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Accessible Published by De Gruyter September 13, 2016

The Art of Building Small

Ben L. Feringa
From the journal Chemistry International


Beginning a fantastic voyage beyond the frontiers of contemporary chemical sciences, the creative power of synthetic chemistry imbues chemists with the confidence needed to enter many unknown molecular worlds. The beauty of Nature’s functional molecular structures offers, of course, a fantastic source of inspiration, yet chemists are not limited by the molecular building blocks selected by evolution to sustain the intricate systems of a living organism. Nature has developed on the principle of the minimal chemistry set—imagine what we can achieve with the whole of chemistry available to us.

Chemistry has already demonstrated its potential, creating, for example, the diverse materials that allow a modern airplane to transport hundreds of people at high speed over thousands of miles. One should note, however, that the materials, as well as the principles of flight, are distinct from those of a bird. In all modesty, we have so far failed to build even a single cell of a pigeon. Biological function is usually the result of complex molecular systems built on a very simple set of principles and components. Although highly effective, these systems are far from efficient. As the frontiers in chemistry shift from structure to function and from molecules to molecular systems, chemists must explore novel strategies to create functional molecular systems. Major challenges include discovering novel functions emerging from the collective behavior of molecules, exploring the dynamic properties of molecular systems, integrating synthetic and biological systems, and studying far-from-equilibrium behavior. This exploration will open unimagined opportunities to address future challenges in materials, sustainable processes, energy carriers, and biomedical applications.

From Molecules to Dynamic Molecular Systems

Confronted with the question of how to realize complex molecular systems with specific dynamic functions, we should reflect on the multifaceted nature of the problem. Besides the obvious structure, reactivity, and functionality of individual molecular components, their correct assembly and organization are crucial to the proper functioning of such dynamic systems. Interfacial phenomena are important, as is elegantly illustrated by membrane-embedded motors and filament-guided transporters in biology, as well as by electronic and sensing devices based on organic-inorganic systems. In integrating structure and function and interfacing the nanoscopic-world with the macroscopic-world, control at different hierarchical levels and length scales, i.e., supramolecular, mesoscopic, and macromolecular, offer additional challenges. An especially intriguing aspect is how we can amplify effects induced at the molecular level via the cooperative action of the individual molecular components. This ability will provide fascinating opportunities, for instance in the design of responsive materials such as artificial muscles, smart surfaces and coatings, and soft robotics.

Responsive behavior also asks for triggering, addressing, and sensing functions, not only to allow one to remotely influence the molecular system, but also to provide the ability to detect as well as act on demand in response to a change in the environment, a specific external signal, or a particular property that is desired. Chemical systems with adaptive or emergent behavior may already be within reach. We should note that biological systems operate far-from-equilibrium and the move from thermodynamic to kinetic, far-from-equilibrium control is the next major step for (supra-) molecular chemistry. In the broader context, synthetic chemistry has only scratched the surface of “chemistry as an information science”, which will become particularly evident as we enter the era of systems chemistry. Signal transduction, feedback loops, repair mechanisms, and autonomous processes are just a few of the additional aspects we have to deal with on our future journey into the world of dynamic molecular systems.

Two examples from our program, although still primitive compared to the sophisticated molecular machinery found in a living cell, illustrate the approaches we take to building responsive molecular systems at the nanoscale. In order to construct a light-responsive nano-valve to enable controlled drug delivery, a switchable MSCL channel protein complex was designed. Here, the MSCL channel of E. Coli. was re-engineered to accommodate synthetic photo-responsive units at specific positions in the protein complex. The whole system was assembled in an artificial membrane, i.e., a giant vesicle, that can be loaded with a molecular cargo, i.e., a drug. When the system is illuminated, the MSCL channel opens a 3 nm pore and the drug is released. In the second example, the focus was on autonomous translational movement. A carbon nanotube was decorated with carboxylic acid groups that allowed covalent anchoring of two enzymes, glucose oxidase and catalase. While the first enzyme converts glucose, generating hydrogen peroxide, the catalase rapidly converts this into molecular oxygen and water. The cooperative action of the two enzymes and the use of glucose as the chemical fuel induces an autonomous propulsion of the carbon nanotube. In this way, taking advantage of biology and synthesis, we built complex nano-systems that operate in an aqueous environment in which the individual components act together and respond to an external optical signal, or a chemical fuel, to perform a novel function. In the first example it is opening-closing of a nano-valve, while in the second example autonomous movement is accomplished by “burning” glucose. In these dynamic systems, we merge biological and synthetic components and integrate them to create advanced functions. With progress in synthetic biology, organic synthesis, and supramolecular chemistry, together with the opportunities offered by photo-and electro-chemistry and catalysis to power motility, the future of hybrid dynamic systems is particularly bright.

