En route to a molecular sheaf: Active metal template synthesis of a [3]rotaxane with two axles threaded through one ring

Article abstract of DOI:10.1021/ja205167e

We report that a 2,2′:6′,2″-terpyridylmacrocycle-Ni complex can efficiently mediate the threading of two alkyl chains with bulky end groups in an active metal template sp³-carbon-to-sp ³-carbon homocoupling reaction, resulting in a r

Full text of DOI:10.1021/ja205167e

ARTICLE
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En Route to a Molecular Sheaf: Active Metal Template Synthesis of a
[3]Rotaxane with Two Axles Threaded through One Ring
Hei Man Cheng,† David A. Leigh,*,† Francesca Maffei,† Paul R. McGonigal,† Alexandra M. Z. Slawin,‡ and
Jhenyi Wu†
†The School of Chemistry, University of Edinburgh, The King’s Buildings, West Mains Road, Edinburgh EH9 3JJ, United Kingdom
‡The School of Chemistry, University of St. Andrews, Purdie Building, St. Andrews, Fife KY16 9ST, United Kingdom
S Supporting Information
b
ABSTRACT: We report that a 2,20:60,200-terpyridylmacrocycleꢀNi complex can effi-
ciently mediate the threading of two alkyl chains with bulky end groups in an active metal
template sp3-carbon-to-sp3-carbon homocoupling reaction, resulting in a rare example of a
doubly threaded [3]rotaxane in up to 51% yield. The unusual architecture is confirmed by
X-ray crystallography (the first time that a one-ring-two-thread [3]rotaxane has been
characterized in the solid state) and is found to be stable with respect to dethreading
despite the large ring size of the macrocycle. Through such active template reactions, in
principle, a macrocycle should be able to assemble as many axles in its cavity as the size of
the ring and the stoppers will allow. A general method for threading multiple axles through
a macrocycle adds significantly to the tools available for the synthesis of different types of rotaxane architectures.
’ INTRODUCTION
have little8aꢀe,g,k,m or no8n binding affinity for the transition
metal ion after rotaxane formation. Thus, the metal ion may be
able to turn over during the reaction, a corollary being that in
some cases only a substoichiometric amount of the metal is
required to achieve the transformation.8a,cꢀe,k Here, we report on
a further consequence of employing such a catalytic template
system: a single active template site in a suitably large macrocycle
is able to mediate the sequential formation of two threads
through one ring, giving rise to a doubly threaded [3]rotaxane.
To do so the cavity of the macrocycle must be large enough
to accommodate two axles yet still small enough to prevent
dethreading. A 35-membered ring with an endotopic 2,20:60,
200-terpyridine (terpy) binding site successfully promotes one-
ring-two-threads [3]rotaxane formation via an active template
Ni-catalyzed homocoupling of alkyl bromides terminated with
tris(t-butylphenyl)methyl groups in up to 51% yield in a simple
one-pot reaction.
Rapid advances in many aspects of template synthesis, ligand
design, and methods for covalent capture are allowing access to
increasingly complex mechanically interlocked architectures.1
However, while there are numerous examples of rotaxanes con-
sisting of several rings threaded onto a single axle,2,3 rotaxanes
featuring multiple axles passing through a single ring remain
rare.4ꢀ6 This disparity is accounted for by the relative structural
demands on the cyclic component(s) and thread(s). The struc-
tural elements used for the synthesis of a [2]rotaxane can, in
principle, be extrapolated to multiring rotaxanes with relative
ease by simply employing an elongated axle with several tem-
plate sites without changing the size and nature of the macrocycle
or stoppers.2 The synthesis of multithread rotaxanes is more
challenging: The ring may require more than one template site to
assemble multiple threads (using traditional template methods),
and must be considerably larger than required for a [2]rotaxane
in order to accommodate more than one axle, an issue that is
further complicated by the sheer size of the stoppers required to
prevent dethreading of large macrocycles.4b,c,e,7 Furthermore,
the macrocycleꢀthread interactions that direct the assembly
of the interlocked components must overcome the sometimes
severe steric clashes that can occur between crowded thread units.
