A metal-complex-tolerant CuAAC 'click' protocol exemplified through the preparation of homo- and mixed-metal-coordinated [2]rotaxanes

Article abstract of DOI:10.1039/b713501g

A series of mono- and bis-metallated [2]rotaxanes has been prepared using a CuAAC 'click' protocol that is compatible with metal-coordinated building blocks and ligands; the methodology provides a general means for appending a metal ion or complex to an organic scaffold via Cu(i)-catalysed 'click' chemistry, even when the molecule contains redox-active or kinetically labile metals or vacant ligand sites. The Royal Society of Chemistry.

Full text of DOI:10.1039/b713501g

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
A metal-complex-tolerant CuAAC ‘click’ protocol exemplified through
the preparation of homo- and mixed-metal-coordinated [2]rotaxanes{
Diego Gonza´lez Cabrera, Bryan D. Koivisto and David A. Leigh*
Received (in Cambridge, UK) 3rd September 2007, Accepted 21st September 2007
First published as an Advance Article on the web 26th September 2007
DOI: 10.1039/b713501g
CuCl2, [1CuCl2], or the kinetically inert CrCl3, [1CrCl3], could be
effectively employed in the CuAAC reaction using a catalytic
amount (10 mol%) of Cu(I) to generate the metal-containing
triazoles [2CuCl2] and [2CrCl3] in 80% and 82% yields, respectively
(Scheme 1).
A series of mono- and bis-metallated [2]rotaxanes has been
prepared using a CuAAC ‘click’ protocol that is compatible
with metal-coordinated building blocks and ligands; the
methodology provides a general means for appending a metal
ion or complex to an organic scaffold via Cu(I)-catalysed ‘click’
chemistry, even when the molecule contains redox-active or
kinetically labile metals or vacant ligand sites.
Attempts to extend this protocol to other first row transition
metal complexes of 2, including [2ZnCl2], [2MnCl2], [2FeCl3] and
[2CoCl2], were unsuccessful, however. Although in some cases
increasing the amount of the Cu(I) catalyst used to . 1 equivalent
enabled the CuAAC reaction to proceed, this also resulted in
displacement of the original metal from the BPA unit by oxidised
Cu(II). In contrast, Cr(III) was not displaced during the formation
or isolation of [2CrCl3], nor did it participate in any electron
transfer reactions. In fact, forcing conditions (1.5 equiv. of KCN,
CH3OH, reflux, 12 h, 80%) were necessary to liberate it from the
derivatised BPA ligand.
Since its discovery,1 the Huisgen–Meldal–Fokin Cu(I)-catalyzed
terminal alkyne–azide cycloaddition (the CuAAC2 ‘click’3 reac-
tion) has attracted great interest4 because of its utility in chemically
bonding functional molecular fragments in a precise, predictable
and efficient fashion under a myriad of conditions and situations.
Despite its exceptional versatility, however, to date there have been
few reports on performing the CuAAC reaction in the presence of
other redox-active metal ions or substrates containing multidentate
binding sites capable of sequestering the copper catalyst.5 The few
examples of metal-coordinated alkynes or azides to have been
successfully employed in the CuAAC reaction thus far include
ethynylferrocene,6 an organometallic iridium complex,7 metallo-
porphyrins,8 a lanthanide-bound cyclen derivative,9 a ruthenium
dimer functionalised with an alkyne10 and Cu(I)-coordinated
rotaxanes.11 While some of these examples offer methods for
attaching specific metals to particular molecular structures, most of
the complexes are kinetically inert and none allow for the ready
variation of the metal.
These results led us to develop a method for coupling homo-
and mixed-metal chelated fragments with the CuAAC reaction,
exemplified through a series of [2]rotaxanes (Schemes 2 and 3). A
functionalised [2]rotaxane, 3, bearing two BPA chelating sites (one
attached to the rotaxane macrocycle, one to the rotaxane thread)
was synthesised using a hydrogen bond-templated clipping strategy
(Scheme 2).13 To a solution of thread 412 and 5 (obtained from
deprotection of 6, Scheme 2, step a) in CHCl3, was added
5-azidoisophthaloyl dichloride14 to yield azido[2]rotaxane 7 (52%,
Scheme 2, step b). Prior to reacting the azido[2]rotaxane
with alkynes [1CuCl2] and [1CrCl3], the BPA tridentate
binding site of the thread was protected by coordination to
Cu(II), generating [7(thread-CuCl2)] (Scheme 2, step c). Complexes
Here we present a strategy for the assembly of multiple (homo-
and mixed-) metal-containing products using the CuAAC reaction
by employing a simple alkyne functionalised tridentate ligand, 1,
capable of coordinating to a variety of transition metal ions
(Scheme 1). Through this synthon, a series of homo- and mixed-
metal-chelated [2]rotaxanes has been prepared (Schemes 2 and 3).
