Programmed dynamic covalent assembly of unsymmetrical macrocycles

Article abstract of DOI:10.1021/ja0745963

Unsymmetrical shape-persistent macrocycles have been prepared from diphenylacetylene monomers using imine formation and metathesis. A sequence-directed approach, in which each monomer is uniquely labeled by its N-donor/C-donor sequence, has been used to c

Full text of DOI:10.1021/ja0745963

Published on Web 08/29/2007
Programmed Dynamic Covalent Assembly of Unsymmetrical Macrocycles
C. Scott Hartley† and Jeffrey S. Moore*
Departments of Chemistry and Materials Science & Engineering, and the Beckman Institute for AdVanced Science
and Technology, UniVersity of Illinois at Urbana-Champaign, Urbana, Illinois 61801
Received June 22, 2007; E-mail: jsmoore@uiuc.edu
Shape-persistent macrocycles are now well-established as an
important class of rigid supramolecular building blocks for organic
materials,1 in part owing to their propensity to self-assemble into
π-stacked structures.2 Both kinetically and thermodynamically
controlled macrocyclization strategies have been used to access this
class of compounds.1a Kinetic approaches offer precise control over
monomer composition (potentially yielding complex, nonsymmetri-
cal products), although the syntheses are generally long with
relatively low overall yields. In contrast, thermodynamic approaches
(using dynamic covalent chemistry, DCC)3 offer high yields and
short syntheses, although the products tend to be symmetrical and
uniformly functionalized. Here we demonstrate a sequence-directed,
dynamic covalent approach to unsymmetrical macrocycles using
imine formation and exchange. Specifically, diphenylacetylene
monomers (1-3) in various combinations undergo a three com-
ponent macrocyclization. This self-assembly of the monomers is
programmed by their sequence of N-donor and C-donor groups and
by the thermodynamic driving force toward the smallest possible
ring size (trimers) in which all groups react. Thus, each monomer
segment can be individually addressed allowing a high level of
control over, for example, side-chain functionalization. To illustrate
the potential of this approach, macrocycles exhibiting a selection
of useful side-chain patterns have been prepared. To our knowledge,
this represents the first example of sequence-directed dynamic
covalent chemistry and offers a thermodynamically controlled route
to unsymmetrical shape-persistent macrocycles as well as basic tools
for the self-assembly of complex organic nanostructures.
sequence-directed; by definition, the directionality of the imine bond
requires the combination of two unique components (i.e., sequences
of a single “bit”). Monomers 1-3 represent binary sequences of
imine-forming groups which are uniquely identified by their
N-donor/C-donor pattern (CN, CC, NN, for 1, 2, and 3, respec-
tively). We wished to explore whether this encoded information
could be used to direct their self-assembly into larger structures
(macrocycles).
Since molecules containing both aldehyde and amino groups
would be difficult to manipulate (because of undesired imine
formation prior to the self-assembly step), we first needed to
establish conditions for one-pot imine formation from a protected
aldehyde. In our earlier work,4 we had used scandium(III) triflate
for self-assembly as it is an effective transimination catalyst.5 It
has also been used to effect imine formation directly from anilines
and dimethyl acetals, at elevated temperatures (refluxing toluene)
and with azeotropic byproduct removal.6 Formation of macrocycle
A6 (Scheme 1) was carried out by treating 1AA with Sc(OTf)3 in
1,2,4-trichlorobenzene (1,2,4-TCB) at 75 °C for 3 h, followed by
stirring under reduced pressure (1 mmHg) at room temperature for
5 h (to drive the reaction to completion). The imines were then
reduced to facilitate handling of the product. Analysis by gel
permeation chromatography (GPC) suggests that A6 was produced
in high yield (77% by deconvolution of the chromatogram7). The
macrocycle was isolated by preparatory GPC (59%), in good purity
(88% based on GPC), and was characterized by 1H and 13C NMR,
MALDI mass spectrometry, and GPC.7 The MALDI spectrum
suggests that the major impurity in the isolated product was the
tetrameric macrocycle (i.e., 4×1AA).
