Active metal template synthesis of [2]catenanes

Article abstract of DOI:10.1021/ja9070317

The synthesis of [2]catenanes by single macrocyclization and double macrocyclization strategies using Cu(I) ions to catalyze covalent bond formation while simultaneously acting as the template for the mechanically interlocked structure is reported. These

Full text of DOI:10.1021/ja9070317

Published on Web 10/06/2009
Active Metal Template Synthesis of [2]Catenanes
Stephen M. Goldup, David A. Leigh,* Tao Long, Paul R. McGonigal,
Mark D. Symes, and Jhenyi Wu
School of Chemistry, UniVersity of Edinburgh, The King’s Buildings, West Mains Road,
Edinburgh EH9 3JJ, United Kingdom
Received August 19, 2009; E-mail: david.leigh@ed.ac.uk
Abstract: The synthesis of [2]catenanes by single macrocyclization and double macrocyclization strategies
using Cu(I) ions to catalyze covalent bond formation while simultaneously acting as the template for the
mechanically interlocked structure is reported. These “active metal template” strategies employ appropriately
functionalized pyridine ether or bipyridine ligands and either the CuAAC “click” reaction of azides with
terminal alkynes or the Cu(I)-mediated Cadiot-Chodkiewicz heterocoupling of an alkyne halide with a
terminal alkyne. Using one macrocyclic and one acyclic building block, heterocircuit (the rings are
constitutionally different) [2]catenanes are produced via the single macrocyclization route in up to 53%
yield by optimizing the reaction conditions and relative stoichiometry of the starting materials. Alternatively,
with the active template CuAAC reaction, a single acyclic unit can be used to form a homocircuit (two
identical rings) [2]catenane in 46% yield through a one-pot, double macrocyclization, procedure. Remarkably,
<7% of the corresponding noninterlocked macrocycle is isolated from this reaction, indicating the efficacy
of Cu(I) as both a template for the catenane and a catalyst for covalent bond formation in the reaction.
strategies,1a “clipping” approaches to rotaxanes and catenanes
(involving single or double macrocyclization of ligands, directed
Introduction
The synthesis of catenanes and rotaxanes was revolutionized
by the application of template-directed syntheses,1 in which the
components are preorganized prior to covalent capture of the
interlocked architecture. Although a large number of different
types of template-directed reactions have been successfully
employed to form rotaxanes in threading-followed-by-stoppering
by the template)2 are rather more demanding and have only
been demonstrated with a small number of different macrocy-
clization reaction types. Of these, Williamson ether synthesis,2
the Huisgen-Meldal-Fokin Cu(I)-catalyzed 1,3-cycloaddition
of azides with terminal alkynes (the CuAAC “click” reaction),3,4
amide or ester bond-forming reactions,5 ring-closing metathesis,6
imine bond formation,1u,6f,7 and metal-ligand coordination8 are
the most commonly used. The effectiveness of these reactions
for catenane synthesis lies in their reactive end groups being
sufficiently stable in solution to react overwhelmingly in the
desired fashion even when accessing the required reaction
geometry is a rare event (as it is for the cyclization of large
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15924 J. AM. CHEM. SOC. 2009, 131, 15924–15929
10.1021/ja9070317 CCC: $40.75  2009 American Chemical Society

Active Template Catenane Synthesis
A R T I C L E S
Figure 1. The active metal template approach to catenane synthesis. (a) Single macrocyclization route: (i) Template assembly of a macrocyclic ligand and
an acyclic ligand about the metal ion (shown in pink) is followed (ii) by a covalent bond-forming reaction between the end groups of the acyclic ligand,
catalyzed by the metal ion, through the cavity of the macrocycle. (iii) Decomplexation affords the metal-free [2]catenane. (b) Double macrocyclization route:
(i) Template assembly of the acyclic ligands about one or more metal ions is followed by (ii) successive or simultaneous macrocyclization reactions. (iii)
Decomplexation affords the metal-free homocircuit (both macrocycles are the same) [2]catenane. The two routes are analogous to the single and double
macrocyclization strategies introduced by Sauvage for the synthesis of catenanes by “passive” metal template methods.2
rings), and hence give predominantly macrocyclic products
under high dilution. The yield of catenane versus noninterlocked
macrocycle then depends on how effectively the template
preorganizes the ring-closing reaction to take place while one
component is threaded through the cavity of the other.
