David A. Leigh

Unidirectional rotation in a mechanically interlocked molecular rotor

Molecular motor proteins are ubiquitous in nature and have inspired attempts to create artificial machines that mimic their ability to produce controlled motion on the molecular level. A recent example of an artificial molecular rotor is a molecule undergoing a unidirectional 120° intramolecular rotation around a single bond; another is a molecule capable of repetitive unimolecular rotation driven by multiple and successive isomerization of its central double bond. Here we show that sequential and unidirectional rotation can also be induced in mechanically interlocked assemblies comprised of one or two small rings moving around one larger ring. The small rings in these [2]- and [3]catenanes move in discrete steps between different binding sites located on the larger ring, with the movement driven by light, heat or chemical stimuli that change the relative affinity of the small rings for the different binding sites. We find that the small ring in the [2]catenane moves with high positional integrity but without control over its direction of motion, while the two rings in the [3]catenane mutually block each others movement to ensure an overall stimuli-induced unidirectional motion around the larger ring.

Artificial Molecular Machines

The widespread use of molecular machines in biology has long suggested that great rewards could come from bridging the gap between synthetic molecular systems and the machines of the macroscopic world. In the last two decades, it has proved possible to design synthetic molecular systems with architectures where triggered large amplitude positional changes of submolecular components occur. Perhaps the best way to appreciate the technological potential of controlled molecular-level motion is to recognize that nanomotors and molecular-level machines lie at the heart of every significant biological process. Over billions of years of evolution, nature has not repeatedly chosen this solution for performing complex tasks without good reason. When mankind learns how to build artificial structures that can control and exploit molecular level motion and interface their effects directly with other molecular-level substructures and the outside world, it will potentially impact on every aspect of functional molecule and materials design. An improved understanding of physics and biology will surely follow. The first steps on the long path to the invention of artificial molecular machines were arguably taken in 1827 when the Scottish botanist Robert Brown observed the haphazard motion of tiny particles under his microscope.1,2 The explanation for Brownian motion, that it is caused by bombardment of the particles by molecules as a consequence of the kinetic theory of matter, was later provided by Einstein, followed by experimental verification by Perrin.3,4 The random thermal motion of molecules and its implications for the laws of thermodynamics in turn inspired Gedankenexperiments (“thought experiments”) that explored the interplay (and apparent paradoxes) of Brownian motion and the Second Law of Thermodynamics. Richard Feynman’s famous 1959 lecture “There’s plenty of room at the bottom” outlined some of the promise that manmade molecular machines might hold.5,6 However, Feynman’s talk came at a time before chemists had the necessary synthetic and analytical tools to make molecular machines. While interest among synthetic chemists began to grow in the 1970s and 1980s, progress accelerated in the 1990s, particularly with the invention of methods to make mechanically interlocked molecular systems (catenanes and rotaxanes) and control and switch the relative positions of their components.7−24 Here, we review triggered large-amplitude motions in molecular structures and the changes in properties these can produce. We concentrate on conformational and configurational changes in wholly covalently bonded molecules and on catenanes and rotaxanes in which switching is brought about by various stimuli (light, electrochemistry, pH, heat, solvent polarity, cation or anion binding, allosteric effects, temperature, reversible covalent bond formation, etc.). Finally, we discuss the latest generations of sophisticated synthetic molecular machine systems in which the controlled motion of subcomponents is used to perform complex tasks, paving the way to applications and the realization of a new era of “molecular nanotechnology”. 1.1. The Language Used To Describe Molecular Machines Terminology needs to be properly and appropriately defined and these meanings used consistently to effectively convey scientific concepts. Nowhere is the need for accurate scientific language more apparent than in the field of molecular machines. Much of the terminology used to describe molecular-level machines has its origins in observations made by biologists and physicists, and their findings and descriptions have often been misinterpreted and misunderstood by chemists. In 2007 we formalized definitions of some common terms used in the field (e.g., “machine”, “switch”, “motor”, “ratchet”, etc.) so that chemists could use them in a manner consistent with the meanings understood by biologists and physicists who study molecular-level machines.14 The word “machine” implies a mechanical movement that accomplishes a useful task. This Review concentrates on systems where a stimulus triggers the controlled, relatively large amplitude (or directional) motion of one molecular or submolecular component relative to another that can potentially result in a net task being performed. Molecular machines can be further categorized into various classes such as “motors” and “switches” whose behavior differs significantly.14 For example, in a rotaxane-based “switch”, the change in position of a macrocycle on the thread of the rotaxane influences the system only as a function of state. Returning the components of a molecular switch to their original position undoes any work done, and so a switch cannot be used repetitively and progressively to do work. A “motor”, on the other hand, influences a system as a function of trajectory, meaning that when the components of a molecular motor return to their original positions, for example, after a 360° directional rotation, any work that has been done is not undone unless the motor is subsequently rotated by 360° in the reverse direction. This difference in behavior is significant; no “switch-based” molecular machine can be used to progressively perform work in the way that biological motors can, such as those from the kinesin, myosin, and dynein superfamilies, unless the switch is part of a larger ratchet mechanism.14

