Interview with Louis Fensterbank
As a specialist in molecular chemistry, Louis Fensterbank is working to develop new synthesis methods that are in line with the greening of his discipline, in the face of the challenges of sustainable development and the energy transition. In 2023, he will hold the Activations in Molecular Chemistry Chair at the Collège de France.
How did you become interested in science ?
Louis Fensterbank : I come from a fairly bipartite family, with several people working in law and commerce on the one hand, and a rural veterinary tradition on the other. When you grow up surrounded by medicines that cure animals, and your ears filled with notions like prophylaxis, it arouses interest. My family owned a pharmacy downstairs, which I remember smelling quite strongly of chemicals So there's always been this proximity to the world of science and technology. Then, at school, the problem was that I was interested in so many things, perhaps too many, until I came across a physics and chemistry teacher in the first year of secondary school, who presented chemistry in such a simple and fun way that I really enjoyed it. Especially organic chemistry - - with its aspects of nomenclature and molecular properties. So I decided to take preparatory classes, where the rest of chemistry is quite descriptive, especially general chemistry, with mathematical treatments that were a little less intuitive. Then, when it came time to sit the competitive entrance exams, I had to decide what I really wanted to do. Two things interested me : public works schools and chemistry. Two seemingly very differentoptions , but united by a common thread : building. I ended up in Lyon, home to a major industrial and academic center for organic chemistry. I spent two years there before doing my PhD at the State University of New York at Stony Brook and returning to France.
You're working on developing new synthesis methods in radical and organometallic chemistry. What does this involve ?
In my thesis, I worked with an assistant professor for whom I was the first doctoral student, and I launched myself into the chemistry of organosilyls, compounds with a carbon-silicon bond that are very rich in synthetic opportunities. Silicon is also the second most abundant element in the earth's crust, which makes it very attractive. With this knowledge of organosilicon reactivity, it was easy for me to embark on a number of radical chemistry projects, which was one of the flagship themes of the Jussieu laboratory - which I had joined as a CNRS research fellow. Radical chemistry is about building new molecular objects. Indeed, a highly reactive radical[1] can be added to a double or triple bond to form a new highly reactive intermediate, which can again be added to an unsaturation, and so on. Our aim was to maximize these addition reactions, but in an intramolecular version, which corresponds to cyclization processes, in other words : we wanted to produce highly complex polycyclic molecules via so-called radical cascades. To promote radical formation, we used a mediator such as tin hydride in the presence of a small quantity of initiators, and based on kinetic data, we discovered many new reactivities, invented reactions that could be transposed to the synthesis of natural products, and so on. The problem with this chemistry is that tin hydride is used stoichiometrically, i.e. in quantities identical to those of the starting products. In addition to its own toxicity, it evolves in the course of the reactions into new derivatives which are also toxic and which pollute the final products of the reaction. Reaction conditions were neither ideal, with the need for heating and the use of benzene as a solvent (banned today due to its toxicity), nor compatible with scale-up. In fact, reactions are carried out at low concentrations, and to obtain a few grams of product, it was necessary to work with balloons of several liters, which is totally absurd. So there was a growing awareness of the need to green chemistry, which set the discipline in motion at the end of the 1990s.
How was the discipline " verdie " ?
The alternatives were not really clear, and the option of generating radicals by redox reaction[2] was still relatively undeveloped, especially using a catalyst[3]. This left the discipline moribund for several years. Then, photo-redox catalysis re-emerged, which was well known among our inorganic colleagues, but hardly used in organic chemistry : a fine illustration of the compartmentalization of communities that has been detrimental on many occasions. This activation method relies on the use of a metal complex or dye as a photo-catalyst, whose excited state has redox properties. In 2010, we were the first in France to re-examine this new way of generating radical intermediates. Today, it has become the method of choice for generating radical species. We then realized that it is possible not only to generate a radical catalytically, but also to engage it in an organometallic nickel coupling ring[4], the two rings working cooperatively through electron exchange. In this way, cross-coupling can be achieved , a synthesis methodology widely used in the pharmaceutical industry for the construction of most drugs, for example, and which relies primarily on palladium as a catalyst. However, while palladium is a very versatile metal, chemically speaking, and therefore widely used, it is also very expensive, and its natural deposits are in the hands of a handful of countries, unlike nickel, which is cheaper and more widespread across the globe. There's clearly a geopolitical dimension to the supply of materials needed for chemistry ! These new cross-couplings resulting from dual photoredox-Ni catalysis also offer milder temperature conditions and enable coupling partners to be varied, thus connecting fragments that open up new molecular spaces richer in properties than the molecular products obtained with palladium couplings. Ultimately, the aim is to propose new protocols for the synthesis of new substrates, based on reliable mechanisms, so that other academic or industrial laboratories can use them for various applications : medicinal chemistry, materials science..
How do green chemistry specifications impact your research ?
