DOI: 10.1002/cphc.

201501155

Minireviews

Wholly Synthetic Molecular Machines

Chuyang Cheng and J. Fraser Stoddart*[a]
The past quarter of a century has witnessed an increasing engagement on the part of physicists and chemists in the design
and synthesis of molecular machines de novo. This minireview
traces the development of artificial molecular machines from
their prototypes in the form of shuttles and switches to their
emergence as motors and pumps where supplies of energy in
the form of chemical fuel, electrochemical potential and light

activation become a minimum requirement for them to function away from equilibrium. The challenge facing this rapidly
growing community of scientists and engineers today is one of
putting wholly synthetic molecules to work, both individually
and as collections. Here, we highlight some of the recent conceptual and practical advances relating to the operation of
wholly synthetic rotary and linear motors.

1. Introduction
With the rise of molecular and cellular biology during the past
half century, biologists have led us to believe that, although
living systems are extremely complicated, there are strong interdependent relationships between small and large molecules
that work in unison to produce, store, and consume energy so
that life can be sustained across a wide range of length scales.
Among the larger molecules that sustain life, motor proteins
have been shown[1] to play an important role in maintaining
metabolism at the cellular level and beyond. For example, the
rotary motor ATP synthase utilizes the proton concentration
gradient across the mitochondrial inner membrane[24] to convert ADP into high-energy ATP; while hydrolyzing ATP, the
linear motor myosin makes its way along actin filaments, creating muscular contractions within a hierarchical structure;[5] an
assembly line on the ribosome produces a wide variety of proteins based on information read out from mRNA.[69] For just
over a couple of decades, with some guidance from physicists,[1013] chemists have started to design and synthesize
wholly synthetic molecules capable of performing some of the
tasks of their biological counterparts.[14] There are a number of
extensive reviews that chronicle the progress that has been
made during this 25-year period.[1527] In this minireview, we
1) introduce the evolving chemical landscape that has engaged artificial molecular machines, 2) identify some of the building blocks commonly used in their construction, and 3) focus
our attention on some recent examples that have appeared in
the primary literature.

common definitions of a machine is a contraption that contains moving parts that are induced to move relative to one
another by some energy source in order to accomplish a particular task. Molecular machinesoften considered inappropriately as analogues of their macroscopic cousinsmust 1) consume energy, 2) have moving parts, and 3) accomplish a task.
In the beginning, many of the artificial molecular machines
designed by chemists displayed (Figure 1) relative motion of

1.1. Evolution of Artificial Molecular Machines

The word machine conjures up a wide variety of disparate
meanings to people in different walks of life. One of the
[a] C. Cheng, Prof. J. F. Stoddart
Department of Chemistry
Northwestern University
2145 Sheridan Rd.
Evanston, IL 60208 (USA)
E-mail: stoddart@northwestern.edu

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Figure 1. Examples of prototype molecular machines powered by thermal

energy. a) An electron-poor ring shuttles back and forth between two electron-rich recognition sites along a dumbbell. b) Structural formulas and molecular models of a hexa-tert-butyl decacyclene molecular rotor together
with STM evidence showing its rotation as a torus image (B and D) compared with a six-lobed image when it is in register with the surrounding
monolayer (A and C). Reproduced with permission from Ref. [32].

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their component parts, fueled by thermal energy from the surrounding environment.[2830]
Our own 1991 solution-based molecular shuttle[31] (Figure 1 a) was no more than a degenerate [2]rotaxane in which
an electron-poor ring darts back and forth around 2000 times
a second at room temperature between two electron-rich recognition sites on its dumbbell component. Yet, it was to serve
as a blueprint for the subsequent design and synthesis of
linear molecular motors, muscles, pumps and assemblies
based on rotaxane constitutions. In 1998, Gimzewski[32] provided evidence (Figure 1 b) for the high-speed rotation driven by
thermal energy of hexa-tert-butyl decacyclene (HTBD) on the
surface of Cu(100) by scanning tunneling microscopy (STM):
the molecular rotor shows a six-lobed image when it is in register with its surrounding molecular monolayer, whereas it reveals a torus-like image when it is not in phase with its two-dimensional supramolecular latticeindicative of relative rotary
movement of molecules on a surface. This observation was to
serve as a fillip, not only for the design and synthesis of rotary
molecular motors, but also for interfacing them with the world
at large.
1.2. Building Blocks and Modes of Movement
To a large extent, the availability of compounds (Figure 2) has
dictated the choice by chemists of the modes of movement
they have incorporated into their molecular machinery. An obvious starting point is the all-too-familiar torsions about single
bonds since they can be employed directly as rotary axles.[3335]
Sandwich-like p-metal complexes can serve a similar purpose:
for example, Aida[36, 37] has employed ferrocene as the rotary
axle in his molecular scissors. On account of their susceptibility
Chuyang Cheng received a B.S. in
Chemistry from Peking University in
2011 under the supervision of Professor Jian Pei. He is currently a Ph.D.
candidate in Department of Chemistry
at Northwestern University under the
supervision of Professor J. Fraser Stoddart. His research is focused on the
design and synthesis of artificial molecular machines that can perform
work repetetively and progressively.
J. Fraser Stoddart received B.Sc., Ph.D.,
and D.Sc. Degrees from the University
of Edinburgh. He currently holds
a Board of Trustees Professorship in
the Department of Chemistry at Northwestern University. His research in molecular nanotechnology involves the
template-directed synthesis of mechanically interlocked compounds and
their applications in new materials and
technologies.