Sequence-Specific Peptide Synthesis by an Artificial Small-Molecule Machine

Ribosomal Rotaxane? The ribosome is an extraordinarily sophisticated molecular machine, assembling amino acids into proteins based on the precise sequence dictated by messenger RNA. Lewandowski et al. (p. 189) have now taken a step toward the preparation of a stripped-down synthetic ribosome analog. Their machine comprises a rotaxane—a ring threaded on a rod—in which the ring bears a pendant thiol that can pluck amino acids off the rod; the terminal nitrogen then wraps around to form a peptide bond and liberate the thiol for further reaction. The system was able to link three amino acids in order from the preassembled rod. A macrocycle threaded on a rod can catalytically insert several amino acids placed along its path into a peptide chain. The ribosome builds proteins by joining together amino acids in an order determined by messenger RNA. Here, we report on the design, synthesis, and operation of an artificial small-molecule machine that travels along a molecular strand, picking up amino acids that block its path, to synthesize a peptide in a sequence-specific manner. The chemical structure is based on a rotaxane, a molecular ring threaded onto a molecular axle. The ring carries a thiolate group that iteratively removes amino acids in order from the strand and transfers them to a peptide-elongation site through native chemical ligation. The synthesis is demonstrated with ~1018 molecular machines acting in parallel; this process generates milligram quantities of a peptide with a single sequence confirmed by tandem mass spectrometry.

A molecular information ratchet

Motor proteins and other biological machines are highly efficient at converting energy into directed motion and driving chemical systems away from thermodynamic equilibrium. But even though these biological structures have inspired the design of many molecules that mimic aspects of their behaviour, artificial nanomachine systems operate almost exclusively by moving towards thermodynamic equilibrium, not away from it. Here we show that information about the location of a macrocycle in a rotaxane—a molecular ring threaded onto a molecular axle—can be used, on the input of light energy, to alter the kinetics of the shuttling of the macrocycle between two compartments on the axle. For an ensemble of such molecular machines, the macrocycle distribution is directionally driven away from its equilibrium value without ever changing the relative binding affinities of the ring for the different parts of the axle. The selective transport of particles between two compartments by brownian motion in this way bears similarities to the hypothetical task performed without an energy input by a ‘demon’ in Maxwell’s famous thought experiment. Our observations demonstrate that synthetic molecular machines can operate by an information ratchet mechanism, in which knowledge of a particle’s position is used to control its transport away from equilibrium.

A synthetic molecular pentafoil knot

Knots are being discovered with increasing frequency in both biological and synthetic macromolecules and have been fundamental topological targets for chemical synthesis for the past two decades. Here, we report on the synthesis of the most complex non-DNA molecular knot prepared to date: the self-assembly of five bis-aldehyde and five bis-amine building blocks about five metal cations and one chloride anion to form a 160-atom-loop molecular pentafoil knot (five crossing points). The structure and topology of the knot is established by NMR spectroscopy, mass spectrometry and X-ray crystallography, revealing a symmetrical closed-loop double helicate with the chloride anion held at the centre of the pentafoil knot by ten CH···Cl(-) hydrogen bonds. The one-pot self-assembly reaction features an exceptional number of different design elements-some well precedented and others less well known within the context of directing the formation of (supra)molecular species. We anticipate that the strategies and tactics used here can be applied to the rational synthesis of other higher-order interlocked molecular architectures.

