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

Artificial Molecular Machines

This review describes a multidimensional treatment of molecular recognition phenomena involving aromatic rings in chemical and biological systems. It summarizes new results reported since the appearance of an earlier review in 2003 in host-guest chemistry, biological affinity assays and biostructural analysis, data base mining in the Cambridge Structural Database (CSD) and the Protein Data Bank (PDB), and advanced computational studies. Topics addressed are arene-arene, perfluoroarene-arene, S⋅⋅⋅aromatic, cation-π, and anion-π interactions, as well as hydrogen bonding to π systems. The generated knowledge benefits, in particular, structure-based hit-to-lead development and lead optimization both in the pharmaceutical and in the crop protection industry. It equally facilitates the development of new advanced materials and supramolecular systems, and should inspire further utilization of interactions with aromatic rings to control the stereochemical outcome of synthetic transformations.

Aromatic rings in chemical and biological recognition: energetics and structures.

Supramolecular chemistry has expanded dramatically in recent years both in terms of potential applications and in its relevance to analogous biological systems. The formation and function of supramolecular complexes occur through a multiplicity of often difficult to differentiate noncovalent forces. The aim of this Review is to describe the crucial interaction mechanisms in context, and thus classify the entire subject. In most cases, organic host-guest complexes have been selected as examples, but biologically relevant problems are also considered. An understanding and quantification of intermolecular interactions is of importance both for the rational planning of new supramolecular systems, including intelligent materials, as well as for developing new biologically active agents.

Binding Mechanisms in Supramolecular Complexes

Applications of Supramolecular Anion Recognition

This comprehensive review surveys developments over the past decade in the field of naphthalene diimides (NDIs). It explores their application toward: supramolecular chemistry; sensors; host–guest complexes for molecular switching devices, such as catenanes and rotaxanes; ion-channels by ligand gating; gelators for sensing aromatic systems; catalysis through anion−π interactions; and NDI intercalations with DNA for medicinal applications. We have also explored new designs, synthesis, and progress in the field of core-substituted naphthalene diimides (cNDIs), and their implications in areas such as artificial photosynthesis and solar cell technology. Also presented are some interesting synthetic routes and procedures that can be used toward further development of NDI-bearing compounds for future applications. Finally, we conclude with our views on NDI chemistry for future research endeavors, and we outline what we believe are the key obstacles that need to be overcome for NDIs to see real world applications.

Functional Naphthalene Diimides: Synthesis, Properties, and Applications

Attractive in theory and confirmed to exist, anion–π interactions have never really been seen at work. To catch them in action, we prepared a collection of monomeric, cyclic and rod-shaped naphthalenediimide transporters. Their ability to exert anion–π interactions was demonstrated by electrospray tandem mass spectrometry in combination with theoretical calculations. To relate this structural evidence to transport activity in bilayer membranes, affinity and selectivity sequences were recorded. π-acidification and active-site decrowding increased binding, transport and chloride > bromide > iodide selectivity, and supramolecular organization inverted acetate > nitrate to nitrate > acetate selectivity. We conclude that anion–π interactions on monomeric surfaces are ideal for chloride recognition, whereas their supramolecular enhancement by π,π-interactions appears perfect to target nitrate. Chloride transporters are relevant to treat channelopathies, and nitrate sensors to monitor cellular signaling and cardiovascular diseases. A big impact on organocatalysis can be expected from the stabilization of anionic transition states on chiral π-acidic surfaces.

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Experimental evidence for the functional relevance of anion– π interactions

Molecular mobility has attracted considerable attention in supramolecular chemistry and biochemistry, but the simple question of whether a small molecule can move directly between different binding sites of a multitopic host without intermediate dissociation has not been addressed so far. To study such processes, we consider hydrogen/deuterium exchange experiments on a model system comprising complexes formed between 18-crown-6 and oligolysine peptides. Because direct binding-site hopping is indistinguishable in solution from a dissociation/reassociation mechanism, here we show that the high vacuum of a mass spectrometer offers a unique environment for probing such processes. The highly dynamic motion of crown ethers along oligolysine peptide chains proceeds mechanistically by a simultaneous transfer of the crown ether from its ammonium ion binding site to a nearby amino group together with a proton. Furthermore, the exchange experiments unambiguously reveal the zwitterionic structure of the 18-crown-6/oligolysine complexes, highlighting the versatility and potential of gas-phase experiments for investigating non-covalent interactions.

Highly dynamic motion of crown ethers along oligolysine peptide chains

The non-covalent interactions of different upper-rim-substituted C(2)-resorcinarenes with tetramethylammonium salts were analyzed in the gas phase in an Electrospray Ionization Fourier-transform ion-cyclotron-resonance (ESI-FTICR) mass spectrometer and by (1)H NMR titrations. The order of binding strengths of the hosts towards the tetramethylammonium cation in the gas phase reflects the electronic nature of the substituents on the upper rim of the resorcinarene. In solution, however, a different trend with particularly high binding constants for halogenated resorcinarenes has been observed. This trend can be explained by a synergetic effect originating from the interaction of the halogenated resorcinarenes with the counter anions through hydrogen bonding. This study highlights the importance of weak interactions in recognition processes and points out the benefits of comparing the gas-phase data with results obtained from solution experiments.

