Constructing a macromolecular K3,3 graph through electrostatic self-assembly and covalent fixation with a dendritic polymer precursor

Article abstract of DOI:10.1021/ja504891x

A triply fused tetracyclic macromolecular K_3,3 graph has been constructed through electrostatic self-assembly of a uniformly sized dendritic polymer precursor having six cyclic ammonium salt end groups carrying two units of a trifunctional carboxylate counteranions, and subsequent covalent conversion by the ring-opening reaction of cyclic ammonium salt groups at an elevated temperature under dilution. The K_3,3 graph product was isolated from the two constitutional isomers by means of a recycling SEC technique, as the hydrodynamic volume of the triply fused tetracyclic K_3,3 product is remarkably contracted in comparison with another isomer having a ladder form in solution.

Full text of DOI:10.1021/ja504891x

Article
pubs.acs.org/JACS
Constructing a Macromolecular K3,3 Graph through Electrostatic Self-
Assembly and Covalent Fixation with a Dendritic Polymer Precursor
Takuya Suzuki, Takuya Yamamoto, and Yasuyuki Tezuka*
Department of Organic and Polymeric Materials, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo 152-8552, Japan
S
* Supporting Information
ABSTRACT: A triply fused tetracyclic macromolecular K3,3
graph has been constructed through electrostatic self-assembly
of a uniformly sized dendritic polymer precursor having six
cyclic ammonium salt end groups carrying two units of a
trifunctional carboxylate counteranions, and subsequent co-
valent conversion by the ring-opening reaction of cyclic
ammonium salt groups at an elevated temperature under
dilution. The K3,3 graph product was isolated from the two
constitutional isomers by means of a recycling SEC technique,
as the hydrodynamic volume of the triply fused tetracyclic K3,3
product is remarkably contracted in comparison with another
isomer having a ladder form in solution.
INTRODUCTION
■
Topologically intriguing molecular skeletons or polymer chain
architectures have continuously been an attractive research
subject.1−4 Cyclic and multicyclic polymers are particularly
unique from the topological viewpoint because of their
elimination of chain termini in contrast to linear and branched
counterparts,4−6 and the flexible conformational motion of
skeletal polymer segments between junctions and between
junction−terminus coincides with a characteristic feature of the
topological geometry.4,7,8
For the synthesis of single cyclic polymers, a number of
effective means have been developed in the past decade, either
by an end-to-end prepolymer linking process9 or alternatively
by a ring-expansion polymerization technique.10,11 In addition,
Figure 1. Graph presentation of fused multicyclic polymer topologies.
Those in blue are so far reported, and those in red are constructed in
this work. In parentheses, topologically equivalent graph constructions
are also shown in black or in green, and the linking positions by the
remarkable topological effects due to their cyclic forms have
now been unequivocally demonstrated by making use of cyclic
polymers having prescribed chemical structures.4,12 Notably,
dendritic precursor used in this work are indicated in the green graphs.
moreover, a variety of topologically attractive, mechanically
linked cyclic molecules, including simple trefoils to complex
employed to form polymer self-assemblies as key intermediates.
