Triply Threaded [4]Rotaxanes

Article abstract of DOI:10.1021/jacs.6b07733

[4]Rotaxanes featuring three axles threaded through a single ring have been prepared through active metal template synthesis. Nickel-catalyzed sp³-sp³ homocouplings of alkyl bromide "half-threads" through 37- and 38-membered 2,2′:6′,2″-terpyridyl macrocycles generate triply threaded [4]rotaxanes in up to 11% yield. An analogous 39-membered macrocycle produced no rotaxane products under similar conditions. The constitutions of the [4]rotaxanes were determined by NMR spectroscopy and mass spectrometry. Doubly threaded [3]rotaxanes were also obtained from the reactions but no [2]rotaxanes were isolated, suggesting that upon demetalation the axle of a singly threaded rotaxane can slip through a macrocycle that is sufficiently large to accommodate three threads.

Full text of DOI:10.1021/jacs.6b07733

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Article
Triply-Threaded [4]Rotaxanes
Jonathan J. Danon, David A. Leigh, Paul R. McGonigal, John W. Ward, and Jhenyi Wu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b07733 • Publication Date (Web): 29 Aug 2016
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Triply-Threaded [4]Rotaxanes
Jonathan J. Danon,† David A. Leigh,† ,‡,* Paul R. McGonigal,‡ John W. Ward† and Jhenyi Wu‡
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† School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, United Kingdom
‡ School of Chemistry, University of Edinburgh, The King’s Buildings, West Mains Road, Edinburgh, EH9 3JJ, United
Kingdom
ABSTRACT: [4]Rotaxanes featuring three axles threaded through a single ring have been prepared through active metal
template synthesis. Nickel-catalyzed sp3-sp3 homocouplings of alkyl bromide ‘half threads’ through 37- and 38-membered
2,2':6',2"-terpyridyl macrocycles generates triply-threaded [4]rotaxanes in up to 11 % yield. An analogous 39-membered
macrocycle produced no rotaxane products under similar conditions. The constitutions of the [4]rotaxanes were
determined by NMR spectroscopy and mass spectrometry. Doubly-threaded [3]rotaxanes were also obtained from the
reactions but no [2]rotaxanes were isolated, suggesting that upon demetallation the axle of a singly-threaded rotaxane can
slip through a macrocycle that is sufficiently large to accommodate three threads.
INTRODUCTION
significant expansion of the stoppers to prevent dethread-
ing of singly-threaded [2]rotaxanes, which in many cases
are necessary intermediates en route to multiply threaded
structures. Furthermore, once one axle has formed in the
cavity the increased steric bulk around the catalytic site
may hinder subsequent thread-forming reactions. To try
to address both of these issues we investigated the effica-
cy of a slightly larger (37-membered ring) macrocycle, 1a,
than we utilized previously, with axle-forming compo-
nents of different lengths (2a-c) in the rotaxane-forming
active template nickel-catalyzed homocoupling reaction
(Scheme 1, full synthetic procedures and characterization
data are provided in the Supporting Information).
Although there are many examples of rotaxanes con-
sisting of several macrocycles threaded onto a single mo-
lecular strand,1 rotaxanes with more than one axle passing
through
a
ring remain rare.2,3 Doubly-threaded
[3]rotaxanes have been prepared3 by active metal tem-
plate synthesis,4 exploiting the ability of the metal atom
bound by the macrocycle to turn over and catalyze for-
mation of a second axle through the ring. However, to
date no rotaxanes have been reported with more than two
strands threaded through a macrocycle. This is likely due
to a ‘Goldilocks requirement’ of the macrocycle needing
to be large enough to accommodate three (or more) mo-
lecular chains threaded through its cavity whilst also hav-
ing to be sufficiently small to prevent the ring slipping
over the stoppers of an individual axle.
RESULTS AND DISCUSSION
A catalytically active macrocycle-Ni(0) complex of 1a
was generated by the in situ reduction of a Ni(II) salt in
N-methyl-2-pyrrolidone (NMP), to which was added 20
equivalents of 2a in tetrahydrofuran (THF). The reaction
mixture was heated at 60 °C for 18 hours before washing
with ammoniacal ethylenediaminetetraacetic acid disodi-
um salt solution (Na2EDTA-NH3 (aq)) to remove the metal
ions (Scheme 1). Purification of the crude organic prod-
ucts by size-exclusion chromatography (SEC) led to the
recovery of unreacted macrocycle 1a (44 %) and the isola-
tion6 of three products, identified by 1H NMR (e.g. relative
integration of axle-to-ring protons) and mass spectrome-
try (e.g. mass of molecular ion) as the non-interlocked
thread 3a, doubly-threaded [3]rotaxane 4a (19 %) and
triply-threaded [4]rotaxane 5a (11 %).
