A catenane assembled through a single charge-assisted halogen bond

Article abstract of DOI:10.1002/anie.201300464

Getting connected: The formation of pseudorotaxane assemblies between a designed macrocyclic halogen bonding (XB) acceptor (red in scheme) and a series of XB donor threading components was templated by a single halogen bond. The strength of the XB assembly between the pyridine macrocycle and iodopyridinium thread was utilized in the ring-closing metathesis clipping synthesis of a [2]catenane. Copyright

Full text of DOI:10.1002/anie.201300464

.
Angewandte
Communications
DOI: 10.1002/anie.201300464
Halogen Bonding
A Catenane Assembled through a Single Charge-Assisted Halogen
Bond**
Lydia C. Gilday, Thomas Lang, Antonio Caballero, Paulo J. Costa, Vꢀtor Fꢁlix, and
Paul D. Beer*
Interlocked molecules have captured chemistsꢀ imagination
owing to their nontrivial topology and the promise of their
potential nanotechnological uses as molecular machines[1] and
in chemical sensor applications.[2] The synthesis of such
sophisticated architectures is a challenge, and as a conse-
quence this has necessitated the implementation of imagi-
native cation,[3] anion,[4] and neutral[5] templation method-
Figure 1. Cartoon of orthogonal halogen-bond-templated pseudo-
rotaxane species. X=halogen atom.
ologies, which use a combination of complementary Lewis
acid–base, electrostatic, and hydrogen-bonding interactions
for component assembly. Halogen bonding (XB) is the
attractive highly directional, noncovalent interaction between
an electron-deficient halogen atom and a Lewis base.[6] The
scope of XB in solid-state crystal engineering has been
intensively explored for a number of years,[7] however, in spite
of the complementary analogy to ubiquitous hydrogen
bonding, it is only in recent times that investigations into
the application of solution-phase XB interactions to molec-
ular recognition processes, self-assembly, and catalysis have
resulted in this field developing rapidly.[8] Indeed, in con-
junction with anion templation, we have used XB to assemble
interpenetrated and interlocked molecular frameworks.[8b–d]
By incorporating a suitable neutral Lewis base XB
acceptor, such as pyridine,[7b,9] into a macrocyclic framework,
we demonstrate herein that a single charge-assisted XB
interaction can be utilized for pseudorotaxane assembly and,
importantly, in the synthesis of a novel interlocked catenane.
The synthetic strategy employed to construct the target
catenane is outlined in Figure 1. An acyclic positively charged
XB-donor component threads through a complementary XB-
accepting pyridine-containing macrocycle, thereby forming
an orthogonal interpenetrative assembly that is stabilized by
a charge-assisted XB interaction. In addition to the incorpo-
rated pyridine XB-acceptor motif, the macrocycle component
1 contains electron-rich hydroquinone groups to facilitate
supplementary secondary aromatic donor–acceptor interac-
tions with electron-deficient positively charged heterocyclic
XB-donor threading derivatives. A range of bromo- and iodo-
functionalized triazolium and pyridinium compounds were
chosen as potential threading components, containing termi-
nal vinyl functional groups, which after successful pseudo-
rotaxane assembly with macrocycle 1, could be used for
catenane synthesis through ring-closing metathesis (RCM)
cyclization (Scheme 1). Macrocycle 1 and halo-functionalized
triazolium and pyridinium derivatives were prepared by using
multistep synthetic procedures described in Schemes S1–S3 in
the Supporting Information.
To establish evidence for interpenetrative assembly in
solution (Scheme 2) and also to determine the strength of any
[*] L. C. Gilday, Dr. T. Lang, Dr. A. Caballero, Prof. P. D. Beer
Inorganic Chemistry Laboratory, Department of Chemistry
University of Oxford
South Parks Road, Oxford OX1 3QR (UK)
E-mail: paul.beer@chem.ox.ac.uk
Dr. P. J. Costa, Prof. V. Fꢀlix
Departamento de Quꢁmica, CICECO and Secżo Autꢂnoma de
CiÞncias da Safflde, Universidade de Aveiro
3810-193 Aveiro (Portugal)
[**] L.C.G. thanks the EPSRC for a DTA studentship. T.L. and A.C. thank
the European Research Council for funding under the European
Union’s Framework Program (FP7/2007–2013) ERC Advanced
Grant Agreement no 267426. P.J.C. thanks FCT for the postdoctoral
grant SFRH/BPD/27082/2006. We thank Dr. T. D. W. Claridge and
Dr. B. Odell of the Oxford NMR facility for help with NMR
experiments.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300464.
