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More Reaction Discovery

The reaction discovery field continues to increase its throughput, on ever-smaller amounts of material. (That link has several previous discussions here imbedded in it). The latest report uses laser-assisted mass spec to analyze aliquots (less than a microliter each) of 696 different reactions and controls, pulled directly from the 96-well plates with no purification. That took the MALDI-TOF machine about two hours, in case you’re wondering – setting up the experiments definitely took a lot longer (!)
The key to getting this to work was having a pyrene moeity attached to the back end of the substrate(s) for reaction discovery. This serves as a mass spec label – it ionizes very efficiently under the laser conditions, and allows excellent signal/noise coming out of all the other reaction gunk that might be in there. You can monitor the disappearance of the starting material and/or the appearance of new products, as you wish. In this case, the test bed was an electron-rich alkyne starting material, exposed to a variety of reacting partners and various metal catalysts. The screen picked up two previously unknown annulations, which were then optimized in a second round of experiments.
I continue to think that this sort of work has the potential to remake synthetic chemistry. Whenever there’s some potential for new reactions to be found (and metal-catalyzed systems are a prime example) these techniques will let us survey the landscape much more quickly. There’s no reason to think that we’ve managed to find even a good fraction of the useful chemistry out there.

2 comments on “More Reaction Discovery”

  1. Anon says:

    I’m surprised they didn’t have solubility problems with that pyrene.

  2. anon the II says:

    This post needs more comments. So here goes. This stuff is rather derivative of the stuff Nuada was trying to do, except that the “Mass Leveler” is a bit more rational. For that reason, it’s probably not as good a leveler and so the quantitation isn’t as good for a large cross section of reactions. But Nuada and tagging reactions was probably a bad idea to start with. “Reaction discovery” techniques should have grown naturally from the comby movement. But it was largely thrown out with the whole lot along with a lot of snarky grumbling. Also, I suspect that analyzing with LC/MS along with a (CLND) nitrogen detector would provide a lot more info along with the quantitation without a huge cost in analysis time. I believe that the methodology to do this kind of thing better existed 10 years ago and got tossed out with the whole comby thing and a lot of chemists.

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