Supramolecular polymerization provides non-equilibrium product distributions of imine-linked macrocycles

Article abstract of DOI:10.1039/c9sc05422g

Supramolecular polymerization of imine-linked macrocycles has been coupled to dynamic imine bond exchange within a series of macrocycles and oligomers. In this way, macrocycle synthesis is driven by supramolecular assembly, either into small aggregates su

Full text of DOI:10.1039/c9sc05422g

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Chemical Science
ARTICLE
Supramolecular Polymerization Provides Non-Equilibrium Product
Distributions of Imine-Linked Macrocycles
Michael J. Strauss, Austin M. Evans, Ioannina Castano, Rebecca L. Li, and William R. Dichtel*
Received 00th January 20xx,
Accepted 00th January 20xx
Supramolecular polymerization of imine-linked macrocycles has been coupled to dynamic imine bond exchange within a
series of macrocycles and oligomers. In this way, macrocycle synthesis is driven by supramolecular assembly, either into
small aggregates supported by π-π interactions, or high-aspect ratio nanotubes stabilized primarily by electrostatic and
solvophobic interactions. For the latter, supramolecular polymerization into nanotubes restricts imine exchange, thereby
conferring chemical stability to the assemblies and their constituent macrocycles. Competition in the formation and
component exchange among macrocycles favored pyridine-2,6-diimine-linked species due to their rapid synthesis,
thermodynamic stability, and assembly into high-aspect ratio nanotubes under the reaction conditions. In addition, the
pyridine-containing nanotubes inhibit the formation of similar macrocycles containing benzene-1,3-diimine-linkages,
presumably by disrupting their assembly and templation. Finally, we exploit rapid imine exchange within weak, low-aspect
ratio macrocycle aggregates to carry out monomer exchange reactions to macrocycles bearing pyridine moieties. Once a
pyridine-containing dialdehyde has exchanged into a macrocycle, the macrocycle becomes capable of nanotube formation,
which dramatically slows further imine exchange. This kinetic trap provides chemically diverse macrocycles that are not
attainable by direct synthetic methods. Together these findings provide new insights into coupling supramolecular
polymerization and dynamic covalent bond-forming processes, and leverages this opportunity to target asymmetric
nanotubes. We envision these findings spurring further research efforts in the synthesis of nanostructures with designed
and emergent properties.
DOI: 10.1039/x0xx00000x
Introduction
Supramolecular polymers are a compelling platform to design structural changes can target diverse nanostructures that are
nanostructures with diverse functionality, long range order, and kinetically stabilized by the function of supramolecular
2
8-30
dynamic properties that are not attainable via traditional assemblies.
1-5
covalent polymerization. Due to the promise of accessing
materials with these sought-after properties, the last decade of
research has seen an emergence in novel supramolecular
polymerization strategies such as ‘sergeant and soldier’ chirality
Using the traditional two-step approach, we have previously
isolated imine-linked macrocycles derived from aromatic
dialdehydes and a bifunctional aryl amine (DAPB); and studied
their aptitude to undergo acid-mediated supramolecular
polymerization into high-aspect ratio nanotubes.
of macrocycles derived from simple aromatic dialdehydes such
6
-9
10-14
amplification, living supramolecular polymerization,
and
3
1-32
In the case
5,
15-18
supramolecular (co)polymerization.
While these
strategies allow access to diverse nanostructures, they all
employ a general two-step process in which the building blocks
are first isolated as a unimolecular species and polymerized in a
second synthetic step. In this process, polymerization is typically
as terephthaldehyde and isophthalaldehyde (IDA, MC 1), high
concentrations of CF CO H (>2000 equiv) were required to
3 2
protonate the imine linkages and drive assembly, while lower
acid concentrations catalyzed macrocycle hydrolysis.3
However, including pyridine moieties (MC 2), which are
more basic than the imine linkages allowed macrocycle
assembly to occur via electrostatic attractions upon pyridinium
formation, even in the presence of sub-stoichiometric acid
1-32
19-23
induced by altering the solvent composition
or changing the
temperature of a monomer solution.5, 24-27 Using this approach,
the chemical structure of the building blocks remain fixed and
diverse nanostructures emerge from the order in which they
assemble. However, supramolecular polymerization under
conditions in which the monomers are can also undergo
31
3 2
loadings. Because of the low concentrations of CF CO H
needed for supramolecular polymerization, we hypothesized
that pyridine-containing macrocycles would form nanotubes
during their covalent synthesis. In this way, the process of
supramolecular polymerization and imine-exchange amongst
pyridine containing species may interact and influence each
other.