When attempting the CuAAC reaction in the presence of
potentially ligating groups, the temptation is to use the Cu(I) salt in
excess quantities to compensate for copper being sequestered by
the ligand. The situation is further complicated if other transition
metal ions are present as they may be displaced, either directly by
Cu(I) or labilised by electron transfer to or from the redox-sensitive
Cu(I). However, during studies to derivatise rotaxanes with metal-
chelating groups,12 we found that an alkyne-derivatised bis-
pyridin-2-ylmethylamine (BPA) tridentate ligand 1 bound to either
School of Chemistry, University of Edinburgh, The King’s Buildings,
West Mains Road, Edinburgh, UK EH9 3JJ.
E-mail: David.Leigh@ed.ac.uk; Fax: +44 131 650 6453;
Tel: +44 131 650 4721
{ Electronic supplementary information (ESI) available: Synthesis and
characterization of all compounds. See DOI: 10.1039/b713501g
Scheme 1 Attempted CuAAC-mediated couplings of various mono-
metallated alkyne substrates, [1MCln], with benzyl azide. a) Propargyl
bromide, Et3N, toluene, reflux, 12 h, 60%; b) MCln, CH3OH, RT, 1 h; c)
benzyl azide, 0.1 equiv. Cu(CH3CN)4PF6, 1.1 equiv. N,N-diisopropylethyl-
amine (DIPEA), CH2Cl2–CH3OH (9 : 1), RT, 12 h.
4218 | Chem. Commun., 2007, 4218–4220
This journal is ß The Royal Society of Chemistry 2007

View Article Online
[3(mac-CrCl3)(thread-ZnCl2)] (Scheme 3, step d). To the best of
our knowledge, this is only the second example of a mixed-metal
coordinated rotaxane.15 The protection of the BPA ligand with
Cu(II) or Cr(III) (which could subsequently be reduced to labile
Cr(II) if it needed to be removed) makes it compatible with the
CuAAC reaction and provides a general means of incorporating
metal atoms or binding sites into organic structures via ‘click’
chemistry.
The diamagnetic complex [3(mac-ZnCl2)(thread-ZnCl2)] was
1
amenable to structural investigation by H NMR spectroscopy.
The partial 400 MHz 1H NMR spectra of the thread (4),
demetallated rotaxane (3), and [3(mac-ZnCl2)(thread-ZnCl2)] in
[D7]-DMF are shown in Fig. 1. The upfield shifts of the coincident
fumaramide olefin protons (Hd and He) in the rotaxane relative to
those of the free thread 4 are typical of benzylic amide macrocycle-
based rotaxanes,13 resulting from shielding of the xylylene rings. In
addition to the appearance of resonances from the second BPA
binding site (HM-R), the distinctive triazole proton (HL) signal is
evident (Fig. 1b and 1c). In the spectrum of compound [3(mac-
ZnCl2)(thread-ZnCl2)] (Fig. 1c) the BPA aromatic protons are
shifted downfield relative to those in 3 (Fig. 1b) due to metal
coordination. Although the fumaramide olefin signals become
separated as their inequivalence is emphasised by the zinc
coordination to one end of the thread (Fig. 1c), the metal
complexation does not appear to significantly change the
conformation or co-conformation adopted by the mechanically
interlocked fragments.
Scheme 2 Assembly of bis-metallated [2]rotaxanes via
a CuAAC
reaction. a) CF3CO2H, CH2Cl2, RT, 12 h; A-21 amberlyst, CH2Cl2–
CH3OH (1 : 1), RT, 1 h, quantitative; b) 5-azidoisophthaloyl dichloride,
CHCl3, Et3N, RT, 12 h, 52%; c) CuCl2?2H2O, CH3OH, RT, 1 h, 95%; d)
[1CuCl2] or [1CrCl3], 0.1 equiv. Cu(CH3CN)4PF6, DIPEA, CH2Cl2–
CH3OH (9 : 1), RT, 12 h.
