Efficient Multicomponent Active Template Synthesis of Catenanes

Article abstract of DOI:10.1021/jacs.8b01602

We describe a simple and high yielding active template synthesis of [2]catenanes. In addition to mechanical bond formation using a single premacrocycle bearing an azide and alkyne moiety, our method is also suitable for the co-macrocyclization of readily

Full text of DOI:10.1021/jacs.8b01602

Subscriber access provided by UNIV OF DURHAM
Efficient Multi-Component Active Template Synthesis of Catenanes
James E. M. Lewis, Florian Modicom, and Stephen M. Goldup
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b01602 • Publication Date (Web): 20 Mar 2018
Downloaded from http://pubs.acs.org on March 20, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Efficient Multi-Component Active Template Synthesis of Catenanes
James E. M. Lewis, Florian Modicom and Stephen M. Goldup*
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK.
Supporting Information Placeholder
proceed at low concentration over long reaction times and require
ABSTRACT: We describe a simple and high yielding active
a large excess of macrocycle precursor to achieve reasonable
yields.
template synthesis of [2]catenanes. In addition to mechanical
bond formation using a single pre-macrocycle bearing an azide
and alkyne moiety, our method is also suitable for the co-
macrocyclisation of readily available bis-alkyne and bis-azide co-
monomers and even short alkyne/azide components which oligo-
merise prior to mechanical bond formation.
13
We recently optimized our small macrocycle modification of
Leigh’s 14AT Cu-mediated azide-alkyne cycloaddition (AT-
CuAAC) reaction for the rapid and efficient iterative synthesis
15
of oligorotaxanes. This suggested an opportunity as, were these
advantages to be maintained in the formation of catenanes, these
conditions might allow efficient pseudo-high dilution reactions.
Here we report that this approach is extremely successful, produc-
ing catenanes in good to excellent yield with short reaction times.
The reaction is general with respect to both macrocycle and pre-
macrocycle structure, allowing the synthesis of small, crowded
catenanes and the use of simple building blocks via a controlled
oligomerization pathway.
1
Although many of the seminal contributions to the synthesis of
2
3
mechanically interlocked molecules focus on catenanes, reports
2i
of rotaxanes have grown to dominate the field, in part due to the
potential for shuttling motions in rotaxanes that makes them at-
4
,5
tractive for the development of molecular machines. However,
the higher synthetic challenge involved in catenane synthesis
probably plays a role; whereas rotaxanes can be synthesized readi-
ly using threading-then-stoppering methodologies, catenane syn-
thesis requires a macrocyclisation event to capture the interlocked
architecture with the attendant competition between cyclisation
and oligomerization. To overcome this, catenanes are typically
formed under high-dilution conditions, leading to long reaction
times and, where the association between the preformed ring and
the macrocycle precursor is weak, diminished yields.
a
Scheme 1. Efficient AT-CuAAC Syntheses of [2]catenanes 3.
Despite these challenges a variety of catenane syntheses have
been disclosed, each with their own advantages and disad-
2
vantages. Reactions that allow the assembly of the new macrocy-
6
cle from small building blocks such as Stoddart’s donor-acceptor
7
and pimer systems, and the amide-templated examples developed
by Vögtle, Hunter and Leigh are particularly attractive due to their
8
synthetic efficiency. Similarly, metal-directed passive template
I
(
PT) approaches, exemplified by Sauvage’s Cu -phenanthroline
methodology, are widely used thanks to the strong metal-ligand
9
interactions that favor association of the components. However,
these strategies also exemplify the drawbacks of many current
methodologies. The former rely on preorganization of the incipi-
ent macrocycle through interactions that simultaneously favor
cyclisation and catenane formation. This leads to high yields in
ideal cases, but minimal structural changes can disrupt these in-
a
Reagents and conditions: 1 in 1 : 1 CHCl -EtOH (25 mM) added
3
8
e
i
teractions, significantly lowering the yield. Conversely, metal-
directed PT approaches require high-dilution conditions to prevent
oligomerization and, although the stability of the precursor com-
plex ensures efficient threading, cyclisation is typically slow. PT
approaches are also ill-suited to the synthesis of sterically hin-
dered products as repulsive interactions disfavor threaded com-
plex formation.
to 2 (25 mM), Pr NEt (2 equiv) and [Cu(CH CN) ](PF ) (0.99
equiv) in 1 : 1 CHCl -EtOH over 4 h. Determined by H NMR
analysis. Isolated yield. Concentration of 1/2a = 100 mM.
