Dynamic combinatorial libraries for the recognition of heavy metal ions

Article abstract of DOI:10.1039/c1ob05976a

We present the use of hydrazone dynamic combinatorial libraries (DCLs) to identify macrocyclic receptors that are selective for alkaline earth metal ions over alkali metal ions. In particular, the toxic heavy metal ions Sr ²⁺ and Ba²⁺

Full text of DOI:10.1039/c1ob05976a

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Organic &
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PAPER
Dynamic combinatorial libraries for the recognition of heavy metal ions†
Jo¨rg M. Klein,a Vittorio Saggiomo,‡a Lisa Reck,b Ulrich Lu¨ning*b and Jeremy K. M. Sanders*a
Received 16th June 2011, Accepted 8th September 2011
DOI: 10.1039/c1ob05976a
We present the use of hydrazone dynamic combinatorial libraries (DCLs) to identify macrocyclic
receptors that are selective for alkaline earth metal ions over alkali metal ions. In particular, the toxic
heavy metal ions Sr2+ and Ba2+ induce characteristic changes in the DCLs. Four macrocycles were
isolated and characterised by LCMS, HRMS, NMR and X-ray crystallography; binding studies by
UV-Vis spectroscopy confirm the selectivity observed in the DCLs.
The reversible interactions used in this study are hydrazone
1
Introduction
exchange23–27 and metal–ligand interactions.28 Recently, we ex-
ploited the reversibility of the hydrazone linkage in ligands con-
taining a 2,6-bis-hydrazonopyridine core (here referred to as N3O2
ligands)29–35 to study their behaviour in dynamic combinatorial
libraries (DCLs).10 Dialdehyde 1 and dihydrazide 2a (Fig. 1) were
combined to generate two different macrocycles. We developed a
protocol for the easy isolation of the first macrocyclic hydrazone
N3O2 ligand and presented its characterisation. Binding studies
showed a striking selectivity of this host for Ba2+ over Ca2+ and
alkali metal ions, and proved the potential of macrocyclic N3O2
ligands.10
Here we extend the family of macrocyclic N3O2 ligands by
introducing a new dihydrazide building block 2b (with a di-
ethyleneglycol linker) and study DCLs that were templated with
alkali and alkaline earth metal ions (Fig. 1). The heavy metal
ions Sr2+ and Ba2+ induced characteristic changes in the product
distribution of the DCLs that were not observed when other
metal ions were added. After the isolation and characterisation
of four different N3O2 macrocycles, binding studies of the larger
2 + 2 macrocycles by HRMS, NMR and UV-Vis confirmed the
selectivity of the macrocycles for Sr2+ and Ba2+.
Heavy metal ions are part of everyday life and much research
has focussed on the extraction of heavy metal ions from organic
or aqueous effluents.1–7 In particular, radioactive isotopes such
as 90Sr and 137Cs have gained renewed attention following recent
accidents in the nuclear power plants in Japan. As recently pointed
out by Chen et al., new organic ligands are needed to further
optimise the extraction and make it a greener process.8 Non-
covalent interactions play an important role in the recognition
between the metal and the organic ligand and have been found to
be a way of tuning the extractant strength.9 We now present the
use of dynamic combinatorial chemistry (DCC) to discover new
organic ligands that are selective for heavy metal ions and could
contribute to more efficient extraction processes; some of these
results have previously been presented in preliminary form.10
Dynamic combinatorial chemistry is concerned with mixtures
of building blocks under thermodynamic control.11,12 The building
blocks can assemble to give different combinations (in this case
macrocycles). The assembly process is reversible thus making the
mixture dynamic. These adaptable mixtures are called dynamic
combinatorial libraries (DCLs) and adapt to external stimuli (e.g.
temperature, pressure, the presence of a template etc.) by changing
the product distribution to minimise the total energy of the system.