thread. This “active metal template” strategy9 takes inspiration
from ligand couplings employed in transition metal catalysis
and opens up a broad range of metal-mediated bond formations
for possible use in the synthesis of rotaxanes, the requirement
being that the key bond-forming reaction can be directed by
the catalyst to proceed through the macrocyclic cavity rather
than external to it. Such active metal template processes, where
a single species acts as both the template and the catalyst for
covalent bond formation, clearly also offer potential for the
synthesis of catenanes (Figure 1). Using a metal ion to
simultaneously bind to and activate the tethered ends of an
acyclic building block to react through the cavity of a macro-
cycle could lead to reactions with unstable intermediates that
would otherwise not lead to interlocked products being used
for possible catenane-forming reactions. Active template pro-
cesses also offer the possibility of traceless assembly9i (as the
coordinating functional groups are often chemically changed
during the reaction into noncoordinating elements) and could
be used to prepare catenanes containing multiple rings or having
only very weak residual intercomponent interactions, molecules
We recently developed9 an approach to rotaxane synthesis
in which a metal ion ligated endotopically within a macrocycle
mediates bond formation between two suitably functionalized
building blocks through the macrocycle cavity to assemble the
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J. AM. CHEM. SOC. VOL. 131, NO. 43, 2009 15925

A R T I C L E S
Goldup et al.
Scheme 1. Active Metal Template Cadiot-Chodkiewicz Synthesis
of [2]Catenane 3 from Bipyridyl Macrocycle 1 and
Alkyne-Bromoalkyne 2a
that are often difficult or impossible to achieve with standard
template-directed approaches. Here, we report on the application
of the active metal template concept to catenane synthesis using
both single macrocyclization and double macrocyclization
strategies. Heterocircuit (the rings are different) and homocircuit
(the rings are the same) [2]catenanes are assembled using
appropriately functionalized bidentate pyridine ether or bipy-
ridine ligands and either the Cu(I)-catalyzed CuAAC reaction
or the Cu(I)-mediated Cadiot-Chodkiewicz10 heterocoupling
of an alkynyl halide and a terminal alkyne.
Active Metal Template [2]Catenane Synthesis Using the
Cadiot-Chodkiewicz Reaction
We initially investigated a modified Cadiot-Chodkiewicz
coupling11 of a bromoalkyne with a terminal alkyne mediated
by a CuI complex of bidentate bipyridyl macrocycle 1,9d due to
its efficacy in active template rotaxane-forming reactions.9g
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a Reagents and conditions: (i) LiHMDS, THF, -78 °C; (ii) CuI (1 equiv),
5 equiv of 2, 80 °C, 72 h, 21% (over two steps). L ) I, Br, or THF.
Acyclic unit 2 has no potential metal-coordinating sites other
than the terminal alkyne and bromoalkyne reactive functional
groups and should cyclize to form a ring of similar size and
shape to others previously demonstrated to accommodate thread-
forming reactions in active template rotaxane syntheses.9
Building block 2 was treated with LiHMDS (LiN(SiMe3)2) at
-78 °C and then added to a solution of macrocycle 1 and CuI
in THF, and the resulting mixture was stirred for 4 days at room
temperature (Scheme 1), a procedure similar to that used
successfully9g for rotaxane formation. However, little of the
desired catenane product (3) was observed, and only a small
amount of 2 was consumed under these conditions. Increasing
the reaction concentration, raising the reaction temperature to
80 °C, and employing a 5-fold excess of 2 ultimately gave
[2]catenane 3 in 21% yield. The proposed mechanism for the
active metal template Cadiot-Chodkiewicz catenane synthesis
is shown in Scheme 1.12 The modest yield illustrates how the
catenane-forming reaction, in which the reactive end groups
must be tethered together, is much more demanding in terms
of conformational requirements of the ligands, and probably
steric effects, than the equivalent rotaxane-forming reaction (for
which nontethered functional groups are reacted through the
macrocycle cavity to form the interlocked thread). The yield of
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Hartbaum, C.; Fisher, H. Chem. Ber. 1997, 130, 1063–1067.
