Using host-guest complexation to fold a flexible linear organic string: Kinetically controlled syntheses of [3]catenanes and a five-membered molecular necklace

Article abstract of DOI:10.1002/anie.201205498

Rings and necklaces: Three [3]catenanes and a five-membered molecular necklace ([5]MN), with up to 60- and 92-membered rings as their centerpieces, respectively, have been synthesized. The synthesis started from the corresponding complexes in which the threaded flexible linear guests were bent at approximately right angles to facilitate kinetically controlled macrocyclizations. Copyright

Full text of DOI:10.1002/anie.201205498

Angewandte
Chemie
DOI: 10.1002/anie.201205498
Template Synthesis
Using Host–Guest Complexation to Fold a Flexible Linear Organic
String: Kinetically Controlled Syntheses of [3]Catenanes and a Five-
Membered Molecular Necklace**
Chia-Fong Chang, Chun-Ju Chuang, Chien-Chen Lai, Yi-Hung Liu, Shie-Ming Peng, and Sheng-
Hsien Chiu*
Unlike rotaxanes, which have attracted much attention as
relevant materials in diverse research fields (e.g., sensing,[1]
drug delivery,[2] gelation,[3] fluid transportation[4]), catenanes
have been less applicable as functional interlocked materials,
possibly because of their synthetic complexity (i.e., the
requirement for efficient macrocyclization). For small-ring
systems, the introduction of heteroatoms or gem-dialkyl
groups[5] into alkyl chains can minimize their preference for
Figure 1. Cartoon representation of the precise folding of a linear
guest within a cage-like host.
forming linear zigzag conformations, thereby facilitating their
cyclization; both effects have much lower influence on the
closing of large rings.[6] Therefore, minimizing the concen-
trations of the reacting species (high dilution) or decreasing
the substrate entropy through conformational control are
frequently used strategies for efficient macrocyclizations.[7]
Two commonly employed approaches toward facilitating
macrocyclizations are 1) positioning a nonlinear organic
macrocyclizations of organic threadlike molecules folded in
such a manner should allow the covalent construction of
complicated, but robust, organic interlocked structures
directly through irreversible (kinetically controlled) organic
reactions—that is, without the need for the self-correction
processes found in reversible (thermodynamically controlled)
reactions.[12] Herein, we report the development of host–guest
complexes in which threaded flexible linear guests are folded
at approximately right angles (ca. 908); we have applied these
complexes to macrocyclizations, producing up to 60- and 92-
membered rings as centerpieces of unique [3]catenanes and
a five-membered molecular necklace ([5]MN), respectively.
Previously, we found that the catechol- and dibenzo[24]-
crown-8 (DB24C8)-like motifs of the molecular cage
1 (Scheme 1) interact selectively with pyridinium and dialkyl-
ammonium ions, respectively.[13] We suspected that if pyridi-
nium and dialkylammonium units were to be connected
through a suitable linker in a linear threadlike guest, then we
could obtain a system in which the dialkylammonium unit
would prefer to be located within the cavity of the DB24C8-
=
junction (e.g., C O group or disubstituted ring system)
within a linear molecule to form a “turn” in its structure[8]
and 2) introducing noncovalent templates to “fold” the linear
molecule (e.g., metal ions in the synthesis of crown ethers).[9]
The use of an organic template to mediate the macrocycliza-
tion of a linear flexible organic molecule remains a challenge,
because the components must interact with sufficient binding
affinity and in a suitable complexation geometry; these
features must be programmed in the molecular design.[10] In
the synthesis of catenanes, however, the host molecule can
theoretically act as a template to “fold” its threaded linear
guest into
a preprogrammed conformation (geometry,
Figure 1), in a similar way to metal ions that bridge the
organic ligands of molecular containers and metal–organic
frameworks (MOFs).[11] Thus this synthetic approach allows
the selective construction, at a normal concentration, of an
interlocked molecule of a particular size. Moreover, the
like opening of 1, while the pyridinium unit would stack with
+
ꢀ ꢀ
the catechol-like aromatic rings. To obtain additional N C
H···O stabilization energy through hydrogen bonding of the
Ha atoms of the pyridinium unit and adjacent ethylene glycol
motifs, we would expect the main axis of the pyridinium unit
to pass through one of the 34-membered rings of the
molecular cage (Scheme 1). Thus, a suitably functionalized
linear thread would be folded at a right angle (908); this
conformation would be stabilized as a result of penetration of
its two recognition sites through adjacent openings of the
molecular cage 1.
[*] C.-F. Chang, C.-J. Chuang, Y.-H. Liu, Prof. S.-M. Peng,
Prof. S.-H. Chiu
Department of Chemistry, National Taiwan University
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.)
