A facile click approach to functionalised metallosupramolecular architectures

Article abstract of DOI:10.1039/c3cc41209a

Herein we describe a CuAAC click methodology for exo-functionalisation of Pd₂L₄ metallosupramolecular architectures. The potentially coordinating 1,2,3-triazole does not affect formation of the desired discrete complexes, nor does this external functional decoration affect the cisplatin-binding ability of the interior cavity of the assembly.

Full text of DOI:10.1039/c3cc41209a

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A facile ‘‘click’’ approach to functionalised
metallosupramolecular architectures†
James E. M. Lewis,a C. John McAdam,a Michael G. Gardinerb and
James D. Crowley*a
Cite this: Chem. Commun., 2013,
49, 3398
Received 14th February 2013,
Accepted 6th March 2013
DOI: 10.1039/c3cc41209a
www.rsc.org/chemcomm
Herein we describe
a CuAAC ‘‘click’’ methodology for exo-
functionalisation of Pd2L4 metallosupramolecular architectures.
The potentially coordinating 1,2,3-triazole does not affect for-
mation of the desired discrete complexes, nor does this external
functional decoration affect the cisplatin-binding ability of the
interior cavity of the assembly.
The synthetic principles for the generation of self-assembled
nanoscale coordination (metallosupramolecular) architectures
are now well established. With judicious choice of the metal
ions and ligands, architectures of the desired shape and size
can almost be generated at will.1 These metallosupramolecular
architectures have been shown to possess a variety of inter-
Fig. 1 Cartoon representations of (a) unfunctionalised (b) endo- and (c) exo-
functionalised M2L4 metallosupramolecular assemblies.
esting physical and chemical properties,2 and have been exten- endo- and exo-functionalisation9 (Fig. 1) have been realised
sively exploited as host molecules for the molecular recognition and a range of biological molecules10 and other functional
of a vast array of organic and inorganic guest molecules.3 groups11 have been incorporated into the ligands with no
Building on these studies other metallo-cage systems have been observed interference towards subsequent formation of the
used as nanoscale reaction flasks4 and catalysts.5 While the intended metallosupramolecular architecture. Despite this
supramolecular host–guest properties of these systems domi- interest, to date there have been no reports of a single mild
nate the area they are certainly not the only potential applica- method for appending a variety of functional moieties on a
tions of these architectures. Metallosupramolecular systems single ‘‘proto-ligand’’ enabling diverse functionalisation and
have also been shown to display interesting biological,6 electronic7 rapid tuning of the resulting architectures’ properties.
and photophysical8 properties. However, for the most part the
We have previously reported12 the synthesis of a PdII2L4 self-
ligands employed for the generation of these systems have been assembling cage architecture capable of encapsulating two
kept relatively simple and free of additional functionality in cisplatin molecules. As part of our work towards exploiting
order to ensure assembly of the desired molecular architectures these cages as stimuli-responsive metallosupramolecular
without interference from other (potentially) coordinating cisplatin drug delivery agents we required a mild, selective,
groups. In order to further enhance the properties and applica- functional group tolerant synthetic method for decorating the
tions of these metallosupramolecular architectures efforts are ligands of these cages to enhance their physical properties.
now focusing on the incorporation of additional functionality The Cu(I)-catalysed 1,3-cycloaddition of organic azides with
into the ligand scaffolds. Cage architectures featuring both terminal alkynes13 (the CuAAC reaction), which has been
extensively exploited in the synthesis of functional molecules
a Department of Chemistry, University of Otago, PO Box 56, Dunedin, New Zealand.
during the past decade, seemed ideal for this propose due to its
reliability, mild reaction conditions and wide substrate scope.