Scheme 1. Structures of macrocycle 1 and threading components 2–
6·BF4.
4356
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 4356 –4360

Angewandte
Chemie
observed for 6·BF4 > 5·BF4. Furthermore, these Ddppm values
are greater for the pyridinium species than for the triazolium
analogues. Notably, no significant evidence of interpenetra-
tion was observed with the bromotriazolium 2·BF4 derivative.
Quantitative analysis of the pseudorotaxane assembly
process was achieved by monitoring the macrocycleꢀs hydro-
quinone protons as a function of the concentration of the
thread component, and winEQNMR2[10] analysis of the
titration data (Figure 2) gave 1:1 stoichiometric association
Figure 2. Titration curves for pseudorotaxane assembly between mac-
rocycle 1 and thread components 3·BF4 (orange), 4·BF4 (blue), 5·BF4
(red), and 6·BF4 (green).
Scheme 2. Pseudorotaxane assembly between macrocycle 1 and iodo-
pyridinium threading component 6·BF4.
constants for pseudorotaxane formation (Table 1). Impor-
tantly, the most stable interpenetrative assembly with macro-
cycle 1 is found with the iodopyridinium thread 6·BF4 with an
association constant value (Ka = 180mÀ1) more than double
that of the pseudorotaxane assembly observed with bromo-
pyridinium thread 5·BF4 (Ka = 80mÀ1). This can be attributed
to the greater halogen-bond-donor ability of the more
polarizable iodine substituent as compared to bromine.
Notably, the interpenetrative assembly with the correspond-
ing protic pyridinium analogue 4·BF4 is significantly weaker
(Ka = 30mÀ1), thus highlighting the essential contribution of
the XB interaction in stabilizing the overall pseudorotaxane
assembly process.
Table 1 shows that although the iodotriazolium compound
3·BF4 forms a measurable pseudorotaxane association with
the pyridine macrocycle 1, the extremely small chemical shift
perturbations noted in the titration experiment with the
bromotriazolium analogue 2·BF4 suggest interpenetration is
not occurring. The reduced supplementary secondary aro-
matic donor–acceptor interactions of the triazolium motif
with the macrocycleꢀs hydroquinone groups in comparison
with pyridinium will also be a contributing factor.
Encouraged by the favorable association between macro-
cycle 1 and iodopyridinium thread 6·BF4, the synthesis of
a novel [2]catenane using a RCM clipping reaction in the
presence a Grubbs catalyst was undertaken (Scheme 3).
Macrocycle 1 and iodopyridinium thread 6·BF4 (1.1 equiv)
in anhydrous CD2Cl2 solution were stirred at room temper-
ature under N2 in the presence of Grubbs(II) catalyst
(10 wt%). After purification using repeated preparative
thin layer chromatography, the target [2]catenane 7·BF4 was
isolated in 6.5% yield.
association between respective macrocycle XB-acceptor and
potential XB-donor heterocycle thread components, the
pseudorotaxane assembly between macrocycle 1 and halo-
functionalized triazolium and pyridinium compounds 2·BF4–
1
6·BF4 in CD2Cl2 solution was investigated by using H NMR
spectroscopy.
Upon addition of thread components 3·BF4, 5·BF4, and
6·BF4 to macrocycle 1, the signals corresponding to the
macrocycle hydroquinone protons were shifted upfield, which
is attributed to aromatic donor–acceptor interactions with the
respective electron-deficient heterocyclic aromatic surface.
These diagnostic changes in the 1H NMR spectrum of the
macrocycle are highly indicative of successful formation of an
interpenetrated species by threading through the annulus of
the macrocycle component. The observed chemical shift
perturbations of the hydroquinone protons with ten equiv-
alents of thread component (Table 1) reveal the iodopyridi-
nium derivative 6·BF4 causes the largest magnitude of
perturbation; the chemical shift perturbation diminishes
with the XB donor capability of the substituent X, as
Table 1: Observed chemical shift perturbations (Dd) of hydroquinone
protons and association constants (Ka) for macrocycle 1 with thread
components 3·BF4–6·BF4. Estimated standard errors are given in
parentheses.