Molecular Switches and Responsive Materials

In materials science and nanotechnology, the use of molecular switches is particularly attractive, as they enable the introduction of responsive behavior and can function as information storage units and basic elements in optoelectronic devices. Again, Nature serves as a source of inspiration—human vision is based on arguably one of the most elegant natural responsive molecular systems, taking advantage of the retinal photo-isomerization as the elementary switching process. Key parameters in designing molecular switches for information technology are robustness in switching behavior, non-destructive read-out, and long-term stability. Although molecular switching can be triggered by a variety of input signals, e.g., redox, light, pH, temperature, or metal ion binding, light offers the distinct advantage as being a non-invasive trigger for a switching process. We built chiroptical molecular switches based on helical-shaped overcrowded alkenes, in which excellent photoreversibility is combined with high fatigue and non-destructive read-out. Here the interconversion of molecules with distinct chirality and shape define a zero-one digital information storage system at the molecular level. Future prospects are high-density nano-scale information storage systems.

In alternative approaches, advantage can be taken of reversible changes in the electronic properties of molecules. Numerous synthetic systems have been reported in the quest for the bottom-up approach toward molecular electronics, but major challenges remain in both the design of novel robust switching elements and the integration of molecular switches in microarray electronic devices. Organic photochromic compounds are attractive as photoswitches, as they have the potential to integrate optics (speed) and electronics, provided switching is not compromised by integrating the organic molecules in semiconductor devices. For example, our program achieved the construction of single molecule optoelectronic switching elements and the integration of photoswitches in large array devices. These, and related photo- and redox- active molecules, offer ample opportunity to explore molecular switches for information technology, but also for imaging and sensing applications.

Supramolecular chemistry is a field that can benefit from responsive functions and molecular switches. A next major step is the introduction of intrinsic switching functions in the components that are designed to undergo self-assembly to form larger supramolecular systems enabling responsive behavior. It will allow the system to react to an external signal, and, for example, adapt and reconfigure into a new assembly with a different function. For instance, we introduced photo-switches in small molecular gelators and could modulate the material between different gel states using a non-invasive light signal. Particularly fascinating is that, with these light-responsive gels, metastable states and out-of-equilibrium assemblies of soft materials can be reached. The introduction of photo-switches in the core part of special designed amphiphiles resulted in multicomponent self-assembled nano-objects, including vesicle capped nanotubes and nanotube enclosed vesicles, that show highly selective responsive properties. Illustrative of more complex responsive behavior at the nanoscale are systems designed to switch between a vesicle and a nanotube structure. The introduction of optical switches in soft matter, polymers, and supramolecular systems is expected to bring a wealth of novel responsive materials. In addition, these and related approaches will likely play a major role in the development of smart surfaces, e.g., for coatings, cell growth, tissue engineering, and sensing applications.

Light on Medicine

Exciting opportunities for the use of light responsive molecules in the biomedical field have emerged in recent years. While photodynamic therapy and a range of sophisticated fluorescence imaging techniques have found widespread application in the clinic, recent developments such as optogenetics, that allow, for instance, the control of neural functions, take advantage of photoactive proteins and have opened up entirely new avenues. From a synthetic perspective the design of small light-responsive bioactive compounds is largely uncharted territory. The introduction of photocleavable groups to existing or new drugs offers opportunities in precision therapy. In more complex molecular systems, sensing, delivery, and therapeutic function are combined, which make theranostics applications possible. The need for more effective medical therapies and responses to major challenges such as antibiotic resistance, stimulates the use of unconventional approaches. For example, photopharmacology can play a major role, combining the power of synthetic chemistry with the precision of light-responsive function. Photopharmacology is based on small molecule bioactive compounds, i.e., a “smart drug” with a photoswitchable function that allows the activation-deactivation of the drug. The photoswitch unit can be appended to an existing drug or built into the design of the pharmaceutical to become an integral part of its structure. The major advantage of photoresponsive molecules is that light allows non-invasive activation of the drug with high spatio-temporal precision. We have focused on light-activated antibiotics to fight antibiotic resistance. Activation with high precision at the point of infection and auto-deactivation away from it prevents the active form of the drug from entering the environment and may both enhance efficacy and provide a novel approach to fight the buildup of bacterial resistance. An additional benefit of the photopharmacological approach is the reduction of side effects, such as being harmful to benificial bacteria in the organism. The incorporation of an azobenzene photoswitch in a broad spectrum quinolone antibiotic not only enabled activation by light, but the stability of the antibiotic’s on-state could also be tuned by molecular design to allow the drug to switch to the off state automatically after a set time. The opportunities offered for high precision therapy go far beyond antibacterial agents, as is illustrated with photoresponsive antitumor agents such as a switchable SAHA anticancer drug. Here the main challenge is to avoid the severe side effects of the more commonly used chemotheurapeutic agents. Once proven effective, a potential future scenario is to translate the information from molecular imaging to guide laser activation of a switchable chemotheurapeutic compound for high precision treatment in a clinical setting. Recently, we have demonstrated patterning of bacterial growth using light activated drugs and interference with bacterial communication and biofilm formation using switchable quorum sensing molecules, while other groups have focused on restoring vision, interfering with neural processes, and controlling cell division, among others. Although the prospects of photopharmacology are bright, major challenges remain, for instance, how to achieve switching with visible and near-IR light to reduce potential toxicity and achieve high tissue penetration. Also, the design of orthogonal photoswitching units in molecular systems to control several biological functions in parallel and achieve up and down regulation of selected pathways in complex biological networks will provide exciting new opportunities at the interface of synthetic chemistry and biology.