To realize this concept, we synthesized the threadlike salt
[2-H]2PF6, containing both dialkylammonium and alkylpyr-
idinium units, in two steps from 4-(3,5-di-tert-butylphenyl)-
pyridine 3[14] and N,N-bis(6-bromohexyl)-p-toluenesulfon-
amide[15] (Scheme 1). The 1H NMR spectrum of an equimolar
[**] We thank the National Science Council (Taiwan) (NSC-100-2119-M-
002-026 and NSC-101-2628-M-002-010) and National Taiwan Uni-
versity (NTU-101-R890913) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205498.
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cage 1 to form the unique [2]pseudorotaxane [1ꢁ2-H]2+
(Figure 1). To confirm our suspicions, we added the bulky
pyridine derivative 3 to a mixture of the molecular cage
1 (13 mm) and the threadlike salt [2-H]2PF6 (26 mm) in
CH3NO2, and obtained the expected [2]rotaxane [4-H]3PF6 in
40% yield after chromatography and ion-exchange processes
(Scheme 1).
We grew single crystals suitable for X-ray crystallography
through liquid diffusion of iPr2O into a MeCN solution of the
[2]rotaxane [4-H]3PF6. The solid-state structure (Figure 3) of
+
[4-H]3PF6 reveals[17,18] that the NH2 center is positioned
Scheme 1. Synthesis of the [2]rotaxane [4-H]3PF6.
(2 mm) mixture of the molecular cage 1 and the threadlike salt
[2-H]2PF6 in CDCl3/CD3CN (3:7) at room temperature
reveals (Figure 2) that the rates of complexation and decom-
plexation were slow under these conditions; we observe three
sets of signals: one for the free molecular cage 1, one for the
free threadlike salt [2-H]2PF6, and one for their complex
formed with 1:1 binding stoichiometry. By using a single-point
method,[16] we determined the association constant (Ka) for
the complex formed between the molecular cage 1 and the
threadlike salt [2-H]2PF6 to be 2000mꢀ1. The splitting of the
originally symmetric signal for the aromatic units of the
molecular cage 1 into four different sets of signals of equal
intensity suggested the nonsymmetrical passage of the thread-
like guest 2-H2+ through adjacent openings of the molecular
Figure 3. Ball-and-stick representation of the solid-state structure of
the [2]rotaxane [4-H]3+
.
within the cavity of one of the 24-membered rings of the cage,
with one of the pyridinium units involved in p stacking and
hydrogen-bonding interactions with the molecular cage
component in such a manner that its axis passes through the
34-membered ring opening. The significant upfield shifts of
the signals of the protons of the “inside” hexyl group and of
the “inside” pyridinium unit (Ha and Hb, Figure 2), relative to
those of the “outside” pyridinium unit (Ha0 and Hb0 ), in the
1H NMR spectrum suggest that the molecular conformation
of the [2]rotaxane [4-H]3PF6 in solution is similar to that
observed in the solid state; that is, one of the pyridinium units
and one of the hexyl chains reside within the cavity of the
molecular cage moiety.
After finding that the molecular cage 1 could contort the
threadlike salt [2-H]2PF6 into an approximately 908 bend, we
wished to extend this concept to the folding of a linear organic
structure with two right angles, with the anticipation of using
such a complex to synthesize a corresponding [3]catenane
and/or [5]MN[19] through irreversible covalent macrocycliza-
tion with spacers of appropriate lengths (Scheme 2). Thus, we
synthesized the threadlike salt [5-H2]4PF6 and investigated its
complexation with two units of the molecular cage 1 (see the
Supporting Information).
As we had observed for the complex [1ꢁ2-H]2+, the
1H NMR spectrum of a mixture of the molecular cage
1 (6 mm) and the linear threadlike salt [5-H2]4PF6 (2 mm) in
CD3CN/CDCl3 (1:1; Figure 4) displayed four singlets of equal
intensity representing the aromatic protons of the complexed
molecular cage 1. Furthermore, only one symmetrical set of
aromatic protons appeared for the threadlike component in
Figure 2. Partial 1H NMR spectra (400 MHz, CDCl3/CD3CN (3:7),
298 K) of a) the molecular cage 1, b) an equimolar mixture of 1 and
the threadlike salt [2-H]2PF6 (2 mm), c) [2-H]2PF6, and d) the [2]rotax-
ane [4-H]3PF6. In the spectrum in (b) the signals of protons in the
complex are indicated by (C).