All three types of dicyclic constructions, i.e., θ (fused), 8 (spiro),
and manacle (bridged) forms have so far been constructed
through the ESA-CF protocol.16 Furthermore, single and
multicyclic polymer precursors (kyklo-telechelics) having as
large as 300-membered atom ring sizes were obtained by the
ESA-CF protocol.17 A variety of tricyclic and tetracyclic
polymer topologies of spiro- and bridged-forms18 and three
doubly fused tricycle (δ-, γ-, and β-graph) forms,19 as well as an
example of a triply fused tetracyclic form (unfolded
tetrahedron-graph)20 were subsequently constructed in con-
pentafoil knots, and a simple Hopf link, i.e., [2]-catenane, to
complex Borromean rings,13 have been constructed by taking
advantage of elaborated self-assembly protocols based either on
biopolymer (DNA) systems3,14 or on noncovalent comple-
mentary interactions by tailored molecular components.2,15
A class of bonded (covalently linked) multicyclic polymer
topologies, including three subclasses of fused, spiro, and bridged
forms, has also been ongoing synthetic challenge in polymer
chemistry.4,8 Selected examples of fused multicyclic topologies
are shown in Figure 1. In order to construct various multicyclic
polymer topologies, we have developed an electrostatic self-
assembly and covalent fixation (ESA-CF) protocol,4,16 in which
linear or star precursors having cyclic ammonium salt groups
carrying plurifunctional carboxylate counteranions have been
Received: May 19, 2014
© XXXX American Chemical Society
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Scheme 1. Synthesis of a Hexafunctional Dendritic Precursor, 4/CF3SO3
junction with a tandem alkyne−azide addition, i.e., click, and
olefin metathesis, i.e., clip, reactions. Yet, a class of topologically
significant fused-multicyclic forms, including α-graph (or K4
graph) and, in particular, a tetracyclic K3,3 form, shown in
Figure1, have still been a challenge.21
molecule having triflate ester end groups, 1, with three units of
a linear molecule having a phenolic group at the center
position, 2, (Scheme 1, and detailed in Supporting Information
[SI]). The star precursor, 1, was obtained by the esterification
reaction of a single-end protected 1,20-eicosanediol with
trimesic acid, followed by the deprotection and the triflate
esterification of the hydroxyl groups with trifluoromethane-
sulfonic anhydride. The linear precursor, 2, was also obtained
through the esterification of a single-end protected 1,20-
eicosanediol with an isophthalic acid derivative having a
protected phenolic group. The coupling reaction of the two
precursors, 1 and 2, was conducted in the presence of Cs2CO3
in acetone. After the deprotection, the six hydroxyl end groups
of the obtained dendritic product, 3-OH, were converted into
trifluoromethanesulfonate ester groups by treatment with triflic
anhydride in the presence of poly(4-vinylpyridine). Finally,
quaternization with N-phenylpyrrolidine was conducted to
The K3,3 graph is a prototypical nonplanar graph, which
cannot be embedded in the plane in such a way that its edges
intersect only at their end points. Interestingly moreover, the
K3,3 graph can be drawn on the torus surface by avoiding such
intersection of the edges.4,8 In this relevance, a trefoil knot and
a Hopf link (2-catenane), having three and two intrinsic
intersections, respectively, are also included in a class of
nonplanar graphs. Therefore, the K3,3 graph having an intrinsic
single intersection is considered as a primary form in nonplanar
graph constructions. Remarkably, in nature, the K3,3 graph
topology has recently been identified in cyclic polypeptides
(cyclotides) produced through the intramolecular S−S bridging
with cysteine residues,22 and their programmed folding
structures are considered to be crucial for their extraordinary
stability and bioactivity.23,24 It is, therefore, inspiring to explore
experimentally how such unique topological properties in basic
graph theories can direct any fundamental characteristics of
flexible polymer molecules. As a first step of this challenge, we
demonstrate herein the successful construction of a macro-
molecular K3,3 graph,25 having uniform-size edge components
of eicosanediol (C20) segments.
−
produce a dendritic precursor, 4/CF3SO3 .
1H and 13C NMR spectroscopic and MALDI-TOF mass
analyses (Figures S1−S12 in the SI) unequivocally confirmed
−
each step to give 4/CF3SO3 . Thus, the signals for the
methylene groups adjacent to the hydroxyl group were visible
at 3.64 ppm in the precursors and were replaced by those for
the triflate ester methylene groups at 4.54 ppm, and finally by
those for the methylene groups adjacent to N-phenyl groups at
3.84 ppm together with the N-phenyl proton signals at 7.45−
−
RESULTS AND DISCUSSION
7.78 ppm. In addition, the obtained 4/CF3SO3 was treated
■
with tetrabutylammonium benzoate to cause the ring-opening
reaction of the pyrrolidinium salt groups. The selective
formation of a covalently converted product was confirmed
Preparation of A Dendritic Macromolecular Precursor
Having Six N-Phenylpyrrolidinium Salt End Groups. A
dendritic macromolecular precursor having six N-phenyl-
1
by H and 13C NMR and MALDI-TOF mass analyses of the
−
pyrrolidinium salt end groups, 4/CF3SO3 , was prepared
through the reaction of one unit of a three-armed star-shaped
product (Figures S13−S15 in the SI).
