A trefoil knotted polymer produced through ring expansion

Article abstract of DOI:10.1002/anie.201411623

A synthetic strategy is reported for the production of a trefoil knotted polymer from a copper(I)-templated helical knot precursor through ring expansion. The expected changes in the properties of the knotted polymer compared to a linear analogue, for exa

Full text of DOI:10.1002/anie.201411623

Angewandte
Chemie
DOI: 10.1002/anie.201411623
Knotted Polymers
A Trefoil Knotted Polymer Produced through Ring Expansion**
Peng-Fei Cao, Joey Mangadlao, and Rigoberto Advincula*
Abstract: A synthetic strategy is reported for the production of
a trefoil knotted polymer from a copper(I)-templated helical
knot precursor through ring expansion. The expected changes
in the properties of the knotted polymer compared to a linear
analogue, for example, reduced hydrodynamic radius and
lower intrinsic viscosity, together with an atomic force micros-
copy (AFM) image of individual molecular knots, confirmed
the formation of the resulting trefoil knotted polymer. The
strategies employed here could be utilized to enrich the variety
of available polymers with new architectures.
a challenging chemical target for which no rational synthesis
has been reported to date, although their formation has been
claimed in polymer systems, often through creativity and luck
during end-to-end ring closure of a linear chain precursor.[11]
Herein, a rational access to knotted polymers is reported,
which combines a highly successful templated synthesis with
ring expansion.
To date, the fabrication of CuI-templated knot precursors
by Sauvage et al. remains one of the most successful examples
of the synthesis of molecular knots (especially for the trefoil
knot, the simplest and yet perhaps most beautiful one). This
method involves the quantitative formation of a helical knot
precursor, readily modifiable terminal groups, and a facile
decomplexation method.[5a–c] Moreover, progress in polymer
science has produced the ring-expansion technique for the
fabrication of cyclic polymers, and this technique allows
concentrated synthesis and facile product isolation.[9a,b]
Through utilizing ring expansion, Kricheldorf et al. success-
fully prepared cyclic polymers by inserting lactones or lactides
K
nots, which initially gained interest in the fields of art and
mathematics because of their attractive and fascinating
structures,[1] have been found in DNA[2] and in proteins.[3] In
the last decades, chemists have been attracted by the synthetic
challenges they pose and their inherent structural beauty, as
well the potential for special properties arising from their
compact twisted forms, reduced entanglement, and topolog-
ical chirality.[4] Thanks to the development of coordination
chemistry, supramolecular chemistry, and new methods of
covalent bond formation, successful syntheses of molecular
trefoil knots[5] and even pentafoil knots[6] have been achieved.
Recently, Sanders and co-workers reported the near quanti-
tative self-assembly of trefoil knots or meso figure-of-eight
knots from naphthalenediimide-based ligands in aqueous
solution with the hydrophobic effect as the driving force.[5l,7]
However, the synthesis of molecular knots with large
molecular weights, such as knotted polymers, remains elusive,
although theoretical calculations indicate that their unique
topologies would have a significant effect on the physical
properties of the polymers.[8]
À
into the Sn O bonds of cyclic dibutyltin alkylene oxides,
where the macrocycles were prepared under kinetic control
with no side reactions observed.[12]
Based on the successes in these fields, we designed a novel
synthetic route (Scheme 1) to address the challenge of trefoil
knotted polymer synthesis: ring closing of the CuI-templated
helical knot precursor affords a trefoil knot initiator, into
which monomer units are inserted to generate the polymer
chains, and a final decomplexation results in a trefoil knotted
polymer. To our knowledge, this is the first report of a rational
synthesis of knotted polymers. This method could potentially
afford a new polymer family with unique properties and
hence novel polymeric materials.[8a,11]
Polymers with topologically interesting structures, such as
cyclic polymers[9] and catenated polymers,[10] have been
synthesized by different strategies. Their distinct properties,
such as reduced hydrodynamic radii and lower viscosity
compared to their linear analogues, have been well studied.