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Figure 2. Some modes of motion present in some simple building blocks of

artificial molecular machines. a) Rotation around single bonds and in sandwich-like p-metal complexes. b) Bending as a consequence of double-bond
isomerization. c) Translational motion of a ring along the dumbbell of a rotaxane. d) Circumrotation motion of rings in a catenane.

to photo-isomerization, double bonds have been incorporated

into molecular machines when bending movements are
deemed to be desirable in addition to rotation. Both azobenzene[3844] and stilbene[4548] have been used widely in the construction of photo-responsive molecular machines.[49] Bending
movements can also be supplied by diarylethene[5053] and spiropyrans,[5458] both of which undergo reversible ring-closing
and ring-opening reactions. Mechanically interlocked molecules (MIMs) in the form of catenanes can also provide access
to rotary movements as a result of the circumrotation of one
ring relative to another. The chief restriction associated with
circumrotation is the fact that mechanical interlocking renders
it impossible to interface this relative molecular movement in
a continuous rotary sense beyond the molecule itself. Fortunately, this restriction does not apply to a rotaxane where both
the rotation of the ring about the axle of a dumbbell and the
translation of the ring along the axle of the dumbbell can be
harnessed beyond the molecule.[5961]
1.3. Sources of Energy
Although the prototypes of artificial molecular machines represented an advance in terms of regulated, as opposed to
random thermal motions, the lack of control of rotational and
translational movements at the molecular level constituted
a serious weakness, stemming from a reliance on thermal
energy alone. In the quest to gain more control over the
moving parts in molecules, it became necessary to introduce
stimuli-responsive components into the prototypes of artificial
molecular machines in order to allow other sources of energy,
such as chemical,[62] electrical,[63] optical,[64] magnetic,[65] and so
forth, besides thermal energy, to power their moving parts.
The stimuli-responsive components generally constitute
switchable recognition sites that also form the basis for complexation and decomplexation in supramolecular systems.
Initially, chemical fuels proved to be an attractive source of
energy because of their ready accessibility based on a multitude of reversible chemical reactions, amongst which the acidbase ones are the most common.[6669] For example, dibenzo[24]crown-8 (DB24C8) forms strong hydrogen bonds with
secondary dialkylammonium ions,[70] leading to the formation
of an interpenetrating 1:1 complex which dissociates as soon
as the -CH2NH2 + CH2- center is deprotonated (Figure 3 a). While

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that light is one of the most convenient sources of energy to
power molecular machines, provided they contain photoresponsive units.[49, 64] For example, trans-azobenzene forms[39] an
inclusion complex with a-cyclodextrin; under the influence of
ultraviolet light the trans-azobenzene undergoes isomerization
to its cis-isomer, resulting in dissociation of the complex (Figure 3 c). What is more, light-powered molecular motors[84] lend
themselves to autonomous operation.

1.4. From Molecular Shuttles to Molecular Switches

Figure 3. Examples of recognition sites commonly used in artificial molecular

machines. a) pH-controlled association and dissociation between dibenzo[24]crown-8 (DB24C8) and a secondary dialkylamine. b) Redox-controlled
radical pairing interaction or Coulombic repulsion between cyclobis(paraquat-p-phenylene (CBPQT4 + ) and viologens. c) Light-responsive encapsulation and release of azobenzene from a-cyclodextrin.

