Catalytic "click" rotaxanes: A substoichiometric metal-template pathway to mechanically interlocked architectures

Article abstract of DOI:10.1021/ja056903f

A route to mechanically interlocked architectures that requires only a catalytic quantity of template is described. The strategy utilizes the Cu(I)-catalyzed 1,3-cycloaddition of azides with terminal alkynes. Chelating the Cu(I) to an endotopic-binding macrocycle means that the metal atom binds to the alkyne and azide in such a way that the metal-mediated bond-forming reaction occurs through the cavity of the macrocycle, forming a rotaxane. Addition of pyridine to the reaction mixture enables the Cu(I) to turn over during the reaction, permitting substoichiometric amounts of the metal to be used. The yields are very high for a rotaxane-forming reaction (up to 94% with stoichiometric Cu(I); 82% with 20 mol % of Cu(I)), and the procedure is practically simple to do (no requirement for an inert atmosphere nor dried or distilled solvents). Copyright

Full text of DOI:10.1021/ja056903f

Published on Web 01/31/2006
Catalytic “Click” Rotaxanes: A Substoichiometric Metal-Template Pathway to
Mechanically Interlocked Architectures
Vincent Aucagne, Kevin D. H a¨ nni, David A. Leigh,* Paul J. Lusby, and D. Barney Walker
School of Chemistry, UniVersity of Edinburgh, The King’s Buildings, West Mains Road,
Edinburgh EH9 3JJ, United Kingdom
Received October 9, 2005; E-mail: david.leigh@ed.ac.uk
The introduction of copper(I)-template strategies by Sauvage and
colleagues in the mid-1980s marked the first practical synthetic
routes to molecular catenanes, rotaxanes, and knots. This seminal
Scheme 1. Proposed Catalytic Cycle for the Cu(I)-Template
Synthesis of [2]Rotaxane 4 from 1, 2, and 3 (ref 9)
1
idea utilizes the tetrahedral coordination geometry of a Cu(I) atom
to hold a pair of bidentate ligands in a mutually orthogonal
orientation creating a crossover point that directs subsequent
macrocyclization or “stoppering” reactions toward threaded archi-
2
tectures. Other template syntheses followed (based on aromatic
stacking, hydrogen bonding, hydrophobic interactions, etc.), leading
to the rich variety of synthetic methods available today. However,
all current approaches require a stoichiometric quantity of template
and generally call for pre-established, strongly binding, recognition
motifs on each of the components of the interlocked molecule. Here
we describe a rotaxane-forming protocol in which the Cu(I) atom
functions as a catalyst as well as a template and turns over during
the reaction, permitting substoichiometric amounts of the metal to
be used. A permanent coordination site is only needed on the
macrocycle. The rest of the interlocked compound is assembled
through functional groups that react together under catalysis of the
metal, which also serves to hold the fragments in position such
that their catalyzed reaction leads to the desired interlocked product.
3
4
The strategy utilizes the Cu(I)-catalyzed 1,3-cycloaddition of
organic azides with terminal alkynes, recently popularized as a
5
3,6,7
“
click” reaction by Sharpless and others.
In organic solvents,
tertiary amines or, better, pyridines, considerably enhance the
reaction kinetics,3 suggesting that a macrocycle bearing an
endotopic ligating nitrogen atom could direct such a catalyzed
b,8
9
reaction through its cavity. The 2,6-disubstituted pyridine macro-
cycle 1, previously used10 as both a mono- and bidentate ligand in
metal-coordinated rotaxanes and catenanes, appeared to be a suitable
candidate to investigate this idea (Scheme 1). Commercially
3 4 6
available Cu(CH CN) PF was chosen as the copper source,
avoiding ligands that might compete too strongly for the metal with
the macrocycle and other reactants.
not H , H , or H . This suggests that the Cu binds to the macrocycle
h
g
f
We were delighted to find that simple overnight stirring of an
equimolar mixture of pyridine macrocycle 1, alkyne 2, azide 3,
and the Cu(I) salt in CH Cl affordedsafter demetalation with
2 2
and thread in the rotaxane via two sets of bidentate N,O donor
interactions (rapidly oscillating involvement between the two
oxymethylene groups in the case of the macrocycle), fixing the
interlocked components in a position consistent with the observed
3
KCNsa mixture of [2]rotaxane 4 (57%) and the noninterlocked
triazole thread 5 (41%), together with some of the unconsumed
shielding effects. In other words, in CDCl , the structure of the
1
starting macrocycle (Table 1, entry 1). The H NMR spectrum of
rotaxane-metal complex corresponds to that of [4Cu]PF shown
6
4
in CDCl
3
(Figure 1b) shows upfield shifts of several signals with
in Scheme 1.
respect to its noninterlocked components 1 and 5 (Figure 1a and c,
respectively). The shielding, typical of interlocked architectures in
which the aromatic rings of one component are positioned face-on
to another component,10 is observed for all the nonstopper
resonances of the axle (Hf-j) in 4, indicating that the macrocycle
is able to access the full length of the thread. In contrast, the
equivalent spectrum (Figure 1d) of the rotaxane re-metalated with
Although halogenated solvents give the highest yields of rotax-
ane, the reaction proved to be tolerant to a range of media, including
semi-aqueous conditions (entry 2). The use of excess 2 and 3
