Chemistry

Gambling Man

Mark Stradiotto’s combination of intuition and luck have yielded commercial success in the chancy field of catalysis.

By Tyler Irving

Designing catalysts for use on laboratory and industrial scales can sometimes seem a bit like gambling, and chemists who do it often have to sit through many bum deals before that perfect hand turns up. Lately, Mark Stradiotto has been on something of a winning streak. In the past 18 months, the professor of chemistry at Dalhousie University has commercialized a new family of catalysts which has become the state of the art for certain types of palladium- catalysed cross-coupling reactions, and there may be more in the cards. ACCN spoke to Stradiotto about strategies for success in a field where every new experiment is a roll of the dice.

Your field has strong industrial links; why did you choose chemistry over engineering?

I was fascinated by molecular complexity, and our ability to exert influence on the atomic scale. When I learned how transition metal chemistry allows you to make and break bonds in ways that can’t otherwise be done, I was hooked. And when I learned that you can apply that knowledge towards making something that’s useful for society, it brought me full circle back to applied science.

How are your catalysts useful for society?

The quest to develop new therapeutics and treatments for a range of ailments — for example Alzheimer’s disease — is obviously important. Pharmacists don’t make compounds, chemists do. Part of it is about making materials we couldn’t make otherwise, but we’re also concerned about making these compounds without having a large negative impact on the environment. We try to simplify processes that take many synthetic steps, each of which is wasteful. Our catalysts play into both of those needs.

Palladium-catalysed cross-couplings won the Nobel Prize in 2010. What drew you to these reactions?

Cross-coupling reactions are powerful because they can put together chemical fragments that are cheap, abundant and available, but that would otherwise have no affinity for one another. They turn otherwise uninteresting molecular fragments into building blocks for valuable pharmaceuticals.

Our current focus is on Buchwald-Hartwig amination, which is a specific type of cross-coupling, named after two scientists who independently developed the reaction and have done the most important work on it over the last 15 years: Stephen L. Buchwald of the Massachusetts Institute of Technology and John F. Hartwig of the University of California at Berkeley. This reaction is a go-to method for making carbon-nitrogen bonds. That’s important because when pharmaceutical chemists think about drugs, they literally put nitrogen on the board first, then start drawing. Eighty per cent of pharmaceuticals have nitrogen in them, and drugs that don’t have nitrogen have a high failure rate.

In a Buchwald-Hartwig amination, an aryl halide reacts with an amine via a catalyst to form a new carbon-nitrogen bond. Although this reaction is well-established for substituted amines, it’s harder to do with simple molecules like ammonia (NH3). Mark Stradiotto has developed a new family of state- of-the-art catalysts that facilitates this reaction and otherslike it, turning readily available molecules into building blocks for valuable pharmaceuticals.

There’s already been a lot of work done on these reactions; what were you trying to improve?

At its core, a Buchwald-Hartwig amination is an aryl halide reacting with an amine [see above example]. Molecular fragments like aryl chlorides and amines are very common, but are hard to clip together. To overcome this, we use a catalyst that consists of a metal atom — often palladium — and a ligand designed to hold on to the metal and to engineer its properties. The aryl chloride binds to the catalyst/ligand complex via oxidative addition, which is followed by amine binding. The resulting intermediate then undergoes dehydrohalogenation followed by reductive elimination, which regenerates the catalyst and couples the other two fragments together via a new carbon-nitrogen bond.

Buchwald-Hartwig amination works pretty well for most amines, especially ones with longer side chains. But one thing that has frustrated the field for years is the difficulty in completing the reaction with the simplest amine of all: ammonia (NH3). Ammonia is made on a massive scale — hundreds of millions of tonnes per year — from atmospheric nitrogen via the Haber-Bosch process. Developing a catalyst to improve the ammonia cross-coupling would allow pharmaceutical chemists to use less expensive starting materials, and make a really big impact both on the cost of drugs, and the amount of waste generated in drug synthesis.

Why is such a simple reaction so hard to complete?

The problem is many-fold. Firstly, ammonia is almost too good at binding to the metal in the catalyst. You can get multiple ammonia molecules coordinating to it, which can actually knock off the ligand that you designed. Problem number two comes once you form the intermediate. Remember, this molecule has to undergo reductive elimination to make that C-N bond and regenerate the catalyst, but with a Pd-NH2 species, the rate of this step is shockingly slow compared with larger amines. Most catalysts end up stalling at that stage. Even worse, these intermediates can bind to each other to form dimers or oligomers.

The final problem comes when you finally make the C-N bond and form the product: phenylamine, also known as aniline. It turns out that aniline has even more affinity for most Buchwald-Hartwig catalysts than the ammonia it was made from. So this product becomes a reactant, and you end up attaching a second and third aryl ring onto the nitrogen, which isn’t what you set out to do. In general, this reaction is trouble.

Ligands developed by Stephen Buchwald of the Massachusetts Institute of Technology use a monophosphine motif, while some of the ligands (e.g. JosiPhos) used by John F. Hartwig of the University of California at Berkeley have a bis-phosphine motif. Both of these bond to the metal atom through the lone pair of electrons on phosphorus. Mark Stradiotto’s ligands, such as Mor- DalPhos, contain one phosphorus and one nitrogen, giving them properties that are intermediate between mono- and bis-phosphines. The bulky adamantyl group (seen in 3D at right) keeps the ligand from dimerizing.

How do you overcome this problem?

You want a ligand that’s electron-rich in order to help out that first step, oxidative addition. But you don’t want it to be too electron-rich, because that will work against the final step, reductive elimination. It’s a balancing act: you’ve got to get a sweet spot where the first step isn’t too easy so that the last step isn’t too hard. You also want the ligand to be big and bulky in order to keep the intermediate molecules from aggregating.

Buchwald has focused largely on ligands that bind to palladium through the lone pair of electrons on a single phosphorus atom [see above]. They work great for many aminations, but Buchwald himself admits they don’t work well when it comes to ammonia monoarylation. On the other side, Hartwig has focused on the use of ligands with two phosphorus atoms. These are actually quite good for the ammonia cross-coupling, but not as good as they could be. We thought “Why not try something in between?”

Previous work on a different reaction had led us to develop ligands with one phosphorus atom and one nitrogen atom. Because nitrogen is less of an electron donor toward palladium than a second phosphorus, it’s a kind of ‘goldilocks’ situation. These ligands are pretty simple and seem like something that others would have tried. But as we looked into it, we realized — shockingly — that people hadn’t.

How did that work out?

By sheer luck, the first one out of the gate worked really well for ammonia, and we published our initial paper in Chemistry – A European Journal in 2010. We called our ligands DalPhos, after Dalhousie University; you have to give them nicknames because their IUPAC names are as long as my arm. The first one we made had a methyl group on the nitrogen, so we called it methyl-DalPhos or Me-DalPhos.

We then tried to optimize this further. There was a summer undergraduate working in my lab, and I was going away to a conference. I just sketched on a piece of paper the six or eight variants of Me-DalPhos that would be easy to make. We chose test conditions that specifically addressed a reaction that Hartwig’s ligand (JosiPhos) could not do well, just to see if we were in the game. When I came back, he told me that one of these variants was able to do the reaction at 84 per cent yield with a selectivity for the desired product of 14 to one, which is off-scale. It’s currently the state-of-the-art ligand for ammonia cross-coupling. Because it had a morpholino group on the nitrogen, we call it Mor-DalPhos. We published this work later in 2010 in Angewandte Chemie.

Both of these are now on the market; how did you do that so quickly?

I can’t possibly do all of the reactions that these things might be useful for. If you want to have other people try them, they have to be able to buy it in research quantities. To do that, you have to get your molecules into the hands of companies that sell research quantities of chemicals, like Sigma-Aldrich, Strem and others.

When we came up with Mor-DalPhos, I received a lot of positive feedback from pharmaceutical companies, and we have a very good relationship with Dalhousie’s technology commercialization office. We wanted to commercialize, pharma companies wanted to buy it, and supply companies wanted to sell it. When everybody’s on board it goes very quickly.

How do you plan to follow up on the success of Mor- DalPhos?

In some of our latest ligands, we replace the nitrogen atom with oxygen, and then put various substituent groups on that. One of these is called OTIPS-DalPhos, which has oxygen bonded to a tri-isopropyl silyl group. While catalysts based on this ligand did not perform well in Buchwald-Hartwig cross-couplings involving ammonia, we also decided to try it in related reactions leading to the synthesis of indoles. Indoles are among the most scrutinized structures in pharmaceutical chemistry: they’re kind of like skeleton keys in that they can bind to a whole host of biochemical receptors. It turns out that OTIPS-DalPhos does indole synthesis really well. Given that Mor-DalPhos is commercialized and selling quite well, my guess is that the OTIPS variant will probably be available in 2013.

These discoveries put you, a young researcher, in competition with giants in this field; how does that feel?

I gave a talk last fall at Berkeley and John Hartwig was in the front row. It was certainly daunting. But I had the confidence of knowing the quality of the work we’ve done, and I don’t feel inferior. There had been success in ammonia cross-coupling before we got into the field, but there were significant limitations to the chemistry. I certainly recognize the status that these people hold, and that I have to earn their respect, and I feel like I have.

There’s a fair amount of luck involved in catalysis; does it ever feel like gambling to you?

A little bit, but also you’re building on the success that other people have laid out. There’s a balance between making something completely derivative where you can already predict its behaviour, versus something that’s so far out there that your probability for success is zero. I was taught early on that you can talk yourself out of any reaction, but the beautiful thing about chemistry, is that we can have an idea on Monday, and have seminal results on Wednesday. It’s exciting to try things and see if they work, but also scary because anyone in the world has the same short timeline, and could beat you to it.

I’m not sitting on top of a mountain, casting down ideas. It all comes out of these wonderful thoughtful discussions you have with the students and post-docs. When they get a glint in their eye and think “Gosh, that might work,” and then it does, it’s extremely gratifying. It’s also humbling at the same time, because you realize that there’s a significant amount of good fortune that’s gone into finding the key to this particular lock. I don’t want science to be like turning a crank. It’s the surprises that make it fun.

Photo Credit: Danny Abriel

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