Sodium ions template the formation of rotaxanes from BPX26C6 and nonconjugated amide and urea functionalities

Article abstract of DOI:10.1002/anie.201304636

Picking up the thread: The macrocycle bis-p-xylyl[26]crown-6 is capable of forming pseudorotaxane-like structures with single, nonconjugated urea or amide moieties when assisted by templating Na⁺ ions (see example). By using this approach, rotaxanes were synthesized with glycine residues or the repeating unit of nylon-6,6 as key components in the threadlike units. Copyright

Full text of DOI:10.1002/anie.201304636

Angewandte
Chemie
DOI: 10.1002/anie.201304636
Template Synthesis
Sodium Ions Template the Formation of Rotaxanes from BPX26C6 and
Nonconjugated Amide and Urea Functionalities**
You-Han Lin, Chien-Chen Lai, Yi-Hung Liu, Shie-Ming Peng, and Sheng-Hsien Chiu*
Pseudorotaxanes and rotaxanes are becoming increasingly
important materials for gelation,[1] drug delivery,[2] and
molecular electronics;[3] therefore, efforts continue toward
developing new threading systems and new methods to
synthesize these intertwined and interlocked molecules.[4]
Although many elegant interlocked molecular compounds
and threaded supramolecular complexes have been prepared
in the past two decades,[5] the number of recognition motifs
that can be exploited for the preparation of these systems
remains limited. This shortcoming arises mainly from our
limited ability to incorporate suitable recognition units in an
appropriate arrangement in the molecular structures of the
host and guest components so that weak noncovalent
interactions can collaborate to stabilize the resulting pseu-
dorotaxane complexes. In addition, the lack of structural
flexibility of the recognition units that can form pseudorotax-
ane complexes hinders the application of their unique
functions or structures into already used materials and/or
biologically important (macro)molecules, many of which do
not contain the necessary, suitably arranged recognition units
in their native molecular structures. One possible solution to
resolve this problem would be to develop a new molecular
recognition system in which a simple and abundant function-
ality—one that is found commonly in many materials—is
recognized by a host macrocycle with no need for structural
preprogramming. Urea and amide units are ubiquitous in
artificial and biological polymers (e.g. polyureas, nylons,
peptides). We thus suspected that if it were possible to
recognize macrocycles at single units of these functionalities,
then the barrier hindering the use of such host/guest
structures in practically useful materials would be decreased
significantly. This would potentially allow many new and
interesting properties to be introduced into molecules and
materials that we encounter widely in our daily lives. Noting
that diamide-based macrocycles have been applied previously
in the recognition of threadlike species containing amides[6]
and conjugated ureas,[7] herein we demonstrate that the
macrocycle bis-p-xylyl[26]crown-6 (BPX26C6) is capable of
forming pseudorotaxane-like structures with single, noncon-
jugated urea or amide moieties when assisted by templating
Na+ ions, thereby allowing the successful syntheses of the
corresponding rotaxanes.[8] By using this metal-templating
approach, we prepared rotaxanes featuring glycine residues
and the repeating units of nylon-6,6 as key components in
their threadlike units. This opens the possibility of employing
this recognition system for the formation of (pseudo)rotaxane
structures from biorelated (macro)molecules (e.g. peptides)
and practically useful materials (e.g. nylon).
We exploited primarily ion–dipole interactions between
=
the C O group(s) of the guest species and spherical alkali-
metal ions to achieve recognition of a single urea or amide
functionality by a macrocycle without requiring the guest
component to feature specific structural characteristics. Our
previous study had shown that an interlocked BPX26C6
moiety in a rotaxane could collaborate with a 2,2’-bipyridine
unit in the threadlike component to allow the mutual
complexation of various metal ions.[9] We thus suspected
that a suitable metal ion would template the threading of
a urea or amide guest through the cavity of BPX26C6 by
coordinating to the binding pocket formed from one dieth-
=
ylene glycol chain of the macrocycle and the C O group of
the guest (Scheme 1). In addition, N-H···O hydrogen bonds
Scheme 1. Structural representation of the concept of threading a non-
conjugated urea or amide moiety through the cavity of BPX26C6 with
the assistance of a templating metal ion.
[*] Y.-H. Lin, Y.-H. Liu, Prof. S.-M. Peng, Prof. S.-H. Chiu
Department of Chemistry and Center for Emerging Material and
Advanced Devices, National Taiwan University
formed between the NH proton of the urea or amide group
and the other diethylene glycol chain of the macrocycle would
presumably also assist in stabilizing the pseudorotaxane. We
suspected that physiologically important and abundant alkali-
metal ions, such as Na+ and K+ ions, might be appropriate
templates because of their relatively strong interactions with
the oxygen atoms of the oligo(ethylene glycol) chains of
crown ethers.[10]
No. 1, Sec. 4, Roosevelt Road, Taipei, Taiwan, 10617 (R.O.C.)