However, mathematically speaking, none of these polymers
are genuine knots since a cyclic polymer is a trivial knot
(unknot) and a catenated polymer is a Hopf link (a type of
two-component link).[4a] Truly knotted polymers represent
The rational design of a CuI-templated trefoil precursor
not only concerns the yield of desired complex formation, but
[*] P.-F. Cao, J. Mangadlao, Prof. R. Advincula
Department of Macromolecular Science and Engineering
Case Western Reserve University
Cleveland, Ohio 44106 (USA)
E-mail: rca41@case.edu
[**] We would like to acknowledge funding from NSF CHE-10-41300. We
would like to thank Allan C. Yago for the molecular modeling
studies. We also thank Agilent technologies and Malvern instru-
ment for technical support.
Scheme 1. Synthetic scheme for the production of trefoil knotted
polymers through templating and ring expansion. DBMT=dibutyldi-
methoxy-tin), ROP=ring-opening polymerization.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201411623.
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also needs to favor the bond
formation in the next step.
Compound 5 was synthe-
sized accordingly with an
overall yield of 32%
(Scheme S1 in the Support-
ing Information). The heli-
cal knot precursor 6 was
obtained quantitatively by
slowly transferring the ace-
tonitrile (CH3CN) solution
of Cu(CH3N)4PF6 to the
dichloromethane solution
of 5. The formation of the
complex was confirmed by
UV/Vis spectrometry (see
the Supporting Informa-
tion), which showed absorp-
tion peaks in the visible
region at 427 nm and
515 nm, which correspond
to the metal-to-ligand tran-
sition (MLCT) and the
ligand-to-metal transition
(LMCT),
respectively.[13]
The significant upfield
1
shifts in the H NMR spec-
trum of the resulting knot
precursor complex 6 com-
pared to that of 5 (Figure S6
in the Supporting Informa-
tion) can also ascribed to
the quantitative formation
of the copper(I)–phenan-
throline complex and sec-
ondary interactions.[4c]
Scheme 2. Synthesis of CuI-templated helical knot precursor 6, trefoil knot initiator 7, and CuI-templated trefoil
knotted polymer 8. The insets show compounds 6 and 7 modeled by using semi-empirical PM3 (tm).
Preorganized stable conformation with two reactive
groups positioned close together will greatly favor the
formation of the desired product, and utilizing secondary
interactions is one important approach to achieving this
target.[4c] In the CuI-templated knot complex, the favorable
conformation, where the two reactive hydroxyl groups are
positioned close together, was not only supported by previous
reports[14] but also confirmed by theoretical calculations (the
calculated structure of 6 (Scheme 2, inset) shows a very stable
twisting phenanthroline moieties and a tetrahedral metal–
ligand conformation.
By adopting a similar method to that reported by
Kricheldorf et al.,[12] caprolactone was utilized as the mono-
mer to afford CuI-templated knot polymer 8 through kineti-
cally controlled ring expansion (Scheme 1 and Scheme 2).
After 18 h of bulk polymerization, crude product was
obtained with monomer conversion calculated to be 75%
1
(see the Supporting information). The H NMR spectrum of
conformation with
a
heat of formation value Hf =
product purified by dialysis showed relatively strong typical
poly(e-caprolactone) resonances at 4.05 ppm and 2.10 ppm,
which suggested successful coordination–insertion polymeri-
zation.[15] Moreover, the presence of absorption peaks at
427 nm and 515 nm in the UV/Vis spectrum of 8 indicate
stability of the CuI–phenanthroline complex during the
polymerization process (see the Supporting Information).
