Two axles threaded using a single template site: Active metal template macrobicyclic [3]rotaxanes

Article abstract of DOI:10.1021/ja9080716

Template approaches to rotaxanes normally require at least n - 1 template sites to interlock n components. Here we describe the one-pot synthesis of [3]rotaxanes in which a single metal template site induces formation of axles through each cavity of a bicyclic macrocycle. Central to the approach is that a portion of the bicyclic molecule acts as a ligand for a transition metal ion that mediates covalent bond formation through one or other macrocyclic cavity, depending on the ligand's orientation, making a mechanical bond. The ligand can then rotate so that the transition metal can catalyze the formation of a second axle through the other macrocycle. Using this strategy with the Cu(I)-catalyzed azide-alkyne cycloaddition (the CuAAC reaction) generates a [3]rotaxane with two identical axles in up to 86% yield. [3]Rotaxanes with two different axles threaded through the macrobicyclic rings can also be created using a single template site, either by having copper(I) sequentially form both mechanical bonds (via the CuAAC reaction) using different sets of building blocks for each axle or by using two different reactions catalyzed by two different metal ions: a palladium(II)-mediated alkyne homocoupling to assemble the first thread through one cavity, followed by a copper(I)-mediated CuAAC reaction to form the second axle through the other ring.

Full text of DOI:10.1021/ja9080716

Published on Web 12/07/2009
Two Axles Threaded Using a Single Template Site: Active
Metal Template Macrobicyclic [3]Rotaxanes
Stephen M. Goldup,† David A. Leigh,*,† Paul R. McGonigal,† Vicki E. Ronaldson,†
and Alexandra M. Z. Slawin‡
School of Chemistry, UniVersity of Edinburgh, The King’s Buildings, West Mains Road,
Edinburgh EH9 3JJ, United Kingdom, and School of Chemistry, UniVersity of St. Andrews,
Purdie Building, St. Andrews, Fife KY16 9ST, United Kingdom
Received September 22, 2009; E-mail: David.Leigh@ed.ac.uk
Abstract: Template approaches to rotaxanes normally require at least n - 1 template sites to interlock n
components. Here we describe the one-pot synthesis of [3]rotaxanes in which a single metal template site
induces formation of axles through each cavity of a bicyclic macrocycle. Central to the approach is that a
portion of the bicyclic molecule acts as a ligand for a transition metal ion that mediates covalent bond
formation through one or other macrocyclic cavity, depending on the ligand’s orientation, making a
mechanical bond. The ligand can then rotate so that the transition metal can catalyze the formation of a
second axle through the other macrocycle. Using this strategy with the Cu(I)-catalyzed azide-alkyne
cycloaddition (the CuAAC reaction) generates a [3]rotaxane with two identical axles in up to 86% yield.
[3]Rotaxanes with two different axles threaded through the macrobicyclic rings can also be created using
a single template site, either by having copper(I) sequentially form both mechanical bonds (via the CuAAC
reaction) using different sets of building blocks for each axle or by using two different reactions catalyzed
by two different metal ions: a palladium(II)-mediated alkyne homocoupling to assemble the first thread
through one cavity, followed by a copper(I)-mediated CuAAC reaction to form the second axle through the
other ring.
Introduction
while rotaxanes consisting of multiple threads passing through
rings are still rare.2j,r,u,w A feature common to almost2n all these
In recent years, template strategies have allowed increas-
ingly elaborate structures featuring multiple mechanical bonds
to be constructed.1 Various examples of rotaxanes,2 pseudo-
rotaxanes,3 catenanes,4 and other types5 of molecular links
with three or more mechanical bonds or components have
been described. Systems with multiple mechanical bonds
between components that are also covalently connected have
also been prepared.6-8 However, the vast majority of
[n]rotaxanes with n > 2 components consist of n - 1 rings
encircling a single thread (linear2a,c,h,j,m-o,q or branched2b,e,j-l,p),
synthetic strategies is that at least n - 1 template sites are normally
required to interlock n components. Here we report on the synthesis
of [3]rotaxanes in which a single metal template site sequentially
induces formation of an axle through each cavity of a bicyclic ring
system. The methodology relies on “active template”9 rotaxane
formation, in which a coordinated metal ion acts as both the
template for the interlocked product and as a catalyst for promoting
the formation of the crucial covalent bond that captures the threaded
architecture. Active template synthesis has previously been used
with a range of transition metal-catalyzed reactions to construct
simple rotaxanes with macrocycles threaded onto a single axle.
However, since the transition metal catalyst/template does not bind
more strongly to the product than the starting material, it can in
some cases9a,c-e turn over during the reaction. It seemed possible
that by positioning the ligand at the junction between two
macrocycle cavities the single template site might be able to direct
active template reactions through each ring. Indeed, our investiga-
tion showed that two axles could be successfully threaded in this
way, either by forming them using the same reaction (e.g., the
Cu(I)-catalyzed azide-alkyne cycloadditionsthe CuAAC reac-
tion10) or via two different reactions which utilize different
transition metal ions (the CuAAC reaction and a Pd(II)-catalyzed
alkyne homocoupling11).
† University of Edinburgh.
‡ University of St. Andrews.