living organisms have evolved sophisticated circulatory systems to transport chemical fuels from one place to another in
order to eliminate chemical waste, chemists have yet to address the challenge of managing simultaneously fuel delivery
and waste transport in artificial systems. As a result, wholly
synthetic molecular machines that are operated by the sequential addition of chemical reagents very quickly experience
an inevitable drop in efficiency and stop working altogether
because of the growing concentrations of waste generated
from chemical reactions. Aprahamian[56] has coupled a pH-controlled molecular switch with a reversible light-activated
proton-release reaction, however, providing an accessible solution to waste management.
As an alternative to developing complicated waste-management circulatory systems, chemists have turned their attention,
in the short term at least, to reactions that involve either only
electron transfers or configurational isomerizations that avoid
the generation of waste. Hence, redox-responsive units, such
as viologens,[7173] tetrathiafulvalene derivatives,[7476] ferrocenes,[7779] naphthalene diimides,[80, 81] and so forth, have been
incorporated into a variety of molecular machines. Cyclobis(paraquat-p-phenylene) (CBPQT4 + ) forms interpenetrating trisradical triscationic complexes with viologens under reducing
conditions[82, 83] that dissociate with the aid of strong Coulombic repulsion on subsequent oxidation (Figure 3 b). Although
this redox reaction can be fueled chemically, it is also possible
to carry out the reaction electrochemically on an electrode surface, where only electrons are being transferred between the
electrode and the molecular machine. Electrode operation,
however, is a contact control method which can also be inconvenient. All these considerations bring us to the realization
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Let us return to the example of the molecular shuttle illustrated in Figure 1 a. The shuttling of a ring between two identical
recognition sites in a [2]rotaxane[31] (Figure 4 a) is somewhat
reminiscent of the rapid and degenerate inversion process undergone by the chair conformation of cyclohexane at room
temperature. In order to go that step further and turn a molecular shuttle into a molecular switch, the degeneracy has to be
removed from the [2]rotaxane in much the same way that the
mono-substitution of cyclohexane leads to the production of
axial and equatorial conformations, that is, bistability is introduced into the molecule. In the case of the molecular shuttle,
the easiest way to confer bistability is to incorporate two (very)
different recognition sites onto the axle of the dumbbell component of a [2]rotaxane (Figure 4 b).[85] This objective can be
achieved by replacing the hydroquinone recognition sites in
the molecular shuttle by tetrathiafulvalene and 1,5-dioxynaphthalene units,[86] as strong and weak recognition sites, respectively, in a wide range of donor-acceptor rotaxanes and catenanes that have found application in catalysis,[8789] molecular
electronic devices[90, 91] and drug delivery systems.[92]

Figure 4. Graphical illustrations showing the operation of a molecular shuttle. a) A molecular shuttle in which the ring is moving randomly between
two identical recognition sites. b) A molecular switch in which the rings position is controlled by a change in one of the recognition sites. c) A molecular machine that can transport a cargo from one place to another.

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1.5. From Molecular Switches to Molecular Motors
On switching reversibly between two or more recognition sites
as a result of outside stimuli, work is undone every time the
switches are reset (Figure 4 b). Molecular switches lack the ability to deliver useful work because they operate essentially
under thermodynamic control. By contrast, Natures motor proteins work under kinetic control away from equilibrium, converting chemical fuels into useful work. To be considered as
a molecular motor, it is necessary to keep pushing a system
away from equilibrium with a continuous input of energy. For
example, let us consider an artificial molecular transporter,[93]
based on a switchable bistable rotaxane (Figure 4 c) in which
1) a cargo is attached to the ring, 2) transported along the
dumbbell of rotaxane, and 3) eventually detached before the
ring moves back to pick up another cargo. While the switching
of a bistable rotaxane has been widely explored, the key to an
artificial molecular transporter is the selective attachment of
the cargo at one recognition site followed by its release at the
other site. The possibility of having the bistable rotaxane do
useful work relies on switching the binding preference of the
cargo for different recognition sites. During the preparation of
this minireview, Leigh reported[94] that a small molecule robotic
arm (Figure 5) can pick up, transport and release a molecular

Figure 5. Operation of an artificial molecular transporter. Thanks to the directional control of the robotic arm by a rotary switch, the small-molecule
cargo can be picked up on one side and released on the other side in an efficient manner. Reproduced with permission from Ref. [94]

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cargo.[95] The small-molecule transporter system has two binding sites for a cargo that can be accessed by reversible hydrazone formation reaction. The robotic arm picks up and releases
the cargo through alternating redox-controlled disulfide bond
formation and cleavage. The picking up of the cargo on one
side and the dropping it off on the other side is driven by a hydrazone-based rotary switch[96100] incorporated between the
arm and the two binding sites.

2. Unidirectional Rotary Molecular Motors

Rotary motors are commonplace in the macroscopic world. Examples include drills, turntables, food processors, and so forth.
Nature has also played its part in the evolution of rotary
motors, such as ATP synthase and bacterial flagella. Abiotic
and biotic motors usually share two important features:
1) they express their rotation continuously in a unidirectional
manner and 2) they perform work when supplied with energy.
In 1999, two articles published back-to-back in Nature, one by
Kelly[101] and the other by Feringa,[102] described ways of achieving unidirectional rotary movements in wholly synthetic molecules. In Kellys[101] design (Figure 6 a), a monoamino-functional-

Figure 6. Unidirectional rotation in wholly synthetic molecules. a) A triptycene unit rotates unidirectionally around a single bond with respect to
a [4]helicene unit, fueled by phosgene. b) Unidirectional rotation in an overcrowded chiral olefin powered by UV light. Reproduced with permission
from Ref. [101] and Ref. [102]