À733 kJmolÀ1). The aromatic CH···O interactions and
gauche effect play an important role in this favorable
conformation.[4c] CuI-templated trefoil knot initiator 7 was
synthesized by refluxing the chloroform solution of 6 with
dibutyldimethoxyl tin (DBMT). UV/Vis analysis indicated
the presence of the CuI–phenanthroline complex, whereas the
NMR spectrum and X-ray photoelectron spectroscopy (XPS)
analysis suggested the insertion of Sn (see the Supporting
Information). According to theoretical calculations, the
formation energy of CuI-templated trefoil knot initiator 7
(Hf = À867 kJmolÀ1) is even lower than that of complex 6
(Hf = À733 kJmolÀ1). As shown in Scheme 2, the optimized
conformation of compound 7 is a bridged structure with
1
The H NMR spectrum of the CuI-templated trefoil knotted
polymer also confirmed the stability of the complex (see the
Supporting Information). These two factors are important in
maintaining the trefoil knot structure during the polymeri-
zation process.
To obtain the genuine trefoil knotted polymer without
copper, decomplexation was performed by adding 10 equiv-
2
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alents of KCN to the polymer solution stirring the mixture
overnight.[10d] An obvious color change (from reddish to
yellow) and the disappearance of the absorption peaks in the
visible region suggested successful decomplexation (see the
Supporting Information). Additional evidence was provided
by downfield shifts of the peaks corresponding to the
aromatic segment in the 1H NMR spectrum of trefoil knotted
polymer (Figure 1A and the Supporting Information). After
decomplexation, the GPC curve of the trefoil knotted
polymer showed a broader peak and smaller hydrodynamic
diameter compared to that of the CuI-templated trefoil
knotted polymer (see the Supporting Information). This is
perhaps due to the relatively high conformational freedom
and more compact structure after removing the CuI template.
It is worth noting that each trefoil knotted polymer had four
poly(e-caprolactone) chains derived from two Sn atoms.
Here, the average degree of polymerization (DPn) was
defined as the sum of two poly(e-caprolactone) chains derived
from the same Sn atom (m + n; Figure 1A). From the
integrations of the methylene groups next to the -OOC (v;
Figure 1A) in the polymer chains and the methylene groups
in the triethylene glycol segments (l + q or m), the average
degree of polymerization (m + n) was calculated to be 83,
which suggested 166 monomers per trefoil knotted polymer.
Hence, the absolute molecular weight (Mn(absolute)) of the
trefoil knotted polymer was calculated to be 21.3 kDa.
Another interesting observation from the 1H NMR spectrum
of the trefoil knotted polymer (9) is its well-resolved features
compared to phenanthroline-based trefoil knotted molecules
with low molecular weight.[5m] This could be due to the more
flexible structure of the trefoil knotted polymer and hence
faster intramolecular reptation process.
To confirm the structure of the trefoil knotted polymer
from its predicted properties, linear poly(e-caprolactone) with
the same Mn(absolute) was synthesized as a control. As expected,
the trefoil knotted polymer showed a much smaller hydro-
dynamic diameter than its linear analogue as a result of its
compact structure (Figure 1B).[11c] Moreover, less inter- and
intramolecular interaction lead to a much lower intrinsic
viscosity (IV): 0.1025 dLgÀ1 for the trefoil knotted polymer
and 0.2678 dLgÀ1 for the linear polymer analogue.[8a]
To provide direct evidence of the structure, atomic force
microscopy (AFM) was also employed to capture an image of
the trefoil knotted polymer. The topography images of the
target molecules in a large area did not provide the necessary
structural information and only showed individual spots. This
is perhaps due to the flexible polymer chains and the compact
polymer structures. However, the phase image afforded more
useful structural information (Figure 2A). The broad size
distribution is attributed to the high polydispersity index of
the poly(e-capralactone). The AFM image of the CuI-
templated trefoil knotted polymer (8) exhibited similar
architecture to a catenated polymer owing to the presence
of the template (see the Supporting Information).[10e] It is
worth noting that after decomplexation, the polymer (9)
appears to adapt a topological C3 symmetry rather than the
previous C2 symmetry shown by 8, in spite of the fact that
absolute C3 symmetry is impossible owing to the presence of
phenanthroline groups. This result suggests an increase in the
degree of freedom, which allows the polymer chains to relax
and transform to give a topological C3 symmetry. This
transformation further indicates successful decomplexation
to afford a genuine trefoil knotted polymer. Among many
topography images of the individual polymers, only very few
of these exhibited an ideal trefoil knot (Figure 2B), perhaps
owing to the relatively large sizes. Basic analysis of the
obtained polymers indicated the successful synthesis of trefoil
knotted polymers. More studies on the properties derived
from this unique structure are still underway.
