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Screening the Mechanism, Not the Products

Some colleagues of mine and I were talking the other day about the number of catalytic photochemistry reactions there are out there now, and how there must be many more of them that haven’t quite been worked out. Now I see that Frank Glorius and his group at Münster are proposing a way to start doing that in a more high-throughput fashion.

Angewandte Chemie calls it “catalyst speed dating”, but then, they would, wouldn’t they? The approach is a mechanistic one – instead of looking for products, the group is looking to see whether particular sorts of substrates can interact with a given catalytic system. They use luminescence spectroscopy to probe a key quenching step in the catalytic cycle(excited catalyst forming a new substrate radical), and see what sorts of starting materials make the cut. (The emission spectra of the catalysts will change noticeably if they can interact with the substrate). This not only gives you some mechanistic insight into what’s going on with the photocatalyst, but it also immediately suggests which systems to use for a more traditional product-based catalytic screen. Note that you don’t have to know the various redox potentials, triplet-state energies, etc. – you just set loose an array of potential substrates and let them tell you.

They ran over a hundred substrates past on of the standard iridium photocatalysts, and identified seven that showed a good interaction. Two were known and had been deliberately included as positive controls, and two more turned out to be known in the literature as well, but three structures were not yet described in catalytic photochemical reactions: benzotriazole, 1-trifluoromethylbenzotriazole, and 4-methoxyphenol. The second of these turned out to be interfering with the luminescence assay, but they took the two remaining compounds, and a set of their derivatives, into another round of luminescence screening with several other known photocatalysts.

These led to combinations that were then tried out with test photochemical reactions (acylation, bromination), and these did, in fact, lead to new transformations. It’s worth noting, though, that in each case there were some outliers – reactions that screened well but did not turn out to be the most efficient combinations, or reactions that could produce product via a different mechanism. The excited-catalyst test that was used in the initial screen is (as the authors note) only one part of the catalytic cycle, albeit a crucial one (and this makes one wonder if some other screening protocol could be developed for other parts of the cycle as well).

Similarly, the paper makes the point that this sort of “mechanistic screening” could well be useful in other reactions systems entirely. The current reaction discovery schemes tend to be mechanism-agnostic, and are just looking for new products. This could be a good complement – given a particular mechanism, what can be done with it? Redox photochemistry would seem to be a particularly good fit, given the diversity of the transformations that have been accomplished with it, but there are others out there as well. And we need all the reactions we can get. . .

9 comments on “Screening the Mechanism, Not the Products”

  1. CMCguy says:

    I am not sure that even hard core synthesis types are really best described as “mechanism-agnostic, and are just looking for new products”. While the objective is ultimately perform a transformations that can be applied, most people do want understand why things are occurring in reaction, if nothing else for control and predictability, however indeed major emphasis is on implementation often in a specific context. Some times the originators will take the time and effort to dig deeper themselves although many will trust to others that have greater interests and expertise to elaborate the details as way to advance the science. Its not so much lack of caring but rather focus of resources on exploiting more than going beyond acceptance of possible MOAs without extensive knowledge and proof behind the execution.

    1. Screen Team says:

      Oh, I wouldn’t say that the synthetic groups are mechanistically-agnostic. No, they are true believers of whatever the trendiest mechanism du jour is and are happy to run some bullshit DFT to “support” their assertion and call it a day. Pull back the curtains, however, and you’ll see that people just screen catalysts to make the reaction go and then screen trendy mechanistic proposals to get the reaction into Science/Nature/JACS

      1. iced says:

        Nominally, I agree with you

      2. Me says:

        As an author of many JACS/Angewandte catalysis papers, I would broadly agree with this statement. At the end of the day, nobody gave a &%$# about the mechanism – just looks at the pretty table of products and the row of ‘9x%’ in the ee section, and there you have it. Outliers that tested the mechanism brushed under the carpet courtesy of journal guidelines.

  2. John Wayne says:

    I think that a lot of the de-emphasis on mechanism is related to the current funding environment in science. If you write a grant to investigate the mechanism of some interesting reactions, you will have to print it out to generate some useful scrap paper.

  3. pharma chemist says:

    The current academic chemists seem enamoured with “mechanism” or “novel catalysts” but from my point of view what is really needed is a return to making structures that can’t be easily made by other methods. Perhaps I’m too cynical, but I think the last thing organic chemistry needs is a new novel reaction mode. What we need, or at least what my colleagues and I need, is ways to make the hard compounds.

    1. Hap says:

      If you can find new reactions, you might be more easily able to find ways to make difficult compounds (and at lest new ones). If what you have doesn’t work, then you might be looking in the wrong place, and methods that expand the room to search might help.

      1. Methyl Acrylate says:

        In principle I agree; however, if you only look in your substrate safe space (e.g. the cookie-cutter molecules that all give 90+% yield; I’m thinking o/m/p methyl and so on) how much have you really “expanded the room to search”? We, as a community, should demand that new methods be put through their paces with difficult substrates and realistic yields rather than wasting years of grad student/postdoc careers finding the 20-40 contrived substrates that give high numbers (and throwing out all the gray data).

  4. Mol Biologist says:

    I do recognize the pioneering nature of Drs. Kaelin and Ivan’s contributions to the field of HIF and PHDs Biology.
    I also have great respect for their next attempt. https://patentscope.wipo.int/search/en/detail.jsf?docId=US77261175&recNum=1&tab=PCTClaims&maxRec=7&office=&prevFilter=&sortOption=Pub+Date+Desc&queryString=FP%3A%28Kaelin%2C+JR.+William+G.%29
    Time changes everything. If you really want to benefit the humanity and uncover the mechanism. Unfortunately you need to be in a contrary position to Dogma of Oxygen Sensing by PHDs.
    Kent Kemmish envisioned the possibility of a peaceful competition for the assets but we have seen a good example of the not-so-beloved Michael Pearson.
    I am proposing a way of humility and start looking for evolutionary process.
    Promiscuous activity originated from evolution pressure and the development of secondary metabolism synthesis allowed for the extensive diversification of the enzymes. The emergence of bacterial secondary metabolism systems received a tremendous impetus from the primary oxygenation event in Earth’s history caused by cyanobacterial biosynthesis. Under new selective pressures these activities may confer a fitness benefit therefore prompting the evolution of the formerly promiscuous activity to become the new main activity. https://en.wikipedia.org/wiki/Enzyme_promiscuity

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