(12) The mechanism of the Cadiot-Chodkiewicz coupling is thought to
proceed in a fashion analogous to that of the Castro-Stephens reaction,
see: (a) Stephens, R. D.; Castro, C. E. J. Org. Chem. 1963, 28, 3313–
3315. (b) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem.,
Int. Ed. 2000, 39, 2632–2657. (c) Bru¨ckner, R. AdVanced Organic
Chemistry: Reaction Mechanisms; Harcourt/Academic Press: San
Diego, CA, 2002; p 538. (d) Siemsen, P.; Felber, B. In Handbook of
C-H Transformations; Dyker, G., Ed.; Wiley-VCH: Weinheim,
Germany, 2005; Vol. 1, pp 53-62, 83, and 84.
(10) (a) Chodkiewicz, W. Ann. Chim. 1957, 2, 819–869. (b) Cadiot, P.;
Chodkiewicz, W. In Chemistry of Acetylenes; Viehe, H. G., Ed.; Marcel
Dekker: New York, 1969; pp 597-647. (c) Alami, M.; Ferri, F.
Tetrahedron Lett. 1996, 37, 2763–2766. (d) Montierth, J. M.; DeMario,
D. R.; Kurth, M. J.; Schore, N. E. Tetrahedron 1998, 54, 1174–11748.
9
15926 J. AM. CHEM. SOC. VOL. 131, NO. 43, 2009

Active Template Catenane Synthesis
A R T I C L E S
Scheme 2. Single Macrocyclization Strategy Active Metal Template
CuAAC Synthesis of [2]Catenane 7 from Pyridyl Macrocycle 5 and
Azide-Alkyne 6a
Figure 2. Partial 1H NMR spectra (400 MHz, CDCl3, 300 K) of (a)
bisacetylene macrocycle 4, (b) [2]catenane 3, and (c) bipyridine macrocycle
1. The assignments correspond to the lettering shown in Scheme 1.
catenane also suffers because the bromoalkyne moiety is present
during treatment of the terminal alkyne of 2 with LiHMDS,
prior to transmetalation with copper. This leads to some
decomposition of the alkyne halide, whereas in the correspond-
ing rotaxane-forming reactions, the terminal alkyne could be
treated with LiHMDS and transmetalated with copper before
the alkyne halide was added to the reaction mixture.
a Reagents and conditions: (i) [Cu(CH3CN)4](PF6), CH2Cl2, or C2H4Cl2;
(ii) EDTA, NH3(aq). L ) CH3CN, alkyne, azide, or donor atom from another
molecule. For the effect of conditions and reagent stoichiometry on the
reaction yield, see Table 1.
As a heterocircuit catenane (the two rings are different), the
interlocked nature of 3 was apparent from both mass spectrom-
etry (m/z of the molecular ion) and 1H NMR spectroscopy. The
1H NMR spectrum of [2]catenane 3 in CDCl3 (Figure 2b)
displays upfield shifts of nearly all of the signals with respect
to those of the noninterlocked components (Figure 2a and c).
Such shielding is typical of interlocked architectures in which
the aromatic rings of one component are face-on to another
component and is most conspicuous for HF, HG, and HH of
macrocycle 1 and Hc, Hh, and Hi of macrocycle 4. The ubiquity
of the upfield shifts implies that the two rings are largely free
to rotate with respect to one another, as might be expected in a
system where there are no strong intercomponent interactions
to stabilize a particular coconformation.
Table 1. Influence of Reaction Conditions and Reagent
Stoichiometry on the Single Macrocyclization Strategy Active Metal
Template CuAAC Synthesis of [2]Catenanes 7 and 9 (Schemes 2
and 3)a
yield (%) of
[2]catenane 5f7
1f9
macrocycle
equiv
conversion to
entry (concentration) of 6 T/°C time/h triazole products (%)
1a 5 (6.5 mM)
1
1
5
5
5
5
RT
80
80 240
80 288
80 500
80 170
24
96
15b
90
>98
>98
50
<5b
16
25
53
50
49
2
3
4
5
6
5 (6.5 mM)
5 (6.5 mM)
5 (1.25 mM)
1 (1 mM)
1 (5 mM)
>98
Active Metal Template [2]Catenane Synthesis Using the
CuAAC “Click” Reaction: Single Macrocyclization
Strategy
a One equivalent of [Cu(CH3CN)4](PF6) was used relative to the
macrocycle (1 or 5). All reactions were carried out in C2H4Cl2, except
entry 1 (CH2Cl2). Yield estimated by H NMR.