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Figure 2. (top) Construction of a triply-fused tetracyclic polymer topologies (5) by the ESA-CF process with a dendritic precursor carrying two
trifunctional counteranions, 4/Tricarboxylate, and (bottom) a scheme showing random combination of the end groups during the covalent
conversion of 4/Tricarboxylate.
Constructing A Macromolecular K3,3 Graph. The six
triflate counteranions in 4/CF3SO3 were subsequently
most abundant mass of the product possessing the expected
chemical structure of C327H480N6O33 plus H+ as 5023.63, which
is expected, given the presence of multiple basic amine
functionalities in the macromolecule and the use of a mildly
acidic matrix.
−
exchanged to two units of trifunctional carboxylate, 1,3,5-
tris(4-carboxylatephenyl)benzene (Figure 2, top), through the
−
precipitation of a THF solution of 4/CF3SO3 into an ice-
cooled aqueous solution containing a large excess of the
tricarboxylate as the Na+ salt. The ion-exchange product,
recovered with retention of a trace amount of water in order to
avoid an uncontrolled ring-opening reaction, was examined by
1H NMR analysis in a solvent of CDCl3 with a drop of CD3OD
due to the solubility of the product (Figure 3, top), where the
phenyl signals from the tricarboxylate anions appear at 7.46−
7.78 ppm and at 8.10−8.12 ppm.
Notably, a pair of constitutional isomer products, i.e., a K3,3
graph form and another ladder-shaped counterpart, are
produced during the covalent conversion of 4/Tricarboxylate,
according to the linking mode of the six chain-ends of the
dendritic precursors by two units of a trifunctional reagent. A
random combination should result in the two isomers in the
ratio of 3:2, and the K3,3 graph product as a minor component
(Figure 2, bottom).
A preparative recycling SEC technique was successfully
applied to resolve and isolate these two constitutional isomers,
possessing distinctive hydrodynamic volumes in solution,
confirmed by the simulation by assuming random coil
conformations.27 The presence of the two components
(fractions 1 and 2, respectively) was disclosed after repeated
recycling (Figure 4), but the eventual resolution was not
obvious at the first cycle. The isomer ratio was 7:3 estimated
from the SEC peak area, with the smaller hydrodynamic
volume component (fraction 2), presumably the K3,3 graph
product, as a minor component. This is comparable with the
statistical isomer ratio of 6:4, and the slight preference of the
major ladder product is reasoned by its smaller ring formation
path involved in the covalent conversion of 4/Tricarboxylate
(Figure 2). The resolved two components having the larger and
smaller elution volumes were subsequently isolated by a
stepwise fractionation after the 17th cycle. (Figure 4)
The isolated two components in 5 (fraction 1 and 2)
Significantly, the obtained electrostatic self-assembly, 4/
Tricarboxylate, tends to produce specific ion-pair forms under
dilution, where the anions and the cations balance the charges
in the smallest number of the components (Figure 2, top). The
ionic intermediate, 4/Tricarboxylate, was then subjected to
heat treatment by refluxing in THF/CH3OH (vol/vol = 9/1) at
a concentration of 0.1 g/L for 12 h, to cause an intramolecular
covalent reaction by ring-opening of the cyclic ammonium salt
groups by carboxylate groups. The soluble product, 5, was
isolated after the reprecipitation into water and subsequent
silica-gel column (CH2Cl2) workup in 17% yield (4.4 mg). The
1
covalent conversion reaction was confirmed by the H NMR
spectroscopic analysis (Figure 3, bottom), where the signals for
the methylene protons adjacent to N-phenyl groups visible at
3.60−3.73 ppm were replaced by the multiplet signal for the
ester-methylene protons at 4.18−4.47 ppm. In addition, the
signals at 7.46−7.76 ppm due to the N-phenyl protons
observed in the ionic 4/Tricarboxylate were replaced by
those at 6.53−6.71 and 7.19 ppm after the covalent conversion.