While the synthesis of A6 is effective, it is also representative
of the limitations inherent to a strategy based on thermodynamic
control. Thus, although macrocycle (AB)3 was obtained in similar
yield and purity from 1AB (Scheme 1 and Table 1), it is impossible
to obtain more complicated substitution patterns without additional
control over the self-assembly (short of separating a complicated
mixture of products). Despite this problem, more sophisticated side-
chain patterns are important as an external means to direct the
intermolecular organization of the functional macrocyclic cores.
Amphiphilic patterns, for example, have been shown to organize
shape-persistent discs (including macrocycles) into complex su-
pramolecular structures.8
A synthetic approach that achieves a balance between the
efficiency of thermodynamic-control and the product complexity
of kinetic-control would enable a broad range of new shape-
persistent macrocycles to be prepared and studied. We reasoned
that 1, 2, and 3 (equimolar) would self-assemble into a macrocyclic
product dictated by their imine sequences (Scheme 2). This
macrocycle is favored in the equilibrium distribution as it is again
the smallest possible ring which satisfies all reactive groups on the
monomers; other products either have dangling reactive sites (e.g.,
linear oligomers), or, by violating the initial 1:1:1 stoichiometry,
We designed monomers 1-3 as part of a larger project on the
construction of two-dimensional molecular grids using DCC.4
Inspired by the use of the information encoded into the hydrogen
bond donor/acceptor sequence to direct the association of comple-
mentary DNA strands, we decided to explore the possibility of
building fully coValent structures using imines to cross-link synthetic
oligomers. In a trivial sense, all imine forming reactions are
†
Present address: Department of Chemistry & Biochemistry, Miami University,
Oxford, Ohio 45056.
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J. AM. CHEM. SOC. 2007, 129, 11682-11683
10.1021/ja0745963 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1 a
amount of the undesired macrocycles resulting from trimerization
of 1 (A6 or (AB)3) was present in the final products.7
We believe the dynamic nature of this chemistry is critical to
the success of these reactions. Under kinetic control, 3-fold
intermolecular macrocyclizations proceed in only low yield (20-
25%).11 The error-correcting aspects of DCC are likely of particular
importance to the self-assembly of macrocycles A5B, A4B2, and
A3B3 as the system must presumably reclaim a variety of unwanted
oligomeric byproducts resulting from initial mismatching of 1-3.
To demonstrate that this system is dynamic, macrocycles A6 and
(AB)3 (unreduced imine forms) were prepared in separate flasks,
then mixed. After it was stirred at room temperature (8 h), the
reaction mixture was reduced as before.7 Analysis by MALDI mass
spectrometry (Figures S1 and S2, Supporting Information) indicates
that the final mixture incorporated all possible macrocycles contain-
ing 1AA and 1AB, and was qualitatively in agreement with the
a (a) Sc(OTf)3, 1,2,4-TCB, 75 °C, 3 h; (b) 25 °C, 1 mmHg, 5 h; (c)
NaBH(OAc)3.
expected 1:3:3:1 equilibrium ratio for 3×1AA (A6), 2×1AA+1AB
,
Table 1. Macrocycle Yields (Crude and Isolated)
1AA+2×1AB, and 3×1AB ((AB)3), respectively. This interchange
of monomers under the reaction conditions confirms the dynamic
nature of this system.
crude
yielda
isolated yield
(puritya)
macrocycle
A6
77%
72%
46%
64%
69%
59% (88%)
69% (90%)
44% (83%)
56% (88%)
58% (90%)
To summarize, we have demonstrated the self-assembly of
diphenylacetylene monomers into complex, unsymmetrical shape-
persistent macrocycles. A series of potentially useful side-chain
patterns, including monofunctionalized and Janus-type structures,
has been demonstrated. We believe this is the first nontrivial
example of the directionality of a dynamic covalent bond being
used to program the construction of an organic nanostructure. We
are currently exploring methods to exploit this process in more
complex, polyfunctional oligomer self-assembly.
(AB)3
A5B
A4B2
A3B3
a Based on the deconvolution of GPC traces.7
Scheme 2 a
Acknowledgment. This work was supported by the National
Science Foundation (Grant CHE-0642413 and DMI-0328162).
Supporting Information Available: Experimental procedures for
monomer synthesis and macrocycle self-assembly, details of the A6/
(AB)3 scrambling experiment, and full characterization data for all
macrocycles. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
(1) (a) Zhang, W.; Moore, J. S. Angew. Chem., Int. Ed. 2006, 45, 4416. (b)
Ho¨ger, S. Chem. Eur. J. 2004, 10, 1320. (c) Yamaguchi, Y.; Yoshida,
Z.-i. Chem. Eur. J. 2003, 9, 5430.