b
1
The qualified success of the catenane-forming active template
Cadiot-Chodkiewicz reaction prompted us to try using the
CuAAC “click” reaction to form [2]catenanes (Scheme 2, Table
1), a reaction that had also been previously successfully applied
to the active template synthesis of rotaxanes9a,d and passive
template syntheses of both rotaxanes1t,13 and catenanes.4 When
an equimolar mixture of macrocycle 5,14 [Cu(CH3CN)4](PF6), and
the acyclic azide-alkyne unit 6 in dichloromethane was stirred
for 24 h at room temperature, a low conversion to triazole prod-
ucts was observed with only trace amounts of catenane apparent
1
in the H NMR analysis of the crude reaction mixture (Table 1,
entry 1). Changing the solvent to 1,2-dichloroethane and raising
the temperature to 80 °C afforded [2]catenane 7 in 16% yield with
near complete conversion of 6 to triazole products (Table 1, entry
2). Finally, by increasing the number of equivalents of 6 relative
to 5 and running the reaction at greater dilution (which required
extended reaction times), the yield of catenane 7 was increased to
a pleasing 53% (Table 1, entry 4). Isolation of the metal-free
catenane was facilitated by washing the crude product mixture with
a basic EDTA solution.
(13) (a) Mobian, P.; Collin, J.-P.; Sauvage, J.-P. Tetrahedron Lett. 2006,
47, 4907–4909. (b) Durot, S.; Mobian, P.; Collin, J.-P.; Sauvage, J.-
P. Tetrahedron Lett. 2008, 64, 8496–8503. (c) Barrell, M. J.; Leigh,
D. A.; Lusby, P. J.; Slawin, A. M. Z. Angew. Chem., Int. Ed. 2008,
47, 8036–8039. (d) Coutrot, F.; Busseron, E.; Montero, J. L. Org.
Lett. 2008, 10, 753–756. (e) Coutrot, F.; Busseron, E. Chem.-Eur. J.
2008, 14, 4784–4787. (f) Coutrot, F.; Romuald, C.; Busseron, E. Org.
Lett. 2008, 10, 3741–3744. (g) Gassensmith, J. J.; Barr, L.; Baumes,
J. M.; Paek, A.; Nguyen, A.; Smith, B. D. Org. Lett. 2008, 10, 3343–
3346. (h) Mullen, K. M.; Gunter, M. J. J. Org. Chem. 2008, 73, 3336–
3350. (i) Coutrot, F.; Busseron, E. Chem.-Eur. J. 2009, 15, 5186–
5190. (j) Mullen, K. M.; Mercurio, J.; Serpell, C. J.; Beer, P. D. Angew.
Chem., Int. Ed. 2009, 48, 4781–4784.
(14) Fuller, A.-M. L.; Leigh, D. A.; Lusby, P. J.; Slawin, A. M. Z.; Walker,
D. B. J. Am. Chem. Soc. 2005, 127, 12612–12619.
9
J. AM. CHEM. SOC. VOL. 131, NO. 43, 2009 15927

A R T I C L E S
Goldup et al.
Scheme 3. Single Macrocyclization Strategy Active Metal Template
CuAAC Synthesis of [2]Catenane 9 from Bipyridyl Macrocycle 1
and Azide-Alkyne 6a
a Reagents and conditions: (i) [Cu(CH3CN)4](PF6), C2H4Cl2, 80 °C, 7-21
d. (ii) EDTA, NH3(aq), 49-50% (over two steps). For the effect of
concentration on the time of reaction, see Table 1.
Figure 4. Partial 1H NMR spectra (400 MHz, CDCl3, 300 K) of (a) triazole
macrocycle 8, (b) [2]catenane 9, and (c) bipyridine macrocycle 1. The
assignments correspond to the lettering indicated for macrocycles 1 and 8
in Schemes 1 and 2, respectively.
apparently very rare event of the groups being in just the right
position to react to form catenane occurs.
