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REVIEW ARTICLE

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Active template synthesis
Cite this: DOI: 10.1039/d4cs00430b

Romain Jamagne,a Martin J. Power,a Zhi-Hui Zhang,b Germán Zango,aBenjamin Gibbera and David A. Leigh *ab
The active template synthesis of mechanically interlocked molecular architectures exploits the dual abilityof various structural elements (metals or, in the case of metal-free active template synthesis, particulararrangements of functional groups) to serve as both a template for the organisation of building blocks
and as a catalyst to facilitate the formation of covalent bonds between them. This enables the entwinedor threaded intermediate structure to be covalently captured under kinetic control. Unlike classicalpassive template synthesis, the intercomponent interactions transiently used to promote the assembly
typically do not ‘live on’ in the interlocked product, meaning that active template synthesis can betraceless and used for constructing mechanically interlocked molecules that do not feature strong
binding interactions between the components. Since its introduction in 2006, active template synthesis
has been used to prepare a variety of rotaxanes, catenanes and knots. Amongst the metal–ion-mediatedversions of the strategy, the copper(I)-catalysed alkyne–azide cycloaddition (CuAAC) remains the mostextensively used transformation, although a broad range of other catalytic reactions and transition metals
also provide effective manifolds. In metal-free active template synthesis, the recent discovery of theacceleration of the reaction of primary amines with electrophiles through the cavity of crown ethers has
proved effective for forming an array of rotaxanes without recognition elements, including compact
rotaxane superbases, dissipatively assembled rotaxanes and molecular pumps. This Review details theReceived 3rd May 2024

active template concept, outlines its advantages and limitations for the synthesis of interlocked

DOI: 10.1039/d4cs00430b

molecules, and charts the diverse set of reactions that have been used with this strategy to date. The
application of active template synthesis in various domains is discussed, including molecular machinery,rsc.li/chem-soc-rev

ab

mechanical chirality, catalysis, molecular recognition and various aspects of materials science.

Department of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK. E-mail: david.leigh@manchester.ac.uk
School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, P. R. China

Romain Jamagne

Romain Jamagne was born inBrussels, Belgium and received his
BSc from the University of Geneva
and his MSc from the University ofStrasbourg. In 2019 he moved to thegroup of Prof. David A. Leigh at the
University of Manchester to pursue
his PhD on mechanically interlocked
molecules, which he completed in
2023. Currently, he is a
postdoctoral researcher with Prof.
Michel Rickhaus at the Universityof Geneva. His research interests
include molecular machines andsupramolecular materials.

This journal is © The Royal Society of Chemistry 2024

Martin J. PowerMartin Power is from Tramore,
Ireland and holds a BA in
Chemistry from Trinity College
Dublin and an MSc in Complex
Systems Chemistry from the
University of Strasbourg. Since
2020, he has been a Marie
Skłodowska-Curie PhD student in
the group of Prof. David A. Leighas part of the ArtMoMa network. His
research interests include molecularmachines, mechanically interlocked
molecules, and their applications toorganic synthesis.

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Introduction

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The synthesis of mechanically interlocked molecules (e.g. catenanes, rotaxanes and knots) has been explored since the middleof the 20th century.1,2 Early methods for their synthesis, such as thestatistical approach of Wasserman3,4 (catenanes) and Harrison andHarrison (rotaxanes)5 or the directed synthesis strategies of Lüttringhaus and Schill,6 resulted in very low yields and/or required
long synthetic schemes. In 1983, Sauvage and co-workers introduced a sea change in synthetic approaches to interlocked molecules by combining macrocycle 1 and diol 2 with Cu(I) to form
complex 3-Cu(I), which subsequently underwent macrocyclisationof the threaded phenanthroline unit with a oligoethylene glycol
chain to form metallo-catenane 4-Cu(I) in 42% yield (Fig. 1a).7,8 The
key feature of this synthesis was the use of the metal ion as atemplate to hold the organic components in a threaded arrangement such that connecting the end groups together resulted in amechanically linked molecule (Fig. 1).
Since this seminal work, numerous strategies for positioning
molecular components for interlocking have been developed,

utilising diverse metal coordination modes and geometries10–12
and/or noncovalent interactions based on aromatic stacking
interactions,13,14 hydrogen bonding,15 and/or hydrophobic
effects16,17 (Fig. 2).18 The classic metal template approach7,9–12
to interlocked molecules involves two distinct processes which
are generally accomplished step-wise (Fig. 2a):(i) Component positioning: in which the well-defined coordination geometry of the metal is used to arrange ligands suchthat joining them together favours the formation of a mechanically interlocked structure.
(ii) Component connecting: a subsequent step in which thethreaded arrangement present in the supramolecular complex is
captured through one or more covalent bond-forming reactions.
As the component positioning step only exploits the coordination geometry of the metal ion, rather than any ability of themetal to promote the formation of covalent bonds that persist
once the metal has been removed, this approach can be
categorised as ‘passive’ metal template synthesis.10 In contrast,‘active’ metal template synthesis19,20,22 (Fig. 2b) proceeds in a

Zhi-Hui Zhang, originally fromYunnan, China, obtained her
MChem degree from Sun Yat-sen
University, where she began her
research journey in Supramolecular Chemistry. In 2015,
she commenced her doctoral
studies as a PhD candidate under
the supervisor of Prof. Stephen M.
Goldup at the University ofSouthampton,
focusingonrotaxanes. Returning to China in
October 2019, she joined the lab of
Zhi-Hui Zhang
Prof. David A. Leigh and Prof.
Liang Zhang at East China Normal University in Shanghai. Her
current research focuses on molecular nanotopology.

Germán Zango was born in
Madrid, Spain. He holds a degreein Chemistry and a PhD in Organic
Chemistry from the Universidad
Autónoma de Madrid, as well as
a Master’s degree in Nanoscienceand Nanotechnology. He worked asa
Marie
Skłodowska-Curie
Postdoctoral Research Fellow in
the group of Prof. David A. Leighat the University of Manchester
between 2018 and 2021. His
research interests range from theGermán Zango
design and development ofmaterials with applications in photovoltaics, to new advanced
supramolecular materials and molecular machines.

Benji Gibber grew up in London,
before receiving his MChem fromthe University of Oxford. In 2018,
he moved to the University ofManchester to join the group of
Prof. David Leigh to undertake
his PhD on allosteric control of
topology
andchirality
insupramolecular chemistry. Afterobtaining his PhD in 2022, hetook a position in Cambridge toqualify as a UK and European
patent attorney in chemistry,
Benjamin Gibber
materials, and life sciences. His
research interests include molecular topology and functional
nanoparticles.

David Leigh obtained his BSc and
PhD from the University of Sheﬃeld.
After postdoctoral research at the
National Research Council (NRC)
in Ottawa he was appointed to a
Lectureship at the University ofManchester Institute of Scienceand Technology (UK). After holding
Chairs at the Universities of
Warwick and Edinburgh, hereturned to Manchester in 2012,
where he currently holds the Sir
Samuel Hall Chair of Chemistry
David A. Leighand is a Royal Society Research
Professor. His research interests include chemical topology andmolecular ratchets.

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Review Article
second, bond-forming, process. In contrast, active templatesynthesis (Fig. 2b) does not involve a stable intermediate, butrather depends upon a catalysed bond-forming reaction occurring faster through a macrocyclic cavity than outside of it,irrespective of whether any attractive noncovalent interactions
between the components are present in the final product.19,20
The active template process is thus kinetically driven and oﬀers
the prospect of assembling thermodynamically unfavourable
interlocked structures.
Active template synthesis oﬀers a number of distinctive
features and potential advantages compared to passive template strategies:(i) The absence of recognition motifs between the components of the final product provides an opportunity for the
traceless synthesis of so-called ‘impossible’ rotaxanes.23–26(ii) Sub-stoichiometric amounts of the metal can often be
used,22,27 which turn over during their catalysis of the covalentbond-forming reaction(s).
(iii) The formation of a sterically shielded threaded structure
can kinetically stabilise otherwise transient intermediates, aiding the elucidation of reaction mechanisms.28(iv) The kinetically driven nature of active template synthesis
allows for the formation of kinetically stable (because of themechanical bond), but thermodynamically unstable, interlocked structures.19,20

Active template Cu-catalysed
alkyne–azide cycloaddition
The concept of catalytically forming mechanical bonds

Fig. 1 Classic examples of the passive metal template synthesis of interlocked molecules. (a) The Sauvage group’s synthesis of catenane 4-Cu(I) in
two sequential steps: coordination of the bidentate ligands to the metal ina tetrahedral geometry, followed by capturing of the threaded structure
through covalent bond formation.7 (b) The Leigh group’s synthesis ofbenzylic imine catenanes by imine formation about an octahedral Zn(II)template, followed by reduction of the imines and extraction of the metal
ions to give wholly organic catenane 5.9 Although the Zn(II) ions promoteformation of the imine bonds in addition to holding the ligands in place,the metal cannot be removed from the imine catenate without a subsequent reduction step to stabilise the covalent framework in the absence ofthe metal. The two-step synthesis of 5 is therefore an example of passive
metal template synthesis.

single step that exploits both the coordination geometry of ametal (in acting as a template to organise ligands into a
threaded or entwined intermediate), and the metal’s ability tocatalyse covalent bond-forming reactions (in order to covalently
capture the interlocked structure).
Passive and active template methodologies diverge in theprinciples that underpin them (Fig. 2).19 The passive templateapproach generally involves the formation of a thermodynamicallyfavourable threaded or entwined intermediate complex (Fig. 2a).18
This minimum energy arrangement of building blocks is subsequently captured, typically by macrocyclisation or stoppering, in aThis journal is © The Royal Society of Chemistry 2024

The concept of combining metal catalysis with template organisation for the assembly of interlocked molecules was introduced by Leigh and co-workers in 2006.22 A macrocycle pyridine
group was used to bind Cu(I) within the macrocyclic cavity suchthat transiently coordinated azide and alkyne ligands wereforced to attach to the tetrahedral Cu(I) centre through opposite
faces of the macrocycle. The endotopic Cu(I) ion (and a second
Cu(I) ion28) then promotes the Cu-catalysed alkyne–azide
cycloaddition (CuAAC) of the attached ligands to form thethreaded axle. The reaction of azide 4, alkyne 5, pyridine
macrocycle 6 and Cu(MeCN)4PF6 produced [2]rotaxane 7 in
up to 94% yield (Fig. 3).22 A sub-stoichiometric amount of theCu(I) catalyst could be used, with loadings as low as 4 mol%still resulting in 82% yield of rotaxane 7. A 2007 study investigated the influence of macrocycle structure, and found that astrongly coordinating mono- or bidentate motif (pyridine or
bypyridine) and minimal steric bulk or rigidity around themetal centre were most effective for rotaxane formation.28
In 2011, the Goldup group found that smaller bipyridine
macrocycles gave higher [2]rotaxanes yields, particularly withshort axles.29 The Crowley group subsequently demonstrated thatfor exo-alcohol-functionalised pyridyl macrocycles, even smaller
macrocycles could be used,30 including 24-membered rings
which begin to approach the limit possible31 for accommodating the thickness of a threaded saturated hydrocarbon chain.