Hybrid organic–inorganic rotaxanes and molecular shuttles

The tetravalency of carbon and its ability to form covalent bonds with itself and other elements enables large organic molecules with complex structures, functions and dynamics to be constructed. The varied electronic configurations and bonding patterns of inorganic elements, on the other hand, can impart diverse electronic, magnetic, catalytic and other useful properties to molecular-level structures. Some hybrid organic–inorganic materials that combine features of both chemistries have been developed, most notably metal–organic frameworks, dense and extended organic–inorganic frameworks and coordination polymers. Metal ions have also been incorporated into molecules that contain interlocked subunits, such as rotaxanes and catenanes, and structures in which many inorganic clusters encircle polymer chains have been described. Here we report the synthesis of a series of discrete rotaxane molecules in which inorganic and organic structural units are linked together mechanically at the molecular level. Structural units (dialkyammonium groups) in dumb-bell-shaped organic molecules template the assembly of essentially inorganic ‘rings’ about ‘axles’ to form rotaxanes consisting of various numbers of rings and axles. One of the rotaxanes behaves as a ‘molecular shuttle’: the ring moves between two binding sites on the axle in a large-amplitude motion typical of some synthetic molecular machine systems. The architecture of the rotaxanes ensures that the electronic, magnetic and paramagnetic characteristics of the inorganic rings—properties that could make them suitable as qubits for quantum computers—can influence, and potentially be influenced by, the organic portion of the molecule.

Catenanes: Fifty Years of Molecular Links

Half a century after Schill and Lüttringhaus carried out the first directed synthesis of a [2]catenane, a plethora of strategies now exist for the construction of molecular Hopf links (singly interlocked rings), the simplest type of catenane. The precision and effectiveness with which suitable templates and/or noncovalent interactions can arrange building blocks has also enabled the synthesis of intricate and often beautiful higher order interlocked systems, including Solomon links, Borromean rings, and a Star of David catenane. This Review outlines the diverse strategies that exist for synthesizing catenanes in the 21st century and examines their emerging applications and the challenges that still exist for the synthesis of more complex topologies.

Influencing intramolecular motion with an alternating electric field

Analogues of mechanical devices that operate on the molecular level, such as shuttles, brakes, ratchets, turnstiles and unidirectional spinning motors, are current targets of both synthetic chemistry and nanotechnology. These structures are designed to restrict the degrees of freedom of submolecular components such that they can only move with respect to each other in a predetermined manner, ideally under the influence of some external stimuli. Alternating-current (a.c.) electric fields are commonly used to probe electronic structure, but can also change the orientation of molecules (a phenomenon exploited in liquid crystal displays), or interact with large-scale molecular motions, such as the backbone fluctuations of semi-rigid polymers. Here we show that modest a.c. fields can be used to monitor and influence the relative motion within certain rotaxanes, molecules comprising a ring that rotates around a linear ‘thread’ carrying bulky ‘stoppers’ at each end. We observe strong birefringence at frequencies that correspond to the rate at which the molecular ring pirouettes about the thread, with the frequency of maximum birefringence, and by inference also the rate of ring pirouetting giving rise to it, changing as the electric field strength is varied. Computer simulations and nuclear magnetic resonance spectroscopy show the ring rotation to be the only dynamic process occurring on a timescale corresponding to the frequency of maximum birefringence, thus confirming that mechanical motion within the rotaxanes can be addressed, and to some extent controlled, by oscillating electric fields.

Rise of the Molecular Machines

The authors thank the EPSRC, ERC, and the Leverhulme Trust for supporting our research programs on molecular machines. E.R.K. is a Royal Society of Edinburgh/Scottish Government Personal Research Fellow.

Three State Redox-Active Molecular Shuttle That Switches in Solution and on a Surface

Although the desirability of developing synthetic molecular machine systems that can function on surfaces is widely recognized, to date the only well-characterized examples of electrochemically switchable rotaxane-based molecular shuttles which can do so are based on the tetracationic viologen macrocycle pioneered by Stoddart. Here, we report on a [2]rotaxane which features succinamide and naphthalene diimide hydrogen-bonding stations for a benzylic amide macrocycle that can shuttle and switch its net position both in solution and in a monolayer. Three oxidation states of the naphthalene diimide unit can be accessed electrochemically in solution, each one with a different binding affinity for the macrocycle and, hence, corresponding to a different distribution of the rings between the two stations in the molecular shuttle. Cyclic voltammetry experiments show the switching to be both reversible and cyclable and allow quantification of the translational isomer ratios (thermodynamics) and shuttling dynamics (kinetics) for their interconversion in each state. Overall, the binding affinity of the naphthalene diimide station can be changed by 6 orders of magnitude over the three states. Unlike previous electrochemically active amide-based molecular shuttles, the reduction potential of the naphthalene diimide unit is sufficiently positive (-0.68 V) for the process to be compatible with operation in self-assembled monolayers on gold. Incorporating pyridine units into the macrocycle allowed attachment of the shuttles to an acid-terminated self-assembled monolayer of alkane thiols on gold. The molecular shuttle monolayers were characterized by X-ray photoelectron spectroscopy and their electrochemical behavior probed by electrochemical impedance spectroscopy and double-potential step chronoamperometry, which demonstrated that the redox-switched shuttling was maintained in this environment, occurring on the millisecond time scale.