Thread
3·BF4
4·BF4
5·BF4
6·BF4
Dd [ppm][a]
0.03[b]
55(3)
0.03
30(2)
0.07
80(2)
0.10
180(20)
Ka [mÀ1
]
[a] After ten equivalents. [b] After five equivalents. CD2Cl2, 293 K.
Angew. Chem. Int. Ed. 2013, 52, 4356 –4360
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
4357

.
Angewandte
Communications
cyclization of the acyclic precursor. Most importantly, the
upfield shift and splitting of the signals of the macrocycle
hydroquinone protons f and g is indicative of aromatic donor–
acceptor interactions between the electron-rich macrocycle
hydroquinone units and the electron-poor pyridinium group.
The downfield shift of the signals of the pyridine protons
a and b is consistent with the withdrawal of electron density
by the formation of the halogen bond. Finally, the upfield shift
of pyridinium proton signal b is a result of catenane inter-ring
halogen-bond formation between the pyridine nitrogen atom
and the iodine substituent.
1
Two-dimensional H–1H ROESY spectroscopy was used
to confirm the interlocked nature of the catenane. At
500 MHz, the spectrum in CDCl3 is broader than at
300 MHz, which is indicative of dynamic behavior on the
NMR timescale. Heating to 708C in CD3CN resulted in
sharper signals in the one-dimensional NMR spectrum, and
through-space correlations between protons in the two ring
Scheme 3. Synthesis of a novel halogen-bond-templated catenane
7·BF4.
1
Evidence for the successful formation of a halogen-
bonded [2]catenane species is provided by electrospray
mass spectrometry and 1H NMR spectroscopy.
The cationic molecular ion peak is readily observed in the
mass spectrum, which suggests the presence of a single
interlocked species, and the high-resolution mass spectrum
reveals the isotopic distribution of the [2]catenane is in good
agreement with the simulated spectrum (see Figure S1 in the
Supporting Information).
components were identified in the H–1H ROESY spectrum
(see Figure S3 in the Supporting Information).
The synthesis of the related protic and bromopyridinium
functionalized catenanes was also attempted with threading
components 4·BF4 and 5·BF4 by applying analogous RCM
reaction conditions using a Grubbs catalyst. Although no
evidence of catenane formation was observed with protic
pyridinium thread 4·BF4, with the bromopyridinium thread
5·BF4 a peak at m/z = 1213.4 corresponding to the [2]catenane
species was detected by electrospray mass spectrometry. In
spite of numerous attempts, however, the catenane could not
be isolated, which suggests it is produced in negligible yield.
To obtain further insights on the structure of catenane
7·BF4, molecular dynamics (MD) simulations were performed
The 1H NMR spectrum of the [2]catenane and those of the
component macrocycle and vinyl-appended precursor are
shown in Figure 3. The disappearance of the multiplet m
(vinylic protons) and the convergence of multiplet l into
a pseudo singlet in the catenane spectrum are attributed to
Figure 3. 1H NMR spectra of a) pyridine macrocycle 1, b) halogen-bonded [2]catenane 7·BF4, c) iodopyridinium RCM precursor 6·BF4 (300 MHz,
CDCl3, 298 K).
4358
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 4356 –4360

Angewandte
Chemie
in explicit chloroform by using the Amber12[11] accelerated
GPU code.[12] The C I···N halogen bond interaction was
À
added to the general Amber force field (GAFF)[13] through
a dummy atom,[14] which was parameterized as described in
Supporting Information.
Four starting co-conformations were generated in the gas
phase, as described in the Supporting Information and are
presented in Figure 4.
Figure 5. Representative co-conformation of 7·BF4 in chloroform solu-
tion for simulation of S1A. The BF4À counteranion is represented in
balls and sticks. The remaining details are similar to Figure 4.
and the pyridine ring of the macrocycle. Additionally, this co-
conformation is stabilized by the stacking interactions
between the iodopyridinium moiety and the hydroquinone
rings, in total agreement with the NMR findings.
The alternative S2 scenarios (A and B) allow the existence
À
of C I···O halogen bonds between the iodopyridinium and
the oxygen atoms of the polyether loop of the pyridine
macrocycle. Indeed, these noncovalent interactions were
intermittently observed during the MD simulations under-
taken with both binding arrangements. This type of halogen
À
bond is more labile than the C I···N ones, thereby leading to
À
a diffuse distribution of the I···O distances and C I···O angles
when they are plotted together, as can be seen in Figure S9 in
the Supporting Information, and therefore these halogen
bonds are not sufficiently stable for XB templation. See the
Supporting Information for a full discussion of the MD
simulations carried out with S2A and S2B.
Figure 4. Starting co-conformations used in the MD simulations; S1A
À
and S1B exhibit a C I···N halogen bond and S2A and S2B present
In conclusion, we designed a XB-acceptor pyridine-
containing macrocycle and demonstrated the formation of
pseudorotaxane assemblies with a series of XB-donor iodo-
functionalized triazolium as well as bromo- and iodo-func-
tionalized pyridinium threading components; the pseudoro-
taxane assemblies are stabilized by a charge-assisted XB
interaction. The strength of the XB interpenetrative assembly
between the pyridine macrocycle and iodopyridinium thread
was exploited in the RCM clipping synthesis of a novel
[2]catenane by using a Grubbs catalyst. The crucial impor-
tance of the single charge-assisted XB interaction between
the two components was highlighted by the fact that no
evidence of catenane formation was observed in an analogous
RCM reaction of the pyridine macrocycle with the corre-
sponding protic pyridinium reactant. Hence we have illus-
trated that XB has real potential in templating the construc-
tion of mechanically bonded molecular architectures.
À
a C I···O halogen bond. Macrocycle 1 is shown with yellow carbon
atoms, and the iodopyridinium macrocycle is shown with gray carbon
atoms. Hydrogen atoms apart those from the methyl groups were
omitted for clarity. The C I···N and C I···O halogen bonds are drawn
as blue dashed lines.
À
À
These structures, S1A, S1B, S2A, and S2B correspond to
two main arrangements: in S1 (A and B) there is an I···N
halogen bond as represented in Scheme 3, whereas in S2 (A
and B) co-conformations the iodopyridinium macrocycle is
À
rotated with the C I bond pointing towards the polyether
loop of the pyridine macrocycle 1. Within the two alternative
binding scenarios, A and B differ mainly in the conformation
of the iodopyridium macrocycle. Subsequently, these four co-
conformations were subject to MD runs in chloroform for
50 ns.
The I···N halogen bond is highly stable throughout the
course of the simulation time in both S1A and S1B co-
conformations, as evident by the plot of the I···N distances
Received: January 18, 2013
Published online: March 11, 2013
À
versus the C I···N angles presented in Figure S7 in the
Supporting Information. A narrow spot centered at an I···N
Keywords: catenanes · halogen bonding ·
supramolecular chemistry · template synthesis
.
À
distance of 3.19 ꢁ and a C I···N angle of 1738 is observed,
which is indicative of the existence of a persistent halogen
bond. A representative co-conformation of 7·BF4 in chloro-
form solution for simulation of S1A is presented in Figure 5.
Simulation of S1B yields a virtually identical co-conformation
(see Figure S8 in the Supporting Information). In this
representative frame, as mentioned earlier, an I···N halogen
bond is established between the iodopyridinium derivative
[1] a) E. R. Kay, D. A. Leigh, F. Zerbetto, Angew. Chem. 2007, 119,
72 – 196; Angew. Chem. Int. Ed. 2007, 46, 72 – 191; b) S. Saha, J. F.
Stoddart, Chem. Soc. Rev. 2007, 36, 77 – 92.
[2] a) S. R. Bayly, T. M. Gray, M. J. Chmielewski, J. J. Davis, P. D.
Beer, Chem. Commun. 2007, 2234 – 2236; b) D. Curiel, P. D.
Beer, Chem. Commun. 2005, 1909 – 1911; c) J. J. Gassensmith, S.
Angew. Chem. Int. Ed. 2013, 52, 4356 –4360
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
4359

.
Angewandte
Communications
Matthys, J.-J. Lee, A. Wojcik, P. V. Kamat, B. D. Smith, Chem.
Eur. J. 2010, 16, 2916 – 2921; d) N. H. Evans, P. D. Beer, Org.
Biomol. Chem. 2011, 9, 92 – 100; e) M. J. Chmielewski, J. J.
Davis, P. D. Beer, Org. Biomol. Chem. 2009, 7, 415 – 424.
[3] a) C. O. Dietrich-Buchecker, J. P. Sauvage, J. M. Kern, J. Am.
Chem. Soc. 1984, 106, 3043 – 3045; b) M. Fujita, F. Ibukuro, H.
Hagihara, K. Ogura, Nature 1994, 367, 720 – 723.
[4] J. A. Wisner, P. D. Beer, M. G. B. Drew, M. R. Sambrook, J. Am.
Chem. Soc. 2002, 124, 12469 – 12476.
[5] D. G. Hamilton, J. K. M. Sanders, J. E. Davies, W. Clegg, S. J.
Teat, Chem. Commun. 1997, 897 – 898.
1674 – 1677; b) N. L. Kilah, M. D. Wise, C. J. Serpell, A. L.
Thompson, N. G. White, K. E. Christensen, P. D. Beer, J. Am.
Chem. Soc. 2010, 132, 11893 – 11895; c) C. J. Serpell, N. L. Kilah,
P. J. Costa, V. Felix, P. D. Beer, Angew. Chem. 2010, 122, 5450 –
5454; Angew. Chem. Int. Ed. 2010, 49, 5322 – 5326; d) A.
Caballero, F. Zapata, N. G. White, P. J. Costa, V. Felix, P. D.
Beer, Angew. Chem. 2012, 124, 1912 – 1916; Angew. Chem. Int.
Ed. 2012, 51, 1876 – 1880; e) M. Erdꢃlyi, Chem. Soc. Rev. 2012,
41, 3547 – 3557; f) F. Zapata, A. Caballero, N. G. White, T. D. W.
Claridge, P. J. Costa, V. Felix, P. D. Beer, J. Am. Chem. Soc. 2012,
134, 11533 – 11541; g) T. M. Beale, M. G. Chudzinski, M. G.
Sarwar, M. S. Taylor, Chem. Soc. Rev. 2013, 42, 0.
[6] P. Metrangolo, F. Meyer, T. Pilati, G. Resnati, G. Terraneo,
Angew. Chem. 2008, 120, 6206 – 6220; Angew. Chem. Int. Ed.
2008, 47, 6114 – 6127.
[9] F. Zordan, L. Brammer, P. Sherwood, J. Am. Chem. Soc. 2005,
127, 5979 – 5989.
ˇ ´
ˇˇ ´
[7] a) D. Cincic, T. Friscic, W. Jones, Chem. Eur. J. 2008, 14, 747 –
753; b) L. C. Roper, C. Prasang, V. N. Kozhevnikov, A. C.
Whitwood, P. B. Karadakov, D. W. Bruce, Cryst. Growth Des.
2010, 10, 3710 – 3720; c) N. S. Goroff, S. M. Curtis, J. A. Webb,
F. W. Fowler, J. W. Lauher, Org. Lett. 2005, 7, 1891 – 1893; d) R.
Liantonio, P. Metrangolo, T. Pilati, G. Resnati, A. Stevenazzi,
Cryst. Growth Des. 2003, 3, 799 – 803; e) D. W. Bruce, P.
Metrangolo, F. Meyer, C. Prasang, G. Resnati, G. Terraneo,
A. C. Whitwood, New J. Chem. 2008, 32, 477 – 482; f) M. T.
[10] M. J. Hynes, J. Chem. Soc. Dalton Trans. 1993, 311 – 312.
[11] AMBER12, D. A. Case, et al. San Francisco, 2012 (see the
Supporting Information).
[12] a) A. W. Goetz, R. Salomon-Ferrer, D. Poole, S. L. Grand, R. C.
Walker, “Routine microsecond molecular dynamics simulations
with AMBER—Part II: Particle Mesh Ewald”, unpublished
results; b) S. Le Grand, A. W. Goetz; R. C. Walker, Comp. Phys.
Comm 2013, 184, 374 – 380.
[13] J. Wang, M. R. Wolf, J. W. Caldwell, P. A. Kollman, D. A. Case, J.
Comput. Chem. 2004, 25, 1157—1174.
ˇ
´
Johnson, Z. Dzolic, M. Cetina, O. F. Wendt, L. ꢂhrstrçm, K.
Rissanen, Cryst. Growth Des. 2012, 12, 362 – 368.
[8] a) M. G. Sarwar, B. Dragisic, S. Sagoo, M. S. Taylor, Angew.
Chem. 2010, 122, 1718 – 1721; Angew. Chem. Int. Ed. 2010, 49,
[14] a) M. A. A. Ibrahim, J. Comput. Chem. 2011, 32, 2564—2574;
b) S. Rendine, S. Pieraccini, A. Forni, M. Sironi, Phys. Chem.
Chem. Phys. 2011, 13, 19508—19516.
4360 www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 4356 –4360