Ion-Pair Recognition of Tetramethylammonium Salts by Halogenated Resorcinarenes

Supramolecular capsules composed of two or more self-complementary monomers held together by hydrogen bonds and other weak interactions such as cation–π and C–H–π interactions are able to encapsulate neutral as well as positively charged guests. This mini review will highlight work on transferring such non-covalently bound aggregates to the gas phase by soft ionisation methods, such as electrospray ionisation, and investigating structure and encapsulation properties under solvent-free conditions. These analyses reveal exact information about complex stoichiometry as well as about structure and stability of capsules composed of multiple building blocks. The review is organised such that each type of capsule introduced contributes a new aspect to the overall picture.

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Host–Guest Chemistry of Self-Assembling Supramolecular Capsules in the Gas Phase

Brownian motion, the rotation of molecules, and vibrations within molecules are typical forms of thermal motion. Fast chemical equilibria, such as the inversion at the ammonia nitrogen atom, the interconversion of conformers in alkanes, or highly dynamic association/dissociation processes in weakly bound noncovalent complexes are also thermally induced. In the context of noncovalent complexes, it is fascinating to examine whether an intracomplex migration of a guest molecule between different binding sites of a multitopic host is possible and how a motion like this could be monitored. Herein, the first five generations (G1–G5) of polyamino propylene amine (POPAM) dendrimers serve as prototypical multitopic hosts. We address the question, whether crown ethers can directly move from binding site to binding site on the dendrimers periphery without intermediate dissociation/reassociation (Figure 1). Furthermore, if this molecular “spacewalk” is indeed possible, it raises the question as to by what mechanism it proceeds. In solution, the detection of such an intracomplex binding-site hopping is challenging if not impossible, because it is always superimposed by dissociation/reassociation equilibria. Therefore, it is necessary to isolate the complexes from each other and from the corresponding free building blocks to suppress any intercomplex guest-exchange reactions. The high vacuum inside a mass spectrometer is ideally suited to achieve the isolation of the complexes as the complexes there are like-charged and thus efficiently separated from each other by charge repulsion. Also, reactions with neutral crown ether molecules can be excluded. Fragmentation of the crown ether/dendrimer complexes would be the only source for the appearance of neutral crown ethers in the gas phase. Therefore, their partial pressure is much too low to result in an efficient reattachment during the short time they spend inside the instrument before being pumped away. However, this approach comes with the difficulty that any intramolecular process does not change the complex ion s molecular mass and thus remains undetectable by a simple determination of the mass-to-charge ratio (m/z). Therefore, a gas-phase reaction is required that probes the guest s motion. Such a reaction must a) proceed energetically below the complex dissociation energy, b) cause a mass shift, and c) be directly linked to the guest movement. To realize this idea, we chose POPAM dendrimers as the multitopic scaffold. These dendrimers have highly branched onion-layer-type structures (Figure 1). From each generation (Gn) to the next, the number of peripheral amino groups doubles from four in theG1 dendrimer to 64 inG5. Their gasphase chemistry has been studied in detail. In the absence of a solvating agent, protonation is likely to occur at interior tertiary amines rather than the peripheral primary NH2 groups. To examine the host–guest chemistry of dendritic molecules in the gas phase is generally a challenging and byand-large unexplored field of research. Only a few examples exist to date. In our study, [18]crown-6 serves as the guest, it binds to primary ammonium ions in solution, and in the gas phase. Dendritic crown ether/ammonium complexes are Figure 1. Chemical structure of [18]crown-6 and a fourth generation (G4) POPAM dendrimer. Starting with a 1,4-diaminobutane core, the nth shell of branches is divergently grown on the (n 1)th generation dendrimer by two Michael additions of acrylnitrile to each branch and subsequent hydrogenolytic reduction of the nitrile groups. The red arrows symbolize the main question of the present study: Can crown ethers move freely along the periphery of POPAM dendrimers without intermediate dissociation of the complex? As this process proceeds in the high vacuum inside a mass spectrometer, we refer to it as a molecular “spacewalk”.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/anie.200990229

Dominik P. Weimann

Papers

Experimental evidence for the functional relevance of anion– π interactions

Highly dynamic motion of crown ethers along oligolysine peptide chains

Ion-Pair Recognition of Tetramethylammonium Salts by Halogenated Resorcinarenes

Host–Guest Chemistry of Self-Assembling Supramolecular Capsules in the Gas Phase

Dynamic Motion in Crown Ether Dendrimer Complexes: A “Spacewalk” on the Molecular Scale†