2
3
4
6
b
1
3
c
d
Precursor 1 was readily prepared and its reaction with macro-
16
cycle 2a investigated with respect to solvent, temperature, con-
centration and rate of addition of 1 to 2a, to identify the variables
that control reaction selectivity. Unsurprisingly, catenane for-
mation was favored when the addition time, temperature and con-
centration of 1 and 2a were balanced to maintain a low instanta-
neous concentration of 2a (see ESI). Using this information, we
designed general conditions for the synthesis of catenanes 3 from
macrocycles 2 (Scheme 1). When one equivalent of 1 was added
1
0
The active template (AT) approach to rotaxanes, has the po-
tential to overcome many of the outstanding challenges in cate-
nane synthesis as AT-reactions typically proceed in high yield and
are extremely general with respect to the substrates employed,
1
1
including sterically hindered examples. However, although
12
Leigh and Saito have disclosed AT catenane syntheses, they
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
i
to macrocycle 2a in the presence of [Cu(MeCN) ]PF and Pr NEt
product than the hetero-cyclization pathway.
4
6
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
over 4 h, 2a was completely consumed and catenane 3a was iso-
lated in 94% yield. Larger macrocycle 2b was 88% converted to
catenane 3b on addition of 1 equivalent of 1. Variation of the
addition rate or reaction temperature did not alter the reaction
selectivity, indicating that macrocycle 3a has an inherently lower
selectivity for mechanical bond formation. When 1.5 equivalents
of 1 (entry 2) were used, 2b was completely consumed and 3b
was isolated in 96% yield. Macrocycle 2c also required modifica-
tion of the conditions to overcome a slower reaction and dimin-
ished selectivity for the catenane compared with 2a; addition of
1
.5 equivalents of 1 to 2c at 80 °C allowed quantitative consump-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
tion of 2c and isolation of [2]catenane 3c in 98% yield (entry 3).
Macrocycle 2d required elevated temperatures to achieve ~94%
conversion to catenane 3d. Co-elution of the 3d with the macro-
cycle derived from 1 precluded addition of excess 1 to increase
the conversion and resulted in a diminished isolated yield of 86%
(
entry 4). Although the reactions of macrocycles 2 with 1 are all
17
extremely efficient, the reaction of 2a with 1 is particularly ro-
bust; 3a was produced in excellent yield (92%) even when the
concentration of 2a was increased to 100 mM (entry 5).
The high selectivity of the reactions to produce catenanes 3
suggested that the AT-CuAAC reaction would be suitable for a
multi-component cyclisation approach to catenanes from small,
simple starting materials by a controlled oligomerization pathway,
a significant benefit for the production of interlocked molecules
on larger scales. To this end, bis-alkyne and bis-azide containing
precursors were prepared and reacted with macrocycle 2a under
our standard conditions and the reactions briefly optimized with
respect to equivalents of precursors and addition time. Using this
approach, catenanes 4 and 5 were produced in good isolated yield
through the co-cyclisation of a di-azide and di-propargyl ether or
2
,6-di-ethynylpyridine respectively (Figure 1). Analysis of the
crude reaction mixtures indicated that the smallest possible
2]catenanes were produced with complete selectivity (Figures
[
S139-40). Our multi-component synthesis is also suitable for the
reaction of α,α`-diazido-p-xylene with either di-propargyl ether
or 2,6-diethynylpyridine to produce catenanes 6 and 7 in isolated
yields of 78% and 72% respectively. In these reactions, the small-
est triazole-containing macrocycle that can lead a [2]catenane
requires the formation of a hetero-tetramer as the corresponding
hetero-dimeric macrocycle is too small to encircle 2a. Once again,
the hetereo-tetrameric species was the only observed interlocked
product (Figures S141-2).
Figure 1. Multicomponent AT-CuAAC [2]catenanes 4-10.