First of all, there are the obvious safety principles : avoid toxic and explosive solvents and reagents, favor their green counterpart from biomass, reduce synthesis effluents, synthesize products with no environmental impact. There are also more " chemical " injunctions, such as saving atoms. The aim is to make the most of the materials initially used, and to reduce waste. Another area for improvement is compressing the number of steps ; in other words, we're going to favor reactions that enable us to go from a molecule Ato a molecule Bin as few steps as possible. Finally, many reactions are not spontaneous and require activation - thermal or photochemical - which requires a considerable investment in energy, and in some cases a very high level. This is why we want to catalyze as many processes as possible. This brings us back to the problem of catalysis: what is a " good " catalyst ? Over the last twenty years or so, homogeneous gold catalysis has given rise to new transformations enabling highly original molecular architectures. Of course, gold is expensive and rare, but its geographical distribution is more favorable. In contrast, there is iron, an extraordinary metal, very abundant, but very complicated, as it easily exchanges electrons and can be very sensitive to oxygen. It generally needs to be dressed with elaborate ligands to control its reactivity. So every system has its limits. We are also aware that certain metals are in short supply, hence the idea of using organic catalysts derived from carbon. Another very interesting element, just below carbon in the periodic table and already mentioned, is silicon. We can imagine using it as a catalytic center, which is quite exciting. And then there are other ways of activating : mechanochemistry - i.e. without solvents, just by mechanical grinding. Biocatalysis, notably with enzymes improved by directed evolution, is also booming. And let's not forget AI-controlled process automation. The field of green chemistry is therefore vast and protean. Progress is rapid, but the situation is urgent !
The development of new functional molecular edifices is essential to many transdisciplinary approaches. As a chemist, how closely do you interact with the fields of application that benefit from your work ?
Indeed, as chemists, we are fabulously fortunate to work at a scale of matter that can be a source of explanations, solutions and progress for many disciplines. In physics, with materials ; in the life sciences, with molecular probes, drugs ; in the heritage field, to study the ageing of pigments in paintings, etc. So we're going to be interacting with numerous colleagues in a wide variety of fields, which in some cases means custom synthesis, but which remains interesting for the simple reason that there's a precise target to hit and we need to produce it in sufficient quantities ! This kind of undertaking can even lead to the development of a new methodology. For a number of years now, we've been looking at how to mobilize the element silicon in living organisms, and in particular how to implant the carbon-silicon (C-Si) bond, which has remained absent despite the abundance of this element. In this context, to introduce a Si(OH)3 function on amino acids, we have developed a new method for forming the C-Si bond. We also work with industrialists, whose expectations can range from acquiring a methodology to understanding the reaction mechanisms involved in processes. Today, transdisciplinarity is much more encouraged through numerous calls for tender. Despite this, we need to maintain our disciplinary focus, because we can only be successful in transdisciplinary research if we remain innovative in the art of molecular synthesis.
You have been in charge of the Paris-Centre Chemistry Master's program for seven years, and in 2023 you will be appointed to the Activations in Molecular ChemistryChairat the Collège de France. What are your expectations of this chair ? What role do you think teaching should play in the life of a researcher ?
I became director of this master's program just as a new syllabus was being drawn up. Together with my colleagues from the Paris-Centre institutions, we realized that we needed to broaden the horizons of our discipline and offer students the opportunity to take cross-disciplinary courses to break down disciplinary barriers. Organics and inorganics, for example, would benefit from dialogue and joint lectures. Similarly, the polymerist community had an incredible amount of knowledge in radical chemistry, but little exchange with radical molecularists... This notion of broad molecular chemistry, which extends from chemical biology to inorganic materials - where the molecule is the keystone - has gradually taken hold throughout the world over the last twenty years, to the benefit of all. Having been a researcher at the CNRS and then a university professor, I've experienced both regimes, which is fortunate. Contact with lectures and students is fundamental for a researcher, as it's a way of constantly confronting excellent questions and therefore re-evaluating knowledge. Chemistry really is a central science that needs committed and passionate players, because today's environmental challenges rely heavily on it, and these questions require investment from the new generation, which I like to stimulate. We need to counter all the nonsense we hear. I'd even go so far as to say that teachers, at whatever level, play an extremely important role in terms of vigilance, transmission and encouragement. I'm very grateful to my peers at the Collège de France for choosing the theme of molecular chemistry and entrusting me with the associated chair. It's a unique megaphone. The lectures and seminars will be an opportunity to keep abreast of developments in established fields, but also to disseminate more emerging themes, and to involve various players on the French and international chemical scene.
Interview by William Rowe-Pirra
Glossary
[1] Radical or radical intermediate :reactive entity possessing an unpaired electron, and in the context of this discussion, the electron is centered on a carbon atom.
[2] Catalyst : agent that accelerates the rate of a chemical reaction without entering into its balance.
[3] Oxidation-reduction : chemical reaction during which an electron is transferred. The chemical species receiving the electron is the oxidizing agent, the species giving it up is the reducing agent.
[4] Cross-coupling: a reaction that links two molecular fragments by forming a carbon-carbon bond with the help of a catalyst.
