Highly efficient one-pot synthesis of hetero-sequenced shape-persistent macrocycles through orthogonal dynamic covalent chemistry (ODCC)

Article abstract of DOI:10.1039/c2cc33078d

A series of hetero-sequenced shape-persistent macrocycles with different shape, size, and backbone (functional group) symmetry have been synthesized through one-pot orthogonal dynamic covalent chemistry (ODCC) in good to excellent yields from readily accessible starting materials.

Full text of DOI:10.1039/c2cc33078d

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Highly efficient one-pot synthesis of hetero-sequenced shape-persistent
macrocycles through orthogonal dynamic covalent chemistry (ODCC)w
Kenji D. Okochi,z Yinghua Jinz and Wei Zhang*
Received 28th April 2012, Accepted 30th May 2012
DOI: 10.1039/c2cc33078d
A series of hetero-sequenced shape-persistent macrocycles with
different shape, size, and backbone (functional group) symmetry
have been synthesized through one-pot orthogonal dynamic
covalent chemistry (ODCC) in good to excellent yields from
readily accessible starting materials.
Imine metathesis26 and olefin metathesis27,28 were selected
as the two orthogonal reactions because they are relatively well
established, and their reaction mechanisms and scopes are well
understood. Imine condensation/metathesis is catalyzed by a
Lewis or Brønsted acid, while olefin metathesis is catalyzed by
a Ru- or Mo-based complex. To the best of our knowledge, there
has been no report of exploring the orthogonality of these two
reactions and utilizing them in the one-pot cyclooligomerization
process. The potential challenges in one-pot synthesis of 2-D
macrocycles through orthogonal imine-olefin metathesis from
multiple building blocks can be envisioned as follows: (i) the acid
catalyst and/or the byproduct water produced by imine condensa-
tion reaction might diminish the catalytic activity of olefin meta-
thesis catalyst, and (ii) the activity of olefin metathesis catalysts can
be inhibited by primary amines which are key reaction compo-
nents in imine metathesis.29,30
Well-defined, two-dimensional (2-D) shape-persistent macro-
cycles have attracted enormous research interest due to their
great importance in development of novel functional materials,
such as liquid crystals, perforated monolayers, electronic device,
etc.1–8 In the past two decades, significant progress has been made
in the construction of covalently bonded, 2-D macrocycles
through thermodynamically-controlled covalent chemistry.2,9–11
Such dynamic covalent chemistry (DCC) exhibits self-correction
behavior and has become a powerful tool for bottom-up materials
synthesis.12–15 However, current DCC approaches rely on a
single type of chemical transformation in the cyclooligomerization
process, and the macrocycles synthesized are usually limited to
highly symmetric, homo-sequenced ones containing one type of
functionality. Hetero-sequenced macrocycles are usually obtained
through kinetic approaches, in which dimer or even longer
oligomer precursors have to be prepared stepwise. Recently,
Moore and coworkers reported the first example of sequence-
directed dynamic covalent assembly of unsymmetrical shape-
persistent macrocycles via imine condensation and metathesis.16
To achieve efficient synthesis of hetero-sequenced macrocycles
from simple building blocks, our attention was drawn to the
orthogonal dynamic covalent chemistry, which offers great
potential to construct 2-D macrocycles with increased macro-
molecular complexity yet well-controlled chemical structures.
Although the concept of orthogonal chemistry is relatively well-
recognized in the area of supramolecular chemistry17–20 and
polymer chemistry,21–24 orthogonal dynamic covalent approach
has rarely been explored.25 Herein, we present the first example of
a highly efficient, orthogonal dynamic covalent chemistry (ODCC)
approach to construct a series of 2-D hetero-sequenced shape-
persistent macrocycles in a modular fashion.
We began our study by examining the feasibility of simultaneous
imine metathesis and olefin metathesis in one reaction system.
Readily available simple substrates, 3-vinyl-5-alkoxyaniline
(Scheme 1, 1a) and 3-vinyl-5-alkylbenzaldehyde (2) were selected
as building blocks for a hexagonal macrocycle with both imine and
olefin functional groups integrated in the macrocycle backbone. To
the solution of 1a and 2 (1 : 1 ratio) in 1,2,4-trichlorobenzene (TCB)
were added trifluoroacetic acid (TFA, 4 mol%) and Grubbs-
Hoveyda 2nd generation catalyst (HG2, 10 mol%). The resulting
mixture was heated at 40 1C. After 18 h, we observed 495%
conversion for both the amine/aldehyde and vinyl groups based on
the NMR spectrum (ESI, Fig. 1). However, even after four days,
there still exists a significant amount of high molecular weight
oligomeric/polymeric species along with the desired macrocyclic
product, as shown in the gel permeation chromatography (GPC)
trace (Trial 1, Fig. 1a, blue curve).
Department of Chemistry and Biochemistry, University of Colorado,
Boulder, CO 80309, USA. E-mail: wei.zhang@colorado.edu;
Fax: (+1) 303-492-5894; Tel: (+1) 303-492-0652
w Electronic supplementary information (ESI) available: Experimental
procedures, and spectroscopic data. See DOI: 10.1039/c2cc33078d
z These authors contributed equally to this work.
Scheme 1 Building blocks for macrocycle synthesis via ODCC.
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product mixture contained higher molecular weight oligomeric
or polymeric species as shown in the GPC trace (Fig. 1a, orange
curve). One complication with this approach is the sluggish
deprotection of t-Boc groups under the reaction condition we
used. Even after two days, the deprotection was still not
complete, which could result in imbalanced stoichiometry of
aldehyde and amine groups. At this stage, given the successful
results from the other synthetic route (discussed below), we did