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ized triptycene is connected by means of a single bond to
a [4]helicene, which carries a hydroxypropyl tether. Rotation of
the triptycene with respect to the helicene is sterically hindered. On the addition of a chemical fuel (phosgene), the
amino group is converted into an isocyanate, which reacts, following rotation, with the primary hydroxyl group on the tether
to form a urethane and, at the same time, traps the molecule
in a high-energy conformation. Random thermal energy is all
that is needed to complete the rotation of the urethane over
the steric barrier. Subsequent cleavage of the urethane produces a conformation in which the triptycene has rotated unidirectionally by ~ 1208 in a clockwise manner with respect to the
helicene. Feringa[102] has designed (Figure 6 b) a light-driven
unidirectional molecular rotor, based on an overcrowded olefin
with two identical chiral components connected by a central
carbon-carbon double bond. Repetitive monodirectional torsion about this bond is achieved during four isomerizations,
two of which are activated by ultraviolet light and two by thermal energy. A combination of axial chirality and two stereogenic centers ensures that the four steps constitute one full rotation through 3608 in one direction only.
In an attempt to realize 3608 unidirectional rotation,
Kelly[103, 104] went on to design a molecule and synthesize a compound thereof, with a trisamino-functionalized triptycene
bonded to a [4]helicene carrying a dimethylaminopyridine
unit, with the intended task of delivering the phosgene fuel to
the nearest blade of the triptycene. Disappointingly, this next
generation of potential unidirectional molecular rotors did not
perform, even after much ingenious cajoling, as anticipated:
one of the pitfalls associated with the outcome of unnatural
product synthesis is that the best-laid plans often go awry. By
contrast, the overcrowded olefinic motor, which has a much
simpler constitution, proved to be a lot easier to modify structurally and to produce derivatives therefrom through numerus
generations. The speeds of rotation of these Groningen-produced molecular rotors have been tuned[105] over a wide range
from 107 Hz all the way down to 1011 Hz. The rotors have also
been attached to the surfaces of nanoparticles and shown[106]
to continue to rotate the way they do in solution. The direction of their rotation can be reversed[107] simply by inverting
the configurations of their stereogenic centers. Moreover, unidirectional motion can be realized[108] in achiral molecules by
appealing to pseudoasymmetry. The rotors have also found applications in the contexts of 1) reversing the enantioselectivity
of an asymmetric catalyst,[109] 2) disassembling of self-assembled vesicle-capped nanotubes with light[110] and 3) driving
a four-wheeled single molecule electrically on a metal surface
in a directionally controlled manner.[111]
2.1. Absolute Stereocontrol of a Catalytic Transformation
Enzymes and synthetic asymmetric catalysts exercise tight stereochemical control over the reactions they catalyze, producing, for the most part, single enantiomers. Reversing the chiral
preference of a catalytic system is a non-trivial task. Feringa,[109]
however, has risen to the challenge by integrating a catalytic
system with a light-driven molecular motor such that both the
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activity and the absolute stereocontrol of an asymmetric transformation has been achieved (Figure 7 a). The motor is functionalized on its rotor segment with a dimethylaminopyridine
unit (Brnsted base, A) and on its stator segment with a thiourea function (hydrogen-bond donor, B) that can act cooperatively as a bifunctional catalyst for a conjugate (Michael) addition. When the motor is activated to undergo photochemically
and thermally induced steps, clockwise rotation of the rotor
around the axle with respect to the stator controls the juxtaposition and helicity (M or P) of the catalytic groups, A and B,
producing catalysts I, II and III in sequence with different activities and enantioselectivities. The catalytic system displays low
catalytic activity and almost no chiral preference when A and
B are far apart (I). The catalytic activity is increased significantly
when A and B are close together, as in II and III, while the

Figure 7. Reversal of enantioselectivity controlled by a unidirectional rotary

motor. a) Graphical representation of the motor motion (top) and structural
formula of the artificial molecular motor in its (2R,2R)-(P,P)-trans form
(bottom). A and B stand for the rotor and stator components, respectively.
Clockwise rotation of the motor leads to the molecule adopting three geometries, namely, I, II, and III, with different catalytic activities. b) Reaction
scheme and conditions for the Michael addition catalyzed by the motor.
c) Reaction kinetics show that the motor functions effectively only when
portion A and B are close enough in its (M, M)-cis form (II) and (P,P)-cis form
(III). d) Chiral HPLC traces (I, II, III, from top to bottom, respectively) illustrates the enantioselectivities and how they can be reversed by the motor.
Reproduced with permission from Ref. [109]

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chiral preference is reversed when the rotor has (M) and (P)
helicities, respectively.