[3(mac-CuCl2)(thread-CuCl2)] and [3(mac-CrCl3)(thread-CuCl2)]
were then obtained in good yield using the standard CuAAC
conditions.
In conclusion, we have outlined a transition metal tolerant
CuAAC protocol for the synthesis of mono- and bis-metallated
[2]rotaxanes using a simple alkyne-functionalised tridentate ligand
and its metal complexes. Indeed the methodology should prove a
useful general way of appending a metal ion or complex to an
organic scaffold, even when it contains redox-active or kinetically
labile metals or vacant ligand sites. The ability to generate homo-
and hetero-metallated [2]rotaxanes should allow for the explora-
tion of non-covalent distance-dependent properties (e.g. electronic,
magnetic and photochemical) between metal centres.
The difference in lability of the metal ions allowed us to remove
the Cu(II) and selectively coordinate other metal ions at the vacant
BPA site(s). Compound [3(mac-CuCl2)(thread-CuCl2)] was fully
demetallated by simple washing with a saturated aqueous solution
of Na4EDTA (tetrasodium ethylenediamine tetraacetate) to give
the metal-free [2]rotaxane 3 (Scheme 3, step a). Addition of ZnCl2
then afforded the bis-Zn(II)-metallated complex [3(mac-
ZnCl2)(thread-ZnCl2)] (Scheme 3, step b). Alternatively, mixed-
metal-chelated [2]rotaxanes could be prepared. Selective removal
of the Cu(II) from [3(mac-CrCl3)(thread-CuCl2)] afforded the
kinetically stable mono-metallated rotaxane [3(mac-CrCl3)]
(Scheme 3, step c). [3(mac-CrCl3)] was then complexed with
ZnCl2 to produce the mixed-bis-metallated rotaxane complex
Fig. 1 Partial 1H NMR spectra (400 MHz, [D7]-DMF, 298 K) of a)
thread 4; b) metal-free [2]rotaxane 3; c) [3(mac-ZnCl2)(thread-ZnCl2)].
Resonances are coloured and labelled as shown in Scheme 2. Peaks shown
in light grey arise from residual nondeuterated solvent.
Scheme 3 Preparation of homo- and mixed-metallated [2]rotaxanes. a)
4 M Na4EDTA (aq), RT, 72%; b) ZnCl2, CH3OH, RT, 1 h, 98%; c) 4 M
EDTA (aq), RT, 71%; d) ZnCl2, CH3OH, RT, 1 h, 90%.
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 4218–4220 | 4219

View Article Online
8 J. P. Collman, L. Zeng, H. J. H. Wang, A. Lei and J. I. Brauman,
Eur. J. Org. Chem., 2006, 2707–2714; D.-M. Shen, C. Liu and
Q.-Y. Chen, Eur. J. Org. Chem., 2007, 1419–1422.
9 R. F. H. Viguier and A. N. Hulme, J. Am. Chem. Soc., 2006, 128,
11370–11371.
We thank the the EPSRC and the EU project STAG for
financial support of this research and NSERC for a Post Doctoral
Fellowship to BDK. DAL is an EPSRC Senior Research Fellow
and holds a Royal Society-Wolfson research merit award.
10 W. Z. Chen, P. E. Fanwick and R. Tong, Inorg. Chem., 2007, 46,
3429–3431.
Notes and references
11 V. Aucagne, K. D. Ha¨nni, D. A. Leigh, P. J. Lusby and D. B.
Walker, J. Am. Chem. Soc., 2006, 128, 2186–2187; P. Mobian,
J.-P. Collin and J.-P. Sauvage, Tetrahedron Lett., 2006, 47,
4907–4909; V. Aucagne, J. Berna´, J. D. Crowley, S. M. Goldup,
K. D. Ha¨nni, D. A. Leigh, P. J. Lusby, V. E. Ronaldson, A. M. Z.
Slawin, A. Viterisi and D. B. Walker, J. Am. Chem. Soc., 2007, 129,
11950–11963.
12 D. S. Marlin, D. Gonza´lez Cabrera, D. A. Leigh and A. M. Z. Slawin,
Angew. Chem., Int. Ed., 2006, 45, 77–83; D. S. Marlin,
D. Gonza´lez Cabrera, D. A. Leigh and A. M. Z. Slawin, Angew.
Chem., Int. Ed., 2006, 45, 1385–1390.