not further optimize the reaction conditions of Route I, and
focused on the macrocycle synthesis via Route II.
In the imine-then-olefin approach, we could take advantage of
the directionality of imine bond formation. Only one dimer (11)
was formed after imine condensation (TFA, 4 mol%, 30 min, rt)
of unprotected amine 1a and aldehyde 2 (1 : 1 ratio). Subsequently,
Grubbs-Hoveyda 2nd generation catalyst (10 mol%) was added
and the mixture was heated at 40 1C for 18 h. At this point, we
did not observe any vinyl groups in the 1H NMR spectrum
(ESI, Fig. 2). However, GPC showed a broad product distribution
without a distinguishable macrocycle peak observed. After
another 24 h, we observed the peak corresponding to the
desired cyclohexamer, along with a broad shoulder in the higher
molecular weight region in the GPC trace. Encouragingly, cyclo-
hexamers 12 and 13 were formed predominantly after 3 days
based on GPC (Trial 3, Fig. 1a, green curve), and MALDI-MS
analyses. Although the reaction was not quite efficient, this
result clearly demonstrates the feasibility of ODCC approach in
macrocycle synthesis. As mentioned previously, since the water
byproduct produced during the imine condensation or the TFA
catalyst could diminish the catalytic activity of the Ru-complex
for olefin metathesis, we reasoned that the cyclooligomerization
reaction rate could be significantly enhanced by removing water
and/or TFA under reduced pressure.
Fig. 1 (a) GPC trace of the crude product mixture of 12 + 13 in trials 1–4:
Trial 1 (Blue); Trial 2 (Orange); Trial 3 (Green); Trial 4 (red).
(b) MALDI-MS spectrum of the crude product mixture of trial 4.
Since the simultaneous imine and olefin metathesis appears
to be sluggish and provides the target macrocycle in low yield
within limited time scale, we turned our attention to the
sequential orthogonal reaction strategies.
Depending on the sequence of the two orthogonal reactions,
there are two possible approaches: olefin-then-imine metathesis
(Route I, Scheme 2); and imine-then-olefin metathesis (Route II,
Scheme 2). We explored these two approaches in parallel. For
Route I, since primary amines could poison the olefin metathesis
catalyst, applying this strategy without using any protecting group
would be problematic. To overcome such an incompatibility issue,
we started with the t-Boc protected vinyl-substituted aniline 1b and
vinyl-substituted benzaldehyde 2 (Scheme 2, Trial 2). Olefin
metathesis (HG2, 10 mol%) proceeded smoothly and provided
around 2 : 1 : 1 mixture of three dimeric trans isomers 8, 9, 10
respectively after 30 min at 40 1C. The sterically less favored
cis isomers were not observed in the 1H NMR spectrum.
Subsequent cyclooligomerization through imine formation
with in situ deprotection of t-Boc groups (20 equiv. TFA, rt,
2 d) provided the desired cyclic hexamers. However, the crude
Accordingly, after imine condensation (TFA, 4 mol%, 30 min,
rt), we stirred the reaction mixture under vacuum (B200 mtorr) for
30 min before adding Grubbs-Hoveyda 2nd generation catalyst. As
expected, the cyclooligomerization proceeded much faster and
provided the cyclohexamers 12 and 13 as the predominant species
after only 16 h at 40 1C, as shown in the GPC trace (Trial 4, Fig. 1a,
red curve) and MALDI-MS (Fig. 1b) of the crude product mixture.
Due to their very similar polarity, separation of the two isomers 12
and 13 after reduction was not possible.
Given the successful preliminary result from the above
proof-of-concept experiment, to illustrate the versatility of
such ODCC approach, we explored the general scope of such
methodology in the synthesis of hetero-sequenced shape-persistent
macrocycles (Table 1). We demonstrate that various complex
macrocyclic structures of defined size and shape can be achieved
in a modular fashion by using different combinations of a small set
of building blocks: ortho-, meta- and para-phenylenes (Scheme 1).
To prevent the formation of two isomeric cyclic hexamers, we
introduced a symmetric building block (dialdehyde 3) in the
synthesis of cyclic hexamer 14. By using the optimized reaction
conditions, imine condensation of 1a and 3, followed by vacuum
exposure, and then olefin metathesis in one pot, provided the
target shape-persistent hexagonal imine-linked macrocycle. For
easy handling, the imine bonds were reduced and the amine-linked
macrocycle 14, which consists of 4 dialdehyde and 2 amine
building blocks (total 6 monomer units) was obtained in excellent
yield (85%). Simply changing the dialdehyde building unit from
Scheme 2 Sequential orthogonal dynamic approach.
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one-pot ODCC approach are evident: it is highly efficient, the
starting materials are readily accessible, and the shape, size,
and building block sequence of macrocycles can be easily
tailored.
In summary, a highly efficient ODCC approach has been
developed that enabled one-pot synthesis of a variety of
hetero-sequenced shape-persistent macrocycles with different
size, shape and backbone symmetry, in good to excellent
yields. Such an approach allows easy incorporation of multiple
different building blocks (functionalities) into a well-defined,
discrete molecular architecture, and thus opens the door to the
development of novel materials with ever-increasing structural
and functional complexity for ever-expanding advanced
applications.
The authors thank National Science Foundation (DMR-
1055705) for funding support.
Table 1 Formation of macrocyclesa
Notes and references
Amine
Aldehyde
Macrocycle
Yield (%)
b
120 + 130
14
15
16
54c
85
68
64
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All the macrocycles (120–16) were purified by flash column
chromatography on silica gel, and fully characterized by
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c
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Chem. Commun.