2
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complexation events in the binding of the threadlike salt [5-
H2]4PF6 to the molecular cage 1 are relatively independent. In
the complex [12ꢁ5-H2]4+, the conformation of the threadlike
unit, presumably featuring two 908 bends, would position the
two pyridyl termini in a favorable arrangement for linking
through a relatively long linear spacer, to obtain a corre-
sponding [3]catenane. Indeed, after stirring a mixture of
1 (8 mm), [5-H2]4PF6 (2 mm), and the dibromide 6 (2 mm) in
MeCN/CHCl3 (1:1) at 318 K for three days, and subsequent
purification by ion exchange (KPF6/H2O) and chromatogra-
phy (SiO2), we isolated the [3]catenane [7-H2]6PF6 in 13%
yield (Scheme 3). Notably, the formation of this [3]catenane
required the macrocyclization of a 60-membered ring from
a linear flexible organic string—a challenging task in most
cases.
Scheme 2. Cartoon representation of the synthetic approach toward
the [3]catenane and the [5]MN.
Scheme 3. Syntheses of three [3]catenanes and a [5]MN.
Figure 4. Partial 1H NMR spectra (400 MHz, CD3CN/CDCl3 (1:1),
298 K) of a) the molecular cage 1, b) a mixture of 1 (6 mm) and the
threadlike salt [5-H2]4PF6 (2 mm), and c) [5-H2]4PF6. In the spectrum
in (b) the signals of protons in the complex are indicated by (c); (uc)
stands for those of the uncomplexed molecule.
In comparison, when we reacted an equimolar mixture of
[5-H2]4PF6 and the dibromide 6 under the same conditions,
but in the absence of 1, we obtained a complicated mixture
with no notable signals corresponding to the [1+1] macro-
cycle (1H NMR spectroscopy, ESI-MS). Thus, the folding and
conformational freezing of the flexible threadlike salt [5-
H2]4PF6 that results from its complexation with the molecular
cage 1 increased the efficiency of the irreversible macro-
cyclization significantly. 2D COSY and NOESY experiments
the complex, thus suggesting that a 2:1 (host–guest) complex
had formed, with the threadlike guest having been folded
twice at right angles. We confirmed the binding stoichiometry
using isothermal titration calorimetry (ITC) and obtained
1
allowed us to identify most of the signals in the H NMR
spectrum of the [3]catenane [7-H2]6PF6 in CD3CN at 298 K
binding constants K1 and K2 of 1.5 ꢀ 105 and 3 ꢀ 104 mꢀ1
,
respectively. Because the value of K1/K2 is close to 4, the two
(Figure 5). The presence of four (two) signals of equal
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pyridinium protons (Ha and Hb)
moved downfield and upfield, respec-
tively (Figure 5), thus suggesting that
a shorter spacer resulted in a change of
the stacking position between the pyr-
idinium ring and the aromatic “roof” of
the molecular cage unit. The appear-
ance of characteristic broad signals at
d = 7.60–7.80 ppm for the NH2+ centers
of all of these catenanes suggested that
ꢀ
N H···O hydrogen bonding was the
primary
noncovalent
interaction
between the host and guest compo-
nents. The signals for the external
methylene protons adjacent to the
+
NH2 center (Hj) were, however,
more downfield for the [3]catenane
[7-H2]6PF6 and the [5]MN [11-
H4]12PF6 than for those of [9-H2]6PF6
and [10-H2]6PF6, thereby implying that
Figure 5. Partial 1H NMR spectrum (800 MHz, CD3CN, 298 K) of the [3]catenanes a) [7-H2]6PF6,
b) [9-H2]6PF6, c) [10-H2]6PF6, and d) the [5]MN [11-H4]12PF6.
+
ꢀ
N-C H···O hydrogen bonding to the
oxygen atoms of the crown ether was
intensity for the aromatic (methyl) protons of the molecular
cage units, together with the symmetry of the signals of the 60-
membered-ring macrocycle, supported our proposed molec-
ular structure for the catenane [7-H2]6+, in which the 60-
membered ring was interlocked with the molecular cage units
by its threading through adjacent 24- and 34-membered rings.
The expectation that a more-rigid spacer might link the
two pyridyl termini of the complex [12ꢁ5-H2]4+ more effi-
ciently was realized by reacting 4,4’-bis(bromomethyl)bi-
phenyl (8)[20] with a mixture of 1 (8 mm), [5-H2]4PF6 (2 mm),
and AgPF6 (4 mm) under conditions similar to those we had
used for the synthesis of [7-H2]6PF6, and we obtained the
corresponding [3]catenane [9-H2]6PF6 in 22% yield
(Scheme 3).[21] Encouraged by this result, we performed
a similar reaction using a mixture of 1 (12 mm), [5-H2]4PF6
(2 mm), and a,a’-dibromo-p-xylene with the anticipation that
this shorter spacer would be less effective at linking the two
relatively distant pyridyl termini in [12ꢁ5-H2]4+, thereby
potentially favoring the formation and isolation of a [5]MN,
which would require the assembly of eight molecular
components through four irreversible chemical reactions.
