Introduction
When we get to the very, very small world … we have a lot of new things that would
happen that represent completely new opportunities for design … At the atomic level
we have new kinds of forces and new kinds of possibilities, new kinds of effects.
The problem of manufacture and reproduction of materials will be quite different …
inspired by biological phenomena in which chemical forces are used in a repetitious
fashion to produce all kinds of weird effects (one of which is the author) … Richard
P. Feynman (1959)[2]
It has long been appreciated that molecular motors and machines are central to almost
every biological process. The harvesting of energy from the sun, the storing of energy,
transporting cargoes around the cell, the movement of cells, generation of force (at
both the molecular and macroscopic levels), replication, transcription, translation,
synthesis, driving chemical systems away from equilibrium, etc.—virtually every biological
task involves molecular machines.[1] Given the success of mankind’s machines in the
macroscopic world, from the Stone-Age wheel to the modern-day smart phone, it was
inevitable that we should one day seek to achieve the ultimate in machine miniaturization.
However, it has taken some time to gain sufficient mastery over the necessary synthetic
and supramolecular chemistry (and related physics) for this field to begin to flourish.
Richard Feynman’s classic 1959 lecture There’s plenty of room at the bottom[2] outlined
some of the promise that man-made molecular machines might hold, a scientific “taster”
that Eric Drexler embraced for his controversial[3] vision of “nanobots” and “molecular
assemblers”.[4] However, whilst inspirational in general terms, it is doubtful whether
either of these manifestos had much practical influence on the development of artificial
molecular machines.[5] Feynman’s talk came at a time before chemists had the synthetic
methods and analytical tools available to be able to consider how to make molecular
machines; Drexler’s somewhat nonchemical view of atomic construction is not shared
by the majority of experimentalists working in this area. In fact, “mechanical” movement
within molecules has been part of chemistry since conformational analysis became established
in the 1950s.[6] As well as being central to advancing the structural analysis of
complex molecules, this was instrumental in chemists beginning to consider dynamics
as an intrinsic aspect of molecular structure and hence a property they could aspire
to control. Artificial systems were designed to exhibit particular conformational
behavior, such as the “cog-wheeling”-correlated motions of aromatic “blades” in triptycenes
and related structures constructed by the groups of Ōki, Mislow, and Iwamura in the
1970s and 1980s (e.g. 1, Figure 1 a).[7] Before long, stimuli-induced changes in conformation
had been used to control molecular recognition properties; two of the seminal examples
being Rebek’s use of allostery[8] (binding at one site influencing binding affinity
at a second site; 2, Figure 1 b) and Shinkai’s azobenzene photoswitch[9] for modulating
the cation-binding properties of crown ethers (3, Figure 1 c). However, the field
of synthetic molecular machines really began to take off with developments that occurred
in the early 1990s.
Figure 1
Correlated intramolecular motions within “proto-molecular machines”: a) Intramolecular
mechanical cog-wheeling (this example, Iwamura et al.; 1983);[7] b) a negative heterotopic
allosteric receptor (Rebek et al.; 1979);[8] c) photoswitchable binding of a crown
ether (Shinkai et al.; 1980).[9]
Architectures for Well-Defined Large-Amplitude Molecular-Level Motions
In many ways the field of artificial molecular machinery began with J. Fraser Stoddart’s
invention of a “molecular shuttle” (4) in 1991 (Figure 2).[10] In this rotaxane (a
molecule with a ring mechanically locked onto an axle by bulky stoppers), the ring
(shown in blue) moves between two preferred binding sites (the two hydroquinone units,
shown in red) by random thermal motion (Brownian motion). The use of template effects
to assemble mechanically linked molecules (catenanes and, later, rotaxanes) had been
introduced by Jean-Pierre Sauvage in the early 1980s;[11] Stoddart’s great insight
was to recognize that the threaded (mechanically interlocked) architecture of a rotaxane
could allow for the large-amplitude motion of molecular-level components in a well-defined
and potentially controllable manner. The authors of the 1991 JACS paper noted: “Insofar
as it becomes possible to control the movement of one molecular component with respect
to the other in a [2]rotaxane, the technology for building ‘molecular machines’ will
emerge.”[10]
Figure 2
The first molecular shuttle (Stoddart and co-workers; 1991).[10]
This statement turned out to be highly prescient and the paper hugely influential.
