Automation in chemistry (especially industrial chemistry) is so pervasive that we hardly even notice it any more. (I have a whole talk that I give that’s partly on that very subject). But what is automation for? That’s the subject of this short piece in ACS Med. Chem. Letters by Jeffrey Pan of AbbVie. The answer would seem obvious, and fits into my rule of thumb that any question that can be phrased in the form “I wonder how come they. . .” has the answer “Money”. The obvious reason for R&D automation is indeed to save money, in those situations where repetitive tasks done by human beings can be sped up and standardized by machine.
But the easy opportunities for this sort of thing have been picked off by now. More capable equipment can take on more complicated jobs, but you have to decide if the throughput of the tasks it can do justifies its higher expense. We all depend on the systems that have shown their worth in labor and time savings (autosamplers!), to the point that we regard them as a necessary part of our work – but many readers will have also experienced the frustration of working with a machine that actually makes your life more difficult under the guise of helping you out. “Can you start this gizmo and then walk away and go to lunch without regretting it?” is a useful question to ask, and to answer honestly. And remember, “Sometimes” is equivalent to “No”.
The other choice is to make the machine’s task simpler and change your processes, but that doesn’t always work out. Pan notes the solid-phase combicham machines that were all over the place in the late 1990s and early 2000s, and how few of those techniques have survived. Solid-phase bead chemistry was a lot easier to automate than liquid-phase, but it also turned out, in the end, not to be as generally useful. The gathering of the dust on such equipment was a common sight as this realization set in. But the article makes some larger points:
. . .the science of chemistry is not advanced by having robots do tasks that would otherwise be done manually. Finally, innovation can potentially be decreased as chemists prioritize simple, automated work- flows over more complex, manual procedures. Encouraging chemists to perform more routine chemistry is unlikely to provide any competitive advantage.
I have to admit that I hadn’t looked at it from that angle, and I’m still turning this over in my mind. I’ve been thinking that as automation frees us up from routine tasks (with the definition of “routine” perhaps gradually changing over time) that chemists would be spending more time on the complicated stuff. If it can’t be done by machine, who else will do it? But Pan’s article has a different answer: if it can’t be done by machine, perhaps no one will do much of it at all.
His solution is to come up machines that actually make new modes of work possible, rather than just speeding up the old ones:
Rather than focusing on labor savings, we paradoxically explore strategies that encourage scientists to do more work. By developing systems that lower the hurdles to access new techniques, scientists are encouraged to investigate how and where to best apply cutting-edge technology. In that way, automation delivers a competitive advantage to our scientists by fostering chemistry innovation. We see automation as a tool to encourage the exploration of new methods. By reducing the cost of experimentation, we aim to lessen the reluctance to performing riskier experiments.
I certainly have no problem with that! As longtime readers will know, I’m generally a fan of new technologies and new synthetic techniques, and if they can be made more available and user-friendly in this way, so much the better. These can range from less-common forms of purification (benchtop supercritical fluid chromatography, counter-current chromatography, etc.) to more accessible flow chemistry for synthesis, better front ends for photochemistry, electrochemistry, etc. They try not to engineer anything from the ground up, but rather to enhance commercial equipment where some of that work has already been done.
There are still plenty of things to be ironed out, of course – one example given is when they set up apparatus to take advantage of a reported flow-chemistry diazomethane technique. Palladium catalysts will let you use that system for cyclopropanation reactions, but the AbbVie team found that the gas-permeable tubing needed for the reaction conditions tended to foul in the presence of the Pd reagents after multiple runs. They reworked it successfully to where the catalyst comes in after that part of the reactor, but this is the sort of thing that you’re only going to find out with experience.
There are numerous other examples given in the paper, with references, and I encourage any fan of automated chemistry to go over them and learn from the AbbVie work. There are similar efforts going on at some of the other large companies too, of course, although not all of them have the explicit “automate things that people aren’t doing at all” mandate. That brings me back around, though, to the question above: does the automation of routine chemistry lead to people spending more time on just that routine chemistry, or does it free up other work?
Comments are welcome. My first thoughts are that such automation may well encourage “the same stuff, just lots more of it” when that is sufficient to solve the problem at hand. If a med-chem project has been needing a way to crank out Buchwald-Hartwig couplings to explore a key SAR feature, than a machine that lets that happen more efficiently is good news. But a machine that encourages everyone to do mostly Buchwald-Hartwig reactions to the exclusion of other chemistries is probably not such good news, overall. That’s what happened with the first generation of Pd bond formation; the compound lists filled up with aryl-aryl couplings, and that’s not the answer to everything (far from it).
But the tricky part is that a lot of medicinal chemistry problems are solvable with enough brute force. Often enough, there is a particular analog that manages to put together properties that are sufficient to advance a project – not perfectly, perhaps, but good enough. I think the important thing is to strike a balance, to enable enough different kinds of chemistry so that same brute force can be applied in many different ways to produce a wide variety of structures. That will both broaden the chemical landscape and reduce the temptation to overuse some particular method just because it has a bigger motorized crank attached to it.