(1) (a) Amabilino, D. B.; Stoddart, J. F. Chem. ReV. 1995, 95, 2725–
2828. (b) Molecular Catenanes, Rotaxanes and Knots: A Journey
Through the World of Molecular Topology; Sauvage, J.-P., Dietrich-
Buchecker, C., Eds.; Wiley-VCH: Weinheim, Germany, 1999. (c)
Breault, G. A.; Hunter, C. A.; Mayers, P. C. Tetrahedron 1999, 55,
5265–5293. (d) Hubin, T. J.; Busch, D. H. Coord. Chem. ReV. 2000,
200, 5–52. (e) Raehm, L.; Hamilton, D. G.; Sanders, J. K. M. Synlett
2002, 1743–1761. (f) Kim, K. Chem. Soc. ReV. 2002, 31, 96–107. (g)
Kay, E. R.; Leigh, D. A. Top. Curr. Chem. 2005, 262, 133–177. (h)
Bogdan, A.; Rudzevich, Y.; Vysotsky, M. O.; Bo¨hmer, V. Chem.
Commun. 2006, 2941–2952. (i) Nitschke, J. R. Acc. Chem. Res. 2007,
40, 103–112. (j) Vickers, M. S.; Beer, P. D. Chem. Soc. ReV. 2007,
36, 211–225. (k) Loeb, S. J. Chem. Soc. ReV. 2007, 36, 226–235. (l)
Lankshear, M. D.; Beer, P. D. Acc. Chem. Res. 2007, 40, 657–668.
ˇ
(m) Dichtel, W. R.; Miljanic´, O. S.; Zhang, W.; Spruell, J. M.; Patel,
K.; Aprahamian, I.; Heath, J. R.; Stoddart, J. F. Acc. Chem. Res. 2008,
41, 1750–1761. (n) Faiz, J. A.; Heitz, V.; Sauvage, J.-P. Chem. Soc.
ReV. 2009, 38, 422–442. (o) Mullen, K. M.; Beer, P. D. Chem. Soc.
ReV. 2009, 38, 1701–1713. (p) Gassensmith, J. J.; Baumes, J. M.;
Smith, B. D. Chem. Commun. 2009, 6329–6338.
Results and Discussion
Macrobicyclic [3]Rotaxanes with Identical Axles. The syn-
thesis of doubly threaded [3]rotaxanes is significantly compli-
9
10.1021/ja9080716  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 315–320 315

A R T I C L E S
Goldup et al.
cated by the sheer size of the “stoppers” required to prevent
dethreading of large rings.2r,u,12 When contemplating how to
achieve multiple threading with active template reactions that
turn over, we were intrigued by the idea of incorporating the
ligating site within a flexible bridging unit that bisected a large
macrocycle into a bicyclic system. This should allow the ligand
to orient the metal ion toward each cavity in turn, catalyzing
covalent bond formation between appropriately derivatized
building blocks through each cavity, producing [3]rotaxanes
(Figure 1).
Bicyclic macrocycle 1a (Scheme 1 and Figure 2) incorporates
a 2,6-disubstituted pyridine unit (previously employed as the
ligating motif in the active template synthesis of simple
[2]rotaxanes9a,c-e) in a bridge separating two identical cavities.
CPK models indicated that with C14 alkyl chains (n ) 2, Scheme
1) the rings should be large enough to accommodate a thread
unit through each cavity while a tris(tert-butyl)-substituted trityl
group should be a sufficiently large stoppering group to prevent
dethreading. The synthesis of 1a was achieved in eight steps
from the commercially available dimethyl acetal of 2,6-
dihydroxylbenzoic acid (for details of the synthesis see the
Supporting Information). Single crystals of a metal-coordinated
Figure 1. Active template synthesis of macrobicyclic [3]rotaxanes. The
metal (purple) coordinates to the binding site. The metal can then promote
formation of a covalent bond through each cavity of the macrocycle in
turn, generating a doubly threaded [3]rotaxane. If the second thread forms
significantly more slowly than the first (negative allostery), then the reaction
can effectively be stopped at the intermediate [2]rotaxane stage and a
different set of building blocks or even a different metal employed in a
different active template reaction to form the second thread of the
macrobicyclic [3]rotaxane. §If the threads being formed are not symmetrical
through the mirror plane formed by the macrocycle, two different diaste-
reoisomers (syn and anti arrangements of the threads) can be formed even
though the threads themselves may be constitutionally identical.