(2) (a) Fischer, M.; Lieser, G.; Rapp, A.; Schnell, I.; Mamdouh, W.; De Feyter,
S.; De Schryver, F. C.; Ho¨ger, S. J. Am. Chem. Soc. 2004, 126, 214. (b)
Ma, C. T. L.; MacLachlan, M. J. Angew. Chem., Int. Ed. 2005, 44, 4178.
(c) Naddo, T.; Che, Y.; Zhang, W.; Balakrishnan, K.; Yang, X.; Yen, M.;
Zhao, J.; Moore, J. S.; Zang, L. J. Am. Chem. Soc. 2007, 129, 6978. (d)
Tobe, Y.; Utsumi, N.; Kawabata, K.; Nagano, A.; Adachi, K.; Araki, S.;
Sonoda, M.; Hirose, K.; Naemura, K. J. Am. Chem. Soc. 2002, 124, 5350.
(e) Sugiura, H.; Takahira, Y.; Yamaguchi, M. J. Org. Chem. 2005, 70,
5698.
a (a) Sc(OTf)3, 1,2,4-TCB, 75 °C, 3 h; (b) 25 °C, 1 mmHg, 5 h; (c)
NaBH(OAc)3.
cause the formation of other byproducts with dangling reactive
sites.9 Owing to the symmetry of monomers 2 and 3, it is not
possible to produce macrocycles with completely arbitrary control
over the side-chain substitution. However, we have demonstrated
a variety of useful patterns, including amphiphilic “Janus” structures
(A3B3), and mono- and difunctionalized macrocycles (A4B2 and
A5B). These latter patterns could be used to incorporate tether points
for attachment to other macromolecules or surfaces.10
(3) Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders, J. K. M.; Stoddart,
J. F. Angew. Chem., Int. Ed. 2002, 41, 898.
(4) Hartley, C. S.; Elliott, E. L.; Moore, J. S. J. Am. Chem. Soc. 2007, 129,
4512.
(5) Giuseppone, N.; Schmitt, J.-L.; Schwartz, E.; Lehn, J.-M. J. Am. Chem.
Soc. 2005, 127, 5528.
(6) Heaney, H.; Simcox, M. T.; Slawin, A. M. Z.; Giles, R. G. Synlett 1998,
640.
(7) See Supporting Information.
(8) For example, see: (a) Shetty, A. S.; Fischer, P. R.; Stork, K. F.; Bohn, P.
W.; Moore, J. S. J. Am. Chem. Soc. 1996, 118, 9409. (b) Hill, J. P.; Jin,
W.; Kosaka, A.; Fukushima, T.; Ichihara, H.; Shimomura, T.; Ito, K.;
Hashizume, T.; Ishii, N.; Aida, T. Science 2004, 304, 1481. (c) Monti,
D.; Venanzi, M.; Stefanelli, M.; Sorrenti, A.; Mancini, G.; Natale, C.;
Paolesse, R. J. Am. Chem. Soc. 2007, 129, 6688.
It is noteworthy that despite many potential byproducts, the crude
yields, isolated yields, and purity of these more complex macro-
cycles were similar to those of A6 (Table 1). A comparison of the
crude yields and GPC traces7 of A6 and A3B3 suggests that there
was only a slight increase in the formation of higher molecular
weight byproducts in the three component case. In all examples,
NMR confirms the reduced symmetry of the macrocyclic core, and
the desired products dominate the MALDI mass spectra. The
MALDI spectra also suggest that only a small (but observable)
(9) For example, undesired formation of A6 or (AB)3 from 3×1 requires that
the leftover 3 equiv of 2 and 3 form an oligomer or strained macrocycle.
(10) Kubowicz, S.; Pietsch, U.; Watson, M. D.; Tchebotareva, N.; Mu¨llen,
K.; Thu¨nemann, A. F. Langmuir 2003, 19, 5036.
(11) Ho¨ger, S.; Meckenstock, A.-D.; Pellen, H. J. Org. Chem. 1997, 62, 4556.
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