Active metal template synthesis8 is a strategy for the construc-
tion of mechanically interlocked architectures in which a macro-
cycle-bound transition metal ion acts as both the template to
entwine or thread the components and as a catalyst to promote
the covalent bond forming reaction that captures the interlocked
structure. Unlike traditional ‘passive’ metal template approaches
to the synthesis of rotaxanes,9 a permanent metal binding site is
only required on the macrocycle—the thread component may
’ RESULTS AND DISCUSSION
We recently reported the discovery of a Ni-catalyzed sp3-
carbon-to-sp3-carbon alkyl bromide homocoupling reaction and
its application to the active metal template synthesis of [2]-
rotaxanes.8n An essential feature of the reaction is the use of
a tridentate nitrogen-donor-atom ligand to inhibit competing
β-hydride elimination of alkyl-Ni intermediates during the Ni-
catalyzed reductive dimerization. [2]Rotaxane formation was
demonstrated using a macrocyclic pyridine-2,6-bisoxazoline li-
gand. However, the bisoxazoline macrocycle and rotaxane were
Received: June 4, 2011
Published: June 30, 2011
r
2011 American Chemical Society
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Scheme 1. Synthesis of [2]- and [3]Rotaxanes via a Nickel-
Catalyzed Active Template Reductive Homocoupling
Reactiona
Figure 1. X-ray crystal structure of (a) macrocycle 1, from a single
crystal obtained by vapor diffusion of diethyl ether into a chloroform
solution, space filling representation, and (b) complex 1 NiCl2, from a
3
single crystal obtained by slow diffusion of methanol into a chloroform
solution, stick representation. Solvent molecules and hydrogen atoms of
1 NiCl2 are omitted for clarity. Nitrogen atoms are shown in blue,
3
oxygen atoms red, chlorine atoms green, nickel atoms cyan (ball),
hydrogen atoms white, and carbon atoms gray. Selected bond lengths
[Å] and angles [°]: N1ꢀNi 2.11, N2ꢀNi 1.97, N3ꢀNi 2.12, Cl1ꢀNi
2.27, Cl2ꢀNi 2.30, N1ꢀNiꢀN2 77.1, N1ꢀNiꢀN3 153.5,
N2ꢀNiꢀCl1 154.0, Cl1ꢀNiꢀCl2 108.0, N2ꢀNiꢀCl2 98.0.
prone to decomposition, limiting the scope of the reaction. Opti-
mization of the Ni-catalyzed dimerization protocol with com-
mercially available substrates revealed that terpy groups are also
suitable catalyst ligands for this transformation and are much
more stable than oxazoline units.8n,10 It appeared that integration
of the robust terpy binding motif into a macrocycle might
overcome the rotaxane stability issue, enabling the Ni-catalyzed
alkyl bromide homocoupling reaction to be rather more synthe-
tically useful.
Macrocycle 1 was synthesized from commercially available
2,5-dibromopyridine and 4-(4-methoxyphenyl)-butyl bromide
in 24% overall yield, with 8 steps in the longest linear sequence
(for details of the synthesis, see the Supporting Information).
Substitution at the 5- and 500- position of the terpy ring system
allows rotation of the pyridyl rings relative to one another11 upon
chelation of NiII and the 120° turn angle of the rigid aromatic
framework induces cavity dimensions appropriate for use in
rotaxane-forming reactions. Single crystals of both macrocycle
1 and the corresponding complex 1 NiCl2 were obtained by
3
slow vapor diffusion of diethyl ether or methanol into chloroform
solutions and the solid state structures determined by X-ray
crystallography (Figure 1). The crystal structure of 1 shows that
the rigid terpy portion of the macrocycle generates an aperture
with a cavity width of up to 13 Å (Figure 1a). The terpyridyl ring
system switches to a cisꢀcis geometry upon coordination to NiII
(Figure 1b), holding the metal center endotopically as required
for a rotaxane-forming active template mechanism.