(2) (a) Amabilino, D. B.; Ashton, P. R.; Beˇlohradsky´, M.; Raymo, F. M.;
Stoddart, J. F. J. Chem. Soc., Chem. Commun. 1995, 747–750. (b)
Amabilino, D. B.; Ashton, P. R.; Beˇlohradsky´, M.; Raymo, F. M.;
Stoddart, J. F. J. Chem. Soc., Chem. Commun. 1995, 751–753. (c)
Amabilino, D. B.; Ashton, P. R.; Balzani, V.; Brown, C. L.; Credi,
A.; Fre´chet, J. M. J.; Leon, J. W.; Raymo, F. M.; Spencer, N.; Stoddart,
J. F.; Venturi, M. J. Am. Chem. Soc. 1996, 118, 12012–12020. (d)
Solladie´, N.; Chambron, J. C.; Dietrich-Buchecker, C. O.; Sauvage,
J.-P. Angew. Chem., Int. Ed. 1996, 35, 906–909. (e) Amabilino, D. B.;
Asakawa, M.; Ashton, P. R.; Ballardini, R.; Balzani, V.; Beˇlohradsky´,
M.; Credi, A.; Higuchi, M.; Raymo, F. M.; Shimizu, T.; Stoddart,
J. F.; Venturi, M.; Yase, K. New J. Chem. 1998, 22, 959–972. (f)
Solladie´, N.; Chambron, J. C.; Sauvage, J.-P. J. Am. Chem. Soc. 1999,
121, 3684–3692. (g) Parham, A. H.; Schmieder, R.; Vo¨gtle, F. Synlett
1999, 1887–1890. (h) Watanabe, N.; Yagi, T.; Kihara, N.; Takata, T.
Chem. Commun. 2002, 2720–2721. (i) Tuncel, D.; Steinke, J. H. G.
Chem. Commun. 2002, 496–497. (j) Klotz, E. J. F.; Claridge, T. D. W.;
Anderson, H. L. J. Am. Chem. Soc. 2006, 128, 15374–15375. (k)
1a complex suitable for X-ray analysis were obtained by slow
cooling of a saturated solution of 1a·PdCl2(MeCN) in aceto-
nitrile and the solid state structure (Figure 2) clearly shows the
metal center orienting its chloride ligands so that they protrude
through opposite sides of one of the macrocyclic cavities, as
required by a rotaxane-forming active template mechanism.9
Carrying out the CuAAC reaction9a,d between alkyne 2 and
azide 3 (5 mol equiv of each) with a stoichiometric quantity of
CuPF6 and bicyclic macrocycle 1a in 1,2-dichloroethane at 70
°C over 24 h generated [2]rotaxane 5a, which was isolated in
41% yield after demetalation with a basic ethylenediaminetet-
raacetic acid-ammonia (EDTA-NH3) solution (Scheme 1;
Table 1, entry 1). However, despite using a large excess of the
alkyne and azide building blocks, only a small amount (e10%)
ˇ
Dichtel, W. R.; Miljanic´, O. S.; Spruell, J. M.; Heath, J. R.; Stoddart,
J. F. J. Am. Chem. Soc. 2006, 128, 10388–10390. (l) Tuncel, D.; Cindir,
N.; Koldemir, U. J. Incl. Phenom. Macrocycl. Chem. 2006, 55, 373–
380. (m) Wenz, G.; Han, B. H.; Mu¨ller, A. Chem. ReV. 2006, 106,
782–817. (n) Fuller, A. M. L.; Leigh, D. A.; Lusby, P. J. Angew.
Chem., Int. Ed. 2007, 46, 5015–5019. (o) Wu, J.; Leung, K. C. F.;
Stoddart, J. F. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 17266–17271.
(p) Taira, T.; Suzaki, Y.; Osakada, K. Chem. Asian J. 2008, 3, 895–
902. (q) Frey, J.; Tock, C.; Collin, J. P.; Heitz, V.; Sauvage, J.-P.
J. Am. Chem. Soc. 2008, 130, 4592–4593. (r) Prikhod’ko, A. I.; Durola,
F.; Sauvage, J.-P. J. Am. Chem. Soc. 2008, 130, 448–449. (s) Li, S. J.;
Liu, M.; Zhang, J. Q.; Zheng, B.; Wen, X. H.; Li, N.; Huang, F. H.
Eur. J. Org. Chem. 2008, 6128–6133. (t) Collin, J. P.; Frey, J.; Heitz,
V.; Sauvage, J.-P.; Tock, C.; Allouche, L. J. Am. Chem. Soc. 2009,
131, 5609–5620. (u) Prikhod’ko, A.; Sauvage, J.-P. J. Am. Chem. Soc.
2009, 131, 6794–6807. (v) Wang, J. Y.; Han, J. M.; Yan, J.; Ma, Y. G.;
Pei, J. Chem.sEur. J. 2009, 15, 3585–3594. (w) Lee, C. F.; Leigh,
D. A.; Pritchard, R. G.; Schultz, D.; Teat, S. J.; Timco, G. A.;
Winpenny, R. E. P. Nature 2009, 458, 314–318.
(4) (a) Sauvage, J.-P.; Weiss, J. J. Am. Chem. Soc. 1985, 107, 6108–
6110. (b) Dietrich-Buchecker, C. O.; Khemiss, A.-K.; Sauvage, J. P.
J. Chem. Soc., Chem. Commun. 1986, 1376–1378. (c) Bitsch, F.;
Dietrich-Buchecker, C. O.; Khemiss, A.-K.; Sauvage, J.-P.; Vandors-
selaer, A. J. Am. Chem. Soc. 1991, 113, 4023–4025. (d) Dietrich-
Buchecker, C. O.; Frommberger, B.; Luer, I.; Sauvage, J.-P.; Vo¨gtle,
F. Angew. Chem., Int. Ed. 1993, 32, 1434–1437. (e) Amabilino, D. B.;
Ashton, P. R.; Reder, A. S.; Spencer, N.; Stoddart, J. F. Angew. Chem.,
Int. Ed. 1994, 33, 433–437. (f) Amabilino, D. B.; Ashton, P. R.; Brown,
C. L.; Cordova, E.; Godinez, L. A.; Goodnow, T. T.; Kaifer, A. E.;
Newton, S. P.; Pietraszkiewicz, M. J. Am. Chem. Soc. 1995, 117, 1271–
1293. (g) Amabilino, D. B.; Ashton, P. R.; Boyd, S. E.; Lee, J. Y.;
Menzer, S.; Stoddart, J. F.; Williams, D. J. Angew. Chem., Int. Ed.