We previously described the synthesis of doubly-
threaded [3]rotaxanes using the one-pot nickel-catalyzed
sp3-sp3 reductive homocoupling of alkyl bromides3a
through a 2,2':6',2"-terypyridyl macrocycle. In that system
the macrocycle-nickel complex is able to turn over, allow-
ing covalent capture of a second thread through a 35-
membered ring. Here we report that modestly increasing
the size of the macrocycle to a 37- or 38-membered ring
enables a third axle to be assembled through the cavity,
generating the first examples of triply-threaded rotaxanes.
One might expect that a modest increase in the size of
stoppers that are sufficiently bulky to form a [2]rotaxane
should enable multiply-threaded rotaxanes to be formed
with a large macrocycle via successive covalent bond-
forming reactions directed through the cavity. However,
experiments5 and molecular modeling both show that
even small increases in macrocycle cavity size require very
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Scheme 1. Active Template Synthesis of [3]- and
[4]Rotaxanes through Nickel-Catalyzed sp3-sp3 Ho-
mocoupling Reactions.a
1
2
3
a
Reagents and conditions: (i) 1. NiCl2·6H2O, Zn, NMP/THF
(1:1), 60 °C, 18 hours. 2. Na2EDTA-NH3 (aq)
.
4
5
6
7
8
The absence of any singly-threaded [2]rotaxane among
the rotaxane products isolated from the active template
reaction was initially surprising, but CPK models show
that tris(tBu-phenyl)methine stoppers can slip through
the cavity of metal-free 1a. However, a singly-threaded
species must be an intermediate in the assembly of the
more highly threaded structures, 4a and 5a. This is possi-
ble because the cavity of the nickel-coordinated macrocy-
cle is considerably smaller than that of the metal-free
ring. It appears that the nickel-complexed singly-threaded
[2]rotaxane intermediate is sufficiently long-lived to react
with two more alkyl bromide molecules and catalyze the
formation of a second axle to form the doubly-threaded
[3]rotaxane 4a before dethreading, either directly or
through transient loss of the metal center (Figure 1). The
[3]rotaxane is kinetically stable and can, in turn, promote
a third active template nickel-catalyzed homocoupling of
thread-forming components 2a to form the triply-
threaded [4]rotaxane, 5a (Table 1, entry 1). The kinetic
stability of nickel-coordinated 2a is also consistent with
the recovery of significant quantities of macrocycle 1a
after the reaction is worked up, despite the use of a large
excess (20 equivalents) of the thread-forming component.
Much of the recovered macrocycle likely results from de-
composition of the nickel-coordinated [2]rotaxane during
the workup procedure, as <30% macrocycle was recovered
in the previously reported active template reactions that
use slightly smaller macrocycles and generate stable
[2]rotaxanes.3a
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Figure 1. Proposed pathway for one-pot active template syn-
thesis of triply-threaded [4]rotaxanes, 5a-f. A Ni(0) center
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a)
b)
M
L
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J
H
O,P,Q
I
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F
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c)
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c
b
d
e
f
g
h
a
9.0
8.0
4.0
3.0
2.0
7.0
1.0
δ / ppm
Figure 2. 1H NMR spectra (600 MHz, CDCl3, 298 K) of a) macrocycle 1a, b) [3]rotaxane 4a, c) [4]rotaxane 5a and d) free thread
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3a. Assignments correspond to labeling in Scheme 1.
(purple) bound to the endotopic terpyridyl coordination site
(red) of a macrocycle (blue) catalyzes the sp3-sp3 homocou-
pling reaction of two alkyl bromide building blocks through
the cavity. The thread and macrocycle can dissociate, either
by transient demetallation forming a larger cavity or through
a slow dethreading process, or the coordinated Ni(0) can
catalyze a second carbon-carbon bond forming reaction be-
tween two more building blocks, to give a doubly-threaded
[3]rotaxane. The presence of a second thread prevents any
further dethreading. A further Ni(0)-catalyzed homocoupling
of thread building blocks generates the triply-threaded
[4]rotaxane 5a-f.