a Reagents and conditions: (i) 1. NiCl2 6H2O, Zn, NMP-THF (1:1),
3
60 °C, 18 h. 2. Na2EDTA-NH3(aq)
.
ethylenediaminetetraacetic acid disodium saltꢀammonia (Na2ED-
TA-NH3) solution.12 Pleasingly, a stoichiometric amount of
stoppered bromide 2 led to complete conversion to homocou-
pled products and formation of the desired [2]rotaxane 4 as
observed by analysis of the crude reaction mixture by 1H NMR
spectroscopy and mass spectrometry. Purification of the crude
reaction mixture by size-exclusion chromatography revealed only
a modest 14% yield of [2]rotaxane 4 (Table 1, entry 1). However,
as the catalytic Ni complex can turn over during the reaction, the
yield of [2]rotaxane could be increased to 48% by employing a
The catalytically active macrocycleꢀNi0 complex was formed
in situ by stirring 1 with NiCl2 6H2O in N-methyl-2-pyrrolidone
3
(NMP) followed by reduction with Zn powder. After addition
of a solution of the ‘stoppered’ alkyl bromide 2 in tetrahydro-
furan (THF), the reaction mixture was heated at 60 °C for
18 h (Scheme 1 and Table 1), then demetalated with a basic
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Table 1. Conversion of Macrocycle 1 to [2]Rotaxane 4 and
[3]Rotaxane 5 (Scheme 1)
entry
equiv 2
[2]rotaxane 4 yielda
[3]rotaxane 5 yielda
1b
2b
3b
4c
2.0
5.0
14%
48%
29%
20%
4%
9%
10.0
30%
20.0
51%
a Isolated yields based on macrocycle 1. b Ten equivalents of Zn. c Fifteen
equivalents of Zn. Inallcases, g95%conversiontohomocoupledproducts
was determined by 1H NMR analysis of the crude reaction mixture.12
Figure 3. X-ray crystal structures of (a) [2]rotaxane 4, and (b)
[3]rotaxane 5, from single crystals obtained by slow diffusion of methanol
into deuterochloroform solutions. Hydrogen atoms and solvent mol-
ecules are omitted for clarity. Nitrogen atoms are shown in blue; oxygen
atoms red; and the carbon atoms of the different components in gray,
gold, and pink.
Figure 2. Partial 1H NMR spectra (500 MHz, CDCl3, 298 K) of
(a) macrocycle 1, (b) [2]rotaxane 4, (c) [3]rotaxane 5, and (d) non-
interlocked thread 3. The lettering corresponds to that shown in Scheme 1.
1
Comparison of the H NMR spectrum (500 MHz, CDCl3,
298 K) of the [2]rotaxane 4 (Figure 2b) with those of its non-
interlocked components (macrocycle 1 and thread 3; Figure 2,
panels a and d, respectively) shows upfield shifts of protons from
the thread and macrocycle typical of regions of mechanically
interlocked structures that spend some time face-on to aromatic
rings. The uniform distribution of the modest shielding effects
suggest that no particular co-conformation is stabilized—the
macrocycle and thread can undergo relatively unrestricted mo-
tion relative to one another, as would be expected in a system
with no strong intercomponent interactions. However, threading
of a second alkyl chain axle through the ring ([3]rotaxane 5,
Figure 2c) results in increased shielding of most of the thread
protons as they are forced to spend more time closer to the
aromatic rings of the macrocycle. Several of the macrocycle
resonances (HAꢀH) are broadened, possibly as a consequence
of the steric congestion between the chains causing some co-
conformational exchange processes, such as macrocycle pirouet-
ting, to slow to rates close to the 1H NMR time scale.