1997, 36, 2070–2072. (h) Amabilino, D. B.; Ashton, P. R.; Balzani,
V.; Boyd, S. E.; Credi, A.; Lee, J. Y.; Menzer, S.; Stoddart, J. F.;
Venturi, M.; Williams, D. J. J. Am. Chem. Soc. 1998, 120, 4295–
4307. (i) Whang, D. M.; Park, K. M.; Heo, J.; Ashton, P.; Kim, K.
J. Am. Chem. Soc. 1998, 120, 4899–4900. (j) Roh, S. G.; Park, K. M.;
Park, G. J.; Sakamoto, S.; Yamaguchi, K.; Kim, K. Angew. Chem.,
Int. Ed. 1999, 38, 638–641. (k) Ashton, P. R.; Baldoni, V.; Balzani,
V.; Claessens, C. G.; Credi, A.; Hoffmann, H. D. A.; Raymo, F. M.;
Stoddart, J. F.; Venturi, M.; White, A. J. P.; Williams, D. J. Eur. J.
Org. Chem. 2000, 1121–1130. (l) Park, K. M.; Kim, S. Y.; Heo, J.;
Whang, D.; Sakamoto, S.; Yamaguchi, K.; Kim, K. J. Am. Chem.
Soc. 2002, 124, 2140–2147. (m) Hutin, M.; Schalley, C. A.; Bernar-
dinelli, G.; Nitschke, J. R. Chem.sEur. J. 2006, 12, 4069–4076. (n)
Gupta, M.; Kang, S. S.; Mayer, M. F. Tetrahedron Lett. 2008, 49,
2946–2950. (o) Patel, K.; Miljanic´, O. S.; Stoddart, J. F. Chem.
Commun. 2008, 1853–1855. (p) Megiatto, J. D.; Schuster, D. I.
Chem.sEur. J. 2009, 15, 5444–5448.
(3) (a) Sleiman, H.; Baxter, P.; Lehn, J. M.; Rissanen, K. J. Chem. Soc.,
Chem. Commun. 1995, 715–716. (b) Ashton, P. R.; Chrystal, E. J. T.;
Glink, P. T.; Menzer, S.; Schiavo, C.; Stoddart, J. F.; Tasker, P. A.;
Williams, D. J. Angew. Chem., Int. Ed. 1995, 34, 1869–1871. (c)
Ashton, P. R.; Chrystal, E. J. T.; Glink, P. T.; Menzer, S.; Schiavo,
C.; Spencer, N.; Stoddart, J. F.; Tasker, P. A.; White, A. J. P.; Williams,
D. J. Chem.sEur. J. 1996, 2, 709–728. (d) Collin, J. P.; Frey, J.; Heitz,
V.; Sakellariou, E.; Sauvage, J.-P.; Tock, C. New J. Chem. 2006, 30,
1386–1389. (e) Kraus, T.; Budesinsky, M.; Cvacka, J. C.; Sauvage,
J.-P. Angew. Chem., Int. Ed. 2006, 45, 258–261. (f) Frey, J.; Tock,
C.; Collin, J. P.; Heitz, V.; Sauvage, J.-P.; Rissanen, K. J. Am. Chem.
Soc. 2008, 130, 11013–11022. (g) Yang, C.; Ko, Y. H.; Selvapalam,
N.; Origane, Y.; Mori, T.; Wada, T.; Kim, K.; Inoue, Y. Org. Lett.
2007, 9, 4789–4792. (h) Yin, J.; Chi, C. Y.; Wu, J. S. Chem.sEur. J.
2009, 15, 6050–6057.
9
316 J. AM. CHEM. SOC. VOL. 132, NO. 1, 2010

Active Metal Template Macrobicyclic [3]Rotaxanes
A R T I C L E S
Scheme 1. Synthesis of Macrobicyclic [2]- and [3]Rotaxanes via an
Active Template CuAAC Reactiona
Figure 2. X-ray crystal structure of 1a·PdCl2(MeCN), from a single crystal
obtained by slow cooling of a saturated acetonitrile solution. Nitrogen atoms
are shown in blue, oxygen atoms are red, chlorine atoms are green, and
palladium is pink. Selected bond lengths (Å) and angles (deg): N1-Pd,
2.02; N2-Pd, 2.01; Cl1-Pd, 2.28; Cl2-Pd, 2.29; Cl1-Pd-Cl2, 178.0.
Structure viewed (a) in the plane of the pyridine ring and (b) to show the
Cl1-Pd-Cl2 axis directed through one of the macrocyclic rings.