The increase in concentration of a particular species is referred to
as amplification. Amplification reflects stabilisation of a particular
species and has guided the discovery of new receptors.13–27
2
Templating of DCLs with metal ions
The building blocks were synthesised according to published
procedures10,36 or as described in the ESI.† Dissolution of
dialdehyde 1 and dihydrazide (2a or 2b) in mixtures of
CHCl3/MeOH/F3CCO2H generated two different sets of DCLs
(Fig. 2 and ESI†). As shown by LCMS analysis, both sets
of untemplated DCLs consisted of almost exclusively 1 + 1
macrocycle (3a and 3b); therefore these smallest macrocycles,
which are inevitably favoured on entropic grounds, represent
the thermodynamically most stable species (Fig. 2 and ESI†).
Addition of alkali metal ions had essentially no effect on the
product distribution whereas addition of alkaline earth metal ions
stabilised larger macrocycles and increased their abundance in
the DCLs. Interestingly, the small differences in the linker unit
of 2a and 2b led to distinctly different responses of the DCLs to
aUniversity Chemical Laboratory, University of Cambridge, Lensfield Road,
Cambridge, UK, CB2 1EW. E-mail: jkms@cam.ac.uk; Fax: +44 (0)1223
336 17
bOtto-Diels-Institut fu¨r Organische Chemie, Olshausenstr. 40, D-24098,
Kiel, Germany. E-mail: luening@oc.uni-kiel.de; Fax: +49-431-880-1558;
Tel: +49-431-880-2450
† Electronic supplementary information (ESI) available: Synthetic and
DCL set up methods, LC-MS, NMR, HRMS and UV-Vis data. CCDC
reference numbers 827938 and 827939. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c1ob05976a
‡ Present address: University of Groningen, Centre for Systems Chemistry,
Stratingh Institute, Nijenborgh 4, 9747 AG Groningen, The Netherlands.
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Fig. 1 Schematic representation of the experiment. A mixture of macrocycles is formed by combining a dialdehyde with a dihydrazide. Addition of a
metal ion leads to the selection of the macrocycle that binds the metal ion better.
the 2 + 2 macrocycle 4a (ESI†).10 These results suggested that the
2 + 2 macrocycle with the pyridyl linker and the 2 + 2, 3 + 3 and
4 + 4 macrocycles with the ethylene glycol linker are good hosts
for the doubly charged guests Ca2+, Sr2+ and Ba2+ while showing
weak or no binding to singly charged guests (alkali metal ions).
Thermodynamic control was demonstrated by reaching the same
library distribution from two different starting points. When the
2 + 2 macrocycles (isolation is described below) were dissolved
under the same conditions as the building blocks, an identical
product distribution was reached (ESI†). The following section
will present the isolation and characterisation of the two 1 + 1
macrocycles 3a and 3b and the two 2 + 2 macrocycles 4a and 4b.
3
Isolation and characterisation of macrocycles
3.1 1 + 1 Macrocycles
The isolation and characterisation of the 1 + 1 macrocycle with
the pyridyl linker 3a was very similar to that of the 1 + 1
macrocycle with the ethylene glycol linker 3b and only the latter is
described here. The information for 3a can be found in the ESI.†
The untemplated DCL of 1 and 2b formed almost exclusively
1 + 1 macrocycle 3b as the thermodynamically most stable species
and the 1 + 1 macrocycles were isolated in a simple three-step
procedure: addition of base (to halt hydrazone exchange) followed
by removal of solvent and finally removal of salts by washing with
water. LCMS analysis confirmed that the isolated material was
indeed the 1 + 1 macrocycle 3b and that the purity of the obtained
sample was high (ESI,† 99%).
