of the repeat
units statistically depends on the reactivity ratio of the
monomers or on an “average” within molecules of varying
compositions. Accordingly the “absolute” sequence is ill-
defined, not precisely controllable, and often statistically
distributed. An exception is the so-called alternating copoly-
merization, giving an ABABAB… regular sequence, by
modulating the reactivity ratio of the monomers by, for
example, the addition of a Lewis acid.[2]
[*] Y. Hibi, Prof. M. Ouchi, Prof. M. Sawamoto
Department of Polymer Chemistry, Kyoto University
Katsura, Nishikyo-ku, Kyoto (Japan)
E-mail: ouchi@living.polym.kyoto-u.ac.jp
sawamoto@star.polym.kyoto-u.ac.jp
Homepage: http://living.polym.kyoto-u.ac.jp/index.html
[**] This research was partially supported by the Ministry of Education,
Science, Sports, and Culture of Japan through a grant-in-aid for
creative science research (18GS0209) for which the authors are
grateful.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103007.
Scheme 1. Sequence-regulated radical polymerizations using a Pd-
templated monomer.
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Table 1: Radical Polymerization of Pd-SPS.[a]
Entry
Initiator
Solvent
T [8C]
t [h]
Conv [%] (S/P)[c]
Polymerization[d]
Structural Analyses[f]
Mn (Mw/Mn)[g]
CE[h]
1
2
3
4
5
6
7
V-65
V-65
V-65
DCE
40
40
40
0.25
0.25
3
48
96
60
11/9
5/7
heterogeneous
heterogeneous
homogeneous
homogeneous
homogeneous
homogeneous
homogeneous
–
–
–
–
–
–
75%
85%
90%
95%
Ethanol
HFPP
HFPP
HFPP
HFPP
HFPP
[e]
61/58
30/30
30/30
58/60
32/33
V-70
ꢀ5
28000 (3.16)
24000 (2.50)
19000 (2.14)
18000 (2.10)
V-70[b]
V-70[b]
V-70[b]
ꢀ30
ꢀ30
ꢀ60
120
[a] Polymerization: [Pd-SPS]0 =50 mm; [Initiator]0 =5 (408C) or 20 (<ꢀ58C) mm. [b] The azo-initiator was irradiated at g=375 nm. [c] The
consumption ratio of the vinyl groups was determined by 1H NMR spectroscopy. [d] The appearance of the polymerization solution; heterogeneous:
some precipitation was observed during the polymerization, homogeneous: the polymerization proceeded homogeneously. [e] The polymerization
proceeded homogeneously, but the product after reprecipitation by adding methanol was insoluble in any solvent. [f] The structures of products were
analyzed after removal of the palladium template through reaction with a bisphosphine ligand (dppp) in the presence of Et3N and H2O: see the
Supporting Information. [g] Determined by size exclusion chromatography (SEC) with poly(methyl methacrylate) calibration (see Figure S4 in the
1
Supporting Information). [h] Cyclization efficiency, estimated by H NMR spectroscopy (see Figure S5 in the Supporting Information).
Herein, we thus turned our template design to metal-
complex frameworks that anchor, through readily cleavable
coordination bonds, more than two monomeric units carrying
different functional groups (Scheme 1B). This approach is
particularly advantageous in anchoring various functional
monomers in a well-defined geometry that ensures a selective
intramolecular propagation into an ABA, ABC, and other
triple-unit alternating sequences. For example, we designed a
palladium-templated structure (Pd-SPS), in which two sty-
rene (S) and one 4-vinylpiridine (P) units are programmed to
align through tridentate 2,6-dicarboxyamido-pyridine and
monodentate pyridine.[5] The strategy is to achieve selective,
intramolecular, and directional double cyclopolymerization
(S!P!S) at the Pd template to form ABA-alternating
copolymers. Upon removal of Pd and hydrolysis of the amide
groups, we receive polymers of repetitive sequences of ABA
functionalities of two amine (A) and one pyridine (B) units.
Crucial in the template design is the p–p-stacking
interaction between aromatic groups of the three monomeric
units to align an array of the three vinyl groups at the Pd
scaffold. The alignment effect contributes to restraints on
unfavorable propagations, for example, the S!S propagation
skipping the central P unit and the predominant attack of a
growing radical onto P skipping the periphery S units, both
leaving dangling alkene units that in turn result in crosslinking
and/or irregular sequences.
precipitates even at earlier reaction stages (Table 1, Entries 1
and 2). The free rotation of the methylene spacer in the outer
S unit probably swings away its vinyl group from the central P
part, and the dangling unsaturated vinyl group thus led to
crosslinking (Figure 1A).
Figure 1. Proposed conformations of the Pd-SPS monomer.