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Fig. 2 Schematic representation of (a) various common passive template strategies for rotaxane synthesis18–20 and (b) active template synthesis ofrotaxanes.19,20,22 (a) The ‘clipping’ and ‘threading-and-stoppering’ approaches involve thermodynamically driven assembly processes followed bycapturing of the interlocked structure by covalent bond formation.18 The ‘slipping’ or ‘slippage’ approach18 involves the macrocycle passing over the
stoppers at an elevated temperature; at lower temperatures the macrocycle is then kinetically trapped on the axle. As a covalent bond does not need to
be broken to disassemble such a threaded structure, such supramolecular assemblies are better described as kinetically stable pseudo-rotaxanes rather
than as rotaxanes (see footnote 194 in ref. 21). (b) Active template synthesis is kinetically driven; component assembly and the covalent capture of theinterlocked structure occur contemporaneously.

Insights into the mechanism of CuAAC catalysis
The pathway of CuAAC catalysis begins with Cu(I) acetylide
formation, followed by [3+2] cycloaddition with an azide,creating a Cu(I)-triazolizide species as a key intermediate.32
In the early-2000s various intermediates for the CuAAC
reaction had been postulated in experimental and computational studies.33–35 However, unambiguous evidence for various
intermediates, and in particular whether one or two Cu(I) atoms
were involved, remained unclear. In 2007 Leigh and co-workers
reported unexpected [3]rotaxane formation during active metal
template synthesis with a pyridine macrocycle (Fig. 4).28 The
trapping of two rings threaded onto an axle produced by theformation of one triazole group, using macrocycles that could
clearly bind to only one metal ion each, provided clear experimental evidence that two distinct Cu(I) atoms are involved in
catalysing the [3+2] cycloaddition, at least with this type ofligand system.
In the proposed reaction pathway (Fig. 4), macrocycle 6 andthe half-axle components bind to Cu(I) to form 7-Cu(I). This

Chem. Soc. Rev.

intermediate then undergoes the Cu(I)-catalysed 1,3-cycloaddition leading to interlocked complex 8-Cu(I) and, ultimately,
metal-free [2]rotaxane 9. Alternatively, the second metal ion of
10-[Cu(I)]2 can be bound to another macrocycle prior to theazide–alkyne cycloaddition occurring, leading to [3]rotaxane 11.
The formation of [3]rotaxane is enhanced by increasing themacrocycle : Cu(I) ratio, consistent with this mechanistic interpretation. Goldup and coworkers later found that high temperatures, non-coordinating solvents and larger macrocycles
can also increase the amount of [3]rotaxane formed.36
Goldup and coworkers have isolated a Cu(I)-triazolizide
rotaxane complex from an active template CuAAC reaction.37
The complex was remarkably stable, even under aqueous conditions, with the tightly threaded macrocycle sterically inhibiting protonation of the Cu–C bond. This was the first triazolide
intermediate isolated from a CuAAC reaction.
These findings illustrate well how mechanical bonding canprovide mechanistic insights into the catalysis manifolds used
for active template synthesis.

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Active template Glaser–Hay oxidative
homocoupling of terminal alkynes

Fig. 3 Introduction of active metal template synthesis by Leigh and coworkers.22

CuAAC-mediated active metal template synthesis of catenanes
and knots
CuAAC-mediated active template synthesis has been used tosynthesise a broad range of rotaxanes, including [2]rotaxanes via
either threading22,28 or clipping,38 heterocircuit [3]rotaxanes,39
doubly threaded [3]rotaxanes40 and triply threaded [4]rotaxanes.41
Its application to other topologies has been somewhat less
explored. In 2009, the Leigh group used CuAAC active templatesynthesis to produce homocircuit and heterocircuit [2]catenanes in
up to 53% yield.42 The Goldup group subsequently improved thescope and yields, making catenanes with smaller macrocycles.43
Their improvement is particularly notable as the earlier active
template syntheses of catenanes42 required high dilution and longreaction times (typically 1–7 days), whereas Goldup’s system gave
yields of up to 98% in 4 hours. Otsuka and co-workers havereported the synthesis of [3]catenanes using CuAAC active template rotaxane formation followed by macrocyclisation of thebis(2,2,6,6-tetramethyl-piperidin-1-yl) disulfide stoppers into acatenane.44
Leigh and co-workers have assembled a trefoil knot 12 using
a combination of passive and active template processes(Fig. 5).45 The trefoil knot is formed in 24% yield from a single
molecular strand, using one Cu(I) ion to coordinate to bothbipyridine units, forming a loop in the strand, while a second
Cu(I) ion acts as the active template site, catalysing the CuAAC
reaction of the alkyne and azide termini through the loop.45

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The Leigh group’s introduction of the active template synthesis
concept22 (Fig. 3) was followed about a year later by Saito andco-workers use of stoichiometric quantities of a preformed
macrocyclic Cu(I)-phenanthroline complex, 13-Cu(I), to promote the Glaser–Hay oxidative homocoupling of alkyne 14(Fig. 6a).46 This generated [2]rotaxane 15 in 72% yield. The
reaction likely proceeds through the pathway shown in Fig. 6a.
First, alkyne 14 adds to 13-Cu(I) to form Cu(I)-acetylide intermediate 16-Cu(I). The Cu(I) centre is then oxidised by I2 and asecond alkyne adds to the resulting Cu(III) species (or possibly abimetallic Cu(II) intermediate) on the opposite face of themacrocycle. Reductive elimination generates the covalent bondthat captures the threaded structure. The Cu(I) is then removed
with KCN to give metal-free [2]rotaxane 15.
Active template Glaser and Glaser-type couplings have subsequently been used to synthesise a variety of interlocked molecules, including [2]rotaxanes,47,50–64 a [2]catenane,65 and doubly
threaded [3]rotaxanes such as 18 (Fig. 6b).48,66 The approach canbe combined with passive template approaches to create moreelaborate architectures such as 19.49 Its suitability for forming
p-conjugated rotaxanes has been utilised to synthesise an array of‘molecular wires’ (see section on sheathed ‘molecular wires’).
Although most active template Glaser couplings use Cu(I)phenanthroline complexes, an exception is [2]rotaxane 17(Fig. 6b), synthesised from a macrocyclic Hamilton-type receptor, albeit in modest (9%) yield.67
Saito and co-workers have investigated the eﬀects of macrocycle size, axle length and stoichiometry on the yields of singly
threaded [2]- and doubly threaded [3]rotaxanes made via active
template Glaser couplings. The ratio of [3]rotaxane to [2]rotaxane was increased using larger macrocycles and longer threadbuilding blocks.48
Interlocked molecules prepared by Glaser couplings arereadily modified by reaction of the diyne, increasing the diversityof structures accessible using this active template reaction. Saito
and co-workers described the post-modification of rotaxane 20 to[2]rotaxane 21 bearing an aryl pyrrole moiety in the axle
(Fig. 6c).50 This allowed the shuttling dynamics of rotaxanes with
diﬀerent levels of steric bulk in the axle to be studied,54 as well aschiral HPLC separation of mechanically planar chiral rotaxanes
with rotationally asymmetric macrocycles.53

Active template Cadiot–Chodkiewicz
heterocoupling of terminal alkynes
with alkyne halides
Active template Glaser–Hay homocoupling reactions result inrotaxanes with a diyne axle with mirror plane symmetry.
Unsymmetrical diyne axle rotaxanes are accessible throughthe active template Cadiot–Chodkiewicz heterocoupling ofalkynes and alkyne halides. An unsymmetrical axle is usefulChem. Soc. Rev.

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Fig. 4 Mechanism of the active template CuAAC reaction leading to [2]- or [3]rotaxanes depending on the ratio of macrocycle to Cu(I).28

Fig. 5 Molecular trefoil knot 12 synthesised through active template CuAAC
synthesis through the macrocyclic loop formed by Cu(I)-coordination to thetwo bipyridine groups.45

for switchable rotaxane-based molecular shuttles, pumps andother types of molecular devices.
The Cadiot–Chodkiewicz active template synthesis of[2]rotaxanes was introduced by Leigh and co-workers in 2008

Chem. Soc. Rev.

(Fig. 7).67 This reaction can be particularly sensitive to the orderin which the building blocks, reagents and catalyst are combined: mixing a terminal alkyne, alkyne halide and bipyridine
macrocycle 22 with an amine base and CuI resulted in a
mixture of desired heterocoupling and undesired homocoupling products.67 In contrast, preforming copper acetylide 23Cu(I), followed by subsequent addition of the macrocycle andalkyne halide 24 increased the rotaxane yield up to 85% withalmost exclusive selectivity for the heterocoupled [2]rotaxane
25. The mechanism appears to proceed through the formationof Cu(I)-acetylide complex 26-Cu(I), which undergoes oxidative
addition of 24 through the opposite face of the macrocycle toform 27-Cu(III). Reductive elimination affords the heterocoupled product, rotaxane 25. The strategy was later extended
to the active template synthesis of heterocircuit [2]catenanes.42
The Cadiot–Chodkiewicz active template reaction has beenused for the synthesis of a variety of interlocked structures,68–71
often with better yields than the comparative Glaser couplings or
enabling the formation of rotaxanes that were not accessible
through alkyne homocouplings.68 It has proved particularly wellsuited for the synthesis of polyyne and cumulene [2]rotaxanes,
which generally show improved stability over their non-interlocked
equivalents (see section on sheathed ‘molecular wires’).
Jasti and coworkers have made an impressive range of fluorescent ‘nanohoop’ [2]rotaxanes and [c2]daisy-chain rotaxanes

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Fig. 6 (a) Proposed mechanism for the active template synthesis of [2]rotaxanes through the Cu(I)-mediated Glaser–Hay homocoupling of terminal
alkynes.46 (b) Selected examples of interlocked structures synthesised by active template Glaser couplings.47–49 (c) Saito’s post-assembly modification adiyne rotaxane to an aryl pyrrole rotaxane.50

through Cadiot–Chodkiewicz active template synthesis. The structures feature a shape-persistent macrocyclic belt containing a 2,6connected pyridine residue (e.g. 26) to endotopically coordinate theThis journal is © The Royal Society of Chemistry 2024

metal that promotes rotaxane formation. The [c2]daisy-chain
rotaxane 27 has a relatively compact structure, apparent fromthe space-filling representation of the X-ray structure (Fig. 8).69,70

