I enjoyed this article at Chemistry World, but fair warning: you may not. I say that based on the response when I’ve written about its subject here before, which is the automation of synthetic organic chemistry. There have been some pretty strong negative reactions to the idea, which fall into several categories. “You’re hyping something that doesn’t even/can’t even exist”, “This is too depressing to read about even if it’s true”, “Organic synthesis is an art form; talk of automating it is ridiculous and/or insulting”, “We’ve heard about this sort of thing for years, and it never works”, and so on. The article itself is fine, and goes over both the promises of automated synthesis and the problems involved in realizing it (as well as the problems it causes for chemists to think about it!)
So with that realistic view of the field, let me put on the goggles and go for the reductio ad absurdum, the Universal Synthetic Chemistry Machine. What would it look like, and what would it do? Right up front, I have to say that I do not necessarily expect anything quite like this. But neither am I quite prepared to bet against it, and I think it’s a good thought experiment to do (see below). Here goes:
The USCM occupies a large vented enclosure. A chemist sends it a structure, and the software runs its inhuman, invisible fingers over the structure file, looking for likely bond disconnections and analyzing potential retrosynthetic pathways. Possible steps would be graded based on feasibility from the machine’s vast, thoroughly curated database of known reactions from the literature, with special emphasis on ones that it has shown to work in its own past syntheses, but it also uses the general synthetic rules that humans have told it about (and the ones that it may have inferred for itself). These are chained together in increasingly long sequences as it searches for a minimum-energy path through the synthesis, which would be the one involving the highest potential yields, the most likely reactions to work (but with the fewest overall steps, when possible), and the most easily available materials and reagents. The analogy to chess-playing software is clear. Chess is a far easier game to model, but the same general mixture of brute force search and decision-tree paring is used. Known and validated preparations are the equivalent of the opening sequences programmed into a chess engine; the real energy is spent on the mid- and end games. As with any system of this kind, the machine is not guaranteed to find you the absolute best synthetic sequence, but by this point in its evolution it has a very good chance of finding a good, workable one. Which is what it’s for.
Since this is a Universal Synthetic Chemistry Machine, it can in theory handle whatever you throw at it, from ibuprofen to palytoxin. In practice, complex natural products are handled by “centaur teams”, machine-assisted humans, who feed the syntheses of various advanced intermediates into the software and use it to rate the likelihood of the various overall strategies. For molecules that can be made in ten to twelve steps, though, there’s really no point: the software will give you a route.
Once you tell it to go ahead and make the compound (and how much to make), it determines the solvents and reagents it needs and start assembling those. The USCM uses reagents in standard-format containers adapted for its handling systems, and calls those up from the automated stockroom to be loaded into its various bins and holding areas. Solvent lines, a whole range of them, are already built in. Cartridges for purification, phase separation, solid-phase extraction and other operations are also standardized and can be dropped in by the hardware and fitted without human intervention.
The machine prefers to work in flow mode, and optimizes its synthetic routes in that direction. But it can switch over to batch reactions when needed. It identifies the likelihood of success for the various steps, and for the ones below a certain cutoff, it switches to analytical condition-searching mode, running an array of small experiments to scout out reaction modes before proceeding with the larger batch. Before starting, it will present the chemists with its options – scout a problematic step that might shorten the synthesis, or take the long way around with reactions that are more likely to work? Order up an unusual reagent or catalyst that looks to help the route, or go with what’s in house? It is programmed, of course, with routines that anticipate scaleup differences in stirring, heating, and so on, and it’s also ready to identify reactions that are potentially energetic.
Most of the time, though, things are quite straightforward. With its array of pressure and flow sensors, the machine is even able to localize potential clogging in the flow lines, and bring on extra heat or ultrasound to free things up. In extreme cases, it will back-drain the system and switch to a DMSO flush or the like, but since its software is also ready to flag structures that look like they would be less soluble back during the planning stage, it approaches those with caution from the start.
The software provides an estimate of when the synthesis will finish, updated along the way as the sequence proceeds, and it checks for purity along the way (and, of course, at the end). The standard mode is to try telescoped reaction sequences, especially when it has evidence from its files that particular combinations are acceptable, and to only purify intermediates further if the increase in yield is justified. And thus another structure is made. For most medicinal chemistry analog arrays, the whole process is routine, because there are some twenty or thirty transformations that make up the great bulk of that work, and they’re well optimized by now.
Here’s the thing: I said at the start that this was a reductio ad absurdum, but you know what? It’s not all that absurd. I have violated no physical laws; I have invoked no devices or programs that we don’t already have in some form. Realizing such a machine is going to take a great deal of engineering prowess, but let me be honest with you: I don’t see any reason why something like this can’t exist. Or shouldn’t. The fact that various people have overpromised over the years in this area does not mean that those promises are impossible to realize.
Here are some points that I made when I spoke about this topic in Manchester a year or two ago: if you work in a well-equipped lab in a first-world environment, you are already surrounded by machines that do a lot of repetitive tasks for you, like queuing up your samples for analysis, collecting your fractions while you run gradient elution purifications, and so on. Making a pile of analogs from a common intermediate is most definitely a repetitive task of its own, and we’re heading towards machines that will do that for us. The same goes for scouting a range of reaction temperatures, solvents, and catalysts.
There are many places around the world, from academic labs to CROs in various countries, where there are no mechanical fraction collectors. The fraction collector has a name, takes a lunch break, and collects a salary, because (for now) human labor is cheaper and more reliable in such places. Many chemists from wealthier environments look at such a situation and get the same feeling that people do if they see someone pulling a rickshaw for a living: this is grunt work. Humans are fit for better than this. And so they are. The same used to be true for the process of washing everyone’s laundry, with a tub and board or even a flat rock down by the river, and in some places it still is. Humans are fit for better.
The uneasiness comes on when automation and mechanization moves into jobs that we don’t feel are all that bad. It’s one thing to haul manure all day, but quite another to make a series of sulfonamides. (The occasional equivalence of sulfonamides and manure is a topic for another time). But the principle is the same – leaving such things to machines frees us for still better tasks. Instead of banging out amides and palladium couplings, we will use our brains to think about what we should be making next, and using our hands for chemistry that’s still too difficult or novel for machines to handle.
Now, there’s a sting in here. You may well need fewer chemists under such a system, although that’s still not for sure. But what is for sure is that the chemists that are around will be working at a generally higher level than most of us do now, because what we bring to the process will be (increasingly) not our hands but our brains. And not everyone is going to be capable of doing that. There used to be more people in the medicinal chemistry labs of high-wage countries who were not there to come up with great project ideas or break new ground in the existing ones, but rather were employed because they were good at banging out series of analogs thought up (for the most part) by other people. That work has been migrating to lower-wage territory for many years now. And the machines are coming for it in turn, and more besides. You may not be willing to credit the Universal Synthetic Chemistry Machine described above, but a Universal Amide/Suzuki Cranker is a lot easier to picture. And that’s a matter of degree – not of kind.