This problem was circumvented by employing a bulky
fluoroalcohol (1,1,1,3,3,3-hexafluoro-2-phenyl-2-propanol;
HFPP) solvent in which the strong affinity of the electron-
deficient hydroxyl moiety to the amide groups of the template
was expected to suppress the rotation of the spacers and
thereby to “fix” the triple vinyl alignment (Figure 1B).[8]
Consequently, the polymerization in HFPP proceeded with-
out any precipitation, and the three vinyl groups almost
equally reacted (conversion after 3 h: S: 61%; P: 58%;
Table 1 Entry 3). The interaction of HFPP with the amide
groups was confirmed by 1H and 13C NMR spectroscopy (see
Figure S3 in the Supporting Information). In the presence of
HFPP (20 v% in CDCl3), the 13C NMR carbonyl peak of Pd-
SPS shifted to downfield (d = 171.1 ppm from d = 171.8 ppm
in pure CDCl3). Furthermore, the styrene aromatic protons
clearly shifted on the addition of HFPP. These observations
support the favorable stacked conformation predominant
through the carbonyl interaction in HFPP.
The stacking interaction in Pd-SPS was indeed confirmed
1
by H NMR spectroscopy (see Figure S1 in the Supporting
Information): The aromatic proton peaks from the S units
clearly shifted to upper field, when the acetonitrile ligand in
the precursor was replaced with a P unit. Molecular mechan-
ics analysis (MM2) demonstrated a p-stacked structure and a
reachable distance (around 0.37 nm) between the neighboring
vinyl groups (see Figure S2 in the Supporting Information).[6]
Despite the seemingly rational design of the Pd-SPS
structure, achieving the double cyclopolymerization was not
straightforward.[7] For example, a diluted free-radical poly-
merization from Pd-SPS (50 mm) with an azo-initiator [2,2’-
azobis(2,4-dimethylvaleronitrile), V-65, 10 h half-life decom-
Although the polymerization homogeneously proceeded
in HFFP at 408C, the resultant polymers were no longer
soluble after reprecipitation into methanol (Table 1, Entry 3).
1
position temperature T = = 518C] at 408C in common solvents
2
[dichloroethane (DCE), ethanol, etc.], soon gave insoluble
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This suggests that crosslinking was not perfectly eliminated
even in HFPP. Thus, to suppress the molecular mobility within
the monomer (flipping a vinyl group into a unsuitable
position), polymerization was performed below ꢀ58C with a
low-temperature radical initiator [2,2’-azobis(4-methoxy-2,4-
1
dimethylvaleronitrile), V-70, T = = 308C] and/or under UV
2
irradiation (Table 1, Entries 4–7). Even at ꢀ608C, the poly-
merization smoothly proceeded, and both styrenic and
pyridinyl vinyl groups were consumed in parallel, indicating
the intramolecularly propagating double cyclopolymerization
on the template.
The isolated polymers were now soluble after reprecipi-
tation, whereas the low mobility of the repeat units, bound to
the metal-complex framework, hampered 1H NMR structural
analyses. Therefore, the Pd template was removed by ligand
exchange with a bisphosphine [1,3-bis(diphenylphosphino)-
propane; dppp] (see Scheme S1 in the Supporting Informa-
1
tion).[9] The products exhibited now well-resolved H NMR
spectra indicative of the expected ABA structure (see Fig-
ure S5 in the Supporting Information): the main chain protons
(a, b, i, and j; 1–2 ppm, 9H), the pendent aromatic protons of
the P units [c, d, and k; d = 6.0–7.3 ppm, 10 H (obd, 9.5H)],
and other protons (g, h, and l; d = 8.0–8.5 ppm, 5H). Though
minor olefinic signals (a’) were observed at d = 5.6 and
5.1 ppm, derived from the unreacted styrene, the relative
intensity of the major signals indicated a high efficiency of
cyclization[10] that increased at lower temperature to reach as
high as over 95% at ꢀ608C.
Figure 2. Sequence analyses by 13C NMR spectroscopy: A) copolymer
obtained from polymerization using the Pd-SPS monomer; B) homo-
polymer of 4-aminomethylstyrene (S); C–E) random copolymers of S
with 4-vinylpyridine (P); F) homopolymer of P. See the Supporting
Information for the conditions of the (co)polymerizations.
149.9 ppm). The peak broadening is known to result from the
sequence and tacticity of the main chain.[11] As shown by
comparison of the positions and the shapes of these peaks, the
broad and multiple aromatic peaks were assigned in terms of
triad sequences of the main chain: the large peak of C1 for the
homopolymer of 4-aminomethylstyrene (S; d = 140.5 ppm,
Figure 2B) of course was attributed to the homotriad S-S-S.
As the relative amount of P increased, the major C1 signals
shifted downfield (Figure 2C–E), and the large peak for the
P-richest copolymer (d = 141.7 ppm; Figure 2E) came from
the P-S-P triad. Accordingly, the C1 peaks of the S-centered
triad appear downfield as a function of the increasing P
content in the order: S-S-S > S-S-P (or P-S-S) > P-S-P. The
intermediate peak in Figure 2C may therefore result from a
mixture of S-S-S and S-S-P sequences, and that in Figure 2D
from a mixture of S-S-P and P-S-P sequences.