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Fig. 7 Proposed mechanism for the active template synthesis of [2]rotaxanes through the Cu(I)-mediated Cadiot–Chodkiewicz heterocoupling ofterminal alkynes and alkyne halides.67

Other copper-mediated active metal
template reactions
In addition to using 13-Cu(I) in Glaser–Hay active template synthesis, Saito and co-workers used the phenanthroline complex in acopper-mediated Ullmann C–S heterocoupling of aryl iodide 28
and thiol 29 (10-fold excess of each) to give [2]rotaxane 30 in amodest (27%) yield (Fig. 9).46
The same Cu(I)-phenanthroline macrocycle has also beenused in a Sonogashira-type active template heterocoupling ofaryl iodides and terminal alkynes, generating rotaxanes in up to
52% yield (Fig. 10).72 Concurrent oxidative homocoupling of
the terminal alkynes occurs in such reactions and so thecorresponding diyne rotaxanes were formed as side-products
in each case. The mechanism is presumed to proceed via theChem Soc Rev

Fig. 9 Saito’s active template synthesis of a [2]rotaxane by Ullmann C–S
coupling of a thiol and aryl iodide.46

formation of Cu(I)-acetylide 31-Cu(I), followed by oxidative
addition of aryl iodide 32 to form Cu(III)-complex 33-Cu(III).
The latter undergoes reductive elimination through the macrocycle cavity to form [2]rotaxane 34. The best yields and selectivity for the heterocoupling product were obtained using theortho-isomer of 32.
Leigh and co-workers have used Cu(I) catalysis in the active
template Goldberg amidation of aryl halides to form [2]rotaxanes with chiral C2-symmetric cyclohexyldiamine macrocycles.73
The mechanism is similar to the active template Cu(I)-mediatedSonogashira-type coupling (Fig. 10), with an aryl amide rather
than an alkyne undergoing ligation with 21-Cu(I). The resulting
chiral rotaxanes were subsequently investigated as ligands forenantioselective metal catalysis (see section on asymmetric,
diastereoselective and other types of catalysts).

Fig. 8 (a) Jasti’s synthesis of a [c2]daisy-chain rotaxane 27 from an active template Cadiot–Chodkiewicz reaction. (b) Space-filling representation of
27.69

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synthesis, apparently because of the poor coordination of Pd(0)leading to detachment of the metal from various macrocycle types
during key steps of the catalytic cycle.27
Leaning on previously reported Pd(II)-mediated passive template syntheses of rotaxanes78–81 and catenanes for the macrocyclic ligand design,82,83 Leigh and co-workers showed that,
despite its square planar coordination geometry, Pd(II) can be asuitable metal for the active template synthesis of [2]rotaxanes
through alkyne homocoupling (Fig. 11).84 The reaction proceeds with the replacement of the trans-chloride ligands of
35-Pd(II) by the Cu(I)-acetylide unit 36 to form a threaded trans37-Pd(II) complex. Isomerisation to cis-38-Pd(II) occurs without
breaking the Pd–acetylide bond, preserving the threaded architecture. Reductive elimination occurs from the cis configuration
to yield diyne [2]rotaxane 39 after decomplexation of the weakly
coordinating Pd(0). Only a catalytic amount of Pd(II) (5 mol%) is
required, together with I2 or O2 to reoxidise the Pd(0) formedin situ, giving rotaxane yields up to 90%.
The oxidative Heck cross-coupling reaction85 is a variant of
palladium cross-couplings that does not feature Pd(0) in themechanism. Accordingly, it is more suitable as the basis for
active template synthesis. Leigh and co-workers demonstrated
its eﬃcacy in the synthesis of a variety of [2]rotaxanes using abipyridine macrocycle and boronic acid and electron-poor

Fig. 10 Saito’s active template synthesis of [2]rotaxanes through theCu(I)-mediated Sonogashira-type coupling of terminal alkynes and aryl
iodides.72

Other transition-metal-mediatedactive template reactions
Copper-catalysed reactions have proved to be particularly successful and robust catalytic manifolds for active template synthesis.
This is because copper catalysis is often promoted by particularligand types (which can form the basis of a suitable macrocycle)
and because of the well-defined 3D coordination geometries ofCu(I) and Cu(III) which aid ligation of the axle building blocks
through opposite faces of the macrocycle. However, copper issomewhat limited in its ability to activate sp3-hybridised carbons
compared to other metals such as palladium,74 nickel,75
rhodium76 and ruthenium.77 In the next sections we give examples
of how reactions catalysed by these, and a number of othertransition metals, have also proved amenable for active templatesynthesis.
Palladium-catalysed active template synthesis
Palladium-catalysed cross-coupling transformations are extensively
employed in organic synthesis for the construction of C–C bonds.
Although Pd(II) has a 2D square planar coordination geometry,
which is poorly suited for endotopic binding within a macrocyclic
cavity compared to the 3D tetrahedral geometry of Cu(I), palladium
offers high catalytic activity in numerous reactions. Attempts by
the Leigh group to use cross-couplings that feature transient Pd(0)in the catalytic cycle proved unsuccessful for active template

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Fig. 11 Active template synthesis of [2]rotaxanes through the Pd(II)mediated oxidative homocoupling of terminal alkynes.84

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Fig. 12 Active template synthesis of [2]rotaxanes through Pd(II)-mediatedoxidative Heck cross-coupling.27

alkene axle building blocks (Fig. 12).27 The catalytic loading
could be as low as 1 mol% while still furnishing a rotaxane yieldof 66%, the largest catalytic turnover number reported to date
for an active template reaction.
The examples in Fig. 11 and 12 demonstrate the significant
potential of palladium for active template synthesis, particularly if macrocyclic ligands can be found that can overcome thelability of Pd(0) so that it remains coordinated to the components during various important steps in the mechanism.
Very high yielding four-component synthesis of rotaxanes by
successive Pd(II)-promoted Michael additions of a-cyano esters toalkyl vinyl ketones has been reported using tridentate pyrroloimidazolone or bisoxazoline pincer macrocycles (Fig. 13).86 The formation of complex 40-Pd(II) enables two consecutive 1,4-conjugate
additions to a,b-unsaturated ketone 41 from opposite macrocycle
faces to quantitatively form [2]rotaxane 42-Pd(II). In this example thetemplate interactions between thread and macrocycle remain in therotaxane product, a rare feature for active template synthesis.
Accordingly, the intercomponent interactions were used to good
eﬀect for the synthesis of rotaxanes with well-defined switching of
the macrocycle position on the axle (molecular shuttles).
Nickel-mediated active template synthesis
An unusual dual Ni-/Cu-mediated alkyne homocoupling active
template reaction has been reported.87 The system uses anoctahedral Ni(II) macrocyclic complex followed by addition of
CuI which results in reductive elimination of the half-axle

Chem. Soc. Rev.

Fig. 13 Active template synthesis of [2]rotaxanes through successive
Pd(II)-mediated Michael additions of four components.86

ligands to yield [2]rotaxanes. The synthesis was high yielding(up to 95%), although stoichiometric quantities of NiCl2 andCuI are required.
Active template synthesis that deletes atoms from the building
blocks while joining them to form a hydrocarbon region of athreaded axle is a particularly appealing target because it iscompletely traceless. The main obstacle to doing so lies in achieving eﬀective and catalytic formation of C(sp3)–C(sp3) bonds usingorganometallic chemistry. This is generally difficult due to slow
rates of oxidative addition of metal centres to C(sp3)–heteroatom
bonds, concomitant with facile b-hydride elimination of theresulting organometallic intermediate.88–91 Most successful
C(sp3)–C(sp3) coupling protocols involve alkyl halides activatedtowards oxidative addition and lacking b-hydrogens.92,93
Adapting the work of Fu and co-workers on the coupling ofunactivated alkyl halides,94–98 the active template synthesis ofalkyl chain axle-region rotaxanes was achieved by Leigh andco-workers through the Ni(0)-catalysed C(sp3)–C(sp3) homocoupling of bromoalkanes (Fig. 14).99 The reaction was initiallythought to likely proceed through a Negishi-type mechanism,91
however mechanistic studies indicate a pathway similar to the
Ni-mediated coupling of aryl halides.100 Oxidative addition ofalkyl bromide 43 to 44-Ni(0) is followed by the one-electronThis journal is © The Royal Society of Chemistry 2024

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Fig. 14 Active template synthesis of traceless [2]rotaxanes through theNi(0)-mediated homocoupling of unactivated alkyl bromides.99

reduction of Ni(II), allowing a second oxidative addition of 43,
ligating the axle building blocks through opposite faces of themacrocycle. Reductive elimination then captures threaded
architecture 44, while Zn(0) reduces the resulting Ni(I) species
to catalytically active Ni(0).
Saito and co-workers have carried out the cross-coupling of
iodoarenes mediated by a dibenzodihydrophenanthroline–Nicomplex.101 This was used for the synthesis of [2]rotaxanes withup to ten para-phenylene units in the axle.
Active template synthesis by Ni-catalysed homocouplings ofalkyl bromides can produce multiply threaded rotaxanes. Leighand co-workers isolated doubly threaded rotaxane 45 in up to
51% yield using a terpyridine 35-membered macrocycle(Fig. 15a).102 During the process, [2]rotaxane 44 was also produced but the ratio of doubly- over singly-interlocked productcould be increased by using 43 in large excess. The mechanism
appears to proceed in a stepwise manner in which the [2]rotaxane is formed first, followed by binding of a second set of axle