Department of Chemistry, Northwestern University, Evanston, IL, 60208 United
States
Electronic Supplementary Information (ESI) Including Experimental Procedures
and Characterization Data Available. See DOI: 10.1039/x0xx00000x
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experiment narrowed, indicating successful macrocycle
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DOI: 10.1039/C9SC05422G
formation (see Supporting Information), which is consistent
with our previous study on how neutral macrocycles form via
3
3
linear polyimines.
Characterization of the resulting
macrocycles by matrix-assisted laser desorption ionization mass
spectrometry (MALDI-MS) revealed single peaks corresponding
to the target macrocycles (Figures S4 and S24). Furthermore,
analysis of the final states of each macrocyclization reaction by
atomic force microscopy (AFM), scanning electron microscopy
(SEM), and transmission electron microscopy (TEM)
demonstrated that MC 2 forms high aspect ratio nanotubes,
while MC 1 yield ill-defined aggregates, which is consistent with
previous reports (Figures 2C-2D and 2F-2G) (see Supporting
3
1, 33
Information).
The assembly of MC 2 into nanotubes under
conditions typical for its synthesis was also observed in the
presence of other acids (HCl, p-toluenesulfonic acid, and
methanesulfonic acid) capable of protonating the pyridine ring
(Figure S40). Contributing factors to the observed rate
acceleration are the inductive nature of the pyridine ring, which
increase the rate of imine condensation to yield acyclic
products, and supramolecular polymerization, which drives
Figure 1. Impacts of pyridine moiety incorporation on macrocycles aptitude to undergo imine-exchange of these undesired intermediates to yield MC 2
acid-mediated supramolecular polymerization, and the impacts of supramolecular
polymerization on imine dynamics.
34-37
A small molecule study in which DFP was condensed with
aniline under conditions typical for macrocycle synthesis
yielded 2,6-diiminophenylpyridine within the first five minutes
of reaction time, which is an order of magnitude faster than the
reaction of aniline with IDA (Figure S114-119). The above
experiments demonstrate that MC 2 assembles into nanotubes
under conditions typical for its synthesis and that its linkages
form more rapidly than those of MC 1. These two factors explain
the rapid and highly selective formation of MC 2, and we
designed follow-up experiments to further explore this
interplay.
Furthermore, we hypothesized that the relative strengths of
non-covalent interactions supporting the assemblies of MC 1
and MC 2 would have profound effects on their kinetic stability
and ability to undergo monomer exchange. Under this
hypothesis, the relatively weak π-π interactions supporting MC
1
,
coupled with the inherent reactivity of IDA and
2
,6-pyridinedicarboxaldehyde (DFP), would enable monomer
exchange to macrocycles bearing pyridine moieties. This
exchange would unlock nanotube formation and provide non-
symmetric macrocycles that are inaccessible by direct synthetic The formation of MC 2 dominates a competition experiment in
methods (Figure 1).
which both dialdehydes compete for a limited number of amine
nucleophiles (Figure 3A). By combining 1 equiv of DAPB with 1
equiv each of DFP and IDA, MC 2 is formed in high yield while
reaction of IDA with small quantities of DAPB yields acyclic
oligomers. In order to ensure that the formation of a small
population of MC 1 was not limited by availability of the acid
catalyst, the reaction was run at an elevated acid loading (10
equiv). The products of this competition reaction were
Results and Discussion
The reactivity of DFP along with the assembly of MC 2 into
nanotubes under reaction relevant conditions accelerates the
formation of MC 2 relative to MC 1 by at least two orders of
magnitude (Figure 2A). The assembly processes of nanotube
formation of charged macrocycles and π-π aggregation of
neutral macrocycles that each drive macrocyclization cause the
relative rates of macrocycle formation to be correlated to the
emergence of an x-ray diffraction (XRD) signal. Tracing the
emergence of the predominant nanotube diffraction feature via
time-resolved XRD (TR-XRD) demonstrates that the formation
of MC 2 occurs before the first data point was obtained (2.5
min), while the formation of MC 1 takes over two hours (Figure
1
characterized by GPC, MALDI-MS, and H NMR spectroscopy.
