A remarkably flexible and selective receptor for Ba2+ amplified from a hydrazone dynamic combinatorial library

Article abstract of DOI:10.1039/c0cc04863a

A new [2+2] tetra-hydrazone macrocyclic receptor was significantly amplified in a dynamic combinatorial library upon templation with alkaline earth metal ions. After optimisation the product could be isolated in 95% yield and its interaction with ions was

Full text of DOI:10.1039/c0cc04863a

Chemical Communications
www.rsc.org/chemcomm
Volume 47 | Number 12 | 28 March 2011 | Pages 3301–3656
ISSN 1359-7345
COMMUNICATION
Jeremy K. M. Sanders et al.
A remarkably flexible and selective
receptor for Ba2+ amplified from a
hydrazone dynamic combinatorial
library
1359-7345(2011)47:12;1-J

This article is part of the
Supramolecular Chemistry web-
based thematic issue
celebrating the International Year of Chemistry 2011
Guest editors: Professors Philip Gale,
Jonathan Sessler and Jonathan Steed
All articles in this issue will be gathered together online at
www.rsc.org/chemcomm/supra.

Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2011, 47, 3371–3373
www.rsc.org/chemcomm
COMMUNICATION
A remarkably flexible and selective receptor for Ba2+ amplified from a
hydrazone dynamic combinatorial librarywz
a
b
b
a
a
¨
Jorg M. Klein,y Vittorio Saggiomo,y Lisa Reck, Mary McPartlin, G. Dan Panto-s,
Ulrich Lu
¨
ning*b and Jeremy K. M. Sanders*a
Received 8th November 2010, Accepted 20th December 2010
DOI: 10.1039/c0cc04863a
A new [2+2] tetra-hydrazone macrocyclic receptor was significantly
amplified in a dynamic combinatorial library upon templation with
alkaline earth metal ions. After optimisation the product could be
isolated in 95% yield and its interaction with ions was investigated
by NMR and UV-Vis spectroscopy.
addition of Ba2+ shifts the equilibrium position to 92% of 4.
Other metal ions had various effects depending on the charge
and size of the cation (Fig. 2). Group 1 metal ions did not
change the library distribution significantly whereas group 2
metal ions did. The order of amplification of 4 was Ba2+
>
Sr2+ > Ca2+ > Mg2+ c group 1. Discrimination among
group 2 metal ions is clearly correlated with their size; large
cations give stronger amplification, presumably due to a better
fit in the binding pocket.
Dynamic Combinatorial Chemistry (DCC)—combinatorial
chemistry under thermodynamic control—has served as an
efficient tool to discover synthetic receptors for various guests.1
A dynamic combinatorial library (DCL) is generated by exchange
and recombination of building blocks that use reversible covalent
or noncovalent interconnections to build higher-order dynamic
entities. Both hydrazone formation and metal–ligand interactions
are dynamic, as they are labile and dissociate and reassociate
under the influence of various chemical and/or physical stimuli.2
Templating of imines by metal ions is well precedented3 but to the
best of our knowledge almost no investigations in metal-ion
templated hydrazone chemistry have been published.4
Thus DCC identified 4 as an interesting host for Ba2+
.
Ironically the yields for the isolation of 4 from a templated
DCL were low due to the better solubility of Ba2+ꢀ4 compared
with 4. In the event, 4 was most easily isolated by exploiting its
low solubility:7 increasing the concentration of 1 and 2 in the
DCL to 30 mM each resulted in the precipitation of pure 4 from
the solution, which could be isolated by filtration in 95% yield.z
Structural proof for receptor 4 came from X-ray analysis.
Crystals suitable for X-ray diffraction were grown by slow
evaporation of a solution of CDCl3/MeOD.z 4ꢀ1.5H2Oꢀ4CHCl3
Herein we present the efficient synthesis of a new type
of a multi-hydrazone based macrocyclic receptor and the
investigation of its complexation properties with alkali and
alkaline earth metal ions using a dynamic combinatorial
approach. Macrocycles 3 and 4 were assembled from DCLs by
the reversible, acid-catalysed polycondensation of dialdehyde 15
and dihydrazide 2z (Fig. 1). The DCLs contained solutions of
building blocks (1 mM per building block) in a mixture of
CHCl3/MeOH/TFA (50 : 50 : 5). Thermodynamic equilibrium
was reached in 9 days.6 The untemplated DCL of 1 and 2 formed
a mixture containing only two hydrazone macrocycles 3 and 4 in
a distribution of 99 : 1 (Fig. 2, no template).
ꢀ
crystallises in the triclinic space group P1 with one molecule in
the asymmetric unit. A solvent water molecule is located
within the macrocycle, forming three hydrogen bonds with
the hydrazone moieties. Receptor 4 adopts a highly twisted
conformation such that planar chirality is observed (Fig. 3).
p–p stacking interactions and several hydrogen bonds stabilise
the folding of the macrocycle (see ESIz for further discussion). As
the space group contains inversion symmetry a racemic mixture
of the two P and M enantiomers is present throughout the lattice.
Adjacent pairs of enantiomers are partially intercalated and
linked together through hydrogen bonding interactions between
the macrocycles and their guest water.
The distribution of products changed significantly upon
addition of a templating metal ion. Most dramatically, the
The strongest amplification of 4 by Ba2+ (Fig. 2) implies that
this metal is likely to form a strong complex with 4. For this
reason we decided to study this complexation process using
1H NMR, NOESY and HRMS techniques. The number of
a University Chemical Laboratory, University of Cambridge,
Lensfield Road, Cambridge, UK CB2 1EW.
E-mail: jkms@cam.ac.uk; Fax: +44 (0)1223 336 017
b Otto-Diels-Institut fur Organische Chemie, Olshausenstr. 40,
1
¨
peaks in the H-NMR spectrum of 4 is consistent with a time-
D-24098 Kiel, Germany. E-mail: luening@oc.uni-kiel.de;
Fax: +49 431-880-1558; Tel: +49 431-880-2450
averaged highly symmetric structure.z When a substoichiometric
amount of Ba2+ was titrated into a solution of 4 (CDCl3/MeOD,
1 : 1, 1 mM) the free macrocycle and the complex were observed
to be in slow exchange on the NMR timescale. Complete
conversion of the host into the Ba2+ꢀ4 complex was observed
after the addition of 1.0 eq. of Ba2+ while further addition
w This article is part of a ChemComm ‘Supramolecular Chemistry’ web-
based themed issue marking the International Year of Chemistry 2011.
z Electronic supplementary information (ESI) available: Synthetic and
DCL set up methods, LC-MS, NMR, HRMS and UV-Vis data.
CCDC 808990. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0cc04863a
1
y These authors contributed equally to this work.
of Ba2+ did not induce any change in the H-NMR spectrum.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 3371–3373 3371