E-mail: shchiu@ntu.edu.tw
Prof. C.-C. Lai
Institute of Molecular Biology, National Chung Hsing University
and Graduate Institute of Chinese Medical Science
China Medical University, Taichung, Taiwan (R.O.C.)
[**] We thank the National Science Council (Taiwan) (NSC-101-2628-M-
002-010 and NSC-102-2119-M-002-007) and National Taiwan Uni-
versity (NTU-102-R890913) for financial support.
To test this hypothesis we synthesized the threadlike urea
1, in which the urea unit is conjugated to two aromatic rings.
As less-polar solvents would promote hydrogen bonding
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304636.
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between the urea unit of the guest and the macrocycle
BPX26C6 as well as their ion–dipole interactions to the metal
ion template, we chose sodium tetrakis(3,5-trifluoromethyl-
phenyl)borate (NaTFPB)[11] as the templating salt because its
ion pair associates relatively weakly in such solvents. Figure 1
1
presents the H NMR spectrum of an equimolar mixture of
BPX26C6 and the threadlike urea 1 (5 mm) in CDCl3; when
we added NaTFPB (5 mm) to this solution, the signals of the
threadlike component underwent significant shifts. This
observation suggested that the efficient threading of 1 through
the cavity of BPX26C6 required the templating of Na+ ions,
and that the rates of complexation and decomplexation were
both fast on the 1H NMR spectroscopic timescale at 400 MHz
and 298 K. The downfield shift of the signal of the NH protons
and the upfield and downfield shifts of those of their adjacent
(Ha) and distal (Hb) aromatic protons, respectively, upon
gradually increasing the concentrations of BPX26C6 and
NaTFPB to 20 mm, from an initial equimolar mixture of the
host, guest, and template (each 5 mm), is consistent with the
formation of a pseudorotaxane between the host and guest
components under these conditions. The BPX26C6 macro-
cycle encircling the urea unit allowed the formation of
N-H···O hydrogen bonds between the NH protons of the urea
moiety and the diethylene glycol chain, thereby leading to
a downfield shift of the signal of the NH protons; concomitant
shielding and deshielding of the Ha and Hb protons, respec-
tively, by the p-xylene motifs of the macrocycle led to upfield
and downfield movements, respectively,
Figure 1. Partial 1H NMR spectra (400 MHz, CDCl3, 298 K) of a) the
threadlike urea 1, b) an equimolar mixture of 1 and BPX26C6 (5 mm),
and c–e) mixtures of 1, BPX26C6, and NaTFPB at concentrations of
c) 5:5:5 mm, d) 5:10:10 mm, and e) 5:20:20 mm.
of their signals in the 1H NMR spectra.[12]
Although this spectroscopic evidence
supports the formation of threaded com-
plexes, we sought to synthesize the
corresponding rotaxanes to prove unam-
biguously that pseudorotaxanes formed
from these recognition elements in solu-
tion.
Accordingly, we synthesized the
threadlike urea-containing species 2–4,
in which the urea units are conjugated to
two, one, and no aromatic rings, respec-
tively (Scheme 2). Di-tert-butylphenyl
isocyanate[6a,13] (5, 500 mm) was added
to a solution of the threadlike species (2,
3, or 4), BPX26C6, and NaTFPB
(100:250:250 mm) in CH2Cl2 and then
the mixture was stirred at ambient tem-
perature for 16 h to afford the corre-
sponding [2]rotaxanes 6–8 in yields of 40,
25, and 8%, respectively, after column
chromatography. The loss of the templat-
ing Na+ ion during the aqueous extrac-
tion and chromatography process sug-
gested that its complexation to the bind-
ing pocket in the [2]rotaxanes was not
particularly strong throughout the syn-
thetic process. The absence of any detect-
able signals for the [2]rotaxane 6 in the
1H NMR spectra of the crude product
obtained when the reaction of 2 was
Scheme 2. Syntheses of the conjugated and nonconjugated urea-containing [2]rotaxanes 6–8.
2
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repeated in the absence of NaTFPB, but
under otherwise identical conditions,
suggested that the Na+ ion template was
crucial for efficient threading of the urea
unit through the cavity of BPX26C6. The
reaction yields suggested that conjuga-
tion of the urea moiety to the aromatic
rings assisted in increasing the concen-
tration of the [2]pseudorotaxane in solu-
tion, possibly because of the increased
acidity of the NH group. Nevertheless,
our successful synthesis of the [2]rotax-
ane 8 reveals that aromatic conjugation
in the structure of the urea guest is not
a necessity; it also suggests that we might
be able to generate BPX26C6-containing
pseudorotaxanes from many other urea-
containing guests—as long as Na+ ion
templates are present.