Fig. 2 LCMS analysis of DCLs generated from building blocks 1 and 2b
in the absence and presence of different metal ions. Cartoons as explained
in Fig. 1. Method A (ESI†).
templating with Ca2+, Sr2+ and Ba2+. The DCLs with the ethylene
glycol linker (Fig. 2) showed amplification of 2 + 2 (4b), 3 + 3 (5b)
and 4 + 4 (6b) macrocycles upon addition of Ba2+ and Sr2+ while
the DCLs with the pyridyl linker showed only amplification of
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The NMR spectrum of 3b showed that this macrocycle adopts
an asymmetric conformation. NOESY cross-peaks (Fig. 3) for
only one of the two imine peaks with the meta-pyridine protons
suggested that the asymmetry arises through different orientations
of the hydrazone moiety on the two sides of the MeO-pyridine ring.
3.2 2 + 2 Macrocycles
Varying building block concentrations in these DCLs (Fig. 5)
showed that, if the concentration of the building blocks were
increased, the 2 + 2 macrocycle 4b precipitated, creating a
useful kinetic trap. The precipitation of 4b shifts the equilibrium
towards its formation, consuming all the building blocks. The
2 + 2 macrocycles were easily isolated by filtration. The group
of Nitschke used this principle (i.e. isolation of a compound
by exploiting a kinetic trap) to convert a dynamic library of
six diastereomeric pairs of enantiomers into a single pair of
enantiomers.37 LCMS analysis of the precipitated macrocycles
showed that the purity of the obtained samples was satisfactory
(95% for 4b, ESI†).
Fig. 3 Overlaid COSY (red cross peaks) and NOESY (blue peaks) spectra
of 3b in CDCl3/MeOD (3 : 1, 500 MHz, 297 K, mixing time = 800 ms).
Cross-peaks are indicated by corresponding colours in the spectrum and
the suggested structures below.
The resonances of the two spin systems A and B could not
be assigned unambiguously by COSY/NOESY and two possible
conformations are shown in Fig. 3.
The solid state structure (Fig. 4) of the macrocycle with
the ethylene glycol linker 3b showed an asymmetric structure,
the two substituents on the pyridine ring adopting different
conformations. The structure obtained from X-ray crystallography
is very similar to the NMR-derived conformation b in Fig. 3,
suggesting that the macrocycle adopts similar conformations in
solution and solid state.
Fig. 5 HPLC analysis of DCLs generated from 1 and 2b at different
building block concentrations. At low building block concentrations
the DCLs are homogeneous and the 1 + 1 macrocycle 3b is the only
detected product. At concentrations above 5 mM the larger macrocycle 4b
precipitates, forming a kinetic trap. Analysis of the mixtures (precipitate
and solution) showed that 4b has become more abundant than 3b.
The NMR spectra of the larger 2 + 2 macrocycles 4a and
4b showed a time-averaged symmetrical structure exhibiting
only half as many peaks as their smaller 1 + 1 analogues 3a
and 3b. This might reflect the symmetrical orientation of the
hydrazone substituents on the pyridine core or the flexibility of
the macrocycles which exist as mixtures of rapidly interconverting
conformations so that only a time average of these conformations
is observed. The cross peak between protons c and e that was used
to gain information about the conformation of the hydrazones in
Fig. 3 was analysed similarly in the NOESY spectra of 4a and 4b
(Fig. 6). However, the information from these two NOESY spectra
cannot be compared easily because the spectra were recorded
in different solvent mixtures to maximise the solubility of the
macrocycles in the NMR solvent. A cross-peak between c and e
was present in the NOESY spectrum of 4b (Fig. 6b), but not in the
NOESY spectrum of 4a (Fig. 6a) suggesting that the conformation
of the hydrazones depends on the linker unit. Both NOESY
spectra showed cross-peaks between aromatic rings suggesting that
Fig. 4 Solid state structure of the 1 + 1 macrocycle 3b.† a) top view; b)
side view; c) different conformations of hydrazones moieties in the same
macrocycle and important H-bonds (dotted lines).
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Fig. 6 Partial NOESY spectra of 4a and 4b in CDCl3/MeOD (1 : 1 and 7 : 3 respectively, 500 MHz, 297 K, mixing time = 800 ms). Cross-peaks are
indicated by corresponding colours in the spectrum and the suggested structures below.
aromatic interactions influence the folding of the macrocycles in
solution.
