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The Huge Landscape of “Just One of Those Things That Happens”

Why do our reactions fail? Why do our darn reactions fail? Every experimental chemist wonders this, because we all have set up reactions that we thought would work (why else would we run them, eh?) only to have them sit there and do nothing – or worse, do everything and turn the color of used lawnmower oil. Every chemical reaction is a tightrope walk. In fact, if you picture them traversing an energy surface it’s a literal tightrope walk, and you can see the narrow path that leads to the product, along with the various pits, slopes, and gulches that things can slide off into instead.

The only way to figure this sort of thing out is to run a lot of careful attempts under well-controlled conditions: scientia est experentia. In the drug industry, process research chemists do this because the stakes are high. People in academia who are trying to get crucial total synthesis steps to work are often in the same position, and (needless to say) so are the folks who are trying to invent new synthetic methods entirely. Most of the rest of us, though, will try a few variations while our thoughts turn to whether there are any different reagents or reactions that might be less complicated and just produce some product already. The reaction landscape is large and complex, and mapping it out in useful detail is actually rather painful.

Here’s a new paper that is trying another automated attack on all this. A group at Merck (with collaborators at Bruker) reports another miniaturized approach to reaction screening, this time using MALDI-TOF mass spec as the analytic end of the process. It would appear to be later work from the same initiative that produced this earlier work on reaction optimization, and for more industrial chemists trying this, see here for some recent work from Pfizer. That paper investigated Suzuki-type couplings, and this new one is going after Buchwald-Hartwig ones (the carbon-nitrogen palladium-catalyzed reaction, famously persnickety about catalysts and conditions). For a pain-in-the-rear reaction, though, it sure does get run a lot. It’s a very worthy place to set the machines loose.

The Merck group looked back through the company’s electronic lab notebooks, and found plenty of such coupling reactions. But they were run under so many different conditions, and with such irregular coverage of chemical space, that it was hard to extract anything useful out of the data set. So they made their own. But they did it differently than the Pfizer group (who used flow chemistry, which requires homogeneous reactions and thus often higher dilution conditions):

. . .Rather than accepting such constraints, we systematically engineered and validated new plate-based nanomole synthesis tools with a general ability to carry out a wide variety of typical synthetic reactions. We identified effective chemically compatible glass microplate reactors, fast 384-tip dosing of reagent solutions in volatile solvents, and designed aluminum sealing blocks that can retain volatile solvents on heating. In addition, we used LabRam resonant acoustic mixing to both agitate reactions and to create milky slurries of solid inorganic bases that can be added to reactions by parallel liquid handling. Finally, we created a nanomole scale photochemistry tool to enable reaction evaluation in the rapidly growing field of photoredox catalysis.

This was not the work of a few idle afternoons. (A lot of information on how this was done is available in the supplementary information file of the paper, by the way). The decision to use MALDI/TOF mass spec was motivated by the time it takes to do LC/MS work – the syringe has to come over, pull up some sample, inject it, get washed and move to the next sample while the first one is making its way down the column, etc. It’s true that you get more information from the LC trace, but the speedup in the solid-phase MALDI technique (where a laser beam blasts the sample off the surface and into the mass spec) is hard to ignore. The group did some optimization there, looking for conditions that would give reliable readouts across a range of substrates, and worked out a procedure where aliquots of each reaction were spotted into the wells of a MALDI analysis plate (with internal standard added – without that, you’re at sea) and the appropriate matrix compound (alpha-cyano 4-hydroxycinnamic acid) was added afterwards in solution, followed by evaporation. A 1536-well MALDI plate could be analyzed in about ten minutes, with automated data collection and analysis on the back end.

A first run of the system looked at four different coupling conditions (iridium/nickel and ruthenium/nickel photoredox, along copper-catalyzed and palladium-catalyzed conditions) to search for functional groups that could poison the reaction conditions (as in the work of the Glorius group on reaction robustness). These four reactions were run with well-performing reactions partners in the presence of 383 other polar molecules with a wide range of functional groups. As always with the automated chemistry work, one’s lip starts to quiver at the thought of doing this sort of thing the traditional way. That is just a lot of work.

What they found was that each of the reactions is subject to poisoning by specific functional groups. For example, the copper-catalyzed reactions are hammered by anything with a thiol group, which makes perfect sense, while the iridium reactions were not only intolerant to SH, but to acids, phenols, oximes, and nitro groups as well. Which is annoying. And when such functional groups appeared in larger, more complex additives, they were almost always just as bad. To add to the fun, there were other large molecules that contained several by-themselves-innocuous functional groups that together managed to poison the reaction as a team. Yep, this is metal-catalyzed coupling chemistry all right. (It’s worth noting that the copper reaction actually had the most permissive profile, thiols aside).

The group then turned to variations in the coupling partners, with a list of 192 aryl halides and 192 secondary amines. If you did all of those, you’d be looking at 36,864 possible products, and across the four reaction types that gives you a cool 147,456 experiments to set up, which was enough even to give these guys pause. They tried a sampling of that space by setting up each bromide with the most simple amine in the set, and each amine with the most simple bromide – that takes you back down to 1536 reactions, a 1% scattering fairly evenly across the possibilities.