Somewhat surprisingly, the CuAAC reaction has not been
extensively examined as a method to functionalise metallo-
supramolecular ligand systems. This is presumably because
the 1,4-disubstituted-1,2,3-triazoles created in the reaction have
the potential to act as N donor ligands14 and interfere with the
E-mail: jcrowley@chemistry.otago.ac.nz; Fax: +64 3 479 7906;
Tel: +64 3 479 7731
b School of Chemistry, University of Tasmania, Hobart, Australia
† Electronic supplementary information (ESI) available: The supplementary
information contains the experimental procedures, 1H, 13C and DOSY NMR,
and ESMS spectra and crystallographic data. CCDC 924182. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c3cc41209a
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3398 Chem. Commun., 2013, 49, 3398--3400
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self-assembly process. In fact 1,4-disubstituted-1,2,3-triazole
containing ligands have even been used in the construction
of metallosupramolecular architectures.15 Azide–alkyne ‘‘click’’
methods16 were exploited to post-synthetically modify discrete
kinetically robust metallosupramolecular metallocycles and
cages, but to date have not been used to functionalise metallo-
supramolecular ligand systems before the assembly is formed.
Herein we report the synthesis of three ‘click’-functionalised
tripyridyl ligands and show that the presence of the potentially
coordinating 1,2,3-triazole units does not interfere with
ability of the ligands to self-assemble into the desired M2L4
Fig. 2 1H NMR (500 MHz, d6-DMSO) spectra of the aromatic regions of (a) 5a,
(b) 6a. For signal labelling refer to Scheme 1.
palladium(II) cage architectures. Furthermore, the presence of there is only one species present in solution (ESI†) and the ratio
the additional exo-functionality does not interfere with the of the diffusion coefficients of the ligands and palladium com-
cages’ ability to bind guest molecules within the interior cavity plexes in d6-DMSO were approximately 2 : 1 (ESI†), consistent
of the architectures.
with the presence of the larger molecular cage species in solution.
HR-ESMS experiments provided additional evidence for the
The azide 4 was selected as our target ‘‘click’’ ligand precursor
and was synthesised from 2,6-dibromo-4-(hydroxymethyl)- formation of the [Pd2L4](X)4 architectures. The ESMS spectra
pyridine 117 in 3 steps with an overall yield of 24% (Scheme 1). (CH3CN–DMSO) of 6a–c show isotopically resolved peaks
Reaction of the azide 4 under standard copper-catalysed ‘‘click’’ consistent with the formulation [Pd2(L)4(X)n(solvent)y](4ꢀn)+
conditions18 gave the phenyl- (5a), ferrocenyl- (5b) and caffeine- (n = 0–2, y = 3–6) along with peaks due to fragmentation of
substituted (5c) ligands in good isolated yields (64–88%). The the cage structure (ESI†). The precise molecular structure of the
1
identity of the ligands was confirmed by IR, H and 13C NMR cage architecture was ultimately proved by single-crystal X-ray
spectroscopy as well as electrospray-mass spectrometry (ESMS) diffraction studies (vide infra §).
(ESI†).
Having demonstrated that the 1,2,3-triazole units do not
The quantitative formation, in less than 5 minutes, of the interfere with the cage formation, it was next examined if the
desired cage complexes (6a–c) was observed using in situ 1H NMR cages retained the guest bind ability of the parent system.
spectroscopy (Scheme 1).‡ Simply mixing stoichiometric amounts Addition of cisplatin to a solution of either 6a or 6b in CD3CN,
of one of the ligands (5a–c) and [Pd(CH3CN)4](BF4)2 salt in a 2 : 1 followed by brief sonication, in both instances resulted in a
ratio in d6-DMSO, resulted in a significant downfield shift in the broadened and downfield shifted Ha proton signal in the
proton signals corresponding to the terminal pyridyl moieties 1H NMR spectrum (ESI†), as we have previously reported for
(Ha–Hd, Fig. 2 and ESI†). The chemical shifts for the remaining the parent system,12 indicating that the cisplatin-binding func-
proton signals were not greatly affected, and importantly the Hg tionality of the interior cavity had been retained.
signal of the triazole proton was actually observed to shift upfield.
The exact nature of the host–guest adduct [6b*(cisplatin)2]4+
This evidence suggested that despite the presence of the poten- was determined by X-ray crystallography (Fig. 3 and ESI†). Small
tially coordinating 1,2,3-triazole moiety within the ligand frame- X-ray quality crystals were grown by vapour diffusion of diethyl
work, coordination was only occurring through the terminal ether into a sonicated DMF solution of 6b and cisplatin. The use
pyridine rings. Further solution phase evidence for the formation of synchrotron radiation enabled the molecular structure of the
of the desired discrete cage architectures was obtained from host–guest adduct to be determined. As previously observed,12
1H DOSY NMR. Each of the proton signals in the individual two cisplatin molecules were found encapsulated within the
spectra show the same diffusion coefficients (D), indicating that cavity of the dipalladium(II) quadruply-stranded cage structure.