Table 1. Conversion of 1a and 1b to Macrobicyclic [2]-and
[3]Rotaxanes (Scheme 1)
entry
macrocycle
equiv 2 and 3
[2]rotaxane yielda
[3]rotaxane yielda
1b
2b
3d
1a
1b
1b
5.0
5.0
41% (5a)
57% (5b)
14% (5b)
e10% (6a)c
40% (6b)
86% (6b)
a Reagents and conditions: (i) [Cu(CH3CN)4]PF6, ClCH2CH2Cl, 70 °C;
(ii) EDTA, NH3.
10.0e
of the accompanying [3]rotaxane 6a was formed (Table 1, entry
1). It seemed that the low yield of [3]rotaxane 6a might be a
result of the second cavity becoming too congested to accom-
modate a threading reaction following formation of [2]rotaxane
5a. We therefore synthesized macrocycle 1b (see Supporting
Information), which possessed an additional four methylene
units in each of the macrocyclic rings. Pleasingly, treating this
larger bicyclic structure (1b) with CuPF6 and 5 mol equiv (2.5
equiv per macrocycle) of 2 and 3 furnished [2]rotaxane 5b in
57% yield together with 40% of [3]rotaxane 6b, a combined
97% yield of interlocked products (Table 1, entry 2). Following
further addition of azide and alkyne (5 equiv of each), the yield
of [3]rotaxane 6b was increased to 86% (Table 1, entry 3).
The structures of the [2]- and [3]rotaxanes were established
unambiguously by mass spectrometry and NMR spectroscopy
a Yields based on macrocycle 1. b Reaction carried out over 24 h.
c
Yield determined by H NMR. d Reaction carried out over 48 h. e Five
1
equivalents of each of 2 and 3 was introduced at the start of the reaction
and again after 24 h.
(see Supporting Information). Comparison of the 1H NMR
spectrum of [2]rotaxane 5b (Figure 3b) with those of its
noninterlocked components (macrocycle 1b and thread 4; Figure
3 panels a and d, respectively) shows upfield shifts of protons
of the axle (Hf, Hh, and Hk) and macrocycle (HA, HE, and HG)
arising from these regions of the mechanically threaded
components spending significant amounts of time face-on to
aromatic rings. As only one of the two macrocycle cavities is
threaded by an axle in [2]rotaxane 5b, the bicyclic host is
desymmetrized with respect to the parent compound 1b (Figure
3a) and the 1H NMR spectrum of the [2]rotaxane is correspond-
ingly more complex (note, for example, HC, HD, and HE in
(5) (a) Chichak, K. S.; Cantrill, S. J.; Pease, A. R.; Chiu, S. H.; Cave,
G. W. V.; Atwood, J. L.; Stoddart, J. F. Science 2004, 304, 1308–
1312. (b) Chichak, K. S.; Peters, A. J.; Cantrill, S. J.; Stoddart, J. F.
J. Org. Chem. 2005, 70, 7956–7962. (c) Cantrill, S. J.; Chichak, K. S.;
Peters, A. J.; Stoddart, J. F. Acc. Chem. Res. 2005, 38, 1–9. (d)
Chichak, K. S.; Cantrill, S. J.; Stoddart, J. F. Chem. Commun. 2005,
3391–3393. (e) Peters, A. J.; Chichak, K. S.; Cantrill, S. J.; Stoddart,
J. F. Chem. Commun. 2005, 3394–3396. (f) Pentecost, C. D.; Peters,
A. J.; Chichak, K. S.; Cave, G. W. V.; Cantrill, S. J.; Stoddart, J. F.
Angew. Chem., Int. Ed. 2006, 45, 4099–4104. (g) Pentecost, C. D.;
Chichak, K. S.; Peters, A. J.; Cave, G. W. V.; Cantrill, S. J.; Stoddart,
J. F. Angew. Chem., Int. Ed. 2007, 46, 218–222.
(6) (a) Bogdan, A.; Vysotsky, M. O.; Ikai, T.; Okamoto, Y.; Bo¨hmer, V.
Chem.sEur. J. 2004, 10, 3324–3330. (b) Wang, L. Y.; Vysotsky,
M. O.; Bogdan, A.; Bolte, M.; Bo¨hmer, V. Science 2004, 304, 1312–
1314. (c) Gaeta, C.; Vysotsky, M. O.; Bogdan, A.; Bo¨hmer, V. J. Am.
Chem. Soc. 2005, 127, 13136–13137. (d) Molokanova, O.; Vysotsky,
M. O.; Cao, Y. D.; Thondorf, I.; Bo¨hmer, V. Angew. Chem., Int. Ed.
2006, 45, 8051–8055. (e) Bogdan, A.; Bolte, M.; Bo¨hmer, V.
Chem.sEur. J. 2008, 14, 8514–8520. (f) Molokanova, O.; Podopry-
gorina, G.; Bolte, M.; Bo¨hmer, V. Tetrahedron 2009, 65, 7220–7233.
9
J. AM. CHEM. SOC. VOL. 132, NO. 1, 2010 317

A R T I C L E S
Goldup et al.