Fig. 1 Schematic representation of the selection of macrocyclic host 4 from a DCL by alkaline earth metal ions.
Fig. 3 A schematic representation of the crystal structure of 4ꢀ
1.5H2Oꢀ4CHCl3. Disorder and solvent molecules removed for clarity.
solution of 4, providing further support for a 1 : 1 stoichiometry
and the complete conversion of the free macrocycle into its
complex.
UV titrations [in CHCl3/MeOH (1 : 1) at 23 1C] confirmed
the relative thermodynamic stability of the metal complexes
Fig. 2 HPLC traces of the DCLs with and without different chloride
that was indicated by the DCC experiments. For alkali metal
salts as templates after 9 days (1 mM per building block, 1 mM of
ions changes in the UV absorption were too small to determine
template). The macrocycles present in solution are shown above the
binding constants, while for alkaline-earth metal ions they
HPLC traces. The templating ions are shown in the middle of each
ranged from 103 Mꢁ1 (Mg2+ and Ca2+ complexes) over
HPLC trace. Only marginal changes were observed when monovalent
2 ꢂ 105 Mꢁ1 (Sr2+ complex) up to >106 Mꢁ1 (Ba2+ complex).
cations were used. Divalent cations amplify 4 (red peaks) at the
Since the binding constant for the Ba2+ complex was too high
expense of 3 (blue peaks). UV traces shown were recorded at 290 nm.
to be determined accurately at 23 1C, it was measured at
elevated temperatures. As expected, the association constants
The NOESY spectrum of the Ba2+ complex exhibits a cross-
peak between Hc (6.9 ppm) and He (8.0 ppm, Fig. 4) which is not
were progressively lower as the temperature increased: Ka
(33 1C) = 5 ꢂ 105 Mꢁ1 and Ka (43 1C) = 3 ꢂ 105 Mꢁ1
.
observed in the NOESY spectrum of the unbound macrocycle.
This suggests that the macrocycle undergoes a conformational
change upon complexation of Ba2+, a process associated with
the notion of induced fit. The molecular ion peak of Ba2+ꢀ4 was
observed in the HRMS after addition of 1.0 eq. of Ba2+ to a
In conclusion, a DCL of multihydrazone macrocycles was
templated with different metal salts. The amplification factors
obtained from the DCLs represented the relative stabilities of the
complexes as determined by UV-Vis titrations. A particularly
c
3372 Chem. Commun., 2011, 47, 3371–3373
This journal is The Royal Society of Chemistry 2011

Fig. 4 Partial NOESY spectra (500 MHz, CDCl3/MeOD (1/1), 300 K, d8 = 800 ms) of (a) 4 and (b) its Ba2+ complex Ba2+ꢀ4. The appearance of
the indicated cross-peak (red dashed line) suggests a conformational change upon binding. Corresponding resonances are connected by black
dashed lines. Residual solvent peaks are marked with an asterisk.
strong complex is formed between 4 and Ba2+. These results
illustrate the ability of DCC to uncover highly flexible and
therefore unpredictable macrocycles with remarkably selective
recognition properties. 4 may be the most selective macrocyclic
Ba2+ vs. Ca2+ receptor yet discovered.8
Weinheim, 2010, ch. 1, pp. 1–22; P. T. Corbett, J. Leclaire, L. Vial,
K. R. West, J.-L. Wietor, J. K. M. Sanders and S. Otto, Chem. Rev.,
2006, 106, 3652.
2 M. Elhabiri and A. M. Albrecht-Gary, Coord. Chem. Rev., 2008,
252, 1079.
3 N. F. Curtis and D. A. House, Chem. Ind., 1961, 42, 1708;
M. C. Thompson and D. H. Busch, J. Am. Chem. Soc., 1962, 84,
We thank the Marie-Curie Research Training Network
(MRTN-CT-2006-035614, J.M.K. and V.S.), Pembroke Col-
lege, Cambridge (G.D.P.) and EPSRC (J.K.M.S) for funding,
Dr Jack K. Clegg for discussions about the crystal structure,
Dr John Davies for recording the X-ray data and Dr Ana
Belenguer for maintaining the HPLC facility.
1762; O. Storm and U. Luning, Chem.–Eur. J., 2002, 8, 793;
¨
¨
V. Saggiomo and U. Luning, Eur. J. Org. Chem., 2008, 4329.
4 S. L. Roberts, R. L. E. Furlan, S. Otto and J. K. M. Sanders, Org.
Biomol. Chem., 2003, 1, 1625.
5 U. Luning, R. Baumstark, K. Peters and H. G. von Schnering,
¨
Liebigs Ann. Chem., 1990, 129.
6 The HPLC traces remained unchanged after 9 days indicating that
thermodynamic equilibrium has been reached. When
4 was
Notes and references
dissolved under the same conditions as the DCL it reequilibrated
to the library distribution obtained from the building blocks
(3 : 4, 95 : 5, ESIz).
z Formula: C62H55Cl12N12O11.5, M 1577.58, triclinic, space group:
ꢀ
P1(#2), a 14.445(3), b 16.454(3), c 16.977(3) A, a 67.62(3)1, b 73.33(3)1,
g 86.05(3)1, V 3570.8(12) A3, Dc 1.467 g cmꢁ3, Z 2, crystal size: 0.46 ꢂ
0.35 ꢂ 0.23 mm, colour: colourless, habit block, temperature: 180(2) K,
l(MoKa) 0.71073 A, m(MoKa) 0.532 mmꢁ1, T(SORTAV)min,max 0.918,
0.981, 2ymax 41.401, hkl range: ꢁ14 14, ꢁ16 16, ꢁ16 16, N 31 757, Nind
7245(Rmerge 0.0244), Nobs 6395(I > 2s(I)), Nvar 963, residuals: R1(F)
7 M. Hutin, J. Cramer, L. Gagliardi, A. R. M. Shahi, G. Bernardinelli,
R. Cerny and J. R. Nitschke, J. Am. Chem. Soc., 2007, 129, 8774.
8 H. Huang, L. Mu, J. He and J. P. Cheng, J. Org. Chem., 2003, 68,
7605; S. H. Mashraqui, T. Khan, S. Sundaram, R. Betkar and
M. Chandiramani, Tetrahedron Lett., 2007, 48, 8487. Both report
K(Ba2+)/K(Ca2+
)
o
18. The only receptor showing better
0.0749, wR2(F2) 0.1992, GoF(all) 1.053, Drmin,max: ꢁ0.789, 0.849 eꢁ Aꢁ3
.
selectivity than our system is [2.2.2]cryptand. In MeOH: K(Ba2+)/
K(Ca2+) = 6.3 ꢂ 104. B. G. Cox, N. Van Truong, J. Garcia-Rosas
and H. Schneider, J. Phys. Chem., 1984, 88, 996.
1 S. R. Beeren and J. K. M. Sanders, in Dynamic
Combinatorial Chemistry, ed. J. N. H. Reek and S. Otto, Wiley VCH,
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 3371–3373 3373