By MALDI-TOF mass analysis,26 the covalent conversion
product showed a peak at m/z = 5024.29, corresponding to the
1
exhibited nearly identical H NMR (Figure 5, left, top and
bottom, respectively) and MALDI-TOF mass spectra (Figure 5,
right, middle, and bottom, respectively). In addition, not only
C
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Figure 3. H NMR (300 MHz) spectra of (top) an electrostatic self-assembly composed of a hexafunctional dendritic precursor carrying two
trifunctional counteranions, 4/Tricarboxylate, (CDCl3/CD3OD at 25 °C, The signals with * are due to the undeutrated fraction of CD3OD and
H2O) and (bottom) the covalent converted product (5) therefrom (CDCl3 at 25 °C).
Figure 4. Recycling SEC traces for the product 5 with insets showing the first and the 17th cycle charts. (CHCl3 as an eluent at a flow rate of 3.5
mL/min, fractionation/isolation started after 17th cycle.)
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Figure 5. H NMR spectra (left) of the isolated two components (fraction 1, top, as major and fraction 2, bottom, as minor components), and
MALDI-TOF mass spectra (right) of (top) the covalent converted product 5 from 4/Tricarboxylate, and (middle and bottom) the two isolated
components by the SEC fractionation. (1H NMR: 300 MHz, CDCl3 at 25 °C; MALDI-TOF mass: linear mode, dithranol with sodium
trifluoroacetate as matrix.)
Figure 6. (top) Construction of doubly-fused tricyclic polymer topologies (6) by the ESA-CF process with a dendritic precursor carrying three
difunctional counteranions, 4/Dicarboxylate, and (bottom) a scheme showing random combinations of the end groups during the covalent
conversion.
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Figure 7. Recycling SEC traces for the product 6 with insets showing the first and the 16th cycle charts. (CHCl3 as an eluent at the flow rate of 3.5
mL/min, fractionation/isolation started after 16th cycle.)
the observed MALDI-TOF peak molar mass but also the
observed fine structures due to the isotope distribution pattern
in the products exactly matched the calculated ones (Figure 5,
right, top, middle and bottom, respectively). On the other
hand, their hydrodynamic volumes in solution, estimated by the
SEC peak molecular weights (Mp) with polystyrene standards
for the calibration as a quantitative measure, i.e., Mp = 3440 and
2990,28 respectively, were distinctly different from each other,
and the hydrodynamic volume ratio of the two isomers
estimated by the SEC, i.e., 2990/3440 = 0.87, was in close
agreement with the simulation result of the ratio of the square
of the radius of gyration (Rg2), i.e., 0.43/0.50 = 0.86.27 Upon
these results, the minor component (fraction 2) having the
smaller 3D size was reasonably assigned as the K3,3 graph
product.