GPC analysis indicated the predominant formation of a single
macrocyclic product, as judged by the narrow peak shape
whose retention time matched purified samples of MC 2, along
with relatively weak signals corresponding to other oligomeric
species (Figure 3B, purple trace). MALDI-MS analysis of the
same product mixture indicated a strong signal corresponding
to the mass of MC 2, along with small oligomers containing IDA
and DAPB species that did not react to form macrocycle (Figures
2
B and 2E). The results of TR-XRD were validated using gel-
permeation chromatography (GPC), in which MC
2
3
C and S82-S86). No signal corresponding to MC 1 was
demonstrated a single narrow elution band after 2 minutes of
reaction time. However, in the case of MC 1, 2 minutes of
reaction time yielded linear polymer and as the major product,
with a small secondary peak corresponding to the target
macrocycle. At longer times, the GPC signal of the MC 1
1
observed. H NMR spectroscopy of the crude products also
indicated the selective formation of MC 2. Similar to the MALDI-
MS analysis, no signals in the NMR spectrum corresponding to
MC 1 were observed (Figure S87). The formation of nanotubes
2
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Figure 2. Probing the kinetics of the assembly processes that govern the formation of MC 1 and MC 2. (A) Scheme of macrocycle formation. (B) TR-XRD patterns from 0 to 240
minutes depicting the formation and assembly of MC 1. (Inset) Normalized integration of the diffraction signal with respect to time. (C) Atomic force micrograph of the aggregates
resulting from the formation of MC 1. (D) Scanning electron micrograph of the aggregates resulting from the formation of MC 1. (E) TR-XRD patterns from 0 to 10 minutes depicting
the rapid formation and assembly of MC 2. Slight decreases in intensity were observed due to x-ray beam damage of the resulting nanotubes. (Inset) Normalized integrations of the
diffraction signal with respect to time. (F) Atomic force micrograph of the nanotubes resulting from the formation of MC 2. (G) Scanning electron micrograph of the nanotubes
resulting from the formation of MC 2.
under the reaction conditions was confirmed by AFM, SEM, and
The most surprising finding of a scrambling experiment was that
TEM; demonstrating that small oligomers containing IDA
MC 1 was not formed in detectable amounts, despite there
moieties did not interrupt the assembly of MC 2 (Figures S89-
being sufficient DAPB to form a 1:1 mixture of MC 1 and MC 2
.
S91). Lastly, the presence of assembled nanotubes in the
reaction solution prior to workup was confirmed by in situ XRD,
which yielded a pattern comparable to the direct synthesis of
MC 2 (Figure S92). Finally, a small molecule competition study
in which IDA (1 equiv), DFP (1 equiv), and aniline (2 equiv) were
condensed under conditions typical for macrocycle synthesis
exclusively yielded 2,6-diiminophenylpyridine, whereas
unreacted IDA remained in solution (Figures S115-S116).
Collectively, these results indicate that pyridine-containing
macrocycles have two factors that favor their formation relative
to benzene-containing derivatives. First, DFP forms imines more
rapidly than IDA. Second, pyridine-containing macrocycles
undergo supramolecular polymerization as they form, which
further drives macrocycle formation over acyclic products. The
This finding suggests that the formation and/or assembly of MC
interrupts the templation process required to form MC 1. A
2
scrambling reaction between DAPB (1 equiv), DFP (0.5 equiv),
and IDA (0.5 equiv) resulted in the selective formation of MC 2
and small IDA-containing oligomers (Figure 3A). In contrast,
both pyridine-2,6-diimine and benzene-1,3-diimine species are
formed in the presence of aniline under the same conditions
(see Supporting Information). The GPC trace of the scrambling
reaction indicated the presence of macrocyclic and oligomeric
species. MALDI-MS of the reaction indicated that only MC 2 was
formed, and that all identifiable peaks corresponding to
oligomers were IDA-containing species (Figures 3B-3C and
1
S63-S68). Furthermore, H NMR spectroscopy of the reaction
mixture showed resonances corresponding to MC 2, but not MC
3
corresponding process for IDA macrocycles requires 10 higher
acid concentrations, such that only more weakly bound
assemblies are present during their synthesis.