In conclusion, although the formation of knotted poly-
mers has previously been claimed, this work represents the
first rational synthesis of a knotted polymer. The trefoil
knotted polymer was synthesized (yield of isolated product:
65%) through ring expansion of the trefoil knot initiator,
which was formed through a ring-closing reaction of the CuI-
templated helical knot precursor. Rational design of the
helical knot ligand (5) not only provided quantitative
formation of trefoil knot complex but also favored the ring-
closing reaction of the trefoil knot initiator. Through insertion
of the monomer, the trefoil knotted initiator grows into the
CuI-templated trefoil knotted polymer, from which decom-
Figure 1. A) 1H NMR spectrum for trefoil knotted polymer 9. The
chemical structure of 9 is not an actual representation because the
two bis-phenanthroline groups are probably far away from each other.
B) Comparative gel permeation chromatography (GPC) curves for the
trefoil knotted polymer and linear polymer with the same absolute
molecular weight. Linear polymer(red curve): Mn(apparent) =15.5 kDa,
PDI=1.795, IV=0.2678 dLgÀ1; trefoil knotted polymer (black curve)0:
M
n(apparent) =6.99 kDa, PDI=1.966, IV=0.1025 dLgÀ1
.
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The Knot Book, W. H. Freeman, American Mathematical Soc.,
Rhode Island, 1994; c) L. Chen, The Complete Book of Chinese
Knotting: A Compendium of Techniques and Variations, Tuttle
Publishing, London, 2007.
[2] a) S. A. Wasserman, N. R. Cozzarelli, Science 1986, 232, 951 –
960; b) L. F. Liu, R. E. Depew, J. C. Wang, J. Mol. Biol. 1976,
106, 439 – 452; c) L. F. Liu, L. Perkocha, R. Calender, J. C. Wang,
Proc. Natl. Acad. Sci. USA 1981, 78, 5498 – 5502; d) M. A.
Krasnow, A. Stasiak, S. J. Spengler, F. Dean, T. Koller, N. R.
Cozzarelli, Nature 1983, 304, 559 – 560; e) A. Stasiak, V.
Katritch, J. Bednar, D. Michoud, J. Dubochet, Nature 1996,
384, 122.
[3] a) C. Z. Liang, K. Mislow, J. Am. Chem. Soc. 1994, 116, 11189 –
11190; b) F. Takusagawa, S. Kamitori, J. Am. Chem. Soc. 1996,
118, 8945 – 8946; c) W. R. Taylor, Nature 2000, 406, 916 – 919;
d) W. R. Taylor, K. Lin, Nature 2003, 421, 25; e) J. R. Wagner,
J. S. Brunzelle, K. T. Forest, R. D. Vierstra, Nature 2005, 438,
325 – 331.
[4] a) R. S. Forgan, J.-P. Sauvage, J. F. Stoddart, Chem. Rev. 2011,
111, 5434 – 5464; b) J.-P. Sauvage, D. B. Amabilino, Supramolec-
ular Chemistry: From molecules to Nanomaterials, Wiley,
Hoboken, 2012; c) J. E. Beves, B. A. Blight, C. J. Campbell,
D. A. Leigh, R. T. McBurney, Angew. Chem. Int. Ed. 2011, 50,
9260 – 9327; Angew. Chem. 2011, 123, 9428 – 9499.
[5] a) C. O. Dietrich-Buchecker, J.-P. Sauvage, Angew. Chem. Int.
Ed. Engl. 1989, 28, 189 – 192; Angew. Chem. 1989, 101, 192 – 194;
b) C. O. Dietrich-Buchecker, J.-F. Nierengarten, J.-P. Sauvage, N.
