My scientific roots are in synthetic organic chemistry, so I enjoyed this paper very much. It’s from a team of authors at Syngenta, GSK, and Lyon, and it goes into useful detail on a technology that not many chemists will have had much experience with: high-throughput electrochemistry. In general, electrochemistry has a well-deserved reputation for being full of hard-to-control variables (heck, hard-to-even-spot variables) that historically has made it labor-intensive to reproduce interesting reactions. The size, shape, composition, and surface condition of the electrodes will obviously affect things, as anything that bears on mixing (such as the size and shape of the vessel and its relation to the size of the electrodes), the distance between those electrodes (and whether you’re using a divided electrochemical cell or not), the choice of solvent and the choice of a supporting electrolyte species in solution, and of course the voltages and currents (and current densities) you operate at.
But when it works, it can be rather magical. Anyone who’s taken a sophomore organic chemistry course has “pushed arrows” to show reaction mechanisms. Every one of those curved arrows is supposed to show the movement of electrons from place to place, and with electrochemistry (and indeed with redox photochemistry) you are injecting (or removing) electrons from your reactants in the most direct way possible. Getting control of where that happens and how, though, that’s the the tricky part. The authors make the case for standardized equipment to explore this landscape in an organized fashion, working through the variables in small parallel batches (such as wells of an experiment plate) or via flow chemistry.
Apparatus for running batch-mode electrochemistry has been introduced in the last few years, and reports of high-throughput work are beginning to appear, using both homebrew/bespoke rigs and commercial equipment. The authors make the case for the “ideal” experimental setup for high-throughput electrochemistry, which they envision as a flow chemistry device designed for turbulent mixing around the electrodes, with those electrodes being commercially standardized (in several different materials and configurations) and disposable between runs so that you’re always starting under the same conditions with the same materials. These desirable features are not so easy to realize, and no kit is currently commercially available that meets these standards. Standardized surface printing of microelectrodes (for either flow or batch equipment) is a promising approach for that part of the problem, but the mixing part is in special need of some engineering work.
That’s because mixing is a pretty turbulent subject all by itself. Most of the time bench chemists don’t think about it too much, because doing small-scale homogeneous reactions puts you in a regime where those details don’t matter as much. But if you have a solid reagent or surface in there, things can get complicated. We tend to get around that problem on small scale by using a lot more of these reagents than we technically really need (hydrogenation catalysts and so on), so we brute-force past the details. But electrochemistry won’t let you do that. The electrode surfaces (and the dividing material of a divided cell, if you’re using one of those) are crucial solid/liquid interfaces. The picture up close around a working electrode is a complex one, with layers of different compositions forming against the surface if nothing is done to break them up. Small-scale flow chemistry might not do that for you, though, because at these scales and viscosities, flow can often be laminar along the sides of the tubing and reaction compartments. What you want here, as mentioned above, is deliberately turbulent flow to be sure that things are mixed up. The Syngenta folks mention in the paper that they’ve worked out an electrochemical flow cell with deliberate turbulence-inducing features that allowed for much higher current densities.
That brings up another issue with going from small-scale electrochemistry to larger scale. The latter reactions tend to run at higher current densities in general, not least because they’re working in a space where turbulent flow is the norm (and where laminar flow would be difficult or impossible to achieve even if you wanted it). You’ll want this for throughput as well; the more electrons you can get in there, the better, as long as they’re doing what you want them to do. Replicating this as much as possible on small batch or flow scales will be crucial to scaling up whatever you do discover, but higher current densities generate more heat and quite possibly bubbles in the reactions, which will mess up your mixing plans something fierce. Another complication when scaling up is that experimental electrochemistry setups are often run at constant potential, while large ones are often run at constant current (potentiostatic versus galvanostatic), so you’ll need to be ready for that as well.
If you decided during that last paragraph that it’s about time to stop reading this post, you’ve experienced another reason why electrochemistry sometimes fights uphill in organic chemistry. A lot of us (chemists) are not exactly electrical engineers and in fact may have found the whole subject a bit opaque back when we studied it. (Re)learning this stuff and getting a useful mental picture of what’s going on in these reactions is indeed a barrier to acceptance.
That’s an opportunity, though, if you’re willing to roll up your sleeves. The undeniable fact that most synthetic organic chemists have avoided the subject means that there’s a likely to be a lot there to be discovered, especially when you consider some of the interesting reactions that already exist and the direct connection between electron flow and organic reactions in general. The sorts of high-throughput refinements detailed in this new paper are just what will be needed for useful exploration of this landscape – in the past, even the willing and enthusiastic have found themselves worn down by the experimental difficulties. Being able to set up some 96-well plates (at the very least) or some overnight flow runs to explore combinations of potential, current, electrode material, and electrolytes would clear a lot of brush.
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