The solid state structure of the macrocycle with the ethylene
glycol linker 4b (Fig. 7) shows clearly different orientations of hy-
drazones in the same macrocycle. The only structural information
concerning unbound N3O2 ligands in the literature comes from
two crystal structures.38,39 In these (both are linear N3O2 ligands)
the hydrazones point away from each other, requiring large
conformational changes upon binding of metal ion guests.29–35
The differences between the published linear ligand and the
macrocycles (3a, 3b, 4a, 4b) in this study can be interpreted
as a result of ring strain imposed on the N3O2 binding motif
by the linker unit. To bind the guest strongly the macrocycles
need the right balance of preorganisation and flexibility. All four
macrocycles (3a, 3b, 4a, 4b) have a partially preorganised binding
pocket but the 2 + 2 macrocycles 4a and 4b are larger and more
flexible and are amplified at the expense of the 1 + 1 macrocycles.
Consequently the right linker unit could increase the ability of
N3O2 ligands to bind metal ion guests by partly preorganising
the binding pocket and still maintaining some flexibility. The
intramolecular hydrogen bonds that are observed in the crystal
Fig. 7 Solid state structure of 4b.† a) top view (perpendicular to the
plane of py); b) side view (parallel to the plane of py); c) and d)
different conformations of hydrazones moieties in the same macrocycle
and important H-bonds (dotted lines).
structure of 4b are expected to be weakened in solution, but they
might still play an important role in preorganising 4b for binding.
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accurately with this method and Ka ª 106 M-1 is given as a
lower limit (ESI,† Fig. 8). Besides proving the strong affinity
of the macrocyclic hosts 4a and 4b for selected alkaline earth
metal ions the binding isotherms strongly suggested a 1 : 1 binding
stoichiometry. Surprisingly, the selectivity of 4a for Ba2+ over Ca2+
is not found in its closely related diethyleneglycol analogue 4b.
It might seem surprising that 4b shows similar affinities for Ca2+,
Sr2+ and Ba2+ while the amplification patterns in the DCL are
different. The two results are consistent if one considers that the
product distribution in the DCL is not only determined by the
interaction of the 2 + 2 macrocycle 4b with the template but by
all interactions between the library members.42 The small Ca2+ ion
binds only to the 2 + 2 macrocycle 4b while the larger Sr2+ and
Ba2+ ions also bind to 5b and 6b in addition to 4b. Therefore,
Sr2+ and Ba2+ amplify 4b, 5b and 6b whereas Ca2+ amplifies only
4b. Furthermore, the metals that amplified 4b in the DCLs also
showed affinity in the UV-Vis study, showing that good receptors
can be discovered by DCC when keeping in mind that DCLs are
complex systems.43–46
4
Binding to alkaline earth metal ions
The binding of the 2 + 2 macrocycles 4a and 4b to alkaline
earth metal ions was studied by NMR, HRMS and UV-Vis. To
ensure stability of the isolated macrocycles, the binding studies
had to be performed in a different solvent system than the
DCLs (i.e. without acid). Since protonated species are significantly
less stabilised in organic solvents compared to water we do
not expect the protonation states of the macrocycles to be very
different. Switching from 2-methoxyethanol/water (80/20) to
ethanol decreases the pKa values of carboxylic acid by ª4.40 Since
we work in even less polar solvent mixtures the stabilisation of
charged species is not expected to be significant.