Armaroli, V. Balzani, L. De Cola, J. Am. Chem. Soc. 1993, 115,
11237 – 11244; c) G. Rapenne, C. Dietrich-Buchecker, J.-P.
Sauvage, J. Am. Chem. Soc. 1999, 121, 994 – 1001; d) P. R.
Ashton, O. A. Matthews, S. Menzer, F. M. Raymo, N. Spencer,
J. F. Stoddart, D. J. Williams, Liebigs Ann. Recueil 1997, 12,
2485 – 2494; e) O. Safarowsky, M. Nieger, R. Frçhlich, F. Vçgtle,
Angew. Chem. Int. Ed. 2000, 39, 1616 – 1618; Angew. Chem.
2000, 112, 1699 – 1701; f) O. Lukin, F. Vçgtle, Angew. Chem. Int.
Ed. 2005, 44, 1456 – 1477; Angew. Chem. 2005, 117, 1480 – 1501;
g) M. Feigel, R. Ladberg, S. Engels, R. Herbst-Irmer, R.
Frçhlich, Angew. Chem. Int. Ed. 2006, 45, 5698 – 5702; Angew.
Chem. 2006, 118, 5827 – 5831; h) E. E. Fenlon, B. R. Ito, Eur. J.
Org. Chem. 2008, 18, 3065 – 3068; i) C. A. Hunter, P. C. Mayer,
Nature 2001, 411, 763; j) J. Guo, P. C. Mayers, G. A. Breault,
C. A. Hunter, Nat. Chem. 2010, 2, 218 – 222; k) P. E. Barran,
H. L. Cole, S. M. Goldup, D. A. Leigh, P. R. McGonigal, M. D.
Symes, J. Wu, M. Zengerle, Angew. Chem. Int. Ed. 2011, 50,
12280 – 12284; Angew. Chem. 2011, 123, 12488 – 12492; l) N.
Ponnuswamy, F. B. L. Cougnon, J. M. Clough, G. D. Pantos,
J. K. M. Sanders, Science 2012, 338, 783 – 785; m) L.-E. Perret-
Aebi, A. Zelewsky, C. Dietrich-Buchecker, J.-P. Sauvage,
Angew. Chem. Int. Ed. 2004, 43, 4482 – 4485; Angew. Chem.
2004, 116, 4582 – 4585.
[6] a) J.-F. Ayme, J. E. Beves, D. A. Leigh, R. T. McBurney, K.
Rissanen, D. Schultz, Nat. Chem. 2012, 4, 15 – 20; b) J.-F. Ayme,
J. E. Beves, D. A. Leigh, R. T. McBurney, K. Rissanen, D.
Schultz, J. Am. Chem. Soc. 2012, 134, 9488 – 9497.
[7] N. Ponnuswamy, F. B. L. Cougnon, G. D. Pantos, J. K. M. San-
ders, J. Am. Chem. Soc. 2014, 136, 8243 – 8251.
[8] a) A. M. Saitta, P. D. Soper, E. Wasserman, M. L. Klein, Nature
1999, 399, 46 – 48; b) Y. Arai, R. Yasuda, K. Akashi, Y. Harada,
H. Miyata, K. Kinosita, Jr., H. Itoh, Nature 1999, 399, 446 – 448.
[9] a) C. W. Bielawski, D. Benitez, R. H. Grubbs, Science 2002, 297,
2041 – 2044; b) B. A. Laurent, S. M. Grayson, Chem. Soc. Rev.
2009, 38, 2202 – 2213; c) A. Bunha, P. F. Cao, J. D. Mangadlao, R.
Advincula, React. Funct. Polym. 2014, 80, 33 – 39.
[10] a) Y. Gan, D. Dong, T. E. Hogen-Esch, Macromolecules 2002,
35, 6799 – 6803; b) Y. Ohta, Y. Kushida, D. Kawaguchi, Y.