Isolated yield.
a
18
Having successfully demonstrated a hetero-oligomerisation-
then-cyclisation approach to [2]catenanes we turned our attention
to the equivalent homo-cyclisation process. Using an azide-alkyne
in which the reactive functional groups are 11 atoms apart led to
catenane 8 in which the triazole-containing 28 membered ring is
homodimeric in 84% yield. In this case, ~10% of the correspond-
ing homo-trimeric catenane was also observed (Figure S*). De-
creasing the distance between the alkyne and azide functional
Catenanes 3-10 were fully characterized by NMR and MS (see
ESI). In addition, catenanes 3b, 3d, 5, 7, and 9 were characterized
by single crystal x-ray diffraction (Figures S146-S150). Their
solid-state structures suggest that, absent the significant stabiliz-
ing intercomponent interactions typically found in interlocked
molecules produced using PT approaches, the rings adopt co-
conformations that maximize weak, stabilizing contacts such as
C-H H-bonding, C-H-π and π-π interactions due to the enforced
proximity of the covalent subcomponents (e.g. Figure 2a). In
keeping with this, longer contacts were observed in catenane 3b
which contains larger, more flexible bipyridine macrocycle 2b.
The solid-state structures of 3b, 3d, 5, 7 and 9 all contain a ra-
cemic mixture of enantiomers that are related by points of inver-
sion (3b, 3d, 5 and 7) or glide planes (9). This is expected in the
1
8
groups to 7 atoms resulted in a 50% yield of catenane 9 in which
the 30 membered triazole-containing ring is homo-trimeric. Both
the corresponding homo-tetramer- and homo-pentamer-derived
catenanes were also observed in a combined ratio of ~1 : 2 with 9
(Figure S*). Finally, using a precursor in which the reactive func-
tionality are 5 atoms apart resulted in a 32% isolated yield of te-
tramer-derived catenane 10. In this case, a range of impurities
were observed up to and including the homo-heptamer-derived
product in a combined ~1 : 2 ratio with 10 (Figure S*). Thus,
although effective, the homo-oligomerisation-then-cyclisation
approach appears to be less selective for a single interlocked
case of 3d which is composed of two C -symmetric macrocycles
s
19
and is thus topologically chiral. However, although 3b, 5, 7 and
9
are expected to be, on average, achiral as they contain at least
one C -symmetric macrocycle, the relative arrangements of the
2v
2
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
two ring components in the solid-state produces enantiomeric co-
that allows a multi-component approach in which readily availa-
ble precursors, too small to cyclize directly, undergo successive
reactions until a final AT-CuAAC reaction gives the interlocked
target. Furthermore, the products reported here contain unusually
small macrocycles of between 26 and 32 atoms and viewing their
structures in space-filling representation (e.g. Figure 2b) serves to
underline the crowded nature of the mechanical bond which belies
the high yield of their formation. Indeed, catenane 3a contains
rings that are 26 and 28 atoms in circumference and yet it forms in
near quantitative yield. In contrast, Sauvage and co-workers found
1
2
3
4
5
6
7
8
9
conformations in which each macrocycle desymmetrizes the oth-
er, leading to structures with similar stereochemical properties to
catenane 3d. This co-conformational stereochemistry is similar to
[
2]rotaxanes in which the relative arrangement of the macrocycle
20
and a C2v or C axle leads to mechanical planar or covalent
point stereogenic elements respectively. However, to our
s
21
knowledge the co-conformational chiral stereogenic element of
catenanes 3b, 5, 7 and 9 has not been highlighted previously.
However, despite their crowded nature and the interactions and
1
1d
stereochemistry observed in the solid state, the H NMR spectra
that otherwise identical catenanes were formed in 42% or
23
of catenanes 3-10 are highly symmetrical with only one triazole
3.3% yield when the macrocycles to be interlocked were 30 or
27 atoms in circumference respectively, demonstrating the sensi-
tivity of the PT approach to destabilizing steric interactions. De-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
resonance observed, suggesting they remain mobile on the H
22
NMR timescale in solution.
1,3
spite the historical significance of catenanes and although exist-
ing methodologies have allowed ever more complex targets to be
24
realized, the relative challenge of catenane synthesis compared
to rotaxanes has contributed to making them less well examined
targets. With this new flexible methodology in hand, AT-CuAAC
catenanes are as easy if not easier to access than their rotaxane
counterparts! Given the wide range of applications for AT-
25
26
CuAAC-derived rotaxanes, including as catalysts, ligands,
2
7
28
hosts/sensors, and molecular machines, and the AT-CuAAC
reaction’s proven ability to access complex threaded systems
29
efficiently, we anticipate a similar surge in applications of AT-
CuAAC catenanes.