Scheme 2. Synthesis of a [3]Rotaxane with Two Different Triazole
Threads via Successive CuAAC Active Template Reactionsa
Figure 3. Partial 1H NMR spectra (400 MHz, CDCl3, 298 K) of (a)
macrocycle 1b, (b) [2]rotaxane 5b, (c) [3]rotaxane syn/anti-6b, (d)
noninterlocked thread 4, and (e) expansion of the region showing resonances
He and Hk in [3]rotaxane syn/anti-6b. The lettering corresponds to that shown
in Scheme 1.
a Reagents and conditions: (i) [Cu(CH3CN)4]PF6, ClCH2CH2Cl, 70 °C;
(ii) EDTA, NH3. 43%.
Figure 3b cf. Figure 3a). Penetration of axles through both
1
macrocycle cavities in [3]rotaxane 6b simplifies the H NMR
yield (Table 1, entry 2). Carrying out a second active template
CuAAC reaction on this [2]rotaxane intermediate utilizing
alkyne 7 in place of alkyne 3 (Scheme 2) generated [3]rotaxane
syn/anti-9b, with different triazole axles threaded through the
spectrum compared to that of [2]rotaxane 5b, and the HE and
HG protons associated with each cavity produce coincident
resonances (Figure 3c). This is in spite of the potential for
stereoisomerism present in [3]rotaxane 6b, which can exist as
both syn or anti diastereomers depending on whether the axles
are threaded in the same direction (syn isomer) through the
cavities or in opposite directions (anti isomer), both of which
would be expected to be produced in the [3]rotaxane-forming
reaction (Scheme 1). Although we could not find HPLC
conditions under which the isomers of 6b were resolved, close
examination (Figure 3e) of the signals corresponding to He and
Hk reveals that they both appear as doubled sets of signals in
[3]rotaxane 6b, suggesting that both stereoisomers are indeed
present in the [3]rotaxane reaction product but that they are
1
two macrocycles, in 43% yield (Scheme 2). In the H NMR
spectrum of syn/anti-9b (Figure 4b) the formation of the second
mechanical bond with a different (unsymmetrical) thread does
not give a simplified spectrum of the bicyclic macrocycle
component in the manner observed for 6b (Figure 3c), with the
signals corresponding to HE, for example, clearly arising from
two chemically different sets of protons.
Macrobicyclic [3]Rotaxanes with Different Axles Assembled
Using Two Different Chemical Reactions. Finally, we attempted
the synthesis of [3]rotaxanes using two different active template
reactions (catalyzed by different transition metals) to sequentially
assemble the two threads via the single template site. A Pd(II)-
catalyzed alkyne homocoupling11 was selected as the second
axle-forming reaction as it has previously been successfully
used9e to assemble simple [2]rotaxanes via active template
syntheses using a 2,6-disubstituted pyridine unit as the ligating
group. However, when [2]rotaxane 5b was subjected to these
reaction conditions with alkyne 10, no [3]rotaxane was detected
in the reaction mixture. We reasoned that this could be because
1
almost indistinguishable by H NMR.
Macrobicyclic [3]Rotaxanes with Different Axles Assembled
by Successive Active Template CuAAC Reactions. We next
investigated whether the single template site could be used
sequentially for the synthesis of [3]rotaxanes in which the thread
components are nonidentical. The slower formation of the axle
through the second cavity (a form of negative allosteric
regulation13) of 5b allows the [2]rotaxane to be isolated in good
(7) For examples of rotaxanes featuring covalently-linked “handcuff”-
type macrocycles, see: (a) Badjic´, J. D.; Balzani, V.; Credi, A.; Silvi,
S.; Stoddart, J. F. Science 2004, 303, 1845–1849. (b) Arico, F.; Chang,
T.; Cantrill, S. J.; Khan, S. I.; Stoddart, J. F. Chem.sEur. J. 2005,
11, 4655–4666. (c) Loeb, S. J.; Tramontozzi, D. A. Org. Biomol. Chem.
2005, 3, 1393–1401. (d) Badjic´, J. D.; Ronconi, C. M.; Stoddart, J. F.;
Balzani, V.; Silvi, S.; Credi, A. J. Am. Chem. Soc. 2006, 128, 1489–
1499. (e) Aprahamian, I.; Olsen, J. C.; Trabolsi, A.; Stoddart, J. F.
Chem.sEur. J. 2008, 14, 3889–3895. (f) Baytekin, B.; Zhu, S. S.;
Brusilowskij, B.; Illigen, J.; Ranta, J.; Huuskonen, J.; Russo, L.;
Rissanen, K.; Kaufmann, L.; Schalley, C. A. Chem.sEur. J. 2008,
14, 10012–10028.
(8) For examples of [2]rotaxanes derived from bicyclic macrocycles, see:
(a) Mahoney, J. M.; Shukla, R.; Marshall, R. A.; Beatty, A. M.;
Zajicek, J.; Smith, B. D. J. Org. Chem. 2002, 67, 1436–1440. (b) Li,
S. J.; Liu, M.; Zhang, J. Q.; Zheng, B.; Zhang, C. J.; Wen, X. H.; Li,
N.; Huang, F. H. Org. Biomol. Chem. 2008, 6, 2103–2107. (c) Wang,
F.; Zhou, Q. Z.; Zhu, K. L.; Li, S. J.; Wang, C.; Liu, M.; Li, N.;
Fronczek, F. R.; Huang, F. Tetrahedron 2009, 65, 1488–1494. (d)
Klivansky, L. M.; Koshkakaryan, G.; Cap, D.; Liu, Y. Angew. Chem.,
Int. Ed. 2009, 48, 4185–4189. (e) Li, S. J.; Liu, M.; Zheng, B.; Zhu,
K. L.; Wang, F.; Li, N.; Zhao, X. L.; Huang, F. H. Org. Lett. 2009,
11, 3350–3353.