Matsushita, A. Takano, Macromolecules 2008, 41, 3957 – 3961;
c) K. Ishikawa, T. Yamamoto, M. Asakawa, Y. Tezuka, Macro-
Figure 2. A) AFM image of the trefoil knotted polymer on mica
substrate. Inset: Enlarged phase image of a trefoil knotted polymer.
B) Topography image of one of the largest trefoil knotted polymers and
its height profile.
plexation renders the genuine trefoil knotted polymer. The
trefoil knotted polymer showed the expected property
changes compared to its linear analogue, namely reduced
hydrodynamic radius and lower intrinsic viscosity. Moreover,
AFM images provide direct evidence for the structure of the
trefoil knotted polymer. We expect that the strategies
employed herein will be useful for the synthesis of polymers
with various types of architectures, and the special properties
of the trefoil knotted polymer may expand the potential
applications of polymer materials. Moreover, new opportu-
nities have been provided to study the effects of topology on
polymer properties.[8a]
Received: December 2, 2014
Revised: January 16, 2014
Published online: && &&, &&&&
Keywords: copper(I) · knotted polymers · ring expansion ·
.
supramolecular chemistry · templated complexes
[1] a) Handbook of Knot Theory (Eds.: W. W. Menasco, M. B.
Thistlethwaite), Elsevier, Amsterdam, 2005; b) C. C. Adams,
4
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
molecules 2010, 43, 168 – 176; d) A. Bunha, M. C. Tria, R.
Advincula, Chem. Commun. 2011, 47, 9173 – 9175; e) P.-F. Cao,
A. Bunha, J. Mangadlao, M. Felipe, K. Mongcopa, R. Advincula,
Chem. Commun. 2012, 48, 12094 – 12096.
[13] P. Yang, X.-J. Yang, B. Wu, Eur. J. Inorg. Chem. 2009, 2951 –
2958.
[14] a) B. Mohr, M. Weck, J.-P. Sauvage, R. H. Grubbs, Angew.
Chem. Int. Ed. Engl. 1997, 36, 1308 – 1310; Angew. Chem. 1997,
109, 1365 – 1367; b) M. Weck, B. Mohr, J.-P. Sauvage, R. H.
Grubbs, J. Org. Chem. 1999, 64, 5463 – 5471.
[15] a) K. R. Yoon, Y. Kim, I. S. Choi, J. Polym. Res. 2004, 11, 265 –
268; b) P. F. Cao, R. Xiang, X. Y. Liu, C. X. Zhang, F. Cheng, Y.
[11] a) M. Schappacher, A. Deffieux, Angew. Chem. 2009, 121, 6044 –
6047; b) E. E. Fenlon, Eur. J. Org. Chem. 2008, 5023 – 5035; c) Y.
Ohta, M. Nakamura, Y. Matsushita, A. Takano, Polymer 2012,
53, 466 – 470.
[12] a) H. R. Kricheldorf, G. Schwarz, Macromol. Rapid Commun.
2003, 24, 359 – 381; b) H. R. Kricheldorf, J. Polym. Sci. Part A
2004, 42, 4723 – 4742.
Chen, J. Polym. Sci. Part A 2009, 47, 5184 – 5193; c) H.
von Schenck, M. Ryner, A.-C. Albertsson, M. Svensson, Macro-
molecules 2002, 35, 1556 – 1562.
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Communications
Knotted Polymers
Knot a problem: A synthetic strategy is
reported for the production of a trefoil
knotted polymer from a CuI-templated
helical knot precursor through ring
expansion. The expected changes in the
properties of the knotted polymer com-
pared to a linear analogue, namely
reduced hydrodynamic radius and lower
intrinsic viscosity, together with atomic
force microscopy images of individual
molecular knots, confirmed the formation
of a trefoil knotted polymer.
P.-F. Cao, J. Mangadlao,
R. Advincula*
&&&& — &&&&
A Trefoil Knotted Polymer Produced
through Ring Expansion
6
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These are not the final page numbers!