The structure of the triply-threaded [4]rotaxane 5a was
modeled with Spartan'14.7 The semi-empirical PM6 geom-
etry minimized structure shows the terpyridyl group tilt-
ed almost orthogonally to the plane of the macrocycle,
which maximizes the size of the cavity to accommodate
the three threaded chains (Figure 3). In adopting this co-
conformation, the stopper groups of the three chains are
brought in close proximity to each other at both ends of
the rotaxane. The protruding phenyl ring of the macrocy-
cle is directed towards the aromatic rings of one of the
stoppers, consistent with the upfield shifts of protons HA
and HB after the third threading event (Figures 2b and
c)
.
1
The H NMR spectra of rotaxanes 4a and 5a (Figure 2b
and c) show several upfield chemical shifts with respect to
that of their non-interlocked components, 1a and 3a (Fig-
ure 2a and d), consistent with face-on interactions of re-
gions of one component with the aromatic rings of anoth-
er. The shifts are generally more pronounced for the
[4]rotaxane (Figure 2c), a consequence of the tight pack-
ing of the axles in the cavity resulting in them spending
more time close to one another and to the macrocycle
aromatic rings. A further indication of the increased steric
crowding in the triply-threaded [4]rotaxane is the broad-
ening of a number of signals (e.g. HH,M,I), likely due to
restricted movement of the components relative to each
other on the 1H NMR timescale.
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cycle 1b, [3]rotaxanes (4d-f) and [4]rotaxanes (5d-f) were
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obtained in similar yields to those obtained using macro-
1
cycle 1a (Table 1, entries 4-6). The H NMR spectra of
[4]rotaxanes 5a and 5d are very similar to each other
(Supporting Information, Figure S3), although the down-
field chemical shift of proton HE (ꢀδ = +0.09 ppm with
the wider cavity) provides some indication that the 38-
membered ring somewhat alleviates the close packing of
the threads.
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When macrocycle 1c was employed in the analogous ac-
tive template reactions, however, no rotaxane products
could be isolated. Apparently the cavity of the 39-
membered ring is too large to be prevented from slipping
over the tris(tBu-phenyl)methine stoppers of a single
threaded axle, even when the macrocycle is coordinated
to a Ni(0) center.
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Table 1. Yields of [3]- and [4]Rotaxane Formation Reac-
tions
Thread
building
block 2a
[3]Rotaxane 4
(% yield)b
[4]Rotaxane 5
(% yield)b
Entry
1c
2a
2b
2c
2a
2b
2c
4a (19)
4b (22)
4c (21)
4d (19)
4e (20)
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5a (11)
5b (7)
5c (7)
5d (4)
5e (7)
5f (3)
2 c
3 c
4 d
5 d
6 d
Figure 3. Spartan'14 semi-empirical PM6 geometry-
minimized structure of [4]rotaxane 5a.7 Hydrogen atoms not
shown for clarity. (a) Viewed through the macrocycle cavity
and (b) side-on.
a
b
20 equivalents. Isolated yields with respect to
amount of macrocycle employed.6 Performed with
macrocycle 1a. Performed with macrocycle 1b. Reac-
c
d
To probe the multiple threading process further, we in-
vestigated the influence of changes in both the axle
length and macrocycle size on the active template rotax-
ane-forming reaction (Table 1). Increasing the distance
between the bromine atom and the stopper of the axle-
forming alkyl bromides from a three-carbon chain in 2a
to six and twelve carbons in 2b and 2c, respectively, had
little effect on the yields of the corresponding [3]- (4b and
4c) and [4]rotaxanes (5b and 5c) (Table 1, entries 2 and 3).
tions carried out under the conditions shown in
Scheme 1. >95 % conversion to homocoupled products
was observed in each case.
CONCLUSIONS
Rotaxanes with multiple axles threaded through the
same ring are challenging to access, requiring a delicate
balance of macrocycle cavity size and conformation to
stopper size, and a threading reaction that can tolerate
increasing steric bulk at the site where the chains are
joined through the ring. The one-pot active metal tem-
plate nickel-catalyzed homocoupling of stoppered alkyl
bromides of various lengths through 37 or 38-membered
2,2':6',2"-terpyridyl macrocycles affords the first examples
of triply-threaded [4]rotaxanes, together with doubly-
threaded [3]rotaxanes and the non-interlocked thread.
