I've been meaning to mention this paper from John Hartwig (and co-worker Daniel Robbins), because it's just the sort of let's-find-something-new idea that I like. Hartwig has made a name in the field of organometallic catalysis, and is looking for new reactions. So how do you find new reactions?
Most published methods for the high-throughput discovery of catalysts evaluate one of the two catalyst-reactant dimensions. In other words, these methods have been used to examine either many catalysts for a single class of reaction or a single catalyst for many reactions. A two-dimensional approach in which many catalysts for many possible catalytic reactions are tested simultaneously would create a more efficient discovery platform if the reactants and products from such a system could be identified.
Well, this paper details a brutally straightforward technique for doing that. They take a list of seventeen reactants, all around the same rough molecular weight range, each of them with a single functional group. They put a mixture of all seventeen into every well of a 96-well plate. Then they take twelve ligands, dispensed one per column of the plate, and then they take eight different metal catalyst precursors and dispense those across the eight rows. And then they take the plate and heat it up.
Can't get much more straightforward than that, can you? But analyzing the wells by mass spec tells you some interesting things, and you can cover a lot of ground. Seventeen substrates, fifteen metal starting points, and 23 ligand (or lack of ligand) combinations gives you a look into tens of thousands of possible reactions. They simplified the mass spec analysis by combining samples for each row, then combining another site for each column, so you only have to run 20 samples per plate to give you the X-Y coordinated of a well that did something. A test plate containing some combinations of known catalytic reactions showed the expected products in the right wells - and it showed some other reactions, too.
Among those were several wells that indicated an alkyne/aniline addition reaction catalyzed by copper. This turned out to be a hydroamination reaction that no one had observed before. There was also a new product in several Ni-catalyzed wells - a set of deconvolution experiments narrowed that one down, and it turned out to be reaction of arylboronic acids with diphenylacetylene to give a triarylalkene - a reaction not previously catalyzed by such a cheap metal as nickel. And while most of the known reactions are syn, this one gives anti addition, with E/Z ratios that vary depending on the ligand used for the metal.
Not bad - two new reactions in what was, in the end, a pretty simple experiment. And any good chemist should be able to see the ways this protocol could be extended. For example:
This approach to reaction discovery holds considerable potential for purposes beyond those revealed in the current work. For example, this system could be used to explore reactions with additives, such as oxidants, reductants, acids, and bases, and to explore reactions of two substrates with a third component, such as carbon monoxide or carbon dioxide. It could also be used to examine the reactivity of a single class of ligand with various organic substrates and transition metal–catalyst precursors. Thus, we anticipate that this approach to reaction discovery will provide a general and adaptable platform suitable for use by a wide range of laboratories for the discovery of a variety of catalytic reactions.
There's going to be some criticism, though, that this is (a) obvious and (b) not elegant. I regard those as features, not bugs. Never be afraid of the obvious. And organometallic catalysis is so complicated that trying to elegantly reason your way right to the good parts is not always a productive use of your time. Do you want to look like a genius, or do you want to discover new chemistry?