Although mechanically interlocked structures are not necessary to construct molecular
machines (see below), they provided the first practical synthetic molecular architecture
through which well-defined large-amplitude molecular-level motions could be selectively
addressed, studied, and utilized.[1b–g] This gave an exciting and compelling reason
to make rotaxanes and catenanes, and the area burgeoned from these molecules being
academic curiosities in the 1960s (when catenanes and rotaxanes were first made by
long and/or inefficient synthetic routes[12]) through to 1989 (when Stoddart and co-workers
made their first catenane,[13] six years after Sauvage and co-workers revolutionized
the strategy for their synthesis through the use of template methods[11]) to the mainstream
area it is now,[14] with hundreds of groups active in this field from the mid-1990s
onwards.
Switching the Relative Positions of Molecular Components—From Molecules to Machines
By desymmetrizing a rotaxane thread to have two different potential binding sites,
or “stations”, whose relative affinity for the ring could be switched, Stoddart, Kaifer,
and co-workers arguably invented the first artificial molecular Brownian motion machine
(5, Figure 3).[15] The cationic ring (shown in dark blue) prefers to reside over the
benzidine group (shown in light blue) rather than the biphenol site (shown in orange).
However, protonation (or electrochemical oxidation) of the benzidine station (now
in purple) renders the biphenol group the preferred binding site for the cationic
ring, thereby causing a net displacement of the ring along the track. This system
marks the first example of a large-amplitude, well-defined, controlled switching of
the position of a component along a molecular track.
Euan Kay received his MChem from the University of Edinburgh in 2002 and his PhD in
2006 under the supervision of David Leigh. He was the recipient of a 2007 IUPAC Prize
for Young Chemists. Following postdoctoral work in Edinburgh, he joined Prof. Moungi
Bawendi at MIT (2008–2010). Since 2011, he has been a Royal Society of Edinburgh/Scottish
Government Personal Research Fellow at the University of St Andrews. His research
interests focus on translating dynamic and stimuli-responsive (supra)molecular systems
into the nanoworld.
David Leigh was born in Birmingham and obtained his BSc and PhD from the University
of Sheffield. After postdoctoral research in Ottawa (1987–1989), he was appointed
to a Lectureship at the University of Manchester Institute of Science and Technology.
After spells at the Universities of Warwick and Edinburgh he returned to Manchester
in 2012, where he currently holds the Sir Samuel Hall Chair of Chemistry. He was elected
a Fellow of the Royal Society in 2009. His research interests include chemical topology
and synthetic molecular-level motors and machines.
Figure 3
The first switchable molecular shuttle (Stoddart, Kaifer, and co-workers; 1994).[15]
The groups of Stoddart and others (notably those of Sauvage, Balzani, Fujita, Hunter,
Vögtle, Sanders, Beer, and Leigh) contributed to the development of many other rotaxane-
and catenane-forming motifs and strategies over the period 1992–2007,[1b,f,g] and
invented many different ways of switching the positions of the components in rotaxane
and catenane architectures with various stimuli (light, electrochemistry, pH value,
polarity of the environment, cation binding, anion binding, allosteric effects, temperature,
reversible covalent-bond formation, etc).[1b,f,g] The next key advance needed was—and
in some respects still is—to find ways to use the change of the position of the components
of a molecular machine to perform useful tasks (see below).
The Invention of Rotary Molecular Motors
In 1999, two papers appeared back-to-back on the subject of controlling the direction
of rotary motion.[16, 17] The group of T. Ross Kelly used chemical reactions—urethane
formation followed by hydrolysis—to bias a 120° rotation of a triptycene residue in
one direction (6, Figure 4).[16] Unfortunately, Kelly was never able to extend this
approach to a system where 360° rotation occurs directionally.