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Review Article
building blocks to the metal coordinated in the [2]rotaxane toyield [3]rotaxane 45 after a second reductive elimination.
A triply threaded [4]rotaxane 46 was obtained using thesame strategy by increasing the size of the macrocycle from a
35-membered ring to either a 37- or a 38-membered ring
(Fig. 15b).103 The increased size meant the macrocycle could
accommodate the formation of a third axle within the cavity.
[2]Rotaxane was not observed in the product distribution using
the larger ring systems, only the doubly- and triply-threaded
products. This suggests that the [2]rotaxane does not have stoppers
large enough to prevent dethreading of the larger macrocycles
unless the metal remains coordinated (which reduces the eﬀective
size of the cavity, and the coordinated metal can then promote theformation of the second and third axle; Fig. 15a). Also consistent
with this, when a slightly larger 39-membered macrocycle wasused only non-interlocked coupled products were observed. To
date, rotaxane 46 is the sole example of a rotaxane containing
more than two axles threaded through a single macrocycle.
The formation of traceless rotaxanes by active templatesynthesis was later extended by the Leigh group to the preparation of unsymmetrical axle [2]rotaxanes by the Ni-catalysedC(sp3)–C(sp3) cross-coupling of alkylzinc with redox-active esters(Fig. 16),104 a reaction introduced by Baran and co-workers.105
Transmetallation of Ni(I)-bipyridine macrocycle 47-Ni(I) withalkylzinc 48, followed by single electron transfer (SET) fromthe Ni(I) to the phthalimide group of redox-active ester 49 andconsecutive decarboxylative fragmentation, leads to cationicintermediate 50-Ni(II).106 Radical recombination renders Ni(III)intermediate 51-Ni(III), which undergoes reductive elimination
through the macrocycle cavity to form [2]rotaxane 52, whileregenerating the catalytic Ni(I) species. [2]Rotaxane 53 was also
formed, resulting from the active template homocoupling ofalkylzinc 48.
Recently, Kimizuka, Yagi and Itami reported a novel Nimediated homocoupling active template reaction employing asimilar bipyridine macrocycle in the synthesis of catenane 54(Fig. 17).107 The threading unit is based on Itami’s previous
synthesis of catenanes and a trefoil knot through a covalentscaﬀold approach,108 and features cyclohexa-1,4-diene units109
that are converted to phenyl groups to form the all-benzene‘nanobelt’ of the final catenane.
Zinc-, cobalt-, ruthenium- and rhodium-mediated active
template synthesis
Although reactions based on copper, palladium and nickel
catalysis are the most popular manifolds for active templatesynthesis, reactions promoted by other metals have also been
explored. Zinc(II) has been used for the active template synthesisof [2]rotaxanes by the Lewis acid-catalysed Diels–Alder cycloaddition of imidazolidones with cyclopentadiene derivatives.110
Rotaxane 55 forms in up to 91% yield using either Zn(II) or Cu(II)ions (Fig. 18). Upon coordination of dienophile 56 to macrocycle
57-Zn(II), the activated threaded complex 58-Zn(II) is formed.
Cycloaddition with cyclopentadiene 59 produces 60-Zn(II), withsubsequent demetallation affording metal-free [2]rotaxane 55.
Only one of the two interconverting isomers of 59 engages in theChem. Soc. Rev.

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Fig. 15 (a) Mechanism of the active template Ni(0)-mediated active template synthesis of rotaxanes with one, two or three axles threaded through asingle macrocycle. (b) Doubly and triply threaded rotaxanes formed using this method.102

active template reaction with a 9 : 1 preference for the endo
adduct observed.
A small number of active metal template reactions have beendeveloped that proceed through radical mechanisms involving aredox process between the metal and the ligand. Co(II)porphyrinates
form nucleophilic radical carbenes that react with olefins to form
cyclopropanes.111–113 Megiatto and co-workers exploited this chemistry for the active template synthesis of rotaxanes with macrocycle
60-Co(II).114 The mechanism involves a radical carbene transfer
reaction between diazo and styrene half-threads (Fig. 19). Coordination of 3,5-diphenylpyridine ligand 61 to the exo-face of theCo(II)porphyrinate (it is too bulky to coordinate to the endo-face)Chem. Soc. Rev.

causes diazo-acetate 62 to react with macrocycle 63-Co(II) inside
the cavity, leading to Co(III)-carbene radical 64-Co(III). Subsequent carbene transfer with styrene derivative 65 generates
rotaxane 66-Co(II). In the absence of 61 the yield of [2]rotaxane
decreased from 95% to 74%,115 demonstrating the importanceof coordination of an exo-ligand for promoting formation of theinterlocked product over the free thread.
The same group reported that a Ru(II)-porphyrinate macrocycle promotes N–H carbene insertion between amines anddiazo half-threads in an active template fashion (Fig. 20).116
Ru(II)-porphyrinate 67-Ru(II) differs from 60-Co(II) in that it is
only composed of aromatic C–H bonds and therefore chemicallyThis journal is © The Royal Society of Chemistry 2024

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Fig. 16 Mechanism of the active template synthesis of traceless [2]rotaxanes through the Ni(I)-mediated heterocoupling of alkylzinc and redoxactive esters.104

inert to Ru(II)-carbenoids. Introduction of a bulky carbene
ligand exo- to the macrocycle forces reaction of diazo 69 tooccur inside the cavity. Addition of amine 68 generates [2]rotaxane 70-Ru(II) in quantitative yield.
The distinctive reactivity and catalytic properties of rhodium
have been exploited for active template synthesis by the Chaplin
group.117–120 They first described the formation of pseudorotaxane 71-Rh(I) by a Rh(I)-promoted terminal alkyne coupling reaction that forms an enyne axle (Fig. 21).117 Ligand exchange
between terminal alkyne 72 and Rh(I) ethylene complex 73-Rh(I)leads to Rh(I)-alkyne complex 74-Rh(I), which undergoes oxidative
addition to give 75-Rh(III). A second equivalent of 72 inserts into
the Rh–H bond in a ‘head-to-tail’ type mechanism to form a Rh(I)gem-alkenyl complex 76-Rh(III) that is sufficiently stable to beisolated. However, upon heating to 80 1C, 76-Rh(III) reductive
eliminates and does not afford the expected Rh(I) gem-enyne
pseudorotaxane 77-Rh(I), but instead quantitatively forms Eenyne pseudorotaxane 71-Rh(I). This suggests a mechanism inwhich b-hydride abstraction of 76-Rh(III) occurs and the equilibrium is driven towards the formation of E-enyne Rh(III) complex
78-Rh(III), which can rapidly undergo reductive elimination toform 71-Rh(I). Only the gem-enyne product is formed when thereaction is performed with an acyclic CNC ligand. This study

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Review Article

Fig. 17 Kimizuka, Yagi, and Itami’s Ni(0)-mediated active template synthesis of [8]cycloparaphenylene catenane 54.107

illustrates how active template synthesis can provide insights onligand tuning to change reaction regioselectivity.118
The Chaplin group developed a Rh-mediated active templatesynthesis of diyne rotaxanes from alkynyl Grignard reagents(Fig. 22).119 Transmetallation of alkynyl Grignard 79 with a macrocyclic phosphinite pincer complex 80-Rh(III) leads to 81-Rh(III).
Subsequent decarbonylation promoted by Me3NO aﬀords diyne[2]rotaxane 82-Rh(I) through reductive elimination (81% yield over
2 steps). The group later reported a similar pincer complex withbulkier stoppers that could be converted to a hydrocarbon-based
rotaxane.120 Demetallation followed by conversion of the phosphine ligands to thiophosphenes gave [2]rotaxanes, while a subsequent clipping reaction was used to synthesise a [2]catenane.

Metal-free active template synthesis
A key feature of active template synthesis is that the reaction
between the thread building blocks is substantially accelerated
through a macrocycle’s cavity compared to outside of it. This canalso be achieved without metal catalysis. As long as the threaded
product resulting from such a process is kinetically stable, it can
provide a useful and eﬀective means of spontaneously assembling

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Fig. 18 Active template synthesis of [2]rotaxanes through the Zn(II)-mediatedDiels–Alder of imidazolidones and cyclopentadiene derivatives.110

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Fig. 19 Megiatto’s active template synthesis of [2]rotaxanes through theCo(II)-mediated radical carbene transfer between diazo and styrene
derivatives.114

rotaxanes under kinetic control. (Note: if the threaded structures
are not kinetically stable under the reaction conditions, anyrotaxane present is the result of conventional ‘passive template’
synthesis under thermodynamic control.)Mock’s cucurbituril-promoted Huisgen azide–alkyne
cycloaddition
In 1989 Mock and co-workers carried out a rotaxane-forming
reaction that can be considered a combination of passive ammonium ion template synthesis and metal-free active templatesynthesis.121 In a mechanistic investigation of the copper-free(Huisgen) azide–alkyne cycloaddition reaction of ammonium
substrates catalysed by cucurbituril macrocycles, [2]rotaxane
product 83 was formed by accelerated axle formation within
the cucurbituril cavity (Fig. 23). The bulky substituents of theazide and alkyne reactants mean that the triazole axle cannot
dethread. The cycloaddition was shown to be substantially accelerated (ca. 105-fold rate increase) due to favourable orientation of
the reactants within the cavity and strain-promoted reactivity.
Similar complexation-driven eﬀective molarity increases toaccelerate axle-forming reactions have been used to assemble(poly)rotaxanes122 and for ‘cooperative capture’ synthesis.123 In
addition to cucurbiturils, other 3D ‘molecular barrels’, such as
cyclodextrins, pillararenes and calixarenes, have been used insuch approaches. For example, Arduini, Credi and co-workers
reported that a tri-urea-calix[6]arene accelerates the alkylation

Chem. Soc. Rev.

Fig. 20 Megiatto’s active template synthesis of [2]rotaxanes via Ru(II)mediated N–H carbene insertion.116

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could stabilize the transition state. No formation of 89 isobserved due to the steric preferences of the non-symmetricalmacrocycle. The authors later carried out the selective synthesisof all three possible orientational isomers of related calix[6]arenebased [3]rotaxanes.126

Metal-free active synthesis of rotaxanes from crown etheraccelerated reactions of amines and nucleophiles

Fig. 21 Chaplin’s active template synthesis through the Rh(I)-mediatedhomocoupling of terminal alkynes to form a threaded E-enyne.117,118

of a complexed pyridylpyridinium guest to form a rotaxane(Fig. 24).124,125 Macrocycle 84 forms a 1 : 1 complex with 85 intoluene, and upon addition of stoppering components 86 and87, [2]rotaxane 88 is formed in up to 70% yield. The macrocycle
accelerates alkylation of the pseudorotaxane 16 faster than
the axle is alkylated in the absence of the macrocycle. The
authors ascribe the rate enhancement to the increase of pyridine nucleophilicity inside the electron-rich cavity of 84 whichcontains multiple aromatic rings, as well as urea groups that

