Once in a while I’ll see someone studying undergraduate organic chemistry, and I’ll mention to them that those reactions that they’re learning – well, a reasonable number of them – actually get used out in the real world. (The students are generally surprised by this news). I think that a prototype of this sort of thing is the Grignard reaction. It’s a staple of sophomore organic chemistry questions in the “Synthesize this compound from these starting materials” format, as it should be: it’s a great way to bring in a “methyl minus” carbanion nucleophile or to functionalize an aryl bromide. And a lot of such courses do one in the lab, or at least they used to. When I was a TA, there was a phenyl Grignard reaction done in ethyl ether, and the poor ventilation in the lab chased me out into the hallway by the time I taught my third lab section of the week. But most of the students got it to work, and I think the “Try crunching up the magnesium, try stirring hard, try adding a crystal of iodine” part of getting the reaction initiated gave them an honest look into what organic synthesis can be like sometimes.
And you can, of course, buy a big long list of commercial Grignard reagents to use at the bench. I’ve also been involved in a couple of scale-ups of more customized Grignard reactions to make material for a first two-week tox run; it really does get used, although I’m sure that no one is enthusiastic about doing it with a hundred-kilo charge of magnesium turnings (although I’m equally sure that it’s done on that scale from time to time!)
The funny thing about the Grignard, though, is that the mechanism is still a bit unclear, even after all these years. There is evidence for a polar mechanism (that carbanion), and there’s evidence in other systems for a single-electron radical mechanism. It’s also obvious that the Schlenk equilibrium is operating, shuttling you back and forth between (at the very least) methylmagnesium bromide (as a prototype), magnesium bromide, and dimethylmagnesium, with the ratio of those things very much dependent on the conditions. That “methylmagnesium bromide” isn’t quite as drawn, either – there are certainly more complex alkylmagnesium halide species in there, in equilibrium with each other as well. The harder you look, the more you see.
This paper is a nice recent overview. It’s an intensive look at methylmagnesium chloride in THF with either acetaldehyde or fluorenone, about as plain-vanilla a set of Grignard conditions as you can imagine (well, short of maybe using benzaldehyde, with which every nucleophilic organometallic species known to science has been reacted at one point or another). High-level calculations indicate that the reaction is indeed balancing on several energetic knife edges, and there are a *lot* of species involved. That diagram at right, for the acetaldehyde case, will give you the idea. You’ll note that the THF solvent is very much a participant, which Grignard aficianados already know well from the sometimes-different reactivity of the diethyl ether solutions versus the THF ones. In the end, as we know, the Grignard is not just one reaction at all:
The coexistence of multiple species in rapid exchange due to the Schlenk equilibrium and the evidence that the activation energy range of all possible reactions is relatively modest indicate that the Grignard reaction should not be described by an individual process. Instead, it should rather be thought of as an ensemble of transformations that can occur simultaneously in solution. It is likely that improvements of the Grignard reaction, for example, by alkali or copper salt additives occur by interference with one or more of the possible pathways. . .
It sure is. The concentration, solvent, counterions, starting halide, and electrophile partner all have roles to play, and that’s even before we start getting fancy with the additives. So when I next see some student working on that section of their first organic chemistry course, I’ll still tell them that the Grignard is real and that the Grignard lives – but that it’s not quite as straightforward as their textbook has it! I’ll also still tell them another famous bit of trivia: that it’s surely the most famous reaction that was actually named after the graduate student (Victor Grignard, who eventually won the Nobel for the work), rather than the professor (Philippe Barbier, of the often-closely-related Barbier reaction). Grignard himself said he would rather have shared the prize with Barbier, actually!