Figure 4
Chemically powered 120° directional rotation of a triptycene residue (Kelly et al.;
1999).[16]
The paper that followed it in the same issue of Nature, however, described an over-crowded
alkene molecule (7) in which the components, upon irradiation with light, rotate directionally
all the way around the alkene axis.[17] This molecule, from the Feringa group, was
the first example of a synthetic rotary molecular motor and, indeed, the first example
of an artificial molecular motor of any kind (Figure 5). Not only does this elegant
design—which exploits, alternately, photoisomerization followed by a strain-induced
diasteromeric helix inversion—achieve complete 360° rotation of one half of the molecule
with respect to the other, it does so continuously as long as the compound is irradiated
with photons and is above a critical temperature.
Figure 5
The first light-powered rotary molecular motor (Feringa and co-workers; 1999).[17]
Over the next decade, many structural improvements were made to this type of motor
molecule, dramatically increasing the rate of rotation[18] and using them to perform
tasks, such as rotating a macroscopic object on the surface of a liquid-crystal medium
(8, Figure 6),[19] switching the chirality of an organocatalyst (9, Figure 7),[20]
and acting as the “motorized wheels” of a “nanocar”.[21]
Figure 6
Rotating a macroscopic object with a molecular machine (Feringa and co-workers; 2006).
Modified from Ref. [19] with permission.
Figure 7
Changing the stereoselectivity of a nucleophilic organocatalyst with a molecular machine
(Wang and Feringa; 2011). Modified from Ref. [20] with permission.
Brownian Ratchet Mechanisms
The problem of constructing a motor by using molecular components which move through
random thermal motions distils down to achieving directional motion of Brownian particles.
This issue has, at various times, intrigued some of the greatest physicists of the
past 150 years: it is the essential process behind the celebrated thought experiments
known as Maxwell’s demon (1871),[22] Smoluchowski’s trapdoor (1912),[23] and Feynman’s
ratchet-and-pawl (1963)[24] (for a discussion of their relevance to artificial molecular
machine design, see Ref. [1f]). In the last two decades of the 20th century, these
superficially abstract deliberations gave way to a flourishing field of (mostly theoretical)
studies that established a range of Brownian ratchet mechanisms through which directional
motion of Brownian particles can be achieved.[25] These provide the mechanistic framework
for the operation of all molecular motors—whether biological or artificial.[26] Unfortunately,
however, chemists failed to appreciate these findings until the mid-2000s; most systems
described as “motor-molecules” in the 1990s and 2000s were actually switches incapable
of doing work cumulatively (i.e. any task performed is undone by the action of resetting
the switch).[1f]
The first application of ratchet mechanisms to the de novo design of artificial molecular
machines resulted in a catenane-based rotary motor[27] and was subsequently developed
further over the next few years in a series of rotaxane-based machines that could
pump macrocycles to higher-energy (non-equilibrium) distributions or states.[28] Yet,
few synthetic linear small-molecule motors have been prepared to date. The first small
molecule able to “walk” along tracks (reminiscent of the mode of transport of kinesin
and other motor proteins) was reported in 2010,[29] with directional versions employing
ratchet mechanisms introduced shortly afterwards (10, Figure 8).[30] Unlike rotaxane
switches (e.g. 4, Figure 2), these walkers move along their tracks progressively,
each cycle in which fuel is consumed potentially causing the motor to take a step
further along the track. Such devices are, in principle, capable of transporting cargoes
directionally. However, current systems are only efficient enough to take a few steps
along short tracks and are not yet sufficiently robust to walk across surfaces or
along polymers.
Figure 8
A small molecule that walks directionally along a molecular track using a light-fueled
energy ratchet (flashing ratchet) mechanism (Leigh and co-workers; 2011).[30]
A number of molecular walker–track systems that are either largely or entirely assembled
from DNA building blocks have been described.[31] Many of these DNA walkers are genuine
motors, since they exhibit all four of the fundamental characteristics of molecular
motors: repetitive, progressive (that is, multiple operations of the motor do work
cumulatively), processive (that is, take multiple steps without dissociating), and
directionally biased transport of a molecular fragment (walker unit) along a track.[32]
However, synthetic DNA walkers are generally of a similar size to, or even larger
than, biological motor proteins such as kinesin-I, and their applications are likely
to be more limited than that of wholly synthetic systems as they are restricted in
terms of both operating conditions and chemical stability. Despite these limitations,
the ease with which complex DNA constructs can be designed and made by automated synthesizers
(often carried out to order by commercial suppliers), has meant that some enormous
(250 000–500 000 Da) DNA-derived molecular machines have been prepared that can perform
sophisticated tasks, such as transporting gold nanoparticles from place-to-place in
a programmable “nano-assembly line”.[33] These systems benefit from the tremendous
advances being made in other areas of DNA nanotechnology, such as DNA origami, DNA
tiles, and DNA computing.[34]
Design Philosophies: Should We Try To Mimic Biological or Macroscopic Machines?