Fig. 22

In 2017, the Leigh group described the synthesis of [2]rotaxanes
with a bifunctional macrocycle designed to stabilise the transition state of the axle-forming reaction (Fig. 25).127 The intention
was that macrocycle 90, with a hydrogen bond donor pyridyl-2,6dicarboxyamide unit at one end and an hydrogen bond acceptor
oligo(ethylene glycol) chain at the other, would be able topromote the addition reaction of a primary amine 91 to a cyclic
sulfate 92 through the cavity by stabilising the reaction transition
state. The [2]rotaxane 93 was formed in 70% yield. Host–guest
studies confirmed that the macrocycle does not strongly bind toeither of the half-thread components, but rather stabilises thetransition state of the reaction proceeding through the cavity.
The control experiments used to interrogate the mechanismof formation of rotaxane 93 included the use of analogues ofmacrocycle 90 that were missing either the two amide groups(intended to stabilise the forming anion in the transition state)or the oligoethylene glycol chain (intended to stabilise theforming cation in the transition state). However, althoughreplacing the glycol units with a hydrocarbon chain led to norotaxane formation, a small amount (5%) of rotaxane was still
formed if the macrocycle amide groups were changed to esters.
This suggested that crown ethers might be able to promote thealkylation of a primary amine through the crown ether cavity.
This is somewhat counterintuitive as amines bind only very
weakly to crown ethers and, when protonated as ammonium
groups (which do bind strongly to crown ethers) then there is
no lone pair with which to act as a nucleophile. Nevertheless,this is exactly what happens (Fig. 26).128
Despite having modest binding constants for the threadbuilding blocks, crown ethers such as 94 accelerate the reactionof primary alkyl- and benzylamines such as 95 with a series ofelectrophiles to form rotaxanes (Fig. 26).128 Kinetic studies
show rotaxane formation with a benzylamine is B26 fasterthan the background thread-forming reaction. The process
allows the reagent-less formation of crown ether rotaxanes ina matter of hours at room temperature, accomplished by simply

Chaplin’s active template synthesis of diyne rotaxanes through Rh(III)-mediated homocoupling of alkynyl Grignard reagents.119

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Fig. 23 Mock’s synthesis of a [2]rotaxane through cucurbituril-promoted
Huisgen azide–alkyne cycloaddition of ammonium-functionalised axle
building blocks.121

mixing together the macrocycle and the two thread-forming
building blocks in toluene.
The rotaxane formation is driven by crown ether hydrogenbonding stabilising the partial positive charges formed in thetransition state, a process that has previously been observed in
ethylene-glycol-oligomer-catalysed aminolysis reactions.130,131
The utility of the metal-free active template reaction wasdemonstrated by the one-step synthesis of (i) pH-switchable
molecular shuttles via aza-Michael addition and (ii) crownether-peptide rotaxanes via N-acylation (Fig. 26).128

Chem Soc Rev
The system was subsequently extended to other electrophiles,
producing crown ether rotaxanes based on (thio)urea, carbamate,sulfonamide and phosphoramidate/phosphinamide-functionalised
axles in up to 95% yield and 4100 : 1 rotaxane-to-free-thread
selectivity.129,132 It also proved possible to use crown ether catalysed
N-arylation of primary amines with electron-deficient aryl halides to
produce rotaxanes with aniline threads. This metal-free active
template N-acylation strategy has been used for the single-stepenantioselective synthesis of mechanically planar chiral [2]rotaxanes(see section on mechanical and topological chirality).133
In an important recent development, the principle of enhancing the nucleophilicity of primary amines by hydrogen bonding
to a macrocycle has been expanded from crown ethers to cyclic
peptides.134 The Leigh group have previously threaded cyclo(proline) macrocycles such as 96 onto diammonium axles toform rotaxanes of cyclic peptides by passive template synthesis
in up to 63% yield.135 Numata and coworkers found that thismacrocycle-ammonium passive template motif could be adapted
to metal-free macrocycle-amine active template synthesis in asimilar manner to the crown ether-ammonium/amine system.134
With a glycine-derived amine nucleophile and phenylalaninederived nitrophenol ester electrophile metal-free active template synthesis generated wholly peptidic rotaxanes (Fig. 27).134

Fig. 24

Credi and Arduini’s cooperative capture synthesis of a [2]rotaxane.124,125

Fig. 25

Metal-free active template synthesis of a [2]rotaxane through transition state stabilisation.127

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Fig. 26 Metal-free active template synthesis of rotaxanes from primary amines, electrophiles and crown ethers.128,129

The yields reported are very modest (B1%), which the authors
ascribe to the tendency of cyclic peptide oxygens to point out of thecavity and the presence of competing intermolecular hydrogenbonds, both of which limit the ability of the macrocycle to form
strong hydrogen bonds with the amine. As well as being a strategy
to mechanically interlocked peptides, the extension of metal-free
active template synthesis from crown ethers to ammoniumbinding cyclic peptides suggests that other ammonium-binding
macrocycles (e.g. cucurbiturils, pillararenes, etc) may prove eﬃcacious at accelerating the reaction of amines through a macrocyclic
cavity for active template synthesis.

Protein metal-free active template synthesis
The metal-free active template concept has also been applied toprotein catenane synthesis.136 The Zhang group used protein
engineering to design a catenane-forming reaction based on a

SpyTag–SpyCatcher complex137 (Fig. 28a) where the catalytic
unit embedded in a cyclic protein promotes isopeptide bondformation of a telechelic protein through its cavity (Fig. 28b).
These entangled topologies displayed enhanced stability
against proteolytic digestion, thermal and mechanical denaturing, without compromising their biological function. The groupalso demonstrated that introducing mutations in the catalytically active SpyStapler protein (SpyStapler003; Fig. 28c) led to
improved efficacy of the active template reaction, which could
be exploited for the synthesis of higher-order protein [n]catenanes in good yields (Fig. 28c).138
The group have also developed a novel protein (‘AT-Snoop’)
for active template protein synthesis.139 AT-Snoop and AT-Spy
both catalyse isopeptide bond-formation but react orthogonallyusing diﬀerent proteins domains. The orthogonality was
exploited for the synthesis of [n]heterocatenanes, including
an asymmetric protein olympiadane.138

Fig. 27 Numata’s metal-free active template synthesis of wholly peptidic rotaxanes from a glycine nucleophile, a phenylalanine-nitrophenol ester
electrophile and cyclo(proline) macrocycle.134

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Fig. 28 Zhang’s metal-free active template synthesis of protein heterocatenanes.136–138 (a) SpyStapler-mediated isopeptide bond formation between
SpyTag and BDTag.137 (b) Active template synthesis of a protein [2]catenane from a cyclic protein incorporating the SpyStapler sequence (c-SpyStaplerPOI) and a linear protein terminated with the BDTag and SpyTag sequences at either end.136 (c) Higher order protein [n]catenanes (n = 2–5) assembled
using a mutated SpyStapler sequence (SpyStapler003).138

Active template assembly of interlocked nanoscale toroids

metal-free active template synthesis (Fig. 29).140 Yagai and co-

A remarkable spontaneous assembly of nanoscale interlocked
supramolecular toroids arises from a process closely related toworkers observed that molecules consisting of a barbiturate
head group, a rigid central core and non-polar tail self-

Fig. 29 Yagai’s self-assembling polycatenanes consisting of B13 nm diameter supramolecular rings.140 The molecules with a polar head group, rigid
segment and non-polar tail assemble into rosettes that stack to form helical strands and toroids. The internal surface of the toroids seed the formation of
new stacks, leading to supramolecular polycatenanes.140

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assemble into supramolecular hydrogen bonded rosettes. The
rosettes stack in an oﬀ-set manner, leading to curvature that
ultimately leads to the formation of toroids of B13 nm diameter. Nucleation of toroid assembly is quicker from sites
within the toroid cavity than outside it (the fundamental
principle behind active template synthesis; see Introduction
and Fig. 2b) resulting in interlocking of the toroids. A range ofinterlocked materials with topologies were obtained, ranging
from Hopf link [2]catenanes, to [5]ring olympiadanes andpoly[n]catenanes.140

Applications of active templatesynthesis
The special characteristics of active template synthesis include
the lack of a requirement for persistent recognition motifs
between the components in the interlocked product, and thatthe threaded structures need not be thermodynamically stable.
This opens the way for the synthesis of interlocked moleculesthat are inaccessible through passive template synthesis. Thesefeatures have led to active template synthesis being explored tomake molecules for fields as diverse as molecular machinery,drug delivery systems, sensing devices, catalysis and materials
science.
Molecular shuttles
Active template synthesis has been used to prepare a number ofrotaxane-based molecular shuttles and switches; that is, rotaxanes
in which the macrocycle incessantly moves from one well-definedsite on the thread to another (resulting in a net change in ring
position in the case of switches).28,67,86,110 The dynamic aspects ofthese systems have been reviewed elsewhere,141,142 but someadvantages of using active template synthesis for their assembly
are illustrated by switchable molecular shuttle 97 (Fig. 30).67
Molecular shuttle 97 was synthesised through an active
template Cadiot–Chodkiewicz heterocoupling, with one alkyne
unit containing an aniline and the other a dimethylaminopyridine (DMAP) group (Fig. 30).67 In its unprotonated form themacrocycle of 97 preferentially coordinates to the aniline site on
the axle through a single hydrogen bond with an intercomponent
binding energy of 3.9 kcal mol1, which would be far too weakto thermodynamically drive rotaxane synthesis. Protonation orLi+ coordination of the DMAP group of 97 triggers the translocation of the macrocycle to the DMAP axle site. This illustrates theefficacy of active template synthesis for the preparation ofrotaxane-based molecular shuttles with much weaker intercomponent interactions (and correspondingly faster dynamics) thanthose required for passive template methods.143
The active template Cadiot–Chodkiewicz reaction has beenused to develop other mechanically interlocked structures
without strong intercomponent binding interactions, such as
the [c2]daisy chain rotaxane 27 described by Jasti and coworkers (Fig. 8). This structure can be switched from a comparatively stable contracted form at temperatures lower than
40 1C to an extended state at higher temperatures.59

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Fig. 30 Active template Cadiot–Chodkiewicz synthesis of molecular
shuttle 97. The position of the macrocycle on the axle is governed byrelatively weak intercomponent interactions.67

Goldup and co-workers used active template CuAAC synthesis to prepare molecular shuttles in which the shuttling of abipyridine ring between bidentate and tridentate coordinatingsites144 could be controlled by metal ions with diﬀerent preferential coordination geometries.145
Weiss, Guldi, Hayashi and co-workers have reported lightswitchable molecular shuttling in a [2]rotaxane based on anelectron donor–acceptor system composed of a Zn–porphyrinbased macrocycle and a fullerene-stoppered thread.146 An
active template CuAAC reaction installs a triazole moiety inthe axle that forms one binding site in the resulting shuttle.
Beer and co-workers have also reported porphyrin-based
molecular shuttles synthesised by active template protocols.
In those examples the position of a pyridine macrocycle (usedto direct the CuAAC reaction) is controlled via the addition of a
Lewis base or anion.147
Mechanical and topological chirality
Active template synthesis has been used to make a range of
mechanically and topologically chiral interlocked molecules, inwhich the chirality arises solely from the orientation of theinterlocked components as opposed to point-chirality embeddedin their structures. Active template synthesis is well-suited for thispurpose as, like enantioselective synthesis, it is inherently underkinetic control. The Goldup group have made extensive use ofactive template CuAAC reactions to prepare mechanically planarchiral rotaxanes and catenanes (Fig. 31).148 A rotationally asymmetric bipyridine macrocycle (98), a sugar-based azide (99) andan alkyne (100) reacted in the presence of Cu(I) to produce adiastereomeric mixture of [2]rotaxane 101. Although the reaction

