Things are pretty quiet around the industry these days, so my blogging thoughts have been turning to Big General Problems. And here's one that I know that people are working on, but which I think we as chemists are going to have to understand much better: localization.
"Say what?" is the usual response to that, but hear me out. What I mean is the trick that living cells use for their feats of multistep synthesis. Enzymes aren't generally just floating around hoping to bump into things - well, some of them are, but a lot of them are tied to specific regions. They're either membrane-bound, or they're expressed in structures where they don't get a lot of chances to diffuse out into the mix. The interior of a cell, on the whole, is a pretty intensely structured place (as it would have to be).
And that allows specific reactions to take place away from other things that might interfere, which is something that we have a hard time doing in the lab. If you have a five-step synthesis, it's a pretty safe bet that you don't dump the reagents for all five steps into the pot at the same time and hope for the best. No, we generally have to fish out the product and take it on separately. It's often a real achievement (especially on larger scale) to be able to "telescope" two steps into one flask and skip any sort of product isolation between them. Doing it with more than one step is even more rare (and more useful when you can bring it off).
There's been a lot of work on one-pot cascade or domino reaction systems, and that's a step toward what we need. But most of these cases are reaction-driven: people find chemistries that can be run in this fashion, and then try to exploit them to make whatever can be made. Nothing wrong with that, but it would be nice to have product-driven approaches, where you'd look at a particular structure and figure out which multicomponent reaction scheme would work best for it. Generally speaking, we just don't have enough worked-out systems to be able to do that.
And that's where I think that some new technologies could help, specifically flow chemistry and/or microfluidics. Instead of figuring out reactions that can exist while all stirring around together in one pot, this approach takes it as a given that many transformations probably just can't be done that way. And if you can't have one big reactor with multiple things in it, then why not make multiple reactors, each with a different thing in it? Flow systems can, in theory, send compounds through a series of isolated reactions, moving the material physically through various zones and reagents. Not every reaction is perfect of course, but you can often use scavenger reagents along the way to strip out potential interfering impurities before the next step.
I like the idea, but there are a lot of things to be done to make it work. Probably the most advanced organic synthesis that's being done is this style is in Steve Ley's lab at Cambridge. I always enjoy reading their flow papers, which make clear that there's some significant optimization that needs to be done before you can throw the switch and stand back. Some other multistep flow work can be found here and here, and the same comment applies: there's a lot of preparation involved.
My hope is that these kinds of things will eventually move toward more of a plug-and-play system, where you put in the various cartridges and choose a protocol from the list of best-general-fits for your planned reactions. We're quite a ways from that, but I don't see why it wouldn't be possible.