Although the cavities of the macrocycles utilized are too
large for [2]rotaxanes to be isolated using the stoppers
employed, the nickel-coordinated macrocycles are small
enough to form [2]rotaxaxane intermediates that can re-
1
A comparison of the H NMR spectra of [4]rotaxanes 5a-c
shows less shielding with increasing chain length (Sup-
porting Information, Figure S2), indicating that the longer
threads can position themselves to minimize unfavorable
steric interactions between the bulky stoppers and the
macrocycle. Nevertheless, the greater steric congestion
from threaded chains close to the metal binding site in
the synthesis of 5a does not significantly affect the ability
of the nickel to catalyze the active template reaction.
Macrocycles 1b and 1c, containing one and two extra
methylene groups in the southern hemisphere, respec-
tively, were prepared to investigate the effect of a modest
increase in cavity size on the ability to trap multiply-
threaded rotaxanes. Using the 38-membered ring macro-
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5, 436–442. (f) Zhang, Z.-J.; Zhang, H.-Y.; Wang, H.; Liu, Y.
act further to form kinetically stable, multiply threaded,
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Angew. Chem., Int. Ed. 2011, 50, 10834–10838.
[3]- and [4]rotaxanes. We anticipate that this approach
will be useful for the synthesis of rotaxanes featuring even
more chains threaded though a single ring, by judicious
choice of template, coupling reaction, macrocycle size
and conformation, and stopper size and shape.
(3) (a) Cheng, H. M.; Leigh, D. A.; Maffei, F.; McGonigal, P. R.;
Slawin, A. M. Z.; Wu, J. J. Am. Chem. Soc. 2011, 133, 12298–12303.
(b) Yamashita, Y.; Mutoh, Y.; Yamasaki, R.; Kasama, T.; Saito, S.
Chem. Eur. J. 2015, 21, 2139–2145. (c) Hayashi, R.; Mutoh, Y.;
Kasama, T.; Saito, S. J. Org. Chem. 2015, 80, 7536–7546. (d)
Movsisyan, L. D.; Franz, M.; Hampel, F.; Thompson, A. L.;
Tykwinski, R. R.; Anderson, H. L. J. Am. Chem. Soc. 2016, 138,
1366–1376.
EXPERIMENTAL SECTION
General Experimental Procedure for the Active Metal
Template Synthesis of [3]- and [4]Rotaxanes
9
(4) (a) Aucagne, V.; Hänni, K. D.; Leigh, D. A.; Lusby, P. J.;
Walker, D. B. J. Am. Chem. Soc. 2006, 128, 2186–2187. (b) Berná,
J.; Crowley, J. D.; Goldup, S. M.; Hänni, K. D.; Lee, A.-L.; Leigh,
D. A. Angew. Chem., Int. Ed. 2007, 46, 5709–5713. (c) Crowley, J.
D.; Hänni, K. D.; Lee, A.-L.; Leigh, D. A. J. Am. Chem. Soc. 2007,
129, 12092–12093. (d) Goldup, S. M.; Leigh, D. A.; Lusby, P. J.;
McBurney, R. T.; Slawin, A. M. Z. Angew. Chem., Int. Ed. 2008,
47, 3381–3384. (e) Berná, 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. (f) Goldup, S. M.; Leigh, D. A.; Long, T.;
McGonigal, P. R.; Symes, M. D.; Wu, J. J. Am. Chem. Soc. 2009,
131, 15924–15929. (g) Crowley, J. D.; Goldup, S. M.; Lee, A.-L.;
Leigh, D. A.; McBurney, R. T. Chem. Soc. Rev. 2009, 38, 1530–1541.
(h) Crowley, J. D.; Hänni, K. D.; Leigh, D. A.; Slawin, A. M. Z. J.
Am. Chem. Soc. 2010, 132, 5309–5314. (i) Crowley, J. D.; Goldup, S.
M.; Gowans, N. D.; Leigh, D. A.; Ronaldson, V. E.; Slawin, A. M.
Z. J. Am. Chem. Soc. 2010, 132, 6243–6248. (j) Goldup, S. M.;
Leigh, D. A.; McBurney, R. T.; McGonigal, P. R.; Plant, A. Chem.