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Fig. 32 Goldup’s diastereoselective active templatemechanically planar chiral rotaxane (Smp)-103.149

Fig. 31 Goldup’s active template synthesis of mechanically planar chiralrotaxanes (Smp)- and (Rmp)-102.148

did not impart stereoselectivity in the reaction outcome, it
enabled simple separation of both diastereomers by chromatography. The chiral sugar could subsequently be replaced by anachiral amine nucleophile, removing the element of point chirality from the interlocked structures resulting in the isolation ofboth [2]rotaxane enantiomers (Smp)- and (Rmp)-102.
The approach was later expanded to diastereoselective
synthesis of mechanically planar chiral rotaxanes by modifying
the stereodirecting moiety in the half-thread building block(Fig. 32).149,150 Excellent diastereomeric ratios of 98 : 2 wereobtained using chiral amino acid-derived azide 102. Postassembly removal of the point chirality source by symmetrisation of the amino acid stereocentre rendered the enantioenriched mechanically planar chiral rotaxane (Smp)-103. Similar
methodology was later applied to the stereoselective preparation of enantiopure topologically chiral catenanes.151
The Goldup group have also demonstrated that this chiralauxiliary can act as an mechanical interlocking auxiliary,23–25
i.e. a group that facilitates the formation of the mechanicalbond but is subsequently cleaved from the structure after
shuttling of the macrocycle to a different part of the axle
(Fig. 33).25 The auxiliary was removed to leave ‘impossible’rotaxane23,24 (Smp)-104, with no recognition motif between theaxle and macrocycle. The group also investigated attaching thechiral auxiliary to the macrocycle, rather than an axle-forming
component.152 This could be used to direct the formation ofChem. Soc. Rev.

synthesisofboth mechanically planar chiral rotaxanes and topologicallychiral catenanes with good stereoselectivity (typically 490% ee).
CuAAC active template synthesis has also been used by the
Papot group for the diastereoselective synthesis of [1]rotaxanes(‘molecular lassos’).153,154 The point-chiral stereogenic unit has
not yet been removed, meaning that a mechanically planarchiral [1]rotaxane with chirality solely arising from the mechanical bond remains to be achieved.
The active template mechanical interlocking chiral auxiliary
systems developed by the Goldup group have been used to makea number of catenanes and rotaxanes with other, previously
unexplored, types of chirality, including co-conformationally‘pseudo-topologically’ chiral catenanes,155 mechanically (butnot topologically) planar catenanes,156 mechanically axiallychiral catenanes and noncanonical mechanically axially chiralrotaxanes.157–159 The topological aspects of these fascinating
systems has recently been reviewed elsewhere.160 The versatility
and efficiency of the active template approach has facilitated the
exploration of new types of chiral interlocked molecules, leading
to a better understanding of aspects of molecular asymmetry.
The Leigh group reported a single-step asymmetric synthesisof mechanically planar chiral rotaxanes by using primary amine
105, activated ester 106a–b with a chiral leaving group andachiral crown ether macrocycle 107 with Cs symmetry in an
application of metal-free active template synthesis (Fig. 34).161
The incorporation of cinchonidine pseudoenantiomers as
directing groups enabled the synthesis of either enantiomerof [2]rotaxane 108 in 40–50% ee. X-Ray crystal structures andcomputational modelling indicated p-stacking between thenaphthalene ring of the macrocycle and the electron-deficientaromatic stopper helps to direct the reaction stereoselectivity.
A diﬀerent approach to mechanically planar chiral rotaxanes, also exploiting metal-free active template synthesis, wasThis journal is © The Royal Society of Chemistry 2024

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Fig. 33

Goldup’s mechanical interlocking chiral auxiliary for the active template synthesis of ‘impossible’ mechanically planar chiral rotaxanes.25

Fig. 34

Single-step asymmetric metal-free active template synthesis of mechanically planar [2]rotaxanes.161

developed by Tian and Zhu.162 Modified bis(chloroaryl) crownethers were used as catalysts for the spontaneous formation of[2]rotaxanes using a range of electrophiles and amine nucleophiles. The prochiral interlocked molecule (with an unsymmetrical axle but a rotationally symmetric ring) then underwent
catalytic desymmetrisation through a Pd-catalysed asymmetricSuzuki–Miyaura reaction to yield the chiral rotaxanes in up to
97 : 3 er.
Asymmetric, diastereoselective and other types of catalysts
In 2015, Leigh and co-workers reported the first use of amechanically chiral [2]rotaxane ligand for enantioselective catalysis, synthesised via active template methodology.73 [2]Rotaxane 109 (Fig. 35) was prepared through Cu(I)-mediatedGoldberg active template synthesis. The chiral interlocked
structure has an endotopic binding site on the macrocycle thatcan bind various transition metals. The chiral rotaxane ligand

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was used for the Ni(II)-catalysed enantioselective Michael addition of diethyl malonate 110 to various nitrostyrene derivatives
111a–f, affording products 112a–f in good yield and enantiomeric enrichment (typically 498% yield and 93 : 7 er). Chiralinduction with the rotaxane ligand was significantly more
effective than with a comparative acyclic chiral ligand (68 : 32er), although considerably longer reaction times were neededwith the rotaxane (27 days compared to 2 days). Both the strong
enantioselectivity and the slow reaction times can be attributed
to the sterically hindered binding pocket of the rotaxane which
results in a catalytic site where the chirality is well-expressed in
all three dimensions.
The Goldup group have demonstrated that chiral rotaxanes
can be used as ligands for diastereoselective catalysis. An active
template CuAAC reaction was used to synthesise the interlocked ligand for [2]rotaxane-gold catalyst 113-Au(I).163 The
catalytic activity could be switched on by the addition ofChem. Soc. Rev.

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Fig. 36 Goldup’s [2]rotaxane precatalyst 113-Au(I) prepared by an active
template CuAAC reaction, and the eﬀect of additives on its catalytic
eﬃcacy in the Toste–Ohe–Uemura cyclopropanation reaction.163

Fig. 35 Mechanically chiral [2]rotaxane 109, synthesised through a Goldberg active template reaction, and its scope as a ligand for the nickelcatalysed enantioselective Michael addition of diethyl malonate and transb-nitrostyrenes.73

catalytically innocent metal cations (Fig. 36). 113-Au(I) was
shown to catalyse Toste’s Au(I)-mediated modification of the
Ohe–Uemura cyclopropanation reaction.164,165
Building on this system, Goldup and co-workers described acatalyst for asymmetric synthesis that relies on the mechanically planar chirality of the rotaxane ligand as the sole source ofchiral induction.166 Ligand (Rmp)-114 was synthesised via adiastereoselective active template CuAAC reaction149 (Fig. 37a)(see section on mechanical and topological chirality). Upon
coordination to Au(I) and activation with a cofactor, (Rmp)-114Au(I) proved an eﬀective catalyst for the Au(I)-mediated
Toste–Ohe–Uemura cyclopropanation, generating a range of
cyclopropanes (e.g. 115) in good yields and stereoselectivities(62–92% de for the cis diastereomer, 9–77% ee; Fig. 37b).
Modelling and transition state calculations suggest that (Rmp)114-Au(I) possesses a well-defined and rigid chiral environment
around the metal centre (Fig. 37c).
The Goldup group have also reported [2]- and [3]rotaxane
organocatalysts, synthesised via CuAAC active template reactions, that promote the anion–p catalysed Michael addition ofmalonic acid monothioester 116 to b-nitrostyrene 117 (Fig. 38).
The selectivity of 62 : 1 with [3]rotaxane catalyst 118 forChem. Soc. Rev.

addition/decarboxylation product 119 was comparable with themost effective non-interlocked catalysts previously reported.167
Computational studies suggested that the high selectivity
observed may be due to p-stacking between the protonatedbipyridine group and the naphthalene diimide.
In catalysis applications other than stereoselective catalysis,
Schmittel and co-workers have exploited the triazole units formed
during CuAAC active template reactions to create binding sites foran allosterically regulated silver(I) catalyst.168 Catalysis by the[2]rotaxane was regulated by steric restrictions on the conformational mobility of the components inhibiting the formation of
catalytically active species. They have also described the design of athree-input logic AND gate with catalytic output using a [2]rotaxane
shuttle prepared by active template synthesis.169
Sensing and molecular recognition
Beer and co-workers have used active template synthesis toassemble [2]rotaxane hosts for molecular recognition andsensing.170 Based on their earlier halogen bonding hostmolecules,171,172 halogen bond donating units were incorporated in both the macrocycle and axle components of a rotaxane
to generate a 3D anion binding pocket. Modification of theactive template CuAAC reaction installed a iodotriazole ring aspart of the rotaxane axle173 with a bis-iodotriazole macrocycle,
generating [2]rotaxane 120 in 25% yield (Fig. 39a). Exotopic
coordination of a Re(I) atom to the triazole ligands was thenused to orient the iodine atoms towards the inner cavity of themacrocycle. Host 120-Re(I) preferentially bound size- andshape-complementary Cl anions over other halide and acetateanions. The group have subsequently explored structurally
related rotaxanes that bind halides in the presence ofwater,174,175 hydrogen and halogen bonding rotaxanes for alkali

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Fig. 37 (a) Goldup’s active template synthesis of mechanically planar chiral rotaxane precatalyst (Rmp)-114-Au(I). (b) Example of a diastereoselective andenantioselective Toste–Ohe–Uemura cyclopropanation reaction promoted by 114-Au(I). (c) Computationally modelled transition state.166

Fig. 38 Goldup’s [3]rotaxane anion–p organocatalyst 118 for the Michael
addition of malonic acid monothioester to b-nitrostyrene.167

metal-halide ion-pair sensing,176,177 and a ferrocene-functionalised
rotaxane for electrochemical sensing of bromide.178 Rotaxanes
121-Zn(II) and 122 (Fig. 39b) proved to be eﬀective fluorescentsensors179 and chiral anion receptors,180 respectively, and several
related rotaxanes have been prepared that can switch between
cationic and anionic binding modes.181
The Beer group have also demonstrated that Cu(I) binding toalkyl-selenium or alkyl-tellurium moieties in a macrocycle canThis journal is © The Royal Society of Chemistry 2024

be used to direct CuAAC active template synthesis through themacrocycle to form chalcogen-derivatised rotaxanes such as
123a–b (Fig. 39b).182 The resulting rotaxanes bind hard and softanions in a broad range of environments.
A range of hydrogen bonding motifs unrelated to the active
template assembly process have been incorporated into mechanically interlocked hosts for the recognition of small molecules andanions. McClenaghan, Tucker and co-workers prepared [2]rotaxane systems containing barbital recognition sites, such as 17(Fig. 6b), via active template copper-catalysed CuAAC and Glaser
reactions.47,183 Beer et al. constructed a neutral [2]rotaxane host foranionic guests using a hydrogen bond donating indolocarbazole
unit as part of the axle.184 A [2]rotaxane host including an amidebinding site was used by the Ghosh group for the electrochemicalsensing of anions.185 Jasti and co-workers used a Cu-catalysed
active template reaction for a family of [2]rotaxanes in which
fluoride-70 or thiolate-186 induced dethreading results in theswitching on of fluorescence.
The Goldup group have used CuAAC active template synthesis
to build a number of rotaxanes for anion187 and cation188–190
binding. Some of the interlocked ligands stabilise distorted metal
coordination geometries with unusual coordination numbers
due to the sterically restricted 3D shape of the binding
pocket.189 This is exploited in a Pt(II)-rotaxane complex, in which
the metal is stabilised towards oxidation and acts as a reversible
stimuli-responsive phosphorescent sensor for Ag(I) ions.190
Prototypes of drug delivery systems
The lack of need for specific functional groups on the axle ofrotaxanes using active template synthesis led to the design ofChem. Soc. Rev.