Consider any machine—for example, an automobile—and ask about the problems of making
an infinitesimal machine like it … Biology is not simply writing information; it is
doing something about it. Richard P. Feynman (1959)
Over the last two decades, various types of molecular architectures have been used
to make molecular “pistons”,[35] “clutches”,[36] “windmills”,[37] “elevators”,[38]
“wheelbarrows”,[39] and even “nanocars”,[40] taking the appearance and modes of operation
of macroscopic machines as their inspiration. However, just because a space-filling
representation of a molecule looks like a macroscopic piston or automobile does not
mean that the molecule can necessarily perform a similar function at the molecular
level. Matter behaves very differently at different length scales, and random thermal
motion, heat dissipation, solvation, momentum, inertia, gravity, etc. take on very
different significances for the operating environment at the molecular level compared
to what is important for macroscopic machine mechanisms.[1f,g, 41] Machines need to
be designed according to the environment they are intended to operate in (for example,
a car, intended for transport on solid ground, would not perform well either on water
or in outer space!). However, mimicking biology is certainly not the only way to achieve
complex functionality: computer chips are manufactured from silicon wafers rather
than being wet and carbon-based like our brains. To date, it remains unproven as to
whether making iconic molecular representations of macroscopic objects or following
the principles of biological machines will be the most effective route for designing
molecular machines with useful functions. Indeed, perhaps the most productive solutions
will be found by following neither of these approaches too closely.
The tasks that molecular machines are best suited to carry out also need careful consideration:
“I can't see exactly what would happen, but I can hardly doubt that when we have some
control of the arrangement of things on a small scale we will get an enormously greater
range of possible properties that substances can have, and of different things that
we can do.”
Richard P. Feynman (1959)[2]
1) Molecular Machines for Molecular Electronics
I can’t see exactly what would happen, but I can hardly doubt that when we have some
control of the arrangement of things on a small scale we will get an enormously greater
range of possible properties that substances can have, and of different things that
we can do. Richard P. Feynman (1959).
In a series of controversial[42] and ground-breaking[43] experiments from about 1997
to 2007, the groups of Stoddart and Jim Heath interfaced switchable rotaxanes and
catenanes with silicon-based electronics in an effort to try to use molecular shuttles
in solid-state molecular electronic computing devices (Figure 9 a). Competing with
the electronic movements in silicon and other semiconductors (which intrinsically
occur billions of times faster than the change of position of the components in rotaxanes)
seems somewhat counterintuitive as a problem suited for solving with abacus-like positional
changes within molecular machines. However, a decade of effort and progress culminated
in the fabrication and testing of a remarkable 160-kbit memory at 1011 bits cm−2 based
on a monolayer of switchable rotaxanes as the data-storage elements.[44] Whether rotaxanes
will ever be effectively employed in electronics remains an open question, but an
important legacy of this pioneering research program is the vast amount learnt regarding
how to interface complex functional molecules with silicon. These efforts also served
to inspire the use of rotaxane-based switches to induce other types of macroscopically
observable property changes through mechanical movement, including chiroptical switching
(2003),[45] fluorescence switching (2004),[46] writing of information in polymer films
(2005),[47] and in controlled-release delivery systems (Figure 9 b, 2005).[48]
Figure 9
a) Rotaxane-based molecular switch tunnel junctions (Stoddart, Heath, and co-workers;
2007).[44] b) Controlled release of guest molecules using a rotaxane valve (Stoddart,
Zink, and co-workers; 2005).[48]
2) Molecular Machines that Can Do Mechanical Work: “Molecular Muscles”
Using controlled molecular-level motion to generate force in the macroscopic world
is an appealing task for molecular machines because this is, of course, how muscles
work. In 2005, the groups of Leigh and Stoddart each reported artificial molecular
machines capable of doing mechanical work. Leigh’s group used the light-induced shuttling
of a surface-bound rotaxane to mask a polarophobic fluorocarbon unit. The change in
surface properties could be used to propel a droplet along a surface and up a slope,
against the force of gravity (Figure 10 a).[49] Stoddart’s group used the contraction
of a rotaxane as a molecular actuator to bend a gold microcantilever beam (Figure
10 b).[50] Recently, Giuseppone and co-workers described the use of light-driven molecular
rotary motors to bring about macroscopic contraction of a gel (11, Figure 10 c).[51]
Figure 10
Artificial molecular machines put to work. a) A rotaxane molecular machine that does
mechanical work by moving a liquid droplet against the force of gravity (Leigh and
co-workers; 2005).[49] b) A rotaxane molecular machine that does mechanical work by
bending a microcantilever (Stoddart and co-workers; 2005).[50] c) Transduction of
molecular rotary motion into macroscopic contraction of a gel (Giuseppone and co-workers;
2015).[51] Parts (a) and (c) modified from Refs. [49] and [51] with permission.