ASSOCIATED CONTENT
Supporting Information
Figure 2. Solid-state structure of catenane 9 in (a) tube and (b)
spacefilling representations. Selected intercomponent distances in
Å: H –N = 2.34, H –N = 2.76; H –N = 2.75, H –N = 2.77; H –
a
1
a
2
a
1
a
2
h
Full synthetic details and characterization data are available free
of charge on the ACS Publications website.
O = 2.86; H –C = 2.94; H –C = 2.96; H –N = 2.99; H –ꢀ =
D
a
D
e
D`
E
2
2
.83; H –ꢀ = 2.81; H –N = 2.44. Atom labels as in Figure 1.
F 1 H
AUTHOR INFORMATION
Corresponding Author
The yield of the reactions presented is particularly striking as
selectivity for both mechanical bond formation and macrocycliza-
tion over uncontrolled oligomerization is required for efficient
catenane synthesis. Our original hypothesis was that this could be
achieved by optimizing the bipyridine-mediated AT-CuAAC
reaction, which is highly selective for interlocked prod-
*s.goldup@soton.ac.uk
10b,13,15,16
ACKNOWLEDGMENT
ucts
as the alkyne and azide reactive functional groups
are projected on opposite faces of the ring in the key bond form-
The authors thank Fluorochem for the gift of reagents. JEML
thanks the European Union’s Horizon 2020 programme for a Ma-
rie Skłodowska-Curie Fellowship (agreement no. 660731). FM
thanks the EPSRC (EP/L505067/1) for funding. SMG acknowl-
edges funding from the European Research Council (Consolidator
Grant Agreement no. 724987).
29e
ing step, to proceed rapidly under pseudo-high dilution condi-
tions in order to maintain a low instantaneous concentration of the
substrates. However, it remained unclear whether secondary inter-
actions between the bipyridine macrocycle and the nascent tria-
zole macrocycle also played a significant role in preorganizing the
reaction intermediates to lead to a single major catenane product,
although the broad substrate scope observed suggested this was
not the case. To investigate this, the reaction of 1 was performed
in the absence of a bipyridine ligand. Analysis of the crude reac-
REFERENCES
1
tion mixture by H NMR and LCMS (Figures S133, S138) re-
vealed selective formation of the corresponding monomeric tria-
zole macrocycle, consistent with a simple pseudo-high dilution
macrocyclization process. Thus, it seems that the origin of the
high yield of our methodology is a combination of the selectivity
of the AT-CuAAC reaction and a rapid macrocyclization process,
leading to the catenane containing the smallest possible triazole-
containing macrocycle. Importantly, the simplicity of this model
allows the rational optimization of conditions for different sub-
strates by balancing the rate of addition and the reaction rate.
In conclusion, we have developed a facile, high-yielding and
general AT-CuAAC approach for the synthesis of [2]catenanes
(
1) (a) Wasserman, E. J. Am. Chem. Soc. 1960, 82, 4433. (b) Wasser-
man, E. J. Am. Chem. Soc. 1960, 82, 4433. (c) Schill, G.; Lüttringhaus, A.
Angew. Chem. Int. Ed. Engl. 1964, 3, 546. (d) Dietrich-Buchecker, C. O.;
Sauvage, J. P.; Kintzinger, J. P. Tetrahedron Lett. 1983, 24, 5095. (e)
Ashton, P. R.; Goodnow, T. T.; Kaifer, A. E.; Reddington, M. V; Slawin,
A. M. Z.; Spencer, N.; Stoddart, J. F.; Vicent, C.; Williams, D. J. Angew.
Chem. Int. Ed. Engl. 1989, 28, 1396.
(2) Reviews on the synthesis and applications of interlocked molecules:
(
a) Vickers, M. S.; Beer, P. D. Chem. Soc. Rev. 2007, 36, 211. (b)
Stoddart, J. F. Chem. Soc. Rev. 2009, 38, 1802. (c) Beves, J. E.; Blight, B.
A.; Campbell, C. J.; Leigh, D. A.; McBurney, R. T. Angew. Chem. Int. Ed.