The 1H NMR spectrum of catenane 9 (Figure 4b) again shows
upfield shifts of most of its signals with respect to its
noninterlocked components (Figure 4a and c). Signals HF and
HG of bipyridine macrocycle 1 are each shifted by ∼0.2 ppm,
consistent with π-π stacking between the aromatic rings to
which HF and HG are attached and the aromatic rings of
macrocycle 8. As in catenane 7, the signals corresponding to
HE appear as an AB system, although this is less pronounced
than in the pyridine macrocycle-derived catenane.
Active Metal Template [2]Catenane Synthesis Using the
CuAAC “Click” Reaction: Double Macrocyclization of
Two Identical Acyclic Building Blocks
Figure 3. Partial 1H NMR spectra (400 MHz, CDCl3, 300 K) of (a) triazole
macrocycle 8, (b) [2]catenane 7, and (c) pyridine macrocycle 5. The
assignments correspond to the lettering shown in Scheme 2.
The active template reactions investigated so far (Schemes
1-3) featured a preformed macrocycle as one of the components
and involved a single macrocyclization step (Figure 1a) leading
to heterocircuit catenanes. We were interested to see whether it
would be possible to extend this concept to an active template
double macrocyclization strategy (Figure 1b) in which a
homocircuit (both interlocked rings constitutionally identical)
[2]catenane was assembled in one pot by two successive
macrocyclization reactions (the final one, at least, having to be
templated by the catalyst) of a single type of building block
(Scheme 4).
Ligand 10 incorporates the terminal alkyne and azide groups
necessary for the CuAAC reaction, together with a pyridine
group for coordination to a Cu ion catalyzing the ring closure
of another molecule of 10. The covalent framework of the ligand
was chosen to mimic macrocycle 5 and acyclic unit 6, which
combine effectively to give catenane in the single macrocy-
clization active template CuAAC reaction (Scheme 2).
Building block 10 was dissolved in C2H4Cl2 with one-half
of an equivalent of [Cu(CH3CN)4](PF6), and the solution was
heated at 80 °C for 5 days (Scheme 4). The yield of [2]catenane
proved to be highly dependent on the reaction concentration
(Table 2), presumably a reflection of the delicate balance
between various types of coordination complexes that can give
rise to oligomers, noninterlocked macrocycles, or catenane.
Carrying out the reaction at an initial 0.3 mM concentration of
10 gave a remarkable 46% yield of metal-free [2]catenane 12,
isolated after workup with a basic EDTA solution and purifica-
tion by column chromatography. Very little (<7% as compared
1
The H NMR spectrum of catenane 7 (Figure 3b) shows
significant upfield shifts of various signals (Hx ∼0.6 ppm, Hm
∼0.4 ppm, HE ∼0.3 ppm, and HF ∼0.3 ppm) with respect to
the components (Figure 3a and c), consistent with its interlocked
architecture. Interestingly, signals corresponding to HC appear
as an AB system, indicating that the two faces of the pyridyl
macrocycle are inequivalent. This is a result of the triazole group
making the ring threaded through the pyridyl macrocycle
inherently unsymmetrical. The chemical shift of Ha of the
triazole group suggests it may form a C-H· · ·N hydrogen
bond15 with the pyridine nitrogen atom of the other macrocycle.
Both pyridyl and bipyridyl macrocycles have been found to
undergo efficient active template rotaxane assembly with the
CuAAC reaction,9d although the kinetics of the reactions are
very different (the bipyridyl macrocycle reaction is considerably
slower) as a result of the reactions proceeding through different
types of intermediates. The same trend was seen with the active
template catenane-forming reaction (Scheme 3 and Table 1,
entries 5 and 6). Although good yields (49-50%) of [2]catenane
9 could be obtained, they required long reaction times (7-21
days) at 80 °C and/or higher reaction concentrations. It is
testimony to the very specific reaction preferences of the azide
and alkyne functional groups under Cu(I) catalysis that they
survive for so long without undergoing side reactions until the
(15) Li, Y.; Flood, A. H. J. Am. Chem. Soc. 2008, 130, 12111–12122.