3) Molecular Machines that Can Make Molecules
Ultimately, we can do chemical synthesis. A chemist comes to us and says, ‘Look, I
want a molecule that has the atoms arranged this and so; make me that molecule.’ Richard
P. Feynman (1959)
From polyketide synthase to DNA polymerases and the ribosome, one of the key uses
of molecular machines in biology is for the construction of other molecules. In 2013
an artificial small-molecule machine was invented that assembled a tripeptide of specific
sequence by travelling along a track loaded with amino acid building blocks (12, Figure
11).[52] This is a (very!) primitive analogue of the task performed by the ribosome
in cells, but arguably one of the most sophisticated performed by an artificial molecular
machine to date. For a synthetic molecular machine it has a truly complex mechanism
of operation, requiring the integrated interaction of several functional component
parts: a reversibly attached reactive “arm” with a regenerable catalytic site and
a peptide-elongation site, a ring that threads the track catalytically with no residual
ring–track interactions to retard the machine’s action, and a track with amino acid
building blocks in a predetermined sequence separated by rigid spacers. Systems with
integrated mechanisms of operations are likely to lead to increasingly ambitious and
potentially useful applications of synthetic molecular machines.
Figure 11
Making molecules with molecular machines: an artificial molecular peptide synthesizer
(Leigh and co-workers; 2013).[52]
Outlook
‘Who should do this and why should they do it?’ Well, I pointed out a few of the economic
applications, but I know that the reason that you would do it might be just for fun
… … have some fun! Richard P. Feynman (1959)
The future for the field of artificial molecular machines appears very bright. There
is already a working nanotechnology based on molecular machines that perform numerous
useful tasks: it is called Biology. The natural world shows us just how exquisite
and diverse the functions are that can be carried out with molecular machines. Advances
in artificial systems over the past 25 years mean that chemists now have the know-how
and synthetic tools available to enable them to make suitable machine architectures
(e.g. catenanes, rotaxanes, over-crowded alkenes, molecules that walk upon tracks).
They can switch the position of components (often by clever manipulation of noncovalent
interactions between the various parts), they understand how to use ratchet mechanisms
to create motor mechanisms, and are learning how to introduce them into more complex
molecular machine systems.
However, there are still basic challenges to overcome. In contrast to motor proteins,
powered by ATP hydrolysis or proton gradients, there are as yet no chemically driven
synthetic small-molecule motors that can operate autonomously (i.e. as long as a chemical
fuel is present), the closest counter-examples being the over-crowded alkene motors
designed by Feringa and co-workers that rotate continuously under irradiation with
light. Furthermore, although there have been some notable successes in using artificial
molecular machines to bring about property changes, few have been shown to perform
useful tasks that cannot be accomplished by conventional chemical means. This contrasts
with the essential roles played by biological machines in numerous cellular processes.
When this last step happens—and the rapid advances of the last few years suggest that
that time is not too far away—then artificial molecular machines will start to become
the extraordinary nanotechnology that Feynman predicted. Making that happen, as he
suggested,[2] will doubtless be fun!