University of Groningen
Carbon-carbon bond formations using organolithium reagents
Heijnen, Dorus
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date: 2018
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Heijnen, D. (2018). Carbon-carbon bond formations using organolithium reagents. University of Groningen.
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
Summary for non chemists
During the 4 years in which this thesis was written, the available methodology for the cross coupling of organolithium reagents was expanded. So what does that mean? Before explaining the theory behind it, it might help to address the practical aspects. Putting it really bluntly, we (organic chemists) mix chemicals, and hope we get the product we (or our boss) want. Sometimes it is really easy, like mixing flour, eggs and some milk in roughly the right ratio, and your product just appears, ready for the next step. More often however it is a bit more complicated, and we have no clue what is going on in our reaction flask. With the help of (expensive) equipment, we can slowly combine pieces of a puzzle. Some machines can give you the weight of your molecule, others tell you the ratio of hydrogen/carbon/oxygen atoms, and the most used one, is like a MRI for molecules. A really big magnet in which you insert your reaction mixture, to look at the interactions of your material with a magnetic field. The interpretation of these types of data, looking at peaks and drawing molecular structures (see also Figure 1) is like a language we all speak, in order to discuss our theories, findings and ideas.
Figure 1 Peaks, molecules and schemes that make perfect sense to an organic chemist.
In order to give an (extremely simplified) overview of how our research is built up and divided, I would like to use the analogy with the car industry to try and visualize what the words in the very first sentence mean. It might be easier to imagine the process (synthesis) of building a car. You would need wheels, a chassis, an engine, and many more parts. But you cannot just pile up all the components and shake it till a car appears, it requires precise handling, and a specific order of steps. Comparable to the vehicle, some people specialize in the general assembly method, while others work in the optimization of the specific parts (the engine, or tires for example), and therefore master the details of one process.
In the comparison to building a car, the field of synthetic organic synthesis can also roughly be divided in two fields. Those who study and master all the details of a single component (the development of methodology), and those who combine the expertise of others to assemble a complex structure such as a (molecular) car (Figure 2).
Figure 3 Schematic overview of assembly of a car (top) and part of the "assembly" of the molecular car (bottom)
In my research I have focused on the formation of carbon-carbon bonds. Its importance is equivalent to making a metal-metal connection (welding, bolting, locking etc.) in a car. In 2013, my predecessor found a new way of making these carbon-carbon bonds in a way that produces just a fraction of the waste, and costs less than half of the existing methods available. So why isn’t the whole (chemical) world using this method already? Going back to the car, the method works great for structures that
are only made of steel, but it requires such extreme conditions that it would immediately destroy all sensitive plastic and glass parts (= functional molecular groups) of the car. Though the chemicals I worked with are cheap, easy to make and produce a relatively innocuous waste, they are so reactive that they catch fire spontaneously upon exposure to air. One of my main challenges was to try and control this extreme reactivity, so we can apply the above mentioned method in the presence of more sensitive parts of the car or molecule. Finally, another goal was to further increase the difficulty of the bond (hard to reach, sterically hindered) we could make, and reduce the cost even further by optimizing the nature of the catalyst.
Taking it one step up in terms of chemistry, I will try to explain the terms catalyst and atom economy. The first word might ring a bell for some people, thinking of a car exhaust, and its definition is : “A component that takes part in a reaction, without being consumed”. In other words, it helps the reaction go, but is still intact after it has done its job. As a consequence, a catalyst can undergo several consecutive reactions, and can therefore often be used in relatively small amounts. For work in this thesis, the amount of catalyst is usually 1-5 % of the product, meaning each catalyst molecule undergoes 100-20 catalytic cycles until the reaction is complete. Palladium is a metal that can do just these things, and the fact that it is expensive is compensated by the small amounts that are necessary for the reactions. (Though I have used several thousands of euros of palladium catalysts throughout my research, sorry Ben).
The above mentioned catalysts help us improve reactions, and have made an impact on us all. Almost every single piece of plastic that you have ever touched, (bio)fuels you have put in your car, pastries you have eaten, and even some of the drugs you have taken are made via catalytic chemical transformations. Without them our cars would emit a lot more toxic fumes, your future car will not have fuel, our plastics would be unaffordable or unavailable, and even some of our food and medicine would not be the same. It would be an understatement to say that research into catalysis and catalysts is extremely important for our current way of living (be it good or bad). One way these catalysts improve chemical transformations, is by lowering the amount of waste that is produced, or the amount of heat or time required to achieve conversion to the product. Only very few people will wonder about the quantity of side products that were created during the synthesis of their painkiller or antitumor medicine. In reality, the ratio between useful drug and generated waste can be as bad as 1: 100 or more (100 grams of waste per gram of active ingredient), and it makes up an appreciable percentage of the price of the drug to (responsibly) treat this waste. It is not only the weight of the unwanted side product that plays an important role, but also its chemical nature. Some side products are toxic, and therefore even more costly to recycle or dispose of.
Figure 3 Chemical "handles" for increased selectivity and reactivity
Figure 3 shows how this waste is produced, and why it can’t always be avoided. The top reaction represents an unselective or unreactive pair of chemicals, which upon mixing gives the undesired (linked on the corner), or no product. Traditional methods for efficiently coupling these two building blocks often require large, expensive or toxic handles, that generate large amounts of (toxic) waste (the red/orange balls in scheme 2). The methodology that we further developed has the advantage of producing a relatively small amount of non-toxic waste (the green balls). The major side product is lithium chloride, a relatively harmless salt which is sometimes even used as a drug itself. The theoretical relation between product and generated waste is described as Atom Economy, and is shown below.
Chemists (should) always try to achieve the highest possible atom economy without compromising other parameters such as product purity, safety, reaction time, space, efficiency or yield. This everlasting search for the increase in atom economy and decrease of waste and energy are essential
for making existing production processes less harmful for the environment, and thus generate greener ways of producing chemical products.
So what is the point and/or relevance of all of this? Beside the curiosity to invent and develop new (chemical) methods, molecules or devices, or in order to explain natural phenomena, fundamental research should not be judged on its immediate output for society. Spending years of research on a topic that was just a curiosity at first, could prove invaluable for the whole world years later. Beside the proof of principle that organolithium reagents can be used for coupling reactions, We have also shown its application in the synthesis of several pharmaceuticals (Figure 4). The methods described and developed in this thesis have no (industrial) application at the moment and despite its great advantages in terms of pollution and cost might also never reach that stage, but already provide an easy lab-scale alternative to existing methods.
Figure 4 Pharmaceuticals made via organolithium cross coupling methodology
Beside the construction of existing pharmaceuticals, we have also shown the tandem coupling with organolithium reagents to synthesize small complex molecules. This method is no cure to a disease itself, but a potentially useful method for the development of new drugs in which the effect of small changes in the structure need to be screened in order to find and create the drugs of the future.