Next, we turned our attention to
whether Na+ ions could also template
the threading of simple amides through
the cavity of BPX26C6 to form the
corresponding pseudorotaxanes. Gratify-
ingly, when we added the isocyanate 5
(500 mm) to a solution of a threadlike
amide (9, 10, or 11), BPX26C6, and
NaTFPB (100:250:250 mm) in CH2Cl2,
we isolated the corresponding [2]rotax-
Scheme 3. Syntheses of the conjugated and nonconjugated amide-containing [2]rotaxanes 12–
14.
anes 12–14 in yields of 73, 14, and 29%, respectively
(Scheme 3). Thus, threading of a single amide unit through
the cavity of the macrocycle BPX26C6 in the presence of
a templating Na+ ion is feasible, even when the amide moiety
is not linked directly to any aromatic rings.[14] Notably, the
threadlike species 11 is a C-amidated glycine residue, thus
opening up the intriguing possibility of applying this recog-
nition system to the synthesis of peptide-based interlocked
molecules.
To eliminate the possibility that the [2]rotaxanes 12–14
were formed from pseudorotaxane-like complexes obtained
after threading the isocyanate 5 into the cavity of BPX26C6 in
the presence of a templating Na+ ion,[15]
for the assembly of the [2]rotaxanes 5–7 and 12–14. Our
results also confirmed the importance of ion–dipole and
hydrogen-bonding interactions between the amide unit and
the templating metal ion and the macrocycle BPX26C6,
respectively, for the generation of the pseudorotaxane
structures in solution. The successful synthesis of the [2]rotax-
ane 17 from the reaction of the threadlike species 9,
BPX26C6, NaTFPB, and triisopropylsilyl triflate in CH2Cl2
(Scheme 4)[16] is consistent with the formation of a [2]pseu-
dorotaxane structure based on the recognition of 9 by
BPX26C6 in the presence of a templating Na+ ion in solution.
The low yield (10%) of this reaction, relative to that for the
we mixed the threadlike ester species 15
with BPX26C6, NaTFPB, and the isocy-
anate 5 under conditions similar to the
synthesis of [2]rotaxane 14 (Scheme 4).
Gratifyingly, we observed no detectable
signals for the corresponding [2]rotaxane
1
in the H NMR spectrum of the crude
product; the dumbbell-shaped species 16
was isolated in 73% yield. Our inability
to synthesize the [2]rotaxane from the
ester-containing threadlike species 15
under conditions similar to those we
had used for the successful syntheses of
the amide-containing [2]rotaxanes sug-
gested that a pseudorotaxane formed
from the isocyanate 5, a Na+ ion, and
Scheme 4. Exploring the synthesis of rotaxanes from ester-containing thread and triisopropyl-
BPX26C6 was not the key intermediate
silyl triflate stopper.
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synthesis of the [2]rotaxane 12, can be rationalized by
considering that the triflate anions released during the
progress of this reaction destabilized the corresponding
[2]pseudorotaxane by weakening the metal ion chelating
and/or hydrogen-bonding interactions among the compo-
nents.[17]
It is known that the cooperation of a few suitably arranged
amino acid residues and their side chains can prevent the
dethreading of interlocked macrocycles;[18] therefore, we
suspected that the construction of rotaxanes from BPX26C6
and pure peptide chains would be possible if a proper
sequence of amino acid residues was positioned at the
terminus. To demonstrate that no additional functionality
need be introduced into the structure of the peptide (unlike
the urea moiety found in the [2]rotaxane 14), thereby
allowing this recognition system to be used to construct
interlocked or interwoven structures featuring pure peptide
chains, we applied a common peptide coupling reaction in the
stoppering process.[19] Gratifyingly, when we added N,N’-
dicyclohexylcarbodiimide (DCC) activated 3,5-di-tert-butyl-
benzoic acid 18 (105 mm) to a solution of the threadlike
species 11, NaClO4, and BPX26C6 (100:250:250 mm) in
CH2Cl2, we isolated the desired [2]rotaxane 19 in 31% yield
after column chromatography (Scheme 5).[20]
Figure 2. Ball-and-stick representation of the solid-state structure of
the [2]rotaxane 19.
units of the former hydrogen bonded to the oxygen atoms of
the latter.
Our successful syntheses of the [2]rotaxanes 14 and 19
suggested that the recognition of BPX26C6 required only
a single amide moiety in a peptide chain, thereby potentially
allowing higher-order [n]rotaxanes to be prepared from
relatively long peptides. Indeed, when we mixed the thread-
like tripeptide 20, which features three BPX26C6-recogniz-
able amide moieties in its GlyGlyGly sequence, with
BPX26C6, NaClO4, and the stoppering agent 18 in CH2Cl2,
we isolated the [2]rotaxane 21 and the [3]rotaxane 22 in 13
and 8% yields, respectively, after column chromatography
(Scheme 5). This result demonstrates the potential applica-
tion of this recognition system in the assembly of interlocked
structures from biomolecules or other polymeric materials.