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
011, 50, 9260. (d) Neal, E. A.; Goldup, S. M. Chem. Commun. 2014, 50,
ESI). A small quantity of analytically pure of 9 was obtained by crystalli-
zation for characterization.
5128. (f) Erbas-Cakmak, S.; Leigh, D. A.; McTernan, C. T.; Nussbaumer,
A. L. Chem. Rev. 2015, 115, 10081. (g) Xue, M.; Yang, Y.; Chi, X.; Yan,
X.; Huang, F. Chem. Rev. 2015, 115, 7398. (h) Lewis, J. E. M.; Galli, M.;
Goldup, S. M. Chem. Commun. 2017, 53, 298. (i) Bruns, C. J.; Stoddart, J.
F. The Nature of the Mechanical Bond; John Wiley & Sons, Inc.: Hobo-
ken, NJ, USA, 2016. (j) Lewis, J. E. M.; Beer, P. D.; Loeb, S. J.; Goldup,
S. M. Chem. Soc. Rev. 2017, 46, 2577.
(19) For selected recent reviews that discuss chirality in interlocked
molecules see ref. 2d,i and: (a) Evans, N. H. Chem. Eur. J. 2018, 24, 3101.
(b) Pairault, N.; Niemeyer, J. Synlett 2018, DOI: 10.1055/s-0036-1591934.
(20) Mochizuki, Y.; Ikeyatsu, K.; Mutoh, Y.; Hosoya, S.; Saito, S. Org.
Lett. 2017, 19, 4347.
(21) (a) Alvarez-Pérez, M.; Goldup, S. M.; Leigh, D. A.; Slawin, A. M.
Z. J. Am. Chem. Soc. 2008, 130, 1836. (b) Carlone, A.; Goldup, S. M.;
Lebrasseur, N.; Leigh, D. A.; Wilson, A. J. Am. Chem. Soc. 2012, 134,
(3) Reviews that focus on catenanes: (a) Evans, N. H.; Beer, P. D.
Chem. Soc. Rev. 2014, 43, 4658. (b) Gil-Ramírez, G.; Leigh, D. A.; Ste-
phens, A. J. Angew. Chem. Int. Ed. 2015, 54, 6110.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8321.
(22) H
that H
1
(4) Reviews on the development of molecular machines: (a) Balzani,
a
of 5 displays a double-doublet splitting by H NMR suggesting
V.; Credi, A.; Venturi, M. Chem. Soc. Rev. 2009, 38, 1542. (b) Coskun,
A.; Banaszak, M.; Astumian, R. D.; Stoddart, J. F.; Grzybowski, B. A.
Chem. Soc. Rev. 2012, 41, 19. (c) Erbas-Cakmak, S.; Leigh, D. A.;
McTernan, C. T.; Nussbaumer, A. L. Chem. Rev. 2015, 115, 10081. (d)
Leigh, D. A. Angew. Chem. Int. Ed. 2016, 55, 14506.
b
are inequivalent. 5 and 7 also exhibit broadening of other signals
which may indicate that pirouetting is slower in these cases.
(23) Dietrich-Buchecker, C. O.; Edel, A.; Kintzinger, J. P.; Sauvage, J.
P. Tetrahedron 1987, 43, 333.
(24) Selected examples: (a) Amabilino, D. B.; Ashton, P. R.; Reder, A.
S.; Spencer, N.; Stoddart, J. F. Angew. Chem., Int. Ed. 1994, 33, 1286. (b)
Leigh, D. A.; Pritchard, R. G.; Stephens, A. J. Nat. Chem. 2014, 6, 978.
(c) Wood, C. S.; Ronson, T. K.; Belenguer, A. M.; Holstein, J. J.; Nitsch-
ke, J. R. Nat. Chem. 2015, 7, 354. (d) Zhu, R.; Lübben, J.; Dittrich, B.;
Clever, G. H. Angew. Chem. Int. Ed. 2015, 54, 2796. (e) Black, S. P.;
Wood, D. M.; Schwarz, F. B.; Ronson, T. K.; Holstein, J. J.; Stefankie-
wicz, A. R.; Schalley, C. A.; Sanders, J. K. M.; Nitschke, J. R. Chem. Sci.
2016, 7, 2614. (f) Sawada, T.; Yamagami, M.; Ohara, K.; Yamaguchi, K.;
Fujita, M. Angew. Chem. Int. Ed. 2016, 55, 4519.