tricyclic α-graph product. The observed isomer ratio was
noticeably different from the statistical ratio of 1:6:8, (Figure 6,
bottom) which is rationalized by preference for linking
processes between chain-ends at structurally closer positions,
as observed before in the relevant dicyclic θ and manacle
isomer formation process.29
Finally, the analytical SEC measurement was conducted of a
series of tricyclic and tetracyclic products, including a K3,3 graph
topology macromolecule, together with the starting dendritic
precursor. (Figure 8) It was clearly seen that the triply fused
Macromolecular Tricyclic Topological Isomers
through Electrostatic Self-Assembly and Covalent
Fixation. The ESA-CF protocol has also been applied for
the construction of tricyclic macromolecular topologies, by the
−
ion-exchange reaction between 4/CF3SO3 and a difunctional
carboxylate, 4,4′-biphenyldicarboxylate (Figure 6, top). Thus,
the electrostatic self-assembly, 4/Dicarboxylate, was subjected
to the covalent conversion reaction in dilute solution to give
three tricyclic constitutional isomers, including a fused-type α-
graph topology and a bridged-type three-way paddle-form
(Figure 6 and Figures S16−S17 in the SI). The preparative
recycling SEC technique was successfully applied, as in the case
of 4/Tricarboxylate, to resolve and isolate the three constitu-
tional isomer components, possessing distinctive hydrodynamic
volumes in solution, which was envisaged also by the
simulation.27 The presence of three components was indeed
demonstrated after repeated recycling (Figure 7), and the three
isomer components were subsequently isolated by first
collecting the larger and smaller elution volume components
with stepwise fractionation after the 16th cycle (Figure 7). The
three isolated components in 6 (fraction 1, 2, and 3,
Figure 8. Analytical SEC charts of dicyclic and tricyclic polymers
obtained in this study with relative hydrodynamic volumes with
reference to the dendritic precursor, obtained after the covalent
conversion of ionic end groups of 4/CF3SO3 . (THF as an eluent at
the flow rate of 1.0 mL/min.)
−
1
respectively) exhibited identical H NMR (Figure S18 in the
tetracyclic K3,3 graph macromolecule is significantly contracted
in its 3D size, in comparison with the starting dendritic
precursor and with other spiro- and bridged-multicyclic
counterparts. Indeed, the hydrodynamic volume ratio of the
SI) and MALDI-TOF (Figure S19 in the SI) spectra, and
confirmed the expected chemical structures of the three
constitutional isomers. The observed isomer ratio was 3:4:3
from the SEC peak area, and the smallest hydrodynamic
volume component (fraction 3) is assignable to a doubly fused
K
3,3 graph macromolecule against the dendritic precursor (Mp =
4840), estimated by the SEC peak molecular weights, was 0.62.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed description of materials and methods, preparation and
reaction procedures for a dendritic precursor, electrostatic self-
assemblies with trifunctional and bifunctional carboxylate
counterions, and covalent conversion products, as well as
1
SEC fractionation of topological isomers, and H NMR and
MALDI-TOF mass spectra of the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
ytezuka@o.cc.titech.ac.jp
Notes
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D.; Grubbs, R. H. Science 2002, 297, 2041−2044. (b) Xia, Y.;
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Am. Chem. Soc. 2009, 131, 2670−2677. (c) Blencow, A.; Qiao, G. G. J.
Am. Chem. Soc. 2013, 135, 5717−5725. For NHC ring-expansion, see
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2596. (e) Culkin, D. A.; Jeong, W.; Csihony, S.; Gomez, E. D.; Balsara,
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. T. Deguchi and Ms. E. Uehara (Ochanomizu
University) for the simulation work. We also acknowledge G.
Matsuura, M. Nakashima, H. Fujimoto, and F. Ando for their
contributions in the initial stage of this project. This work was
supported partly by KAKENHI (26288099 T.Y. and 23350050
Y.T.).
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(25) The triply-fused tetracyclic K3,3 graph and ladder topologies
constructed in this study are expressed as IV6(0,6)[0a-0b-0c-0a-0b-0c]
and IV6(0,6)[0a-0b-0c-0c-0b-0a], respectively, according to the system-
atic notation (ref 8) .
(26) See Figure 5 (right, top) for a MALDI TOF mass spectrum of
the product, 5.
(27) The radius of gyrations (Rg) of the two tetracyclic and three
tricyclic polymers shown in this work were estimated by the simulation
according to the method outlined before (Uehara, E.; Deguchi, T. J.
Phys. A., Math. Theor. 2013, 46, 345001, and Uehara, E.; Tanaka, R.;
Inoue, M.; Hirose, F.; Deguchi, T. React. Funct. Polym. 2014, 80,
48−56). The relative Rg2 values of each fractions with respect to the
starting dendritic precursor were: 0.50 (fraction 1 in 5), 0.43 (fraction
H
dx.doi.org/10.1021/ja504891x | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX