Metathesis: around the catalytic cycle

There is a fundamental need to develop efficient new routes to create the pharmaceuticals, agrochemicals, electronic components and other chemicals needed by modern society. Industrial syntheses need to combine high productivity with stereoselectivity to manufacture products under mild conditions. Alkene metathesis is one such route to these products. Following the acquisition of Materia’s metathesis intellectual properties in early 2018, Umicore has positioned itself as the leading provider in metathesis technologies.

This metathesis roundtable discussion gathered three Umicore employees: Jessica Gomes-Jelonek, Philip Wheeler and Dick Pederson. Each has extensive experience in metathesis R&D ranging from business development to lab research.

To first establish a bit of background, how would you describe alkene metathesis?

Dick Pederson: Alkene metathesis is all about making and breaking carbon–carbon double bonds. It works by allowing us to effectively ‘swap’ the substituents of two alkene molecules to build more complex molecules. If a reactant contains a carbon–carbon double bond, then there is an opportunity for a metathesis reaction. Creating new carbon–carbon bonds is often challenging, but with the use of a metathesis catalyst, you can make use of a very forgiving and very efficient reaction pathway.

Philip Wheeler: For me,what makes this reaction so important is the nature of the bonds that we are able to create. Carbon–carbon bonds are among the most important bonds throughout chemistry. They are, quite literally, the building blocks of life.

What makes metathesis so advantageous is everything else it does, in addition to the synthesis

Jessica Gomes-Jelonek

Jessica Gomes-Jelonek: I think what makes metathesis so advantageous is everything else it does, in addition to the synthesis. Since there are likely many routes to the target molecule, a chemist will need to consider additional factors that aid them. What makes it so important is everything else it can do: it is green, efficient, selective and high-yielding, and offers significant advantages over other alternative reaction pathways.

Wheeler: I should also stress that metathesis encompasses a wide range of reactions that differ depending on where the alkene moieties lie. It can be used to open or close rings to create macrocycles or other interesting cyclic molecules. One of the other areas that is interesting for researchers is polymerisation reactions – creating long polymers all from simple alkene feedstocks. And one of the more challenging metathesis reactions, in the sense of controllability, is what is known as cross metathesis. This type involves two disjointed alkene reactants to form the desired product and typically ethene as a by-product.

Since metathesis is one of many possible reaction routes, what would make a chemist choose metathesis over any of the alternative reactions?

Pederson: I think what sets metathesis apart from other reactions is how forgiving the catalyst is in a reaction. It’s an equilibrium reaction and will produce a statistical mixture of products, which means when the wrong products are formed, they can be recycled to make the desired product. Additionally, many of the cross metathesis reactions can be run very concentrated or neat, without the need for excessive solvent. This makes it very attractive from both a sustainability and cost perspective: there is no need to buy, remove and recycle or dispose of any excess solvent!

Gomes-Jelonek: I would agree that sustainability is a key differentiator for any industrial company. But alkene metathesis is also sometimes the only route capable of performing some of the more difficult reactions that might otherwise have needed multi-stage cascading reactions. For instance, lactams – amide functional group molecules – are important in many aspects of medicinal chemistry. Structurally, they can be complex cyclic molecules making synthesis challenging. But there have been multiple incidences where researchers have applied Grubbs catalysts and metathesis to synthesise these molecules in a high-yield in a two-step process. And then there have been other examples performed in the Grubbs laboratory offering improved chemoselectivity or activity.¹

Wheeler: Chemistry is also a lot like choosing the right tool for the job at hand. If we think of every chemical reaction as just a tool in a chemist’s toolbox, then for any reaction, a chemist will pick the right tool for the right application. Often, they’ll be able to suggest multiple plausible reaction routes and, in these cases, it comes down to identifying the other advantages the reaction can bring to the table.

Pederson: And alkene metathesis is a very versatile reaction. If we look at the thermodynamics of the reaction, it is relatively enthalpy neutral. Unless ring strain is introduced or mitigated, there is very little exchange of heat between the reagents, because the start and end points of the reaction are often very similar in terms of energy. This means the reactions are either driven by entropy or the removal of products. Take the metathesis of 1-hexene to create 5-decene. In this case, the second product of the reaction will be ethene, which can quickly be removed, driving the reaction towards product formation.

Wheeler: I’d just also like to note an additional advantage of only generating the ethene by-product. Compare the formation of ethene with the by-products formed during alternative reactions, such as the commonly used Wittig or Heck reactions. In the Wittig reaction, triphenylphospine oxide is formed as a stoichiometric by-product and is often difficult to remove from your desired reaction. In comparison, ethene is a relatively innocuous molecule that is easy to remove. It comes down to the superiority of catalytic reactions, such as metathesis, over stoichiometric ones like the Wittig reaction. The Heck reaction is catalytic, but it requires pre-activation of one partner as a halide, which is then liberated as a by-product. Alkene metathesis is also more atom-efficient, as even chloride has a greater atomic weight than ethene (35 vs 28 g/mol).

How well do you think metathesis has been adopted by the industry?

Pederson: Metathesis as a commercial reaction has been around for a relatively long time (approximately 20 years), and since then it has been adopted in a range of industries for various applications. Adoption has been particularly high in the pharmaceutical industry as a method to synthesise novel active pharmaceutical ingredients. Part of the reason for this heavy adoption is the amount of funding available in the pharmaceutical industry to investigate new reaction routes.