4.1 UV-Vis
To quantify the binding affinity between the host macrocycles
(4a and 4b) and metal ion guests we performed UV-Vis titrations
(ESI† and Fig. 8) and fitted the obtained binding isotherms to
a published model.41 The macrocycle with the pyridyl linker 4a
bound weakly to Mg2+ and Ca2+ (ESI,† Ka ª 103 M-1) and strongly
to Sr2+ and Ba2+ (ESI†, Ka ª 105–106 M-1) with one of the best
Ba2+/Ca2+ selectivities reported to date.10 Macrocycle 4b bound
Mg2+ with an affinity of Ka ª 105 M-1. The binding constants
between Ca2+, Sr2+, Ba2+ and 4b were too large to be determined
Comparing 4a with 4b shows that small differences in the linker
units can lead to unpredictably different host–guest chemistries.
These differences can be observed in the DCLs as well as when the
isolated compounds are studied.
4.2 HRMS and NMR
After addition of 1.0 eq. of metal ion salt (MgCl2, CaCl2, SrCl2
and BaCl2) to 4a and 4b, the Ba2+ and Sr2+ complexes (1 : 1) were
observed by HRMS as singly (loss of one proton) and doubly
charged molecular ion peaks. The complexes of Mg2+ and Ca2+
with 4a and 4b were not observed by ESI-HRMS.
Well-resolved NMR spectra were obtained when SrCl2 or BaCl2
were added to solutions of 4a (ESI†) or 4b (Fig. 9). The largest
shifts upon addition of the metal salt were observed for protons
c, e and h confirming the involvement of the N3O2 binding
motif. A possible explanation for the observed shifts is that c
and e are shifted through inductive effects resulting from the
metal ions binding to the nitrogen lone pairs. The upfield shift
of proton h, upon binding of the metal ion, can be explained by a
conformational change that moves h out of the deshielding region
of the carbonyl oxygens.
5
Conclusions
In conclusion, we have presented the use of dynamic combi-
natorial libraries to study hydrazone receptors for metal ions.
Small variations in the building block design lead to different
molecular recognition properties of the DCLs. Through exploiting
a kinetic trap in the system, the receptors could be isolated
and characterised. Solution and solid state studies showed that
the macrocycles are potent receptors for Sr2+ and Ba2+ while
alkali metal ions are not measurably bound. Therefore, hydrazone
DCLs provide a useful platform for the discovery of metal ion
receptors with unpredictable selectivities. This opens a poten-
tial route to new receptors for the extraction of heavy metal
ions.
Fig. 8 UV-Vis titrations of ethylene glycol-based 4b with BaCl2 in
CHCl3/MeOH (7 : 3). a) UV-Vis spectra of 4b with different amounts
of BaCl2. Increasing and decreasing bands are indicated by arrows. b)
Binding isotherm resulting from a plot of the change in absorption DA at
320 nm against the guest concentration. Experimental data represented as
dots and calculated binding isotherm represented as a solid line.
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Fig. 9 NMR spectra (500 MHz, 297 K) of 4b and its Sr2+ and Ba2+ complexes in CDCl3/MeOD (7 : 3).
12 P. T. Corbett, J. Leclaire, L. Vial, K. R. West, J.-L. Wietor, J. K. M.
Sanders and S. Otto, Chem. Rev., 2006, 106, 3652–3711.
13 S. Otto, R. L. E. Furlan and J. K. M. Sanders, Science, 2002, 297,
590–593.
14 S. Otto and S. Kubik, J. Am. Chem. Soc., 2003, 125, 7804–7805.
15 R. T. S. Lam, A. Belenguer, S. L. Roberts, C. Naumann, T. Jarrosson,
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16 P. T. Corbett, J. K. M. Sanders and S. Otto, J. Am. Chem. Soc., 2005,
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Acknowledgements
We thank the Marie-Curie Research Training Network (MRTN-
CT-2006-035614, J.M.K. and V.S.), EU (U.L.) and EPSRC
(J.K.M.S) for funding, Dr John Davies for solving the X-ray
structures, Fabien Cougnon for proof-reading the manuscript and
Dr Ana Belenguer for maintaining the HPLC facility.
17 Z. Rodriguez-Docampo, S. I. Pascu, S. Kubik and S. Otto, J. Am. Chem.
Soc., 2006, 128, 11206–11210.
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