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Seven Degrees of Screening for Generality

(with apologies to Maimonides and Nozick)

1. Screening on only one substrate before assessing the substrate scope. This is the “ordinary means” in methods development.
2. Screening on one substrate, but choosing a substrate that worked poorly in a previous study (e.g.). This can be thought of as serial multi-substrate screening, where each substrate is a separate project, but the body of work achieves greater generality over time.
3. Screening on one substrate at a time, but rescreening catalysts when you find problematic substrates (e.g.). This amounts to serial multi-substrate screening within a single project.
4. Intentionally choosing a variety of catalysts up front and screening this set of catalysts for each new substrate class (e.g.), thus achieving a high degree of generality with a family of catalysts, but without attempting to systematically quantify the generality of each catalyst in this set.
5. Choosing a handful of model substrates instead of just one, but otherwise doing everything the same as one would normally (e.g., pages S24–S29).
6. Intentionally choosing a large, diverse panel of substrates and screening against this panel to quantify catalyst generality over a given region of chemical space. This is essentially what we and the Miller group did recently (and others, etc).
7. The same, but incorporating robotics, fancy analytical methods, generative AI, or whatever else.

When I present the “screening for generality” work, I often get the response “this is cool, but my reaction doesn’t work in 96-well plates/I don’t have an SFC-MS/my substrates are hard to make.” The point of this taxonomy is to illustrate that there are a lot of ways to move towards “screening for generality” that don’t involve 96-well plates.

If you have the time and resources for robotics or SFC-MS, that’s great—you’ll be able to screen more quickly and cover more ground. But you can still start to consider more than a single model substrate even without any specialized equipment. It’s a mindset, not a recipe.