Molecular Motors

In our body, many of the essential functions are controlled by biomolecular motors, ranging from ATP synthesis to muscle function and cell division. In modern society, the motors that power our machines, cars, and planes are ubiquitous. However, synthetic chemists have only recently begun to design molecular systems that show motor function at the nanoscale. At the heart of the nano-machines and robots of the future will be molecular motors providing the power for these systems to do work. In taking up the challenge to exploit motion at the nanoscale to perform useful tasks, one should realize that these systems operate at low Reynolds numbers in an environment of continuous Brownian motion. Furthermore, a comparison between machines and robots in the macroworld and those in the cell should be taken into account in design strategies aimed towards molecular motors and machines. Whereas in macromachines size, friction, and inertia play a dominant role, these parameters are insignificant in molecular machines, where inter-and intra- molecular interactions and interfacial phenomena are key. By translating lessons taken from nature into the design of synthetic molecular motors, we were able to demonstrate for the first time unidirectional rotary motion in a molecular system powered by light. Here the complexity is not so much in the molecular structure, but in the multitude of parameters that enable controlled rotary motion. These include chirality to control directionality of motion, multiple isomerization processes to achieve continuous rotation, and photo-responsive behaviors to power the motor by light. With the principle of a rotary molecular motor established, the foundation was laid for several generations of molecular motors with expanded properties and functions. For instance, the power of synthetic chemistry is shown once again with the construction of motors whose rotary speed could be controlled over several orders of magnitude. Meanwhile rotary motors have been used to control polymer folding and the organization of molecules in liquid crystal films in a dynamic way, driving these systems out of equilibrium. It is a fascinating experience to see how the availability of molecular rotary motors opens unforeseen possibilities, such as the transmission and amplification of motion, as was also demonstrated with light-driven rotating micro-objects and adaptive self-assembled nanostructures. Taking advantage of the cooperative action of rotary motors, a nanocar was constructed, enabling the conversion of rotary motion into directional translational motion on a surface at the nanoscale. Motors can be used as multistage responsive systems to control function, as was shown in multitasking chiral catalysts for enantioselective synthesis. In a typical Dutch design, “a nanoscale windmill park”, comprising self-assembled monolayers of rotary motors, was constructed with the prospect of responsive and adaptive surfaces and nanoscale energy converters.

In dynamic molecular systems based on rotary molecular motors, many of the key elements discussed earlier merge. These elements range from the essential parameters that govern rotary motion in the motor structure itself to the control elements that allow, for instance, the assembly and proper functioning of a collection of motors on a surface or in a liquid crystal thin film. With the discovery of the first molecular motor and the development by other groups of molecular systems that show controlled translational and rotary motion, the question arises as to what opportunities these systems offer. Molecular motors are arguably a fascinating starting point for the bottom-up construction of molecular machines and nano-robots. Although some might consider this the domain of science fiction, the fact that chemists are now able to design, control, and use motor-type function at the molecular level sets the stage for entirely new possibilities in science and industry. Programming molecules to enable responsive and adaptive functions cumulating in controlled motion is a major step from molecules to dynamic molecular systems. Incorporating dynamic functions in novel materials offers exciting opportunities for responsive surfaces and coatings, self-healing polymers, biomedical materials for tissue engineering, and the control of cell growth, among others. The integration of information technology and responsive materials will open an exciting new domain for the “synthesis of function”, especially when these systems are biocompatible. Roving sensors, smart delivery systems, responsive implants, and precision therapy are areas where dynamic molecular function can likely offer entirely new perspectives.


The beauty and strength of synthetic chemistry is that we can build our own molecular world, as evident in the wealth of chemical products that sustain modern society. Facing the challenges of sustainable processes and products and of our future materials, medical, and energy needs, the practitioner of the art of building small will need to reach new levels of sophistication. Dynamic molecular systems, responsive functions, and control of motion offer fascinating opportunities, as illustrated above and in elegant examples that can be found in recent literature. In this endeavor, Nature’s motors and machines can guide the molecular explorer. However, at the start of our next journey we should remind ourselves of the words of Leonardo da Vinci “Where Nature finishes producing its own species man begins, with the help of Nature, to create an infinity of species”.

Essay based on the presentation of the “Chemistry of the Future Solvay Prize 2015” awarded to Professor Ben L. Feringa, Brussels, Belgium, November 2015.

Online erschienen: 2016-9-13
Erschienen im Druck: 2016-9-1

©2016 by Walter de Gruyter Berlin/Boston