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Fig. 39 (a) Beer’s active template synthesis of [2]rotaxane 120-Re(I) for anion sensing. (b) Other examples from the Beer group of halogen- andchalcogen-bonding rotaxane hosts prepared by active template synthesis.170,179,180,182

enzyme-sensitive [2]rotaxane 124 by Papot, Leigh and co-workers
for the controlled release of the anticancer drug paclitaxel intumour cells (Fig. 40).191 Prodrug stopper 125 and hydrophilic
fragment 126 were coupled through a self-immolative macrocycle(127) containing a Cu(I)-coordinating pyridine group. While thenon-interlocked thread undergoes rapid esterase hydrolysis inplasma, the macrocycle in 124 acts as a shield, protecting theester group in the axle from enzymatic degradation. However,cancer cells overexpress b-galactosidase, which triggers a cascadeof reactions that culminate in the opening of the macrocycle andrelease of the active form of the drug.
Besides providing temporary shielding of an axle, rotaxane
formation can be used to transiently modify the solubility andabsorption properties of molecular components. Lewis et al.
reported the use of an a CuAAAC active template [2]rotaxane asa triggerable cage for G-quadruplex (G4) DNA binders.192 The[2]rotaxane has better cell permeability than the analogous
non-interlocked DNA binder, but lower cytotoxicity (probably
due to the macrocycle inhibiting access to the G4 DNA binder).
Enzymatic or light-triggered cleavage of one of the rotaxane
stoppers liberates the G4 DNA binder within the cell, restoring
its binding properties and cytotoxicity with high spatiotemporal control. Goldup, Tavassoli and coworkers have designed a
triggered Curtius rearrangement immolative system wheremacrocycles can be functionalised at a late stage to incorporatea range of diﬀerent cargos and trigger units.193 The approach
was demonstrated with bipyridine macrocycles for CuAAC
active template reactions and, notably, with crown ethers formetal-free active template synthesis.

Chem. Soc. Rev.

Sheathed ‘molecular wires’: rotaxanes and catenanes withextended-conjugated components
Active template alkyne homocoupling and alkyne–alkyne heterocoupling reactions have been used to prepare a wide rangeof polyyne rotaxanes with p-conjugated axles. The groups ofAnderson, Tykwinski,51,61,62,71 and Gladysz52,58,59 have exploredthe synthesis of polyyne rotaxanes using active template Glaserand Cadiot–Chodkiewicz couplings. Long polyyne chains areprone to degradation and a threaded sheath structure canprovide substantially improved stability.61–63 Sheathed polyynes also show some modifications in photophysical behaviour
compared to the non-interlocked components,64,68 leading totheir investigation as molecular wires.
The Anderson group have used active template Glaser couplings for the synthesis of p-conjugated rotaxanes with Zn(II)porphyrin stoppers at either end (Fig. 41).60 Porphyrin [2]rotaxane 128 was elaborated into [4]catenane 129 in 62% yield using
130 as a radial template for the interlocked architecture.
[7]Catenane 131 was also formed as a Vernier template byproduct of the synthesis.
The Anderson and Jasti groups have both used masked
phenyl and alkyne units to extend the number of pconjugated units in the axle and increase the diversity ofaccessible polyyne rotaxane and catenane structures. Jasti andco-workers used cyclic precursors to [n]cycloparaphenylene
nanohoops for the synthesis of p-conjugated rotaxanes andcatenanes via active template Cadiot–Chodkiewicz heterocouplings (Fig. 42).194 The bent cyclohexadiene moieties in 132
facilitate endotopic metal binding, which is difficult to achieve

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Fig. 40

Review Article

Papot and Leigh’s active template CuAAC synthesis of b-galactosidase-cleavable [2]rotaxane 124, which releases paclitaxel in tumour cells.191

with cylindrical [n]cycloparaphenylenes. Reductive aromatisation of the cyclohexadienes furnishes the nanohoops in [3]rotaxane 133 and catenanes 134–135. The group later expanded themethodology to CuAAC active template synthesis, producing
triazole catenanes in high yields.195
Anderson and co-workers have employed indane196 andbicyclo[4.3.1]decatriene197 as photolabile masked-alkyne equivalents as well as dicobalt carbonyl complexes that can be unmaskedby oxidative decomplexation.198 These synthons have been used in
active template Glaser and Cadiot–Chodkiewicz syntheses of rotaxanes and catenanes, including polyyne [3]rotaxane 136 (Fig. 43)
which has 14 contiguous alkyne units in the axle stabilised by thenanohoop sheath. The strategy was later used to prepare a polyrotaxane with an extraordinary 34(!) contiguous triple bonds inthe axle and four threaded macrocycles.199 This polyyne rotaxane is in a length regime where the electronic properties ofpolyynes converge to those of carbyne. The rotaxane displayedelectronic properties similar to those predicted for an infinite
carbyne, illustrating the potential of polyyne rotaxanes to act as
molecular wires.
The synthesis of catenanes with this method has also beenreported, however, unmasking of the alkynes resulted in acomplex mixture of products that could not be purified.

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The CuAAC active template reaction has been used by thegroups of Ngo, D’Souza and Goldup for the synthesis of porphyrinoid rotaxanes.200,201 These compounds displayed similar
photophysical properties to the free thread component, but thethreaded macrocycles inhibit intermolecular interactions
between axles including p-stacking-driven aggregation andligand-driven dimerisation.
Modification of chemical and physical properties
Mechanically interlocking molecular components can significantly alter both chemical and physical properties.202 Active
template synthesis is particularly useful in this regard as itenables components with otherwise weak binding aﬃnities tobe locked in close proximity, a situation that is hard to achievein other ways.
Leigh and co-workers have used metal-free active templatesynthesis to make compact amine-crown ether rotaxanes thatexhibit exceptional basicity (Fig. 44).203 The super-basicity
results from three main factors: (1) the formation of stronghydrogen bonding and electrostatic interactions in the protonated salt of the rotaxane; (2) the forced proximity (and lack ofconformational and co-conformational freedom) of the amineand ethylene glycol functional groups, resulting in electrostatic

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Fig. 41

Anderson’s assembly of [4]- and [7]catenanes from [2]rotaxanes prepared by active template Glaser homocouplings.60

repulsion between the interlocked macrocycle and thread; (3) ahigh degree of preorganisation of the components in the freebase rotaxane that favours amine protonation.

Chem. Soc. Rev.

A range of compact rotaxane superbases was prepared bymetal-free active template in 1–3 steps from commerciallyavailable starting materials. The compact rotaxane superbases

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Fig. 42

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Jasti’s assembly of interlocked nanocarbons via active template Cadiot–Chodkiewicz synthesis.194

had pKaH+ values as high as 32.2 for 137 in acetonitrile(13 pKaH+ units higher than the non-interlocked components,
substantially larger than that of typical crown ether-amine
rotaxanes), which are comparable to some phosphazene
superbases. The highest basicities were generated with thesmallest macrocycle (21-crown-7) and the most electron-richdibenzylamine axles. The most efficacious compact rotaxane
superbases showed minimal nucleophilicity and excellent
hydrolytic stability in comparison to conventional commercial
superbases.
Rotaxane formation, either by active or passive synthesis,
can also be used to tune photophysical properties. An illustrationis the Goldup and Zysman-Colman groups use of CuAAC active
template synthesis to prepare carbazole-benzophenone-based
rotaxanes that display thermally activated delayed fluorescence(TADF).204 A large increase in photoluminescence quantum yield
results from threading one or two rings around the TADF
emitting unit. The interlocked structure also increases photostability of the emitters and altered their emission wavelength,
shifting it slightly to the red compared to the non-interlockedThis journal is © The Royal Society of Chemistry 2024

thread. These properties arise from the close proximity between
the macrocycle and axle and resulting weak interactions thatfinely tune the HOMO energy level, the singlet–triplet energy gap,
and the energy gap between the charge transfer states of theemitters.
A [2]rotaxane system capable of reversible electronic energy
transfer (REET) between chromophores attached to the axle
and macrocycle of a rotaxane has been reported by the McClenaghan and Goldup groups.205 Delayed luminescence and long
luminescence lifetimes result from the close proximity of thechromophores.
Interlocked systems accessible through active template synthesis have also been investigated as single-ion magnets. The rigid
coordination environment present in compact rotaxanes was used
to design cobalt(II) ligands that form complexes that show magnetic anisotropy and field-induced single-ion magnet behaviour.206
The restriction of interlocked component (co-)conformational freedom in relatively compact rotaxanes accessible byactive template synthesis can manifest itself in eﬀects observable by EPR207 and/or NMR spectroscopy.208 The restricted

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Fig. 43 Anderson’s extended polyyne rotaxane 136 synthesised via a Cadiot–Chodkiewicz active template reaction followed by oxidative unmasking of
the bridging alkynes.198

Fig. 44 Spontaneous assembly by metal-free active template synthesis ofcompact rotaxane superbase 137.203

dynamics influences EPR resolution207 and hydrogen bonding
interactions208 can be directly probed through 1H–15N multiple
quantum coherence NMR experiments.
Oligomers, polymers and other materials
Mechanically interlocked polymers are appealing materials dueto the structural stability conferred by the mechanical bond andtheir potential for stimuli-responsive behaviour.209 Most
poly[n]rotaxanes are prepared under thermodynamic control(i.e. conventional passive template synthesis) or by the polymerisation of pre-formed rotaxane monomers. However, Goldup
and co-workers have shown that well-defined oligo[n]rotaxanes
can be prepared through iterative CuAAC active template synthesis (Fig. 45).210 A series of monodispersed rotaxane oligomers ofcontrolled length was prepared using small bipyridine macrocycles, such as 138, and functionalised monomer 139 in a series