13 See, for example, G. Brancato, F. Coutrot, D. A. Leigh, A. Murphy,
J. K. Y. Wong and F. Zerbetto, Proc. Natl. Acad. Sci. U. S. A., 2002,
99, 4967–4971; J. S. Hannam, T. J. Kidd, D. A. Leigh and A. J. Wilson,
Org. Lett., 2003, 5, 1907–1910; D. A. Leigh and E. M. Pe´rez, Chem.
Commun., 2004, 2262–2263; E. M. Pe´rez, D. T. F. Dryden, D. A. Leigh,
G. Teobaldi and F. Zerbetto, J. Am. Chem. Soc., 2004, 126,
12210–12211; J. S. Hannam, S. M. Lacy, D. A. Leigh, C. G. Saiz,
A. M. Z. Slawin and S. G. Stitchell, Angew. Chem., Int. Ed., 2004, 43,
3260–3264; E. R. Kay and D. A. Leigh, Top. Curr. Chem., 2005, 262,
133–177; M. N. Chatterjee, E. R. Kay and D. A. Leigh, J. Am. Chem.
Soc., 2006, 128, 4058–4073.
14 K. Lamara and R. K. Smalley, Tetrahedron, 1991, 47, 2277–2290.
15 M. Andersson, M. Linke, J. C. Chambron, J. Davidsson, V. Heitz,
J.-P. Sauvage and L. Hammarstrom, J. Am. Chem. Soc., 2000, 122,
3526–3527; M. Andersson, M. Linke, J. C. Chambron, J. Davidsson,
V. Heitz, L. Hammarstrom and J.-P. Sauvage, J. Am. Chem. Soc., 2002,
124, 4347–4362.
1 C. W. Tornøe, C. Christensen and M. Meldal, J. Org. Chem., 2002, 67,
3057–3064; V. V. Rostovtsev, L. G. Green, V. V. Fokin and
K. B. Sharpless, Angew. Chem., Int. Ed., 2002, 41, 2596–2599.
2 For reviews of the CuAAC reaction, see: V. D. Bock, H. Hiemstra and
J. H. van Maarseveen, Eur. J. Org. Chem., 2005, 51–68; Q. Wang,
S. Chittaboina and H. N. Barnhill, Lett. Org. Chem., 2005, 2, 293–301;
P. Wu and V. V. Fokin, Aldrichimica Acta, 2007, 40, 7–17.
3 For reviews and discussion of the ‘click chemistry’ concept, see:
H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem., Int. Ed.,
2001, 40, 2004–2021; H. C. Kolb and K. B. Sharpless, Drug Discovery
Today, 2003, 8, 1128–1137; P. Ball, Chem. World, 2007, 4(4), 46–51.
4 For a list of publications featuring ‘click chemistry’, the vast majority
employing the CuAAC reaction, see: http://www.scripps.edu/chem/
sharpless/click.html.
5 T. R. Chan, R. Hilgraf, K. B. Sharpless and V. V. Fokin, Org. Lett.,
2004, 6, 2853–2855; T. L. Mindt, H. Struthers, L. Brans, T. Anguelov,
C. Schweinsberg, V. Maes, D. Tourwe and R. Schibli, J. Am. Chem.
Soc., 2006, 128, 15096–15097; R. J. Detz, S. A. Heras, R. de Gelder,
P. van Leeuwen, H. Hiemstra, J. N. H. Reek and J. H. van Maarseveen,
Org. Lett., 2006, 8, 3227–3230.
6 J. M. Casas-Solvas, A. Vargas-Berenguel, L. F. Capitan-Vallvey and
F. Santoyo-Gonzalez, Org. Lett., 2004, 6, 3687–3690; J. M. Holub,
H. J. Jang and K. Kirshenbaum, Org. Biomol. Chem., 2006, 4,
1497–1502; C. Ornelas, J. R. Aranzaes, E. Cloutet, S. Alves and
D. Astruc, Angew. Chem., Int. Ed., 2007, 46, 872–877.
7 X. Y. Wang, A. Kimyonok and M. Weck, Chem. Commun., 2006,
3933–3935.
4220 | Chem. Commun., 2007, 4218–4220
This journal is ß The Royal Society of Chemistry 2007