Single crystals of 4 and 5 suitable for X-ray diffraction were
grown by slow diffusion of methanol into solutions of each rot-
axane in deuterated chloroform. The crystal structures (Figure 3)
confirm the constitution of both rotaxanes and the doubly
threaded nature of [3]rotaxane 5—the first time a one-ring-
two-thread [3]rotaxane structure has been determined in the
solid state. In the solid state, the alkyl chain of the thread of
[2]rotaxane 4 (Figure 3a) adopts a folded conformation where it
passes through the ring (CꢀCꢀCꢀC dihedral angles 50° e ϕ e
160°), apparently to occupy as much of the space within the
macrocyclic cavity as possible, driven by crystal packing forces. In
2.5-fold excess of bromide 2 (Table 1, entry 2). To our surprise,
when a 5-fold excess of bromide 2 was used in an attempt to
further increase the amount of 4 formed, the isolated yield of
[2]rotaxane fell to 29% (Table 1, entry 3). The reason behind
this unexpected drop in yield of 4 became apparent during the
size-exclusion purification procedure: a substantial amount of
material eluted before the [2]rotaxane indicating another pro-
duct with a larger hydrodynamic volume. 1H NMR spectroscopy
and mass spectrometry revealed that the second product was the
one-ring-two-thread [3]rotaxane 5 (Scheme 1).13 Repetition of
the reaction protocol using less equivalents of 2 (Table 1, entries
1 and 2) confirmed small amounts (<10%) of 5 are also formed
under those conditions. The [3]rotaxane proved to be the major
product when using a 10-fold excess of bromide 2, producing a
total of 71% interlocked products of which 51% was [3]rotaxane
5 (Table 1, entry 4). As complete conversion of 2 occurred and
unconsumed macrocycle 1 could be recovered, the yield of
interlocked products reflects the proportion of intermediate
dialkyl-Ni species that react with the axle precursors protruding
from opposite faces of the macrocycle (leading to rotaxane 4 or
5) or from the same face (leading to the non-interlocked axle 3).
Unlike the bisoxazoline-macrocycle rotaxanes previously pre-
pared using the Ni-catalyzed active metal template sp3-carbon-
to-sp3-carbon homocoupling reaction,8n the terpy-macrocycle-
based [2]rotaxane 4 and [3]rotaxane 5 proved completely stable
(no degradation observed over several months, vide infra).
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and for the stepwise assembly of more complex interlocked
architectures, such as heterocircuit Borromean rings.
’ CONCLUSIONS
2,20:60,200-Terpyridyl macrocycle 1 is a highly effective ligand
for the Ni-catalyzed active template sp3-carbon-to-sp3-carbon
homocoupling of alkyl bromides to form chemically robust and
kinetically stable rotaxanes. The axles of the rotaxanes are simple
alkyl chains (terminated with suitably bulky groups to prevent
dethreading) rendering the synthesis effectively traceless in
terms of the structure of the threads. The cavity of the 35-
membered ring of 1 is sufficiently small that tris(t-butylphenyl)-
methyl groups can act as the stoppers, but large enough that two
alkyl chain threads can be accommodated within the cavity. A
one-ring-two-thread [3]rotaxane 5 was isolated in up to 51%
yield in a simple one-pot procedure from a five component
reaction that features two mechanical bond-forming steps. A
small increase in macrocycle size may enable higher order multi-
ply threaded rotaxanes to be synthesized, for example, a ring
clasping three threads in its cavity, a type of molecular architec-
ture for which no examples exist to date. Ways of using this,
presently unique, synthetic tool for assembling sheaves15 of mole-
cular chains with no recognition elements6 are currently being
investigated in our laboratory.