Sci. 2010, 1, 383–386. (k) Lahlali, H.; Jobe, K.; Watkinson, M.;
Goldup, S. M. Angew. Chem., Int. Ed. 2011, 50, 4151–4155. (l)
Langton, M. J.; Matichak, J. D.; Thompson, A. L.; Anderson, H. L.
Chem. Sci. 2011, 2, 1897–1901. (m) Weisbach, N.; Baranová, Z.;
Gauthier, S.; Reibenspies, J. H.; Gladysz, J. A. Chem. Commun.
2012, 48, 7562–7564. (n) Lewandowski, B.; De Bo, G.; Ward, J.
W.; Papmeyer, M.; Kuschel, S.; Aldegunde, M. J.; Gramlich, P. M.
E.; Heckmann, D.; Goldup, S. M.; D’Souza, D. M.; Fernandes, A.
E.; Leigh, D. A. Science 2013, 339, 189–193. (o) Winn, J.;
Pinczewska, A.; Goldup, S. M. J. Am. Chem. Soc. 2013, 135, 13318–
13321. (p) Bordoli, R. J.; Goldup, S. M. J. Am. Chem. Soc. 2014, 136,
4817–4820. (q) Noor, A.; Moratti, S. C.; Crowley, J. D. Chem. Sci.
2014, 5, 4283–4290. (r) Noor, A.; Lo, W. K. C.; Moratti, S. C.;
Crowley, J. D. Chem. Commun. 2014, 50, 7044–7047. (s)
Baranová, Z.; Amini, H.; Bhuvanesh, N.; Gladysz, J. A.
Organometallics 2014, 33, 6746−6749. (t) De Bo, G.; Kuschel, S.;
Leigh, D. A.; Lewandowski, B.; Papmeyer, M.; Ward, J. W. J. Am.
Chem. Soc. 2014, 136, 5811–5814. (u) Hoekman, S.; Kitching, M.
O.; Leigh, D. A.; Papmeyer, M.; Roke, D. J. Am. Chem. Soc. 2015,
137, 7656–7659. (v) Barat, R.; Legigan, T.; Tranoy-Opalinski, I.;
Renoux, B.; Péraudeau, E.; Clarhaut, J.; Poinot, P.; Fernandes, A.
E.; Aucagne, V.; Leigh, D. A.; Papot, S. Chem. Sci. 2015, 6, 2608–
2613. (w) Franz, M.; Januszewski, J. A.; Wendinger, D.; Neiss, C.;
Movsisyan, L. D.; Hampel, F.; Anderson, H. L.; Görling, A.;
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Neal, E. A.; Goldup, S. M. Chem. Sci. 2015, 6, 2398–2404.
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To a solution of the terpyridine macrocycle (1a or 1b, 1
equiv.) and NiCl2·6H2O (1 eq.) in NMP (2.5 mL) under an
inert atmosphere of nitrogen was added activated Zn powder
(20 equiv.) and the resulting suspension stirred vigorously
for 1 hour, resulting in a color change from greenish yellow to
deep purple. A solution of the stoppered bromide (2a, 2b or
2c, 20 equiv.) in THF (2.5 mL) was added and the resulting
mixture stirred at 60 °C for 18 h. The reaction mixture was
diluted with EtOAc (200 mL) and washed with a 17.5 %
aqueous solution of ammonia saturated with Na2EDTA (2 ×
50 mL), H2O (3 × 50 mL) and brine (50 mL). The organic
layer was dried over MgSO4, the solvent removed under re-
duced pressure and the resulting residue purified by size
exclusion chromatography (CH2Cl2 as eluent, see Supporting
Information Figure S1) to yield the corresponding [3]- and
[4]rotaxanes (4a-f and 5a-f, respectively) as colorless pow-
ders or clear films.
ASSOCIATED CONTENT
Supporting Information.
Synthetic procedures and characterization data. This materi-
al is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* David.Leigh@manchester.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the EPSRC National Mass Spectrometry Centre
(Swansea, U.K.) for high-resolution mass spectrometry and
Miriam R. Wilson and Javier Jaramillo-Garcia for their assis-
tance with the graphics and molecular modeling.
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(6) The rotaxane yields reported are with respect to the
macrocycle, the limiting reactant employed. The reactions
typically proceeded with >95% conversion of the alkyl bromide
building blocks, used in excess, to the combined homocoupled
axle products (non-interlocked thread and [3]- and [4]-
rotaxanes).
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