As suggested by the aforementioned sporting methods, the
presence of the potentially coordinating 1,2,3-triazole moieties
did not disrupt formation of the thermodynamically favourable,
discrete cage architectures. Intriguingly the crystal lattice con-
sists of intercalating alternating 1D chains of [6b]4+ and the
host–guest adduct [6b*(cisplatin)2]4+ (ESI†). As observed for the
unfunctionalised parent system12 the host–guest adduct con-
tains two molecules of cisplatin within the cavity of the cage,
rotated 1801 with respect to each other; hydrogen bonds between
the cisplatin and cage (N–Hꢁ ꢁ ꢁNPy and Clꢁ ꢁ ꢁH–CPy) as well as a
metal–metal interaction19 between the platinum atoms of the
guests were observed (Fig. 3).
Ferrocene has been appended onto a number of metallo-
supramolecular architectures with the goal of generating
Scheme 1 Reactants and reagents: (i) TMS–acetylene, Pd(PPh3)2Cl2, CuI, triethylamine,
electrochemically active systems.11 As such we examined the
toluene, RT, N2, 24 h; 3-iodopyridine, DBU, H2O, RT, N2, 24 h, 44%; (ii) PPh3, CBr4,
electrochemistry of the ligands (5a–b) and cages (6a–b) in DMF
solution (ESI†). For 5a and 5b a cathodic sweep to ꢀ2.0 V
DCM, RT, N2, 16 h, 60%; (iii) NaN3, DMF, RT, 3 h, 92%; (iv) CuSO4ꢁ5H2O, sodium
ascorbate, R-alkyne, H2O–DMF, RT, 16 h; (v) [Pd(CH3CN)4](BF4)2, d6-DMSO.
c
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Notes and references
‡ Subsequently the cage architectures 6a–c were synthesised on a
preparative scale and isolated in good yields (68–76%, ESI†).
§ Crystal data for 6b: C64H52.50ClFe2N13O2.75PdPt0.50, M = 1398.79,
%
triclinic, space group P1, cell parameters a = 14.809(3), b = 21.668(4),
c = 24.158(5) Å, a = 105.56(3), b = 94.22(3), g = 90.62(3)1, V = 7444(3) Å3,
T = 173(2) K, Z = 4, Dc = 1.248 mg mꢀ3, l (synchrotron) = 0.71073 Å,
158 104 reflections measured, 41 676 unique (Rint = 0.0724, complete-
ness = 87.2. R1 = 0.0945 and wR2 = 0.2832 (I > 2s(I)), GOF = 1.020;
max/min residual density 4.104/ꢀ3.383 eÅꢀ3. CCDC 924182.
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Pd1ꢁ ꢁ ꢁPd10 11.595(3), N50ꢁ ꢁ ꢁN8 2.88(1), N51ꢁ ꢁ ꢁN2 3.10(1), Cl51ꢁ ꢁ ꢁC33 3.627(9),
Cl51ꢁ ꢁ ꢁC1 3.396(8), Cl50ꢁ ꢁ ꢁC19 3.347(8), Cl50ꢁ ꢁ ꢁC51 3.497(7), Pt2ꢁ ꢁ ꢁPt20
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In conclusion we have developed a methodology for facile
‘‘click’’ modification of tripyridyl ligands which, despite the
potentially coordinating 1,2,3-triazolyl moiety, still assemble
into discrete Pd2L4 metallosupramolecular cage architectures
in the presence of Pd(II) ions. Having demonstrated that this
facile CuAAC ‘‘click’’ functionalisation does not interfere with
formation of the desired cage complexes, this methodology
could easily be applied to other discrete metallosupramolecular
systems, allowing simple and diverse augmentation of various
chemical and physical properties of the architectures. It is
foreseeable that this methodology could be easily applied to a
variety of ligand frameworks that have been previously shown
to form nanoscale architectures, and ready access to these
functionalised metallosupramolecular systems could open up
new applications for these species. Additionally, in view of our
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‘‘click’’ ligands and their palladium cage complexes.
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