(25) (a) Hoekman, S.; Kitching, M. O.; Leigh, D. A.; Papmeyer, M.;
Roke, D. J. Am. Chem. Soc. 2015, 137 (24), 7656. (b) Galli, M.; Lewis, J.
E. M.; Goldup, S. M. Angew. Chem. Int. Ed. 2015, 54, 13545.
(26) (a) Winn, J.; Pinczewska, A.; Goldup, S. M. J. Am. Chem. Soc.
2013, 135 (36), 13318. (b) Noor, A.; Lo, W. K. C.; Moratti, S. C.; Crow-
ley, J. D. Chem. Commun. 2014, 50, 7044. (c) Noor, A.; Moratti, S. C.;
Crowley, J. D. Chem. Sci. 2014, 5, 4283. (d) Ngo, T. H.; Labuta, J.; Lim,
G. N.; Webre, W.; DSouza, F.; Karr, P. A.; Lewis, J. E. M.; Hill, J. P.;
Ariga, K.; Goldup, S. Chem. Sci. 2017, 8, 6679.
(27) (a) Langton, M. J.; Xiong, Y.; Beer, P. D. Chem. Eur. J. 2015, 21,
18910. (b) Brown, A.; Lang, T.; Mullen, K. M.; Beer, P. D. Org. Biomol.
Chem. 2017, 15, 4587. (c) Lim, J. Y. C.; Bunchuay, T.; Beer, P. D. Chem.
Eur. J. 2017, 23, 4700. (d) Lim, J. Y. C.; Marques, I.; Thompson, A. L.;
Christensen, K. E.; Félix, V.; Beer, P. D. J. Am. Chem. Soc. 2017, 139,
3122. (e) Denis, M.; Qin, L.; Turner, P.; Jolliffe, K.; Goldup, S. M. An-
gew. Chem. Int. Ed. 2018, DOI: 10.1002/anie.201713105. (f) Denis, M.;
Pancholi, J.; Jobe, K.; Watkinson, M.; Goldup, S. M. Angew. Chemie Int.
Ed. 2018, DOI: 10.1002/anie.201712931.
(28) See (11) and: (a) Lewandowski, B.; De Bo, G.; Ward, J. W.; Pap-
meyer, 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. Sci-
ence. 2013, 339, 189. (b) De Bo, G.; Kuschel, S.; Leigh, D. a; Lewan-
dowski, B.; Papmeyer, M.; Ward, J. W. J. Am. Chem. Soc. 2014, 136,
5811. (c) De Bo, G.; Gall, M. A. Y.; Kitching, M. O.; Kuschel, S.; Leigh,
D. A.; Tetlow, D. J.; Ward, J. W. J. Am. Chem. Soc. 2017, 139, 10875.
(29) (14b) and: (a) Goldup, S. M.; Leigh, D. A.; McGonigal, P. R.;
Ronaldson, V. E.; Slawin, A. M. Z. J. Am. Chem. Soc. 2010, 132, 315. (b)
Barran, P. E.; Cole, H. L.; Goldup, S. M.; Leigh, D. A.; McGonigal, P. R.;
Symes, M. D.; Wu, J.; Zengerle, M. Angew. Chem. Int. Ed. 2011, 50,
12280. (c) Bordoli, R. J.; Goldup, S. M. J. Am. Chem. Soc. 2014, 136,
4817. (e) Neal, E. A.; Goldup, S. M. Chem. Sci. 2015, 6, 2398. (f) Neal, E.
A.; Goldup, S. M. Angew. Chem. Int. Ed. 2016, 55, 12488.
(5) Nobel lectures on the subject of molecular machines: (a) Sauvage, J.
P. Angew. Chem. Int. Ed. 2017, 56, 11080. (b) Stoddart, J. F. Angew.
Chem. Int. Ed. 2017, 56, 11094. (c) Feringa, B. L. Angew. Chem. Int. Ed.
2
017, 56, 11060.
6) See ref (1e) and: (a) Fahrenbach, A. C.; Bruns, C. J.; Cao, D.;
(
Stoddart, J. F. Acc. Chem. Res. 2012, 45, 1581. (b) Fahrenbach, A. C.;
Bruns, C. J.; Li, H.; Trabolsi, A.; Coskun, A.; Stoddart, J. F. Acc. Chem.