This is a much harder row to hoe. Adding an internal standard is necessary, but a lot trickier to work out across so many reactions and structural types. The group had run that previous experiment in traditional LC/MS and found a good correlation in the results (once you normalized to the internal standard) but these 1536 experiments had a lot more scatter in them. Backing down to a pass/fail on the MALDI data (with an arbitrary cutoff) gave a much better correlation with the more comprehensive LC/MS data, so you can at least search reaction space in a “what’s bad?” mode, with analysis of the properties of each compound for steric hindrance, number of nitrogens, cLogP, hydrogen bond donors, etc. Rather particular structural features turn out to be reproducibly important for success and failure in the Cu-catalyzed versus the Pd-catalyzed reactions, and several of these cannot predicted by our current understanding of the reactions.

The paper refers to the “dark matter” of chemical reactivity, and there’s some of it for you: things that you wouldn’t have known would affect the reaction, and do so for reasons that aren’t yet clear. These coupling reactions are particularly tricky to work out, but there are plenty of other examples in all fields of synthetic chemistry. (Going back to my grad school work, I can give examples of small changes across carbohydrate structures that totally change their reactivity, in ways that I often discovered in the most painful ways possible!) Every class of compounds and every class of reactions has things like this, results that just make you throw up your hands. If there’s a way to start mapping out the vast “Just One of Those Things” spaces, we’ll learn a lot more about the chemistry we’re supposed to already understand by doing it.

20 comments on “The Huge Landscape of “Just One of Those Things That Happens””

  1. Dcm says:

    Like you needed 150k experiments to tell you the only functional group ni fotoredox tolerates is alkane.

  2. Uncle Al says:

    Do a Gabriel amine synthesis on an alpha-bromoacetophenone and get the expected alpha-phthalimido intermediate. Do it late on Friday, work it up on Monday, get a phthalimdo epoxide. It made for a merry Monday morning until the structure came forth. The joke was that it offers a curious route to alpha-derivatization without cracking the phthalimide.

  3. Jose says:

    This is serious spawn-of-combichem stuff. It’s fantastic to see all that dreck finally get directed towards something productive! That said, has no-one heard of DOE?! You can definitely do this in more efficient ways.

    1. Some idiot says:

      I love DOE. It is one of the few ways to get a very clear answer to things. But it too has its limitations, and in my view the biggest limitation is dealing with non-numerical variables in a useful and intuitive fashion. I know that there has been work done in order to try to replace these non-numerical variables with mathematical derived variables, but (a) in my opinion these are interesting, but not yet useful, and (b) I have great difficulty seeing how DOE could have gotten anything like the amount of info that this study has. 🙂

  4. Anonymous says:

    In reply to Derek’s first three sentences. It’s been told here before. But here it is again.

    During his talk at the 1978 Leermakers Woodward Symposium, Jerry Berson commented on the quinine synthesis and his admiration of the EtONO ring cleavage – oximation that, mechanistically, preserves the carefully constructed cis-piperidine stereochemistry. He said he “always wondered if that was a planned reaction.” When RBW took the podium at the end of the day, he replied to many Qs and put Berson’s wondering to rest: “Yes, Jerry, it was a planned reaction … just like the 25 others that we tried before it that failed.” (Quotes are approximate but close. Anybody have the video of that Symposium?)

  5. Anon says:

    Why Science??

    1. Anon2 says:

      Who cares? It’s about the paper, not the journal (nor the institute/nor the PI). Apparently the editor thought it was cool, or was good friends with one of the authors.
      I do think you should look less at which journal people publish in.

    2. Sans sheriff says:


  6. Bo says:

    Working in the field of carbohydrate myself: I would love to hear a few of those “examples of small changes across carbohydrate structures that totally change their reactivity” stories! 🙂

    1. anon says:

      It’s called stereoelectronics and ring conformations. It’s a shame phys org died a few decades ago and no one is trying to understand anything anymore. just brute force 20000 conditions.

      1. AVS-600 says:

        This is a fun comment. In the first sentence, you suggest that the field of carbohydrate chemistry is well-understood enough that a simple four-word answer can predict any idiosyncratic reaction chemistry. Then in the second sentence you lament that no one is trying to understand new things anymore.

      2. Bo says:

        I’m aware of thing things like that, it’s just that it would be fun to hear about them in a “there was this one day in the lab” context…

  7. Anon says:

    Does Merck has anyone still left who can think and do chemistry with clarity? Another mindless experiments leading to nowhere! It used to be that organic chemists were well trained to read literature on a given topic, go back to the lab and run the reaction that in his best estimate can work nicely (akin to placing bet). No more, if the present work finds more takers. A well trained monkey can deliver the Science quality paper described herein. Sadly none of these technology as in the present case or the one that delivered mixtures of analogs (combichem) has accelerated our drug discovery process. Sad indeed!

    1. Derek Lowe says:

      How is reading up on the best conditions from the literature more exalted or honorable then going and finding the best conditions yourself?

      1. drsnowboard says:

        I think you could argue it takes less time….and resources.
        I have blown my top on several occasions in the past when people obstinately refuse to try the ‘best’ conditions in the literature or the patent literature. Obviously first, then you can go and riff on your variations

        1. Russ says:

          “A week in the lab saved me an hour in the library” S. Danishefsky

          1. drsnowboard says:

            Not Frank Westheimer?

          2. Russ says:

            I heard it from Sam in 1978 – perhaps he got it from Frank.

  8. Daniel says:

    Are you going to start up a “Just One Of Those Things…” blog? Because I see a *lot* of potential war stories getting swapped around…

  9. Marcus Theory says:

    “rather than accepting such constraints” — always fun to see rivals throwing shade at each other in scientific publications.

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