As expected, we isolated the [5]MN [11-H4]12PF6, with
a 92-membered ring as its centerpiece, in 4% yield after ion
exchange and column chromatography, together with the
corresponding [3]catenane [10-H2]6PF6 (6%). The electro-
spray ionization (ESI) mass spectrum of [11-H4]12PF6
revealed intense peaks at m/z 2370.6 and 1741.7, correspond-
ing to the ions {[11-H4]9PF6}3+ and {[11-H4]8PF6}4+, respec-
tively (Figure 6). The good matches between the observed
and calculated isotope patterns (Figure 6) for these ions
support the successful synthesis of the [5]MN [11-H4]12PF6.
We identified the signals in the 1H NMR spectra of the
[3]catenanes [9-H2]6PF6 and [10-H2]6PF6 in CD3CN at 298 K
through 2D COSY, NOESY, or ROESY experiments. Upon
decreasing the length of the spacer in the [3]catenane [7-
H2]6PF6 to that in [10-H2]6PF6, the two signals of the
Figure 6. ESI mass spectrum of the [5]MN [11-H4]12PF6 exhibiting
peaks corresponding to the molecular ions {[11-H4]8PF6}4+ and {[11-
H4]9PF6}3+ and their calculated (a,b) and observed (c,d) isotopic
distributions.
weakened through structural distortion of the latter two
compounds.
We have demonstrated that host–guest complexation can
be used to bend a flexible linear organic molecule into
a particular shape for the successful synthesis of [3]catenanes
and a [5]MN, with up to 60- and 92-membered rings as their
centerpieces, respectively, through host-templated macrocyc-
lizations.
4
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F. M. Raymo, G. K. H. Shimizu, J. F. Stoddart, D. J. Williams,
Chem. Commun. 1996, 487 – 490.
Received: July 12, 2012
Published online: && &&, &&&&
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Keywords: catenanes · macrocyclizations ·
.
molecular necklaces · molecular recognition · template synthesis
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=
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;
m(CuKa) = 1.134 mmꢀ1
;
T= 200(2) K; yellow
prism; 23750 independent measured reflections; F2 refinement;
R1 = 0.1191; wR2 = 0.3287.
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6794 – 6807; d) Y. Liu, J. Rawlston, A. T. Swann, T. Takatani,
C. D. Sherrill, P. J. Ludovice, M. Weck, Chem. Sci. 2011, 2, 429 –
438.
[9] a) G. W. Gokel, Crown Ethers and Cryptands, Royal Society of
Chemistry, London, 1992; b) J. W. Steed, J. L. Atwood, Supra-
molecular Chemistry, 2nd ed., Wiley, Chichester, 2009.
[10] Using 1,5-dihydroxynaphthalene and ferrocene derivatives as
templates allows cyclobis(paraquat-p-phenylene) and cyclobis-
(paraquat-4,4’-biphenylene), 28- and 36-membered ring macro-
cycles, respectively, to be synthesized from their corresponding
linear pyridinium salts; see: a) C. L. Brown, D. Philip, J. F.
Stoddart, Synlett 1991, 462 – 464; b) P. R. Ashton, S. Menzer,
[20] A. Conejo-Garcꢆa, L. Pisani, M. C. NfflÇez, M. Catto, O.
Nicolotti, F. Leonetti, J. M. Campos, M. A. Gallo, A. Espinosa,
A. Carotti, J. Med. Chem. 2011, 54, 2627 – 2645.
[21] The reaction proceeded much slower in the absence of AgPF6.
Addition of this salt did not improve the reaction efficiency,
however, in the synthesis of the [3]catenane [7-H2]6PF6.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Template Synthesis
C.-F. Chang, C.-J. Chuang, C.-C. Lai,
Y.-H. Liu, S.-M. Peng,
S.-H. Chiu*
&&&& — &&&&
Using Host–Guest Complexation to Fold
a Flexible Linear Organic String:
Kinetically Controlled Syntheses of
[3]Catenanes and a Five-Membered
Molecular Necklace
Rings and necklaces: Three [3]catenanes
and a five-membered molecular necklace
([5]MN), with up to 60- and 92-membered
rings as their centerpieces, respectively,
have been synthesized. The synthesis
started from the corresponding com-
plexes in which the threaded flexible
linear guests were bent at approximately
right angles to facilitate kinetically con-
trolled macrocyclizations.
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!