1
, as well as oligomers containing IDA (Figure S70). Isolation of
MC 2 by precipitation into CH Cl resulted in an isolated
2
2
macrocycle yield of 72-94% with respect to DFP, corresponding
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MC 1 formation was also inhibited in the presence of a pure
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DOI: 10.1039/C9SC05422G
sample of MC 2, further validating that MC 2 nanotubes prevent
the self-templation necessary for MC 1 formation. Furthermore,
MC 2 was stable to the reaction conditions, despite the
presence of free aldehydes, amines, and acid catalyst.
Independently synthesized MC 2 nanotubes were added to a
3 2
solution of DAPB (1 equiv), IDA (1 equiv), and CF CO H (10
equiv) and left undisturbed for 3 days (Figure 4A). Analysis of
the reaction by GPC yielded results analogous to the scrambling
reaction in which several elution bands were observed,
corresponding to discrete macrocycles and imine-linked
oligomers (Figure 4B). Subsequent analysis by MALDI-MS
demonstrated that MC 2 was retained throughout the process
by the lack of oligomers containing DFP moieties as well as no
evidence of IDA moieties exchanging into MC 2. The MALDI-MS
spectrum contained signals corresponding to IDA-containing
oligomers with no DFP incorporation, consistent with the
results of the scrambling reactions (Figure 4C). These findings
demonstrate that either free MC 2 or nanotubes comprised of
MC 2 disrupt the formation of MC 1. This inhibition may result
from the association of IDA-containing oligomers with
pyridinium moieties within the MC 2 nanotubes, thereby
hampering the reactivity of the oligomeric species, but a specific
mechanism of inhibition remains unclear. These experiments
and previous studies point to a templation process driving
macrocycle formation, which is disrupted in the presence of
monomeric or assembled MC 2 species (Figure 2B).
Monomer exchange experiments demonstrate that imines
within acid-mediated nanotube assembles are far less dynamic
Figure 3. Probing the interplay of kinetic preference and chemical stability of MC 2 than those in weak assemblies or monomeric species. Due to
through competition and scrambling experiments. (A) Scheme of the competition and
scrambling experiments. (B) Representative gel permeation chromatograms of the
combination of supramolecular polymerization and the
competition experiment (purple) and the scrambling experiment (blue). (C)
the stability of the imine linkages of MC 2, through a
inherent chemistry of pyridine-2,6-diimine moieties, attempts
Representative MALDI-MS spectra of the results of the competition experiment (purple)
+
+
and the scrambling experiment (blue). MC 2 was observed as the [M+H] , [M+Na] , and to exchange its DFP moieties for IDA moieties failed. A
+
[
M+K] adducts.
previously synthesized sample of MC 2 was resuspended in 1,4-
to half of the available DAPB reacting to yield macrocycles
Table S3). Similar to the direct synthesis of MC 2 and the
(
previous competition experiment, AFM, SEM, and TEM images
confirmed the formation of nanotubes that drive macrocycle
formation (Figures S72-S74). Lastly, the in situ XRD pattern of
the scrambling reaction demonstrates an extended structure
analogous to the direct synthesis of MC 2 (Figure S75). These
combined findings indicate that the scrambling experiment,
conducted at 25 mM DAPB and 12.5 mM each of DFP and IDA,
forms MC 2 with no IDA incorporation, as well as no evidence
MC 1 formation. In contrast, when 12.5 mM of DAPB and 12.5
mM of IDA are reacted in the absence of DFP, MC 1 is formed in
high yield. This suppression of MC 1 formation in the presence
of MC 2 was also observed at four other starting concentrations
Figure 4. Control experiment demonstrating the effects of MC 2 nanotubes on the
selective synthesis of MC 1. (A) Scheme depicting the control experiment in which
previously synthesized MC 2 nanotubes are combined with DAPB, IDA, and CF CO H
3 2
under conditions which in the absence of MC 2 nanotubes selectively yields MC 1. (B)
Gel permeation chromatogram of the inhibited MC 1 synthesis. (C) MALDI-MS spectra
(12.5 mM, 8.5 mM, 6.40 mM, and 5.10 mM with respect to
DAPB) of the scrambling experiment (see Supporting
Information). The results of the scrambling experiment, of the results of the inhibited MC 1 synthesis depicting the recovery of MC 2, with no
hydrolysis artifacts, and oligomers containing IDA moieties. MC 2 was observed as the
[
chromatogram of the direct synthesis of MC 1. (E) Representative MALDI-MS spectra
of the direct synthesis of MC 1.