2.2. Gel Contractions Induced by Molecular Motors

When we start asking ourselves how wholly synthetic molecular motors might perform work, there is a range of different
length scales on which these motors can drive integrated systems away from equilibrium. The length scales can be identified, somewhat arbitrarily, at the molecular, nanoscopic, microscopic and macroscopic levels. There are a number of examples in the literature of macroscopic changes that have been
induced by the operation of artificial molecular machines.[113115]
Recently, Giuseppone[112] has incorporated Feringas second
generation light-driven molecular motors that rotate at high
frequencies into polymer gels and achieved contractions of
these materials at both the nanoscopic and macroscopic levels
(Figure 8). For these purposes, the motor is adorned with four
arms, two poly(ethylene glycol) (PEG) chains terminated by

propargyl groups, and the other two PEG chains with azide
functions at their termini. On performing copper-catalyzed
azide-alkyne cycloaddition (CuAAC) reactions under high-dilution conditions, 8-shaped macrocyclic motor conjugates are
formed. The macrocycles can be coiled up by light activation,
thus reducing their size to that of nanoscopic objects which
can be identified by AFM as isolated coiled 8-shaped polymers
on mica surfaces. When the CuAAC reaction is carried out at
much higher concentrations, the result is mechanically activated entangled gels in which the polymer chains become coiled
up by the light-activated rotations of the entrapped motors,
reducing the overall dimensions of the millimeter-sized gels.

3. Linear Molecular Motors

Electric motors are commonly of the rotary variety whereas automobiles are driven by internal combustion engines with
linear reciprocating strokes that are converted into rotary motions by a combination of crankshafts and universal joints.
Linear motors dominate the field in biological systems. Kinesins, which transport vesicles inside cells through microtubules,
and myosins, which walk along actin filaments, are all linear
motor proteins. They serve as an inspiration to chemists to try
and mimic their walking motions. Leigh[116118] has investigated
wholly synthetic molecular walkers in which small-molecule
fragments are induced to walk along molecular tracks. In
a recent full paper, he has reported[119] the spontaneous migration of a-methylene-4-nitrostyrene from one amino group to
the next along oligoethyleneimine tracks up to eight repeating
units in length (Figure 9). The rearrangements result from
a series of reversible intramolecular Michael-retro-Michael reactions between neighboring amino groups on the tracks. The
rearrangements are best described by a random walk in one
dimension with the a-naphthylmethylamine terminus of the
track acting as a thermodynamic sink on account of its providing a source of donoracceptor stabilization with respect to
the p-nitrophenyl unit on the molecular walker. Although
translational (linear) motion has been demonstrated in a synthetic small molecule, the system as a whole tends towards
equilibrium and so does not qualify to be described as a linear
molecular motor.
3.1. Artificial Molecular Muscles

Figure 8. Size-reduction of nanoscopic objects and macroscopic entangled

gel contractions driven by artificial molecular motors. a) Reaction schemes
and conditions for incorporating artificial molecular motors into an 8-shaped
polymer under high dilution conditions and into mechanically activated entangled gels at much higher concentrations using click reactions. b,c) Graphical illustrations showing the 8-shaped polymer and the mechanically activated entangled gels coiling up under light activation. d) AFM images
before (top) and after (bottom) light activation of the 8-shaped polymer indicate a significant size decrease. e) Snapshots of a movie (taken at 0, 60,
120, and 170 min after light irradiation, respectively) illustrating macroscopic
gel contractions over time. Reproduced with permission from Ref. [112]

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The primary literature is replete with examples of artificial molecular muscles based either on palindromic doubly bistable
[3]rotaxanes or bistable [c2]daisy chains. In a classic experiment
from a decade ago, a derivative of a donoracceptor [3]rotaxane, in which disulfide tethers were attached covalently to
both rings, was introduced as a self-assembled monolayer
onto a silicon cantilever array coated on its topside with a thin
20 nm layer of gold. When the device, housed within a solution
cell, was treated alternatively with chemical oxidants and reductants, the cantilevers were shown optically to bend back
and forth over at least 25 cycles.[114, 120] [c2]Daisy chains are covalently linked, self-complementary ring/dumbbell dimers in
which the monomers can be induced chemically, electrochemi-

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Figure 9. Spontaneous migration of a small-molecule fragment towards a thermodynamic sink. a) Structural formulas of a molecular walker illustrating the
spontaneous migration of a-methylene-4-nitrostyrene towards an a-naphthylmethylamine thermodynamic sink in the presence of 6 equiv of iPr2NEt. b) Partial
kinetic 1H NMR spectra show the spontaneous migration process (the colors of the signals correspond to the structural formulas shown in (a)). Reprinted with
permission from Ref. [119]. Copyright 2013 American Chemical Society.

cally, and photochemically to slide past one another in a linear

fashion, giving rise to molecular contractions and elongations.
A number of switchable [c2]daisy chains[121] have been assembled by templation and shown to operate in a muscle-like
fashion at the single-molecule level. Sauvage,[122124] who pioneered the design and synthesis of bistable [c2]daisy chains,
drew attention to the fact that the switching of the rings between two recognition sites on their respective dumbbells
causes a significant change in the overall length of the molecules. The challenge more than a decade later is to find ways
of integrating these molecules into larger arrays and so amplify
their movements at a macroscopic level in much the same
way as hierarchically organized myosin and actin filaments do
in muscle cells. This challenge has been addressed recently
with some limited, but significant, success by Buhler and Giuseppone.[125, 126] They employed the recognition between
CH2NH2 + CH2 centers and macrocyclic polyethers with the
[24]crown-8 constitution in their design of a pH-switchable
[c2]daisy chain with terpyridine end groups (stoppers) that are
capable of forming stable octahedral 2:1 complexes with Fe3 +
ions (Figure 10). Employing the metallo-supramolecular approach as a means of polymerization produces giant polymer
chains containing up to 3000 bistable [c2]daisy chain repeating
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tion. The [c2]daisy chains, which can be actuated by a change

