Monday, September 25, 2017

How many substrates are enough for robustness?

Also in this week's C&EN, a good article by Tien Nguyen about a "robustness screen" proposed by Frank Glorius: 
...Last month, researchers at the University of Münster proposed a screening tool that could help chemists figure out in a matter of days how well their reactions might work with functional groups on various substrates. Led by Frank Glorius, the team assembled a set of 15 commercially available additives that, when introduced to a new reaction, could tell chemists how well a sampling of functional groups responds to a particular reaction (J. Org. Chem. 2017, DOI: 10.1021/acs.joc.7b01139). 
Glorius readily admits that the additives approach, which builds on a “robustness” method reported earlier by his group (Nat. Chem. 2013, DOI: 10.1038/nchem.1669), simplistically tests functional groups rather than whole substrates. So it can’t tell chemists how the size, location, or electronic nature of the functional groups in the context of the entire molecule will affect a reaction, which is information typically provided by traditional substrate scope testing...
Interesting responses:
...Responding to C&EN’s poll, Eindhoven University of Technology’s Timothy Noël says it’s a good thing that standards are on the rise. However, he says, smaller research groups may suffer because they lack the resources needed to achieve the “monster” substrate tables now seen in elite journals. Noël’s group recently published a light-catalyzed decarboxylation method with 58 substrates (ACS Catal. 2017, DOI: 10.1021/acscatal.7b03019). The work was done by one graduate student and partly by a master’s student, which required a huge effort on their part, he says. 
Uttam Tambar, a synthetic chemist at the University of Texas Southwestern Medical Center, says the strategy for evaluating substrate scope seems to have changed over the past decade or so, since he was a graduate student. “The way we were taught is every substrate in your substrates table should teach you something about the reaction,” says Tambar, whose lab has also used Glorius’s robustness screen as a time-saving measure (Nature 2017, DOI: 10.1038/nature22805). “Now it’s almost become a numbers game. People want to shock and awe you with the quantity of the substrates rather than the quality of substrates.”...
 Gotta say, a list of "this reaction doesn't work with that" from the authors would also be helpful. 


  1. Thank goodness somebody is trying to address this. The only thing that monster substrate tables show is how little regard some PI's have for their graduate students' time.

    I find it especially wasteful when substrates are thrown in with no attempt to further analyze the results through kinetics or other means.

  2. I've long thought that inclusion of substrates that worked poorly or not at all should be a semi-requirement for methodology papers. This is a good alternative.

  3. For all the things that grate my nerves about the methodology papers coming from the Baran group, I do appreciate that they remark on the limitations of their reactions either in the body of the paper or the Supporting Info.

  4. In protein crystallography they have been using sparse matrices when screening for crystallization conditions for ages. It's about time that someone did principal component anaylsis on any of those *&@! tables with substrates.

  5. As a process chemist I loved having big substrate tables for particular reactions to review because even if invariably did not include exact substrate (or appended functional groups) of interest often could garner enough related or pseudo-related compounds to determine if was worth looking at (plus how much further optimization likely). I therefore appreciated the regard PIs took to expand utility and examples, especially if commented/learned many entries were produced by undergrad/summer interns that hopefully provided effective training while also demonstrating another type of robustness of user-friendly chemistry. Although I think the majority probably would like to execute well reasoned strategy in selection of materials to try in the end defaults to CRAP (cheap readily available purchasing) mode.


looks like Blogger doesn't work with anonymous comments from Chrome browsers at the moment - works in Microsoft Edge, or from Chrome with a Blogger account - sorry! CJ 3/21/20