Wheeler: Capital investment can play a large role in how well reactions can be implemented. The cost of the actual catalyst is often offset by how little is needed to perform the metathesis reaction. But it is also often the case that the cost of performing a reaction will depend a lot on the application in question. If we need a specialist catalyst that is the only option to perform a challenging ring-closing metathesis reaction, for instance, obviously this is going to be more expensive and require more dedicated knowledge than a more run-of-the-mill reaction.

Gomes-Jelonek: But metathesis is not just limited to the pharmaceutical industry. While I agree that this is one area that has seen significant investment in terms of research and development, there are other industries that have also seen a significant improvement based on the technology. For instance, metathesis has been used to synthesise the coatings for electronics, pheromones and other fine chemicals, such as those materials used in the automotive industry. It is a wide-ranging reaction that will only continue to grow and evolve as more technology is developed.

Would you like to highlight any specific examples in an industrial application?

Wheeler: It is difficult to highlight just one example where metathesis has impacted the chemicals industry. The prevalence of carbon–carbon bonds in a range of products means metathesis can be useful everywhere.

Gomes-Jelonek: In terms of the agricultural industry I am thinking of one specific example: the synthesis of insect pheromones. They are a nice sustainable method of helping protect crops from falling victim to insects by disrupting mating, acting as the female’s natural scent to attract mates. Saturating the orchard with the female’s pheromone confuses the male insect and prevents him from finding the female, which prevents mating and the next generation of larvae that damages the fruit and trees. Insect pheromones are selective and target the pest without harming beneficial insects. There are lots of examples in the literature that have shown how metathesis catalysts have selectively synthesised insect pheromones. One that comes to mind was the use of Grubbs catalysts to selectively synthesise cis-alkenes in preference to trans-alkenes to a high yield.² Isn’t pheromone development how you got involved in metathesis, Dick?

Pederson: Yes it was. Bob Grubbs and I are the inventors of the first patents to use his metathesis technology to produce insect pheromones.³  It was in the late 1990s and I was trying to synthesise more cost-effective insect pheromones to be used in mating disruption. Traditional reactions (acetylenic chemistries and dissolving metal reductions) to produce insect pheromones were expensive and I was interested in trying some alternatives. I heard about using alkene metathesis, so I called him up and he sent me some of his first generation metathesis catalyst and I was able to make a business out of it. But there is another application I want to mention that was part of a Materia project back in 2016. This involved synthesising a polymer to insulate oil pipes that were then submerged at depths beyond 10,000 feet (3000m). They had to create a polymer material that could cope with the temperatures and the pressures at those depths, and it turned out that metathesis was the best route to the insulating polymer they decided to use. It was a really cool piece of work.

What challenges would a company have to overcome if they wanted to investigate metathesis as an alternative to their current synthetic methods?

Gomes-Jelonek: Broadly speaking, there are really two different categories of challenges that the industry will face: those general to the reaction of metathesis and those specific to the application. Because each reaction is truly bespoke, the needs of each catalyst, customer and reaction will be different. It is difficult to say what the major challenge will be, as it really is considered on a case-by-case basis.

In addition to screening the typical variables such as catalyst, temperature, pressure and so on, we would also look at Brønsted and Lewis acid additives.

Philip Wheeler

Pederson: Jessica is absolutely right. I think in general there are certain things that every company needs to consider. Given the product I want to make, can I get a viable reaction from readily available starting materials? If yes, can I get these reagents easily in bulk? This is why quite often seed oils are advantageous as they are cheap, available reagents. Sometimes identifying the best route can be as easy as performing a retrosynthesis: for instance, seeing where we can insert a double bond that is later hydrogenated, or if the product does contain a double bond, we need to perform retrosynthesis based on its position.

Wheeler: There are other factors to consider too. Many groups including our own have been optimising industrial metathesis reactions for a long time now, so there is a lot known about how to improve industrial properties such as yield, product selectivity and catalyst turn-over number. For instance, in addition to screening the typical variables such as catalyst, temperature, pressure and so on, we would also look at Brønsted and Lewis acid additives. These additives can help mitigate the coordination of polar groups to the catalyst centre and, in some cases, alter the substrate conformation to favour product formation.

Where do you all foresee the next biggest innovation in metathesis catalysis being developed?

Gomes-Jelonek: I think we will see cross metathesis increase in popularity among industries. One case we have seen recently is in the shortening of fatty acid carbon chains.⁴  Often fatty acid chains cannot be used for specific applications since they are too long, which leads to unfavourable properties. But through metathesis reactions and appropriate ligand selection, we can customise the length for a given application such as the biotechnology industry by creating polymers or surfactants.⁵

Pederson: I think one of the more exciting areas where metathesis reactions can be adopted is in stereoselective synthesis. We’ve already discussed this in terms of insect pheromone research, but it is very common in other industries. If we can provide our customers with a reaction where we can say definitively: ‘If you have a cis-alkene, you get a cis-alkene product; if you have a trans-alkene, you get a trans-alkene product.’ That is useful to so many industries! Not just for guaranteeing the stereochemistry of products, but also for the potential subsequent reactions that are then performed; for example, chiral oxidation and hydrogenation and so on.

Wheeler: I think one of the final barriers left is in the minds of the chemists themselves. When chemical engineers or chemists think of reactions involving alkenes, some of the reactions that first come to mind are the classic organic chemistry reactions like Wittig or Horner–Wadsworth–Emmons, but these are inefficient when compared with alkene metathesis. It is my vision that metathesis will soon be the first port of call for any alkene reaction, simply as a result of how successful the chemistry can be.