in pH, produce differences in the lengths of the polymer
chains which exceed 6 mm. This kind of amplification between
the molecular and microscopic regimes represents an important step towards the goal of incorporating bistable [c2]daisy
chains in switchable mechanically interlocked polymer chains
which could then self-assemble to form bundles that could
constitute stimuli-responsive fibers in artificial muscle-like materials.
3.2. Artificial Molecular Pumps
Mass transfer is an everyday event both in large-scale production in the chemical industry and in the control of metabolism
at the cellular level in biological systems. While pumps are crucial for regulating the transport of raw materials and feedstocks by the ton in the heavy chemical industry, they are also
required to control the passage of ions and small molecules at
the cellular level in living systems. Left to its own devices,
water flows spontaneously downhill in the world as we know
it, while ions and small molecules, given half a chance, diffuse
spontaneously from regions of high to low concentrations. In
order to defy these spontaneous events, pumps need to be
supplied with energy to enable them to do work against the

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threading of the ring by what is essentially a flashing energy
ratchet mechanism. In a subsequent article,[128, 129] the Bologna
group describe how replacing the DB24C8 ring with 2,3-dinaphtho[24]crown-8 leads to the demonstration of light-powered autonomous and unidirectional motion in a dissipative
supramolecular system without the assistance of a competitive
guest. Hence, under photostationary conditions, where the
same wavelength of light can be used to switch and reset the
azobenzene because of energy transfer from the crown ethers
naphtho units, the ring threads onto the axle from the azobenzene end and dethreads from the cyclopentyl end over and
over again. Relative unidirectional translation, fueled autonomously by light, has also been demonstrated[130] in a donoracceptor pseudorotaxane composed of a CBPQT4 + ring that becomes bound to a centrally located 1,5-dioxynaphthalene rec-

Figure 10. Amplification of muscle-like contraction and extention within

a synthetic metallo-supramolecular [c2]daisy chain polymer. a,b) Structural
formulas and graphical representations of the polymer in its extended state
at lower pH and in its contracted state at higher pH, respectively. c) The
metallo-supramolecular polymer with ~ 3000 repeating units shows
a change in length of over 6 mm when switched under acidbase conditions
as a result of amplification of nanometer scale length change in each repeating unit. Reproduced with permission from Ref. [125]

odds. In living systems, molecular pumps, such as bacteriorhodopsin, using either light or ATP as sources of energy, transport
ions and small molecules across lipid bilayer membranes so as
to create concentration gradients and establish potential differences across the membranes. A number of researchers all
across the world are engaged in the synthesis of artificial molecular pumps that have been designed to mimic the functions
of biological counterparts.
In 2012, Credi[127] announced the unidirectionally controlled
threading of a ring with respect to a constitutionally asymmetric axle as the first step towards the realization of an artificial
molecular pump (Figure 11). The pseudorotaxane is composed
of a DB24C8 ring that becomes bound to a centrally located
CH2NH2 + CH2 recognition site (S) with a passive cyclopentyl
stopper (D) located at one end and a bistable photoswitchable
azobenzene stopper (a-P) at the other end. Initially, the ring
threads onto the axle over the azobenzene unit in its transconfiguration for kinetic reasons, affording a pseudorotaxane
in which the ring encircles the recognition site S. Irradiation
with UV light causes the trans-azobenzene unit to isomerize to
its cis-configuration (b-P), creating a significantly increased
steric barrier to the rings dissociation. Adding K + ions as
a competitive guest for the crown ether ring results in the
dethreading of the ring over the D end of the axle. Reset is
achieved by either photochemical or thermal isomerization of
the cis-azobenzene back to its trans-configuration (a-P) and reChemPhysChem 2016, 17, 1780 1793

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Figure 11. Unidirectionally controlled threading of a ring with respect to

a constitutionally asymmetric axle. a) Structural formulas and graphical representations of the constitutionally asymmetric axle and the ring. b) Graphical illustrations and corresponding energy profiles (free energy versus ringaxle distance) show the strategy for photo-induced unidirectional threading
of a ring with respect to a constitutionally asymmetric axle. The number of
green dots indicates the distribution of the rings, and slower processes that
do not take place under the conditions are represented by shaded cartoons
and dashed lines. Reproduced with permission from Ref. [127].