9
318 J. AM. CHEM. SOC. VOL. 132, NO. 1, 2010

Active Metal Template Macrobicyclic [3]Rotaxanes
A R T I C L E S
Scheme 3. Synthesis of a [3]Rotaxane with Bisacetylene and
Triazole Threads via Sequential Active Template Reactionsa
Figure 4. Partial 1H NMR spectra (400 MHz, CDCl3, 298 K) of (a)
noninterlocked thread 8, (b) mixed-triazole-thread [3]rotaxane syn/anti-9b,
(c) [2]rotaxane 5b, (d) bisacetylene-thread-triazole-thread [3]rotaxane 10b
and (e) noninterlocked thread 11. The lettering corresponds to that shown
in Schemes 2 and 3. The [3]rotaxane spectra contain minor impurities that
§
we were unable to fully remove. Mixture of syn and anti isomers.
the triazole ring of the already threaded axle in 5b could
potentially coordinate14 to the Pd(II) and inhibit the second
active template reaction. We therefore tried switching the order
in which the axles were formed, attempting to form the threaded
axle from the active template Pd(II)-alkyne homocoupling first
and then applying the Cu(I)-catalyzed alkyne-azide cycload-
dition with fresh alkyne and azide building blocks (Scheme 3).
The reaction sequence was carried out without purification
of the intermediate [2]rotaxane (12b). Bicyclic macrocycle 1b
was subjected to the Pd(II)-mediated alkyne homocoupling
conditions (5 mol % 1b·PdCl2(MeCN), 30 equiv 10, iPr2NH,
CuI, I2, benzene) with stoppered alkyne 10. After 5 days, all
a Reagents and conditions: (i) 10 (30 equiv), diisopropylamine (10 equiv),
CuI (2 equiv), I2 (0.5 equiv), room temp, benzene; (ii) (1) alkyne 3 (5 equiv),
azide 4 (5 equiv), [Cu(CH3CN)4]PF6, ClCH2CH2Cl, 70 °C; (2) EDTA, NH3;
4% yield over both mechanical bond-forming steps: ∼10% for the first
(formation of 12b); ∼40% for the second (formation of 13b). For full details
of experimental procedures see the Supporting Information.
catalyst and subjected to the CuAAC reaction conditions.
[3]Rotaxane 13b, with both bisacetylene and triazole threads
was isolated in 4% yield over these two synthetic steps (Scheme
3). While the yield is certainly modest (largely the result of the
Pd(II)-promoted homocoupling being so poor, the second axle
is threaded through the [2]rotaxane intermediate 12b in ∼40%
yield), it nonetheless demonstrates that it is possible to direct
1
the alkyne had been consumed although H NMR suggested
only ∼10% conversion to the [2]rotaxane, 12b, which was not
isolated. The solution was extracted with Na4EDTA and filtered
to remove residual Pd, and then the reaction vessel was charged
with azide and alkyne building blocks 3 and 4 and the Cu(I)PF6
(11) (a) Liu, Q.; Burton, D. J. Tetrahedron Lett. 1997, 38, 4371–4374. (b)
Lei, A.; Srivastava, M.; Zhang, X. J. Org. Chem. 2002, 67, 1969–
1971. (c) Gevorgyan, V. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E.-i., Ed.; Wiley-VCH: Weinheim,
Germany, 2002; Vol. 1, p 1463-1469. (d) Marsden, J. A.; Miller,
J. J.; Haley, M. M. Angew. Chem., Int. Ed. 2004, 43, 1694–1697. (e)
Oh, C. H.; Reddy, V. R. Tetrahedron Lett. 2004, 45, 5221–5224. (f)
Bandini, M.; Luque, R.; Budarin, V.; Macquarrie, D. J. Tetrahedron
2005, 61, 9860–9868. (g) Batsanov, A. S.; Collings, J. C.; Fairlamb,
I. J. S.; Holland, J. P.; Howard, J. A. K.; Lin, Z.; Marder, T. B.;
Parsons, A. C.; Ward, R. M.; Zhu, J. J. Org. Chem. 2005, 70, 703–
706. (h) Gil-Molto´, J.; Na´jera, C. Eur. J. Org. Chem. 2005, 4073–
4081. (i) Li, J.-H.; Liang, Y.; Xie, Y.-X. J. Org. Chem. 2005, 70,
4393–4396. (j) Li, J.-H.; Liang, Y.; Zhang, X.-D. Tetrahedron 2005,
61, 1903–1907. (k) Shi, M.; Qian, H. Appl. Organomet. Chem. 2006,
20, 771–774. (l) Chen, C.; Ai, Z.; Lin, J.; Hong, X.; Xi, C. Synlett
2006, 2454–2458. (m) Yang, F.; Cui, X.; Li, Y.; Zhang, J.; Ren, G.;
Wu, Y. Tetrahedron 2007, 63, 1963–1969. (n) Hoffmann, M.; Wilson,
C. J.; Odell, B.; Anderson, H. L. Angew. Chem., Int. Ed. 2007, 46,
3122–3125.