9
15928 J. AM. CHEM. SOC. VOL. 131, NO. 43, 2009

Active Template Catenane Synthesis
A R T I C L E S
Scheme 4. Double Macrocyclization Strategy Active Metal
Template CuAAC Synthesis of [2]Catenane 12 from Azide-Alkyne
10a
Figure 5. Partial 1H NMR spectra (400 MHz, CDCl3, 300 K) of (a)
macrocycle 11, (b) [2]catenane 12, and (c) azide-alkyne building block
10. The assignments correspond to the lettering shown in Scheme 4.
in a reaction geometry in which interlocking is significantly
enhanced, as shown in Scheme 4. As the two Cu(I) centers are
linked via both a bridging ligand, L, and coordination to the
alkyne, the azide is forced to approach the reactive center
through the cavity of macrocycle 11 for the CuAAC reaction
to occur, leading predominantly to catenane.
The structure of [2]catenane 12 was confirmed by mass
spectrometry (fragmentation and MS-MS studies) and 1H NMR
spectroscopy. The 1H NMR spectrum of catenane 12 in CDCl3
is shown in Figure 5b. The upfield shifts of the signals as
compared to macrocycle 11 (Figure 5a) and building block 10
(Figure 5c) show the same general trends found in the
heterocircuit catenane produced by the single macrocyclization
active template CuAAC reaction, 7 (Figure 3).
a Reagents and conditions: (i) [Cu(CH3CN)4](PF6), C2H4Cl2, 80 °C, 5 d.
(ii) EDTA, NH3(aq). L ) CH3CN, alkyne, azide, or donor atom from another
molecule. For the effect of concentration on catenane yield, see Table 2.
Conclusions
The active template concept developed for rotaxanes can be
successfully extended to the more demanding requirements of
catenane synthesis. Heterocircuit [2]catenanes were prepared in
21-53% yields through Cu(I)-mediated active template single
macrocyclization strategies employing the Cadiot-Chodkiewicz
(forming a symmetrical bisacetylene-containing macrocycle) or
CuAAC “click” reaction (forming an unsymmetrical triazole-
containing macrocycle) and preformed monodentate or bidentate
macrocyclic ligands. The CuAAC reaction could also be used
to assemble homocircuit [2]catenanes from a single type of
acyclic building block in a one-pot procedure in up to 46% yield,
a remarkable catalytic assembly reaction notable for its selectiv-
ity for the interlocked architecture over noninterlocked macro-
cyclic products. The application of such strategies to higher order
interlocked structures is currently under investigation in our
laboratory.
Table 2. Influence of Concentration on the Double
Macrocyclization Strategy Active Metal Template CuAAC
Synthesis of [2]Catenane 12 (Scheme 4)a
[10]
conversion to
ratio catenane
yield of
entry (mM) triazole products (%) 12:macrocycles 11 and 13 [2]catenane 10f12 (%)
1
2
3
4
5
6
7
15
6
3
1
0.3
>98
>98
>98
>98
>98
65
2:3
2:3
5:2
3:1
7:1
1:1
1:6
8
16
25
30
46
40
6
0.08
0.03
25
a One-half of an equivalent of [Cu(CH3CN)4](PF6) was used relative
to 10. All reactions were performed in C2H4Cl2 at 80 °C over 120 h.
to 46% [2]catenane) of noninterlocked macrocycles 11 and 13
were isolated from the reaction reported in Table 2, entry 5. It
is intriguing that even at these relatively low concentrations the
double macrocyclization reaction is more selective for the
[2]catenane than the corresponding single macrocyclization
employing pyridine macrocycle 5 and 1 equiv of the acyclic
azide-alkyne building block 6 (Scheme 2 and Table 1, entry
2). A possible explanation could be that the second Cu(I) ion
involved in the mechanism of these reactions3,9d becomes
coordinated to the triazole nitrogen of macrocycle 11, resulting
Acknowledgment. We thank Juraj Bella for assistance with the
high field 13C NMR studies and Syngenta for a Ph.D. studentship
(to P.R.M.). D.A.L. is an EPSRC Senior Research Fellow and holds
a Royal Society-Wolfson research merit award.
Supporting Information Available: Experimental procedures
and spectral data for all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
JA9070317
9
J. AM. CHEM. SOC. VOL. 131, NO. 43, 2009 15929