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ognition site following passage of the ring over a neutral 2-isopropylphenyl stopper, rather than over a positively charged
3,5-dimethylpyridinium stopper. Upon reduction, the
CBPQT2(C +) ring dethreads selectively over the charged stopper
on account of 1) the donoracceptor site being annulled and
2) a decrease in Coulombic repulsion following a halving of
the positive charge on the ring. In the presence of the photosensitizer tris(bipyridine)ruthenium(II) and the electron relay
phenothiazine, visible light is the only energy needed to drive
the unidirectional motion of the ring autonomously with respect to the axle.
Both of these systems,[128, 130] however, exhibit a couple of
fundamental deficiencies. First of all, the unidirectional transport is occurring in solution in supramolecular systems where
the rings are threaded onto a constitutionally asymmetric axle
from one end out of the bulk solution and then dethreaded
from the other end of the pseudorotaxane back into the solution. The result of this on-one-end, off-the-other-end mechanism is that no useful work is done during the operation of
the cycle. Secondly, and perhaps more importantly, the attractive interactions associated with the recognition sites in both
the hydrogen bonding and donoracceptor cases are only
weakened, that is, they do not become repulsive when
switched off. The consequence is that the potential to perform
useful work is severely limited and leads to low energy conversion efficiencies. The pumping efficiencies can only be improved if large enthalpic changes can be realized when the
recognition sites are switched off,[131134] that is, when the sites
become repulsive. By employing radical-pairing interactions as
the source of the recognition between CBPQT2(C +) rings and viologen radical cations under reducing conditions, when the
highly stable trisradical tricationic complex is oxidized, the reinstatement of six positive charges gives rise to strong Coulombic repulsions with a lot more potential for real work to be
done.[135] When this radical mechanism and redox processes
were incorporated into the design of an artificial molecular
pump (Figure 12), it became possible, for the first time, to
transfer rings repetitively and progressively onto collecting oligomethylene chains.[26, 136, 137] The operating portion of the
pump contains a 3,5-dimethylpridinium end group which acts
as a one-way gate that allows only CBPQT2(C +) rings to pass
over it under reducing conditions when the recognition site is
a 4,4-bipyridinium radical cation (BIPYC + ). On oxidation, Coulombic repulsion comes into play and a second neutral oneway gate in the shape of an isopropylphenylene unit on the
other side of the erstwhile recognition site allows the CBPQT4 +
rings to pass over it with the aid of some thermal energy
under oxidative conditions. These three components of the operating portion, along with the ring, serve as the basis for
a flashing energy ratchet mechanism to pump rings under
redox control. So far, experiments have demonstrated that
a two-cycle operation is capable of trapping two rings in highenergy states with high efficiencies on an undecamethylene
chain. The fact that the kinetics associated with the passage of
the two rings are almost identical augurs well for being able
to pump multiple rings onto longer oligomethylene chains. A
deficiency of the artificial molecular pump is that currently the
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Figure 12. Artificial molecular pump. a) Graphical representations and structural formulas of the ring and dumbbell with notes describing the function
of each component in the molecule design. b) Graphical representations of
the pumping mechanism, which operates in response to redox cycling, with
simplified illustrations of the corresponding energy profiles. The green and
red arrows indicate fast and slow movements, and the colors in the energy
profiles correspond to positions of dumbbells of the same colors.

chemical fuel is added in a laborious sequential manner. Although rings can be trapped in a high-energy state, a way has
still to be found for the away-from-equilibrium system to dissipate its energy. There is still a long way to go!

4. Artificial Molecular Assembly Lines

The complexity of a single living cell far outstrips that of
a large manufacturing facility. Nonetheless, both living cells
and modern factories work at extremely high levels of efficiency: one reason for these efficiencies is their reliance on assembly-line production. DNA, one of the most important molecules
in living cells, exists as double helices, assembled hierarchically

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into chromosomes. The synthesis of double-helical DNA, as
part of the process of replication, requires that the enzyme
DNA polymerase attaches itself to a single DNA polymer chain
prior to identifying the complimentary nucleotide and catalyzing the formation of a phosphate ester bond before moving to
the next nucleotide. Many processive enzymes of this kind
have a toroidal shape which allows them to encircle the biopolymer while moving along its length.[138] Nolte[139142] has designed a rotaxane that mimics the action of these processive
enzymes to catalyze many reactions, one after another in
a row (Figure 13). His catalyst consists of a substrate-binding
cavity within a triangular structure incorporating a manganese(III) porphyrin complex capable of oxidizing olefins to expoxides inside its toroidal cavity. When the catalyst threads onto
a polybutadiene strand, it can epoxidize the double bonds
along the polymer chain in a processive manner.
Another rotaxane-like catalyst has been reported by
Harada[143] who has employed cyclodextrins (CDs) as both catalysts and sliding clamps in the processive polymerization of dvalerolactone (Figure 14). b-CDs are able to bind, activate, and
ring open lactones and so can act as polymerization catalysts.
By linking a second a-CD ring to the b-CD active site, an artificial molecular clamp is provided in order to hold the growing
polymer chain while protecting the active site. This clamp-catalyst dimer reached conversions of up to 95 %, yielding polyesters with number-averaged molecular weights of 16 500.