(9) (a) Aucagne, V.; Ha¨nni, K. D.; Leigh, D. A.; Lusby, P. J.; Walker,
D. B. J. Am. Chem. Soc. 2006, 128, 2186–2187. (b) Saito, S.;
Takahashi, E.; Nakazono, K. Org. Lett. 2006, 8, 5133–5136. (c)
Crowley, J. D.; Ha¨nni, K. D.; Lee, A.-L.; Leigh, D. A. J. Am. Chem.
Soc. 2007, 129, 12092–12093. (d) Aucagne, V.; Berna´, J.; Crowley,
J. D.; Goldup, S. M.; Ha¨nni, K. D.; Leigh, D. A.; Lusby, P. J.;
Ronaldson, V. E.; Slawin, A. M. Z.; Viterisi, A.; Walker, D. B. J. Am.
Chem. Soc. 2007, 129, 11950–11963. (e) Berna´, J.; Crowley, J. D.;
Goldup, S. M.; Ha¨nni, K. D.; Lee, A. L.; Leigh, D. A. Angew. Chem.,
Int. Ed. 2007, 46, 5709–5713. (f) Goldup, S. M.; Leigh, D. A.; Lusby,
P. J.; McBurney, R. T.; Slawin, A. M. Z. Angew. Chem., Int. Ed. 2008,
47, 3381–3384. (g) Berna´, J.; Goldup, S. M.; Lee, A.-L.; Leigh, D. A.;
Symes, M. D.; Teobaldi, G.; Zerbetto, F. Angew. Chem., Int. Ed. 2008,
47, 4392–4396. (h) Sato, Y.; Yamasaki, R.; Saito, S. Angew. Chem.,
Int. Ed. 2008, 48, 504–507. (i) Crowley, J. D.; Goldup, S. M.; Lee,
A. L.; Leigh, D. A.; McBurney, R. T. Chem. Soc. ReV. 2009, 38, 1530–
1541. (j) Goldup, S. M.; Leigh, D. A.; Long, T.; McGonigal, P. R.;
Symes, M. D.; Wu, J. J. Am. Chem. Soc. 2009, 131, 15924–15929.
(10) (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
67, 3057–3062. (b) Rostovstev, V. V.; Green, L. G.; Fokin, V. V.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596–2599.
(12) Saito, S.; Nakazono, K.; Takahashi, E. J. Org. Chem. 2006, 71, 7477–
7480.
9
J. AM. CHEM. SOC. VOL. 132, NO. 1, 2010 319

A R T I C L E S
Goldup et al.
two different metal-catalyzed reactions sequentially through
different (chemically identical) cavities through the action of
one bridging ligating group. As with the other rotaxanes reported
in this paper, [3]rotaxane 13b was unambiguously characterized
by NMR spectroscopy and mass spectrometry (see Supporting
with different axles, although this is less efficient (65% per axle
using the CuAAC reaction twice), particularly when employing
chemical reactions catalyzed by different metal ions (∼10% and
∼40%, respectively, for a Pd(II)-catalyzed alkyne homocoupling
followed by a Cu(I)-catalyzed CuAAC reaction). The ability to
form multiple mechanical bonds via a single template site is a
potentially significant addition to the toolbox for interlocked
molecule assembly. It may prove useful for constructing
heterocircuit Borromean rings,15 for example, (through the use
of cleavable bridging ligands) and other currently inaccessible
higher order links that require the threading of multiple different
axles through large rings.
1
Information). The H NMR of [3]rotaxane 13b (Figure 4d) is
not complicated by the diasteroisomerism present in syn/anti-
6b and syn/anti-9b since the bisacetylene thread component is
symmetrical.
Conclusions
We have demonstrated that it is possible for a suitably located
ligand to successively promote covalent bond forming reactions
through each cavity of a bicyclic structure, a coordinated
transition metal ion simultaneously acting as a catalyst and a
template for mechanical bond formation each time. Using the
CuAAC reaction of azide and alkyne building blocks, the
formation of [3]rotaxanes is remarkably effective, proceeding
in up to 86% yield (>94% per axle). Even with this first
generation system it is possible to form two mechanical bonds
Acknowledgment. We thank 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 and the details of the X-ray
analysis of 1a·PdCl2(MeCN) including cif file. This material
is available free of charge via the Internet at http://pubs.acs.org.
JA9080716
(13) Monod, J.; Wyman, J.; Changeux, J. P. J. Mol. Biol. 1965, 12, 88–
118.
(14) Barrell, M. J.; Leigh, D. A.; Lusby, P. J.; Slawin, A. M. Z. Angew.
Chem., Int. Ed. 2008, 47, 8036–8039.
(15) Loren, J. C.; Yoshizawa, M.; Haldiman, R.; Linden, A.; Siegel, J. S.
Angew. Chem., Int. Ed. 2003, 42, 5702–5705.
9
320 J. AM. CHEM. SOC. VOL. 132, NO. 1, 2010