Res. 2014, 47, 482.
(7) Barnes, J. C.; Fahrenbach, A. C.; Cao, D.; Dyar, S. M.; Frasconi,
M.; Giesener, M. A.; Benítez, D.; Tkatchouk, E.; Chernyashevskyy, O.;
Shin, W. H.; Li, H.; Sampath, S.; Stern, C. L.; Sarjeant, A. A.; Hartlieb, K.
J.; Liu, Z.; Carmieli, R.; Botros, Y. Y.; Choi, J. W.; Slawin, A. M. Z.;
Ketterson, J. B.; Wasielewski, M. R.; Goddard III, W. A.; Stoddart, J. F.
Science. 2013, 339, 429.
(8) (a) Vögtle, F.; Meier, S.; Hoss, R. Angew. Chem. Int. Ed. Engl.
992, 31, 1619. (b) Hunter, C. A. J. Am. Chem. Soc. 1992, 114, 5303. (c)
1
Johnston, A. G.; Leigh, D. A.; Pritchard, R. J.; Deegan, M. D. Angew.
Chem. Int. Ed. Engl. 1995, 34, 1209. (d) Vögtle, F.; Dünnwald, T.;
Schmidt, T. Acc. Chem. Res. 1996, 29, 451. (e) Leigh, D. A.; Venturini,
A.; Wilson, A. J.; Wong, J. K. Y.; Zerbetto, F. Chem. Eur. J. 2004, 10,
4
960.
9) (a) Dietrich-Buchecker, C. O.; Sauvage, J. P.; Kintzinger, J. Tetra-
(
hedron Lett. 1983, 24 (46), 5095. (b) Dietrich-Buchecker, C. O.; Sauvage,
J. P.; Kern, J. M. J. Am. Chem. Soc. 1984, 106, 3043.
(10) (a) Crowley, J. D.; Goldup, S. M.; Lee, A.-L.; Leigh, D. A.;
McBurney, R. T. Chem. Soc. Rev. 2009, 38, 1530. (b) Denis, M.; Goldup,
S. M. Nat. Rev. Chem. 2017, 1, 61.
(11) Lewis, J. E. M.; Bordoli, R. J.; Denis, M.; Fletcher, C. J.; Galli,
M.; Neal, E. A.; Rochette, E. M.; Goldup, S. M. Chem. Sci. 2016, 7, 3154.
(12) (a) Sato, Y.; Yamasaki, R.; Saito, S. Angew. Chem. Int. Ed. 2009,
4
8, 504. (b) Goldup, S. M.; Leigh, D. A.; Long, T.; McGonigal, P. R.;
Symes, M. D.; Wu, J. J. Am. Chem. Soc. 2009, 131, 15924. (c) Ito, K.;
Mutoh, Y.; Saito, S. J. Org. Chem. 2017, 82, 6118.
(13) Lahlali, H.; Jobe, K.; Watkinson, M.; Goldup, S. M. Angew.
Chem. Int. Ed. 2011, 50, 4151.
(14) (a) Aucagne, V.; Hänni, K. D.; Leigh, D. A.; Lusby, P. J.; Walker,
D. B. J. Am. Chem. Soc. 2006, 128, 2186. (b) Aucagne, V.; Berna, J.;
Crowley, J. D.; Goldup, S. M.; Hänni, 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.
(15) (a) Lewis, J. E. M.; Winn, J.; Cera, L.; S. M. J. Am. Chem. Soc.
016, 138, 16329. (b) Lewis, J. E. M.; Winn, J.; Goldup, S. M. Molecules
017, 22, 89.
2
2
(
16) Lewis, J. E. M.; Bordoli, R. J.; Denis, M.; Fletcher, C. J.; Galli,
M.; Neal, E. A.; Rochette, E. M.; Goldup, S. M. Chem. Sci. 2016, 7, 3154.
17) 2a and 2b produce 3a and 3b respectively as the sole interlocked
products (Figures S134-5). The crude reaction mixtures of 2c and 2d
contained traces of [2]catenanes derived from the homodimer of 1 (Figure
S136-7).
(
(18) The isolated yield of 9 was determined from the mass of a purified
sample contaminated with ~ 20% dimeric triazole macrocycle S14 (see
4
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
TOC Graphic
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
ACS Paragon Plus Environment