Figure 14. An artificial molecular clamp catalyzing a polymer synthesis.

a) Structural formulas of the molecular clamp and reaction Scheme of polyester synthesis employing d-valerolactone monomers. b) Proposed mechanism for the polymer synthesis in which the b-CD rings bind, activate, and
ring-open lactones in order to catalyze the ring-opening polymerization and
the a-CD rings act as artificial molecular clamps to protect the active site by
holding the growing polyester chain. Reproduced with permission from
Ref. [143].

4.2. A Sequence-Specific Peptide Synthesizer

Figure 13. A processive catalyst that can oxidize a polymeric substrate.

a) Structural formulas and a computer-modeled structure of the processive
catalyst b) Graphical representation of the processive catalytic epoxidation
of polybutadiene. When the catalyst threads onto a polybutadiene polymer
strand, it can epoxidize the double bonds along the polymer chain in a processive manner. Reprinted with permission from Ref. [141]. Copyright 2013
American Chemical Society.

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The ribosomeacting at its role as a molecular machineassembles amino acids from tRNA building blocks to produce
polypeptides with a sequence of monomers defined by sequence of mRNA which reads the information of the mRNA
strand it moves along. Leigh[144, 145] has designed a wholly synthetic molecular machine that mimics the function of the ribosome, employing it to synthesize sequence-defined peptides
(Figure 15). A relatively rigid rod carrying three different protected amino acids connected by weak phenolic ester linkages
was prepared. A [2]rotaxane was synthesized by the threadingfollowed-by-stoppering approach using the CuAAC click reaction. While the ring can move back and forth along the rod, its
translational movement is blocked by the first amino acid.
Once the protecting group has been cleaved, the thiolate
anion, associated with the cysteine function on the ring, acts
as a nucleophile and attacks the closest phenolic ester. A transacylation occurs and the amino acid ends up attached to the
ring which is now free to approach the next amino acid on the
rod. The process can be repeated until the ring, carrying a sequence-specific tripeptide, dethreads into solution following
the attachment of the third (and final) amino acid. Hydrolytic
cleavage of the ring affords the tripeptide. The Manchester
group have described[146] subsequently an improved sequencespecific synthesis involving a so-called rotaxane-capping strategy. They speculate that this strategy could lead ultimately to
the sequence-specific synthesis of polymers using unnatural

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Figure 15. A sequence-specific peptide synthesizer. a) Structural formulas of the peptide synthesizer in its initial state with a ring on a dumbbell containing
three amino acid fragments in the form of phenolic esters. b) Graphical representations show the proposed mechanism during sequence-specific peptide synthesis by the molecular machine. The machine is actuated by acid cleavage of Boc and Trt protecting groups, after which a series of nucleophilic substitution
and transacylation reactions happen sequentially associated with the ring shuttling along the dumbbell, resulting in the production of a sequence-specific tripeptide after reductive cleavage of the macrocycle. Reproduced with permission from Ref. [144].
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building blocksa goal that has still to find a general and
practical solution in polymer science.

5. Reflections
Based on the flood of reviews[2427, 58, 63, 89, 118, 121] and feature articles,[147, 148] not to mention remarkable, high-profile
papers[43, 53, 56, 61, 87, 88, 94, 108, 112, 128, 135, 136, 144, 146]
and
news
&
views,[95, 129, 137, 145] that have surfaced in the scientific literature
which enjoy glamour status during the past couple of years,
research into wholly synthetic molecular machines appears to
have reached a tipping point. If this point in the rise of molecular machines[24, 25] has indeed been reached, then the questions which arise are what next and where next? The latter
question is the easier of the two to answer: if the history of
science tells us anything, it is that applications which find their
way into our everyday lives are a prerequisite for the recognition of a new field of science. It is all too easy for us researchers to write glibly about potential applications in the concluding paragraphs of our most recent publications presenting advances of a fundamental nature and then simply to continue
to pursue research in essentially the same vein. It requires
some considerable effort to address what next in the context
of accepting that where next should deliver something that
stands a good chance of entering our homes and gardens, our
offices and cities, and our different modes of transport, be
they by land, sea or air.
In answering what next, we need to embrace[149] matters of
length scales, robustness, reproducibility and efficiency. It
would seem to us that, although there is surely room to go in
search of applications across all length scales, we do need to
devote much more time and effort in working out how to harness and amplify the output of molecular motors operating
collectively and efficiently away from equilibrium in robust settings within sustainable surroundings.[13, 128130, 135, 150, 151]

[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]

[34]

[35]

Acknowledgements

[36]
[37]

This review is supported by a grant (CHE-1308107) from the National Science Foundation. We thank Mr. Edward Dale for proofreading the manuscript and providing useful comments.

[38]

Keywords: dissipative systems mechanostereochemistry

molecular machines molecular motors rotaxanes
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Manuscript received: December 13, 2015

Accepted Article published: February 2, 2016
Final Article published: March 1, 2016

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