The copolymer obtained from the Pd-SPS monomer
exhibited neither S-S-S nor P-S-P signals but a signal located
between them (d ꢁ 140.9 ppm; Figure 2A), which was, how-
ever, different from the similar intermediate peak for the S-
rich random copolymer with mixed S-S-S and S-S-P sequen-
ces (Figure 2C); note that the nominal S/P compositions are
rather similar in the Pd-SPS product (69:31) and this S-rich
copolymer (75:25).
The Pd-free polymers were subsequently subjected to
acidic hydrolysis to remove the tridentate ligand. A sample
(vinyl conversion around 60%; Table 1, Entry 6) was heated
with concentrated hydrochloric acid for 36 h, followed by
reprecipitation into an aqueous sodium hydroxide solution.
1
The H NMR spectrum of the ligand-free polymer was quite
similar to that of statistically random copolymers of 4-
aminomethylstyrene (S) and 4-vinylpyridine (P) with a similar
composition (see Figure S6 in the Supporting Information).
The S/P ratio was 69:31 and agreed well with that (67:33 or
2:1) of the original product of the Pd-SPS monomer. These
results further support a fair control of the repetitive
sequential propagation (S!P!S) along with clean and
quantitative removal of the template, and the final product
is nominally an S-P-S alternating terpolymer obtaind by
template-assisted regulation of the polymer sequence.
Finally, the sequence of repeat units was analyzed by
13C NMR spectroscopy.[11] Figure 2A shows the aromatic
region of a 13C NMR spectrum (d = 138–146 ppm) of the
product after template cleavage. For comparison, a series of
statistically random copolymers as well as homopolymers of S
and P with varying compositions were separately prepared
and analyzed similarly [Figure 2B–F; S/P = 100/0 (B), 83/17
(C), 50/50 (D), 17/83 (E), and 0/100 (F)]. The copolymeriza-
tion reactions were almost random, and thus the composition
of the copolymers at low conversion was close to the initial
ratio of the comonomer feed.
On the basis of these arguments, the large C1 NMR peak
of the Pd-SPS product is most likely assigned to predominant
S-S-P triads (or S-P-S for P-centered triads; namely, …-S-P-S-
S-P-S-S-P-S-…). A comparison of the C4 NMR peaks appears
to support the periodic sequence. This in turn shows that the
sequence of the main chain in the Pd-SPS homopolymer is an
ABA (S-P-S) alternating terpolymer, as targeted and built by
the tridentate palladium template. These repetitive regular
All the samples exhibited two sets of broad signals
assignable to two aromatic carbon atoms of the 4-amino-
methylstyrene unit (S): C1 adjacent to the main chain (d =
139.9–141.8 ppm) and C4 in para position to C1 (d = 141.8–
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sequences of functional groups, such as the amine–pyridine–
amine sequence obtained from the Pd-SPS monomer, possi-
bly lead to specific functions, and these results will be
presented in future.
In summary, repetitive ABA sequences were achieved
with a palladium-templated monomer, Pd-SPS. Crucial in the
synthesis were the p–p-stacking interactions between the
aromatic side groups to array the three vinyl groups, and the
interactions were enhanced in a bulky fluoroalcohol solvent
through inhibition of spacer rotation. Thus, double cyclo-
polymerization was achieved through radically propagating
species in fluoroalcohol (CE ꢁ 95%) to give soluble poly-
mers. Removal procedures for the template led to sequence-
regulated copolymers consisting of amine–pyridine–amine
sequences, which were confirmed by NMR analyses. This
study opens the door to controlled sequences of functional
groups in copolymers.
[5] A. M. Fuller, D. A. Leigh, P. J. Lusby, I. D. H. Oswald, S.
Parsons, D. B. Walker, Angew. Chem. 2004, 116, 4004; Angew.
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[6] The distance is reasonable for the ordered propagation because
the distance between radical species and styrene monomers is
estimated as 2.3 ꢀ in the transition state: S. Edizer, B. Veronesi,
O. Karahan, V. Aviyente, I. Degirmenci, A. Galbiati, D. Pasini,
Macromolecules 2009, 42, 1860 – 1866.
[7] Quite recently, Osakada et al. first achieved a double cyclo-
polymerization of triene monomers by palladium catalysis. To
our knowledge, this is the only example for double cyclo-
polymerization in the past: K. Motokuni, T. Okada, D. Takeuchi,
K. Osakada, Macromolecules 2011, 44, 751.
[8] a) K. Yamada, T. Nakano, Y. Okamoto, Macromolecules 1998,
31, 7598; b) W. H. Liu, T. Nakano, Y. Okamoto, Polym. J. 2000,
32, 771.
Received: May 2, 2011
Published online: June 29, 2011
Keywords: copolymerization · palladium · radicals
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