combined with small molecule experiments and concentration
M+H]+, [M+Na]+, and [M+K]+ adducts. (D) Representative gel permeation
dependent controls, suggest that MC 2 nanotubes disrupt
formation of MC 1
.
4
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dioxane with IDA (10 equiv), and excess CF
ARTICLE
2
CO H (Scheme S6). linkages, such that peaks were observed correVsiepwoAnrtdicilenOgnlitnoe
3
The reaction mixture was sonicated and held at room macrocycles containing 0, 1, 2, or 3 5-brDoOmI:o1i0s.o10p3h9a/Ch9laSlCd0e5h4y2d2Ge
temperature for 3 days (Figure 5A). Analysis of the monomer moieties (Figure S114). These observations indicate that IDA can
exchange product by GPC confirmed the formation of discrete exchange into macrocycles that contain similar linkages. IDA’s
macrocycles (Figure S93). However, analysis of the solution by inability to exchange into MC 2 under similar conditions arises
MALDI-MS showed full recovery of MC 2, with no incorporation either from the increased stability of the pyridine-2,6-diimine
1
of IDA (Figure 5D). H NMR spectroscopy of product of the moiety or the kinetic persistence of macrocycles in acid-
attempted monomer exchange demonstrates recovery of MC 2 mediated assemblies.
with no resonances corresponding to IDA-containing species
When the previous exchange experiment was run in reverse,
(
Figure 5C). Based on the lack of monomer exchange as
DFP was able to exchange into MC 1 (Figure 5B). However, the
major product of the exchange is a macrocycle containing only
one pyridine-2,6-diimine moiety, despite DFP being used in 10-
fold excess with respect to MC 1. MALDI-MS of the products
revealed the presence of macrocycles containing a mixture of
IDA and DFP subunits (Figure 5D). The spectrum clearly shows
1
demonstrated by MALDI-MS and H NMR, we hypothesized that
3 2
upon exposure to CF CO H, MC 2 assembled into nanotubes
which, along with the inherent stability of pyridine-2,6-diimines,
prevented reaction of the imine linkages. This hypothesis was
supported by AFM, SEM, and TEM, which depicted the
formation of nanotubes akin to the direct synthesis of MC 2
no evidence of remaining MC 1 or the fully exchanged MC 2
.
(Figures S97-S99). Lastly, the in situ XRD pattern of the failed
However, the relative amounts of singly and doubly exchanged
monomer exchange matches well with that of the direct MC 2
synthesis (Figure S100). Collectively, the inability to exchange
the DFP moieties out of nanotubes assembled from MC 2
highlights the chemical persistence and kinetic stability of the
imine linkages within the protonation driven molecular
1
macrocycles are not clear. H NMR spectroscopy of the reaction
indicated that 86% of the macrocycles contained a single
pyridine moiety and 14% contained two pyridine moieties
(Figures 5C and S106). Given the rapid and complete formation
of MC 2 from DAPB and DFP, even in the presence of IDA,
coupled with the thermodynamic preference for pyridine-2,6-
32
assembly.
Although IDA does not exchange into MC 2 nanotubes, it readily diimine linkages; the selective formation of singly and doubly
exchanges into macrocycles linked by other substituted exchanged macrocycles under these conditions strongly suggest
isophthalaldehydes. Macrocycles were synthetized using a 5- that incorporation of a single pyridine unit drives nanotube
3 2
bromoisophthalaldehyde monomer, which assemble similar to formation in the presence of CF CO H and results in a kinetic
MC 1 (Scheme S8) (Figures S111-S112). Monomer exchange of trap en route to the thermodynamically favored MC 2. Indeed,
the 5-bromoisophthalaldehyde linked macrocycles with IDA nanotubes were observed in these exchange experiments by
resulted in the formation of macrocyclic species, as evident by AFM, SEM, and TEM (Figures S107-S109). The results of the
the narrow elution band in the corresponding GPC trace three monomer exchange experiments highlight the diminished
(Scheme S9) (Figure S113). MALDI-MS depicts scrambling of the reactivity of imine linkages within acid-mediated assemblies.
