In the wake of yesterday's revelation about the latest breakthrough in amide formation, one point that's come up is whether we getting into the era of diminishing returns in finding new synthetic methods.
My opinion? We may well - but we shouldn't have to be. It is true that we know how to do an awful lot of transformations. And I'd also subscribe to the view that we can, given no constraints of time, money, or heartbreak, synthesize basically any stable organic molecule that anyone can think up. In what we're pleased to call the real world, though, constraints of money and time (related by a similar equation to Einstein's mass-energy one) are always with us. (Heartbreak, well, that seems to be in constant supply).
So even though we can do so many things, everyone realizes that we need to be able to do them better. That applies even to amide formation. There are eleventy-dozen ways to form amides in the literature. But as some of the comments to yesterday's post show, sometimes you have to go pretty far down the list to get one that meets your needs. There is no set of conditions that is simultaneously easy, fast, cheap, nonracemizing, nontoxic, tolerant of all other functional groups, and generates a benign waste stream. Finding such a universal reaction is a fearsome goal, especially considering the number of alternatives that have already been tried.
This is why stoichiometric samarium metal is such a ridiculous idea. There are a lot of good ways to form amides. And there are a lot of lesser-known ways that might save you in tough situations. And there are lots of stupid, crappy ways. The world does not need another one of the latter. So what does it need?
Well, if you're going to stick with amide formation, you're going to have to find something closer to that ideal reaction, which won't be easy. Several other transformations are in that same category - lots of alternatives available, so something new had better be good. There are, though, plenty of other reactions that don't work so well, where improvements don't require you to approach so near perfection. A person's time might be better spent there than on trying to find the Perfect Amide Reaction, although the impact of finding the latter would probably be greater. Neither possibility excuses time spent on finding Another Lousy Amide Reaction.
And there are a lot of transformations that we can't do very well. Turn a phenol into an aromatic aldehyde in one step. Selectively epoxidize aromatic double bonds. Staple a secondary amine in where an aliphatic C-H used to be. Fluorinate at will. You can go beyond that to reactions that you can't even think up a mechanism: go around a benzene ring, switching out carbon for nitrogen. Pyridine, pyrimidine, pyrazine. . .I have no clue how to do that, or if it's even possible. Change a given oxazole into its corresponding thiazole. Turn a methoxy back into a methyl group. And so on - we sure can't do those, and the list goes on.
Hard stuff! But there are plenty of non-science-fictional possibilities out there, too. An eye to applications beyond pure synthetic chemistry helps. Look, for example, at Barry Sharpless and the copper-catalyzed triazole formation (click chemistry). That's a nice little transformation, and there are people who probably would have just made a nice little Org Lett paper out of it if they'd discovered it themselves. But it's such a versatile way to stitch things together that it's finding uses all over the place, and the end is not in sight. The world could most definitely use more chemistry that can take off in such fashion, and surely it's out there to be found.
I realize that we had this discussion just back in August, and earlier in the summer. But it keeps coming up. Seeing someone form amides with a pile of elemental samarium brings it right back to mind.