generates high yields (up to 94%) of [2]rotaxane with respect to
the amount of macrocycle used (entries 3 and 4); however,
significant quantities of the noninterlocked thread (5) are produced
in all the noncontrol entries in Table 1. Carrying out the reaction
using the conditions of entry 4 but with no macrocycle present and
starting with a stoichiometric equivalent of rotaxane (4) or thread
3
Cu(CH CN)
4
PF
6
3
(CH COCH
3
, RT, 1 h, quantitative) shows pro-
with respect to 5 (Figure 1c) but
nounced shielding of H
j
and H
k
2186
9
J. AM. CHEM. SOC. 2006, 128, 2186-2187
10.1021/ja056903f CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Variations in the Experimental Conditions and Reactant
Stoichiometry for the Synthesis of [2]Rotaxane 4
as well as a cycloaddition catalyst. When using 20 mol % (with
respect to 1) of Cu(CH CN) PF at room temperature, the reaction
3 4 6
a
equiv equiv
of of
entry 2 and 3 CuPF
conversion
yield of
appeared to stop after rotaxane equivalent to the amount of copper
present had been formed (entry 5). This suggests that the multi-
dentate rotaxane sequesters the transition metal during the reaction,
inhibiting further catalytic activity. Addition of pyridine as a
competing ligand enabled the catalyst to turn over producing a
substoichiometric reaction (entries 6 and 7), but the reaction was
extremely slow at 25 °C. Elevating the temperature (entry 9) gives
an improved yield (82%) of rotaxane 4 in a reasonable period of
time (36 h) using only 4 mol % Cu(I) with respect to both 2 and
to triazole [2]rotaxane
6
solvent
T (°
C)
duration
2
+3f4+5
1f4
1
2
3
4
5
6
7
8
1
1
3
5
1
1
5
1
1
1
1
1
CH
O/tBuOH
CH Cl
CH Cl
2
Cl
2
25
25
25
25
25
25
25
12 h
10 days
24 h
>95%
>95%
>95%
92%
30%
>95%
44%
57%
22%
83%
94%
20%
38%
59%
0%
H
2
2
2
c
2
2
72 h
0.2 CH
0.2 CH
0.2 CH
2
2
2
Cl
Cl
Cl
2
10 days
10 days
20 days
b
b
2
2
0
ClCH
2
CH
2
Clb 25 then 70 12 h then trace
3.
7
2 h
Clb 25 then 70 12 h then 94%
The requirement for only a catalytic amount of a template
9
5
0.2 ClCH
2
CH
2
82%
2
4 h
represents a new development in the strategies available to
mechanically interlocked architectures. Chelation to catalytic centers
could lead to rotaxane- and catenane-forming protocols based on
other metal-mediated reactions, including cross-couplings, conden-
sations, and other cycloaddition reactions.
a
All reactions were carried out at 0.1 mM concentration with respect to
and 3, with 1 equiv of macrocycle 1, and without the need for an inert
2
atmosphere nor distilled or dried solvents. A general experimental procedure
is provided in the Supporting Information. b With 3 equiv of pyridine. c To
assess the efficacy of the rotaxane and thread as ligands for a catalytic
copper species, the reaction conditions from entry 4 were repeated with no
macrocycle present but starting with 1 equiv of 4 or 5 instead. The resulting
conversions of 2 + 3 f 5 were 2 and 9%, respectively.
Supporting Information Available: General synthetic experimental
procedure and characterization and spectroscopic data for 4, 5, and their
precursors. This material is available free of charge via the Internet at
http://pubs.acs.org.
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(
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(
7) The 1,3-cycloaddition of azides to terminal alkynes has previously been
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to accelerate the reaction by organizing the reactants and increasing their
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Figure 1. 1H NMR spectra (400 MHz, CDCl3, 298 K) of (a) macrocycle
1
, (b) [2]rotaxane 4, (c) thread 5, (d) [2]rotaxane-CuPF6 complex [4Cu]PF6,
e) macrocycle-CuPF6 complex [1CuL2]PF6. The assignments correspond
to the lettering shown in Scheme 1.
(
(8) Lewis, W. G.; Magallon, F. G.; Fokin, V. V.; Finn, M. G. J. Am. Chem.
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(
6
e,f
9) Kinetic studies
indicate that the ligand-free aqueous alkyne-azide
(5) instead gave low conversions to the triazole (2 and 9%,
cycloaddition involves two, probably bridged, metal centers. In contrast,
little is known about the details of the ligand-promoted reaction in organic
respectively; see Table 1 footnote b), showing that both rotaxane
and thread are poor ligands for generating a catalytic copper species.
Clearly, the noninterlocked thread produced in the rotaxane-forming
reactions arises from the macrocycle-promoted Cu catalysis being
able to take place around, rather than solely through, the cavity of
6
solvents. It is not yet clear whether the formation of [4Cu]PF proceeds
via single copper atom intermediates, binuclear species, or structurally
more complex aggregates. Further studies are ongoing.
(
10) (a) Fuller, A.-M.; Leigh, D. A.; Lusby, P. J.; Oswald, I. D. H.; Parsons,
S.; Walker, D. B. Angew. Chem., Int. Ed. 2004, 43, 3914-3918. (b) Leigh,
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12619. (d) Leigh, D. A.; Lusby, P. J.; Slawin, A. M. Z.; Walker, D. B.
Chem. Commun. 2005, 4919-4921.
1. We are currently exploring the noninterlocked:interlocked
selectivity of other ligand designs.
We next investigated the use of substoichiometric amounts of
copper to determine whether the metal would turn over as a template
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