Figure 4. Active metal template synthesis of [3]rotaxanes. A macro-
cyclic ligand (blue) with an endotopic binding site (red) coordinates to a
metal ion (purple). The metal can mediate the construction of inter-
locked products by promoting the formation of covalent bonds through
the cavity. If the ring is large enough to accommodate two threads and
the catalytic metal center can turn over, a doubly threaded [3]rotaxane
can be assembled in a simple one-pot procedure.
contrast, both alkyl chains of [3]rotaxane 5adopt fully extended zigzag
conformations (CꢀCꢀCꢀC dihedral angles ϕ ≈ 180°)—there
is comparatively little unfilled space remaining in the cavity of the
doubly threaded macrocycle—and are offset from one another
by approximately 4.5 Å along the vector of the thread which
minimizes steric clashes between the bulky trityl stoppers.
Avoiding stopperꢀstopper repulsion, perhaps through the use
of longer threads, may be an important factor for extra-
polating this methodology to the preparation of rotaxanes in
which more than two axles are threaded through a single ring,
particularly as the stopper size required to prevent dethreading
increases dramatically with only small increases in macrocycle
size.4b,c,e,7
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
spectral data for all compounds and the details of the X-ray
analyses of 1, 1 NiCl2, 4, and 5 including cif files. This material is
3
available free of charge via the Internet at http://pubs.acs.org.
The formation of [3]rotaxane 5 likely proceeds in a stepwise
manner via a [2]rotaxane intermediate as depicted schematically
in Figure 4. After active template assembly of the first axle (to give
[2]rotaxane 4), the catalytically active metal center is regene-
rated and can then gather another pair of building blocks and
mediate the formation of a second covalent bond, furnishing the
[3]rotaxane. Other active template reactions may also have the
potential to form multiply threaded rotaxanes. However, the
macrocycles used in previous studies have not possessed a cavity
of a size capable of accommodating more than one thread and a
metal ion simultaneously.8
’ AUTHOR INFORMATION
Corresponding Author
David.Leigh@ed.ac.uk
’ ACKNOWLEDGMENT
We thank the EPSRC for funding and the EPSRC National
Mass Spectrometry Service Centre (Swansea, U.K.) and the
services at the University of Edinburgh for mass spectrometry.
The paucity of doubly threaded rotaxanes in the literature4
stems from the delicate balance that must be struck between the
relative dimensions of the components in order to successfully
entrap two axles in one ring—the macrocycle must possess a
cavity large enough to accommodate both threads but should
not be so large as to be able to slip over the stoppering groups.
Indeed, in previously reported syntheses of doubly threaded
[3]rotaxanes around an octahedral metal template4c or using
DNA building blocks,4e removal of the template interaction
results in metastable structures that dethread over several hours
or days at ambient temperature, illustrating the general trade-
off between synthetic accessibility and stability for such struc-
tures. Neither [2]rotaxane 4 nor [3]rotaxane 5 showed any signs
of dethreading over several months at ambient temperature or
upon heating for several hours at 60 °C (see the Supporting
Information). As [2]rotaxane 4 is stable, isolable, and can be
obtained in good yield (up to 48%; Table 1, entry 2), it may be
useful as an intermediate for the synthesis of [3]rotaxanes with
two constitutionally different threads,4a,e ring-in-ring complexes14
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using the bisoxazoline macrocycle and 2.2 equiv of alkyl bromide at
room temperature in DMF. In the present study with the terpyridylꢀ
macrocycle (1), the use of a 1:1 mixture of THFꢀNMP enabled all of
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the reactants to be in solution at the start of the reaction. Heating to
60 °C was necessary to allow reactions with >5 equiv of 2 to reach
completion within 18 h. The proportion of interlocked and non-
interlocked products was unchanged when the reactions were carried
out with DMF as solvent and/or at room temperature (other conditions
as for Table 1, entry 2).
(13) Two-ring-one-thread [3]rotaxanes have previously been observed
as byproducts in Cu-catalyzed azide-alkyne cycloaddition (CuAAC) active
metal template reactions, see ref 8d.
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(15) A “sheaf” (plural: sheaves) is a bundle of objects held together
by a band or other mechanical binder. Familiar examples include the way
that wheat, rye, and other cereals are traditionally bound with straw or
twine after reaping.
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