Toward this goal, when we treated the
We grew single crystals suitable for X-ray crystallography
through liquid diffusion of hexane into a solution of the
[2]rotaxane 19 in CH2Cl2. The solid-state structure of 19
reveals[21,22] the expected [2]rotaxane geometry (Figure 2), in
which the amide groups of the threadlike component
penetrate through the BPX26C6 component, with the NH
threadlike species 23, which contains
a single repeating unit of nylon-6,6, with
BPX26C6, NaClO4, and the stoppering
agent 18 in CH2Cl2, we isolated the
corresponding [2]rotaxane 24 in 7%
yield (Scheme 6). Thus, the Na+ ion
assisted threading of amides through the
cavity of the macrocycle BPX26C6 can
also be applied directly to form inter-
woven or interlocked structures from
common peptides and polymers without
altering their key molecular structures.
We have discovered a new molecular
recognition system in which a single con-
jugated or nonconjugated urea or amide
functionality is recognized by the macro-
cycle BPX26C6 through the templating
effect of a Na+ ion. We have also demon-
strated that this recognition system can be
used to synthesize rotaxanes from impor-
tant and practically useful artificial or
biological (macro)molecules featuring
glycine residues or nylon-6,6 repeating
units as threading components. We
believe that the extremely high structural
flexibility of the guests for this recogni-
tion system will facilitate the introduction
Scheme 5. Syntheses of C-amidated glycine-based rotaxanes.
of interlocked or interwoven structures
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Scheme 6. Synthesis of a [2]rotaxane containing a nylon-6,6 repeating unit.
ether 1/5DNP38C10 in the presence of
two templating Li+ ions; see a) G. Kaiser,
T. Jarrosson, S. Otto, Y.-F. Ng, A. D.
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[12] Titration of BPX26C6 with NaTFPB in CDCl3 resulted in
negligible shifts in the 1H NMR signals after 1 equiv of Na+ ions
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BPX26C6 and a Na+ ion is infinite, mathematical fitting of the
titration curve for the addition of an equimolar mixture of
BPX26C6 and NaTFPB to 1 in CDCl3 gave an association
constant (Ka) of (176 Æ 5)mÀ1 for the binding of the Na+ ion
complexed BPX26C6 to the urea 1.
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[14] Using NaClO4 in place of NaTFPB in the synthesis of 12 under
similar conditions yielded only 18% of the [2]rotaxane 12, thus
confirming the importance of the counterion of the templating
Na+ ion. When we used KTFPB in place of NaTFPB in the
synthesis of 14 under similar conditions, the yield of the
[2]rotaxane dropped to 8%, which suggests that Na+ ions are
better templates than K+ ions in this system.
Published online: && &&, &&&&
Keywords: amides · molecular recognition · pseudorotaxanes ·
.
rotaxanes · template synthesis
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ane and the Na+ ion. Further anion exchange, aqueous
extraction, and column chromatography were necessary to
obtain the pure [2]rotaxane 19.
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[20] When we replaced NaClO4 by NaTFPB and performed the
reaction under similar conditions, the yield of the isolated
[2]rotaxane 19 was 29%, but the purification process became
more tedious. Signals of the protons of the TFPB anion
remained in the 1H NMR spectrum of purified 19, possibly
because of relatively strong interactions between this [2]rotax-
[21] CCDC 917834 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[22] Crystal data for 19: C56H78O8N2, Mr = 907.2, triclinic, space
group P-1, a = 10.1895(8), b = 10.417(1), c = 13.3620(11) ꢂ, V=
1333.4(2) ꢂ3, 1calcd = 1.130 gcmÀ3 m(CuKa) = 1.134 mmÀ1
, , T=
295 (2) K, colorless plate, 4,846 independent measured reflec-
tions, F2 refinement, R1 = 0.1284, wR2 = 0.3959.
6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 7
These are not the final page numbers!

Angewandte
Chemie
Communications
Template Synthesis
Y.-H. Lin, C.-C. Lai, Y.-H. Liu, S.-M. Peng,
S.-H. Chiu*
&&&& — &&&&
Sodium Ions Template the Formation of
Rotaxanes from BPX26C6 and
Nonconjugated Amide and Urea
Functionalities
Picking up the thread: The macrocycle
bis-p-xylyl[26]crown-6 is capable of form-
ing pseudorotaxane-like structures with
single, nonconjugated urea or amide
moieties when assisted by templating
Na+ ions (see example). By using this
approach, rotaxanes were synthesized
with glycine residues or the repeating unit
of nylon-6,6 as key components in the
threadlike units.
Angew. Chem. Int. Ed. 2013, 52, 1 – 7
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!