1
Figure 5. Monomer exchange of imine-linked macrocycles. (A) Monomer exchange of MC 2 with IDA. (B) Monomer exchange of MC 1 with DFP. (C) H NMR spectra of macrocycles
resulting from each monomer exchange. (D) MALDI-MS comparison of the macrocycles resulting from each monomer exchange.
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Furthermore, supramolecular polymerization into nanotubes ECCS-1542205); the MRSEC program (NSF; DMR-1720139) at
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DOI: 10.1039/C9SC05422G
served as a kinetic trap in the full conversion of MC 1 to MC 2
which allows access to non-symmetric macrocycles.
,
the Materials Research Center; the International Institute for
Nanotechnology (IIN); the Keck Foundation; and the State of
Illinois. This work was also supported by the Northwestern
University Keck Biophysics Facility and a Cancer Center Support
Grant (NCI CA060553). Parts of this work were performed at the
DuPont-Northwestern-Dow Collaborative Access Team (DND-
CAT) located at Sector 5 of the Advanced Photon Source (APS)
at Argonne National Lab. This research used resources of the
Advanced Photon Source and the Center for Nanoscale
Materials, both U.S. Department of Energy (DOE) Office of
Science User Facilities operated for the DOE Office of Science by
Argonne National Laboratory under Grant No. (DGE-1324585).
We acknowledge Prof. Julia Kalow for the use of her GPC
instrument. We acknowledge Prof. Doug Philp for helpful
discussions in the preparation of this manuscript.
Conclusions
In conclusion, we have developed a system in which
supramolecular polymerization is coupled to dynamic covalent
bond-forming processes in the synthesis of imine-linked
macrocycles. We have demonstrated that the formation of MC
2
is kinetically favored relative to MC 1, and its imine linkages
are stabilized as a function of acid-mediated supramolecular
polymerization and the inherent chemistry of the linkage itself.
These three factors led to the selective synthesis of MC 2
dominating a competition experiment with MC 1. Additionally,
the mere presence of nanotubes assembled from MC 2 proved
to interrupt the synthesis of MC 1, presumably by disrupting the
self-templation that guides its selective synthesis. Lastly, References
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1
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1
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and resulted in the kinetic trapping of chemically diverse
macrocycles not attainable by direct synthetic methods. These
findings highlight the complex interplay of covalent and non-
covalent synthesis that can give rise to complex dynamic
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Conflicts of Interest
There are no conflicts to declare
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Acknowledgements
This work was funded by the Army Research Office through the
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Multidisciplinary University Research Initiative (MURI; W911NF- 10 R. D. Mukhopadhyay and A. Ajayaghosh, Science, 2015, 349
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,
2
1
5-1-04477, to W.R.D.). M.J.S was supported by the National
1
1 J. Kang, D. Miyajima, T. Mori, Y. Inoue, Y. Itoh and T. Aida,
Science, 2015, 347, 646-651.
2 S. Ogi, K. Sugiyasu, S. Manna, S. Samitsu and M. Takeuchi, Nat.
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Science Foundation (NSF) through the Graduate Research
Fellowship Program (GRFP) under Grant No. (DGE-1842165).
A.M.E. was supported by the NSF through the GRFP under Grant
1
No. (DGE-1324585). I.C. was supported by the NSF through the 13 S. Ogi, V. Stepanenko, K. Sugiyasu, M. Takeuchi and F.
Würthner, J. Am. Chem. Soc., 2015, 137, 3300-3307.
GRFP under Grant No. (DGE-1842165). I.C. is partially supported
by the Ryan Fellowship and the International Institute for
Nanotechnology. This work made use of the Integrated
Molecular Structure Education and Research Center (IMSERC)
1
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