Chem. Soc. Rev.

of sequential coupling and deprotection steps. Homo[n]rotaxanes
such as 140 and 141, as well as hetero[n]rotaxanes incorporating
diﬀerent macrocycles threaded in sequence, were synthesised inhigh overall yield (90–92% per step). The reduced reactivity ofsequential active template reactions around a branched central
unit due to the steric bulk of incoming macrocycles was later
harnessed for the stepwise synthesis of [3]- and [4]rotaxanes froma 1,3,5-triethynylbenzene core.41
The Goldup and Tavassoli groups have prepared oligonucleotidebased rotaxanes by adapting click DNA ligation211,212 to active
template CuAAC synthesis.213 Using a bipyridine macrocycle andoligonucleotide strands functionalised with an alkyne or azide
group in the 30 and 50 positions in their chain termini, two diﬀerent
mechanically interlocked DNA strands could be prepared ingood yield. The threaded macrocycle had a shielding eﬀect on
duplex formation, inhibiting DNA hybridisation and PCR amplification of the oligonucleotide rotaxanes compared to noninterlocked analogues.
Hybrid organic–inorganic interlocked structures offer analternative class of materials. Szyszko and co-workers have used
CuAAC active template synthesis for the assembly of a series ofhybrid organic–inorganic rotaxanes incorporating cubic silesquioxanes as one of the stoppering elements.214 The hybrid
rotaxanes demonstrated improved thermal stability in the solidstate compared to wholly organic analogues.
Mullen and co-workers have reported the CuAAC active
template synthesis of [2]rotaxanes on polymer resins.215 This

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Fig. 45

Goldup’s synthesis of homo[6]rotaxane 134 through iterative high-yielding active template CuAAC reactions.210

Fig. 46

A rotaxane-based peptide synthesiser 135, assembled through CuAAC active template synthesis.216

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generated higher yields of interlocked products than comparable passive template solid phase synthesis.

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Molecular machinery
The well-defined large amplitude dynamics possible in rotaxane and catenane architectures, together with active templatesynthesis being under kinetic control, has led to its exploitationin both the synthesis and operation of artificial molecularmachines. Leigh and co-workers have used CuAAC active templatesynthesis to assemble rotaxane machines (e.g. 142) that perform
sequence-selective synthesis in a manner reminiscent of the ribosome (Fig. 46).216–221 The rotaxane design features a catalyst-bearing
macrocycle that moves along the threaded axle, removing the aminoacid barriers that block its path, transferring them to the growing
peptide chain in the sequence it encounters them along the track(Fig. 46). Active template synthesis was also used to make a rotaxane
synthon that could be added to longer tracks, resulting in higher

Chem Soc Rev
overall yields than the original strategy.217 The concept was later
extended to connect other types of building blocks in sequence toform oligomers and polymers, including nonproteinogenic
b3-amino acids,218 leucine-ester-derivatised polystyrene chains,219
and oligomers joined through iterative carbon–carbon bondformation.220 Parallel operation of two molecular peptide synthesisers in the same pot was used to assemble a decapeptide.221
Catalysis-driven metal-free active template synthesis has beenused to demonstrate the mechanism of chemically fuelled molecular pumps. Molecular pump 143 contains an activated ester
electrophile that causes 24-crown-8 (94) to thread through its
accelerated reaction with benzylamine 105, forming amide rotaxane 144 (Fig. 47).222 Subsequent addition of a bulky N-Boc groupforms 145, with the macrocycle shuttling to the oligo(ethylene
glycol) collection thread. Substitution of the amide to form
phenolic ester 146, followed by another crown ether threading
active template reaction, generates [3]rotaxane 147.

Fig. 47 (a) A stepwise-operated molecular pump that makes use of successive metal-free active template transamidation reactions.222 Macrocycles are
pumped onto the axles by a sequence of: (1) an active template transamidation reaction, (2) Boc-addition, and (3) substitution by an activated ester. (b)[5]Rotaxane 148 formed after two pumping cycles from a thread with pump motifs at either terminus. X-Ray crystal structure of 148. (c) [4]Rotaxane 149,
in which the macrocycles have been threaded onto the axle in a controlled sequence.

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Every pumping cycle can add an additional macrocycle tothe thread for each activated ester present, and so [5]rotaxane
148 is obtained after only two transamidation pumping cycles
from a thread with pumping modules at both ends. In this highenergy, kinetically locked, structure an array of weak CH–O
hydrogen bonds between the components is apparent from
X-ray crystallography (Fig. 47b). By carrying out pumping cycles
with different crown ether derivatives, it was also possible tosynthesise rotaxanes with specific sequences of threaded
macrocycles, such as 149 (Fig. 47c).
Metal-free active template synthesis also enables the designof molecular pumps that operate autonomously, in whichmacrocycles are continuously pumped onto an axle, away froma state of equilibrium, powered by a chemical fuel.223 Catalysisdriven molecular pump 150 features a free benzylic amine at
one end and a bulky stopper at the other (Fig. 48). The poorbinding aﬃnity of crown ether macrocycles for triazoles meansthat a vanishingly small proportion of macrocycles are threadedon the axle at equilibrium. However, an Fmoc-derived chemicalfuel, 151, acts as an electrophile for a crown ether metal-free
active template reaction, forming [2]rotaxane car-152 (the italicised prefix refers to the position of the ring on the axle). The

Review Article
Fmoc-carbamate group prevents macrocycle dethreading andthe restricted steric environment around the carbamate site
results in the macrocycle being displaced to the catchment
region of the thread (tri-152). The presence of i-Pr2NH base in
the reaction mixture triggers decomposition of the Fmoccarbamate group faster when the bulky macrocycle is distantfrom the carbamate group. The trifluoromethyl group (shownin red in Fig. 48) is suﬃciently large (a molecular ‘speed bump’)
that it slows dethreading of the macrocycle from the catchment
region oﬀ the open amine-terminated end of the thread.224
Therefore pumping of another crown ether onto the axle occurs
faster than dethreading of the ring already on the axle, leading
to the formation of [4]rotaxane 153. Macrocycles are thus
continuously pumped onto the axle until all of the Fmoc-fuelis depleted, after which the rings dethread to regenerate theoriginal ring equilibrium distribution in solution.
Unusual reactivity and mechanistic insights
As noted earlier, active template synthesis can provide mechanistic
information about the catalytic manifolds employed, for example
when more than one ring is unexpectedly threaded onto an axle ormultiple strands are encircled by a single ring.28,36,39,40,48,61,102,103
Sometimes the mechanical bond can lead to other unexpectedreaction outcomes. Chaplin et al. reported the selective formationof E-enyne products in their Rh(I)-mediated active template formation of pseudorotaxanes (Fig. 21)117 and have observed unusual
C–C s-bond oxidative additions118 (see section on zinc-, cobalt-,ruthenium- and rhodium-mediated active template synthesis).
Goldup and co-workers found an unusual tandem process
occurred during the active template CuAAC synthesis of[2]rotaxanes involving propargylic alcohol 154 as the alkyne
substrate. When small bipyridine macrocycle 155 was used, apost-assembly rearrangement of the stabilised Cu(I)-triazolide
interlocked derivative was triggered rendering the unexpected
acrylamide rotaxane 156 (Fig. 49).225 Mechanistic studies suggestthat mechanical bond stabilisation of the triazolide intermediate
and the steric constraints imposed during rotaxane formation
alters the chemoselectivity of the metal-catalysed reaction.

Conclusions

Fig. 48 An autonomous catalysis-driven artificial molecular pump 150
which operates continuously in the presence of chemical fuel 151.223

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The active template synthesis of entwined and interlocked
structures is an eﬃcacious and versatile strategy that complements conventional passive template synthesis. In addition tooften requiring only sub-stoichiometric quantities of metalsalts (or no reagents whatsoever in the case of metal-free active
template synthesis), other key advantages include that its use
can be traceless, without the need for binding sites in bothcomponents to be threaded or interlocked. Furthermore, theassembly process is carried out under kinetic control, enabling
the synthesis of interlocked products that are not necessarily
thermodynamically stable. Accordingly, threaded structures canbe generated with functional groups held in close proximity toeach other in (co)-conformations that might not be accessible
through other synthetic strategies. Active template synthesis

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Fig. 49

Chem Soc Rev

Proposed mechanism of the tandem active template CuAAC rearrangement reported by Goldup and co-workers.225

often proceeds in high yields, with simple experimental procedures and readily available starting materials. Rotaxanes formed
through active template chemistries are currently being investigated for potential applications in fields as diverse as sensing,catalysis, drug delivery, materials and molecular machinery.
Much of the early work in this field focussed on expanding
the toolbox of catalytic reactions suitable for active templatesynthesis. A particularly attractive target remains finding a way
to maintain the coordination of Pd(0) to a component throughout the catalytic cycle so that Pd(0)-mediated cross-coupling
reactions can be used. Other challenges arise from functionalgroup tolerance, and the ligand requirements of particular
metal-catalysed reactions for active template synthesis if the
preparation or handling of the building blocks is problematic.
Finally, while substantial progress has been made in thesynthesis of interlocked molecules over the last four decades,
practical applications of rotaxanes and catenanes remain
scarce. The lack of requirements for permanent binding motifs
may make active template synthesis more amenable for making
practically useful interlocked structures than other synthetic
strategies. Active template synthesis appears a promising routeto rotaxanes and catenanes with applications in nanoelectronics and biotechnology. Further exploration of diﬀerent
metal-mediated and metal-free active template methodologies,
coupled with potential applications of newly accessible structure types, augurs well for the continued advancement18 of thechemistry of mechanically interlocked molecules.

Author contributions
This Review was written through the contributions of all authors.

Data availability
No primary research results, software or code have been
included and no new data were generated or analysed as partof this review.

Chem. Soc. Rev.

Conflicts of interest
There are no conflicts of interests to declare.

Acknowledgements
We thank the EPSRC Centre for Doctoral Training in Integrated
Catalysis (EP/S023755/1, studentship to R. J.), the European
Union Marie Skłodowska-Curie Actions Innovation Training
Network ArtMoMa 860434 (studentship to M. P.), the Engineering and Physical Sciences Research Council (EPSRC; EP/
P027067/1) and the European Research Council (ERC Advanced
grant 786630) for funding.

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