This is a good look at the most recent “metal coupling without metals” controversy in the synthetic organic chemistry literature, and at the vexing history of that whole field. The organic chemists in the crowd can tell everyone how valuable metal-catalyzed coupling reactions have become over the years, and palladium is the king of the catalyst metals. I don’t imagine that anyone could come up with an accurate count of how many different Pd-containing catalysts have been described in the literature, and most of these can be used under a wide range of possible reaction conditions – different solvents or solvent mixtures (sometimes outright two-phase ones), additives, bases, what have you. I’ve also lost track of the number of times I’ve repeated myself by saying that any metal-catalyzed coupling reaction can be optimized to a useful yield if you’re just willing to spend enough of your life doing it, but I say that because I really think it’s true (!)

Although palladium really is magical stuff, though, it would be nicer if we could run all these neat reactions without it. The stuff is intrinsically expensive, for one thing, and it can also be hard to purify out of the reaction mixtures, especially if you’re in the drug business where someone is going to eat your final reaction product. Palladium is not exactly a dietary supplement – if someone manages to prove that it’s an essential part of the human diet, I think I’ll finally make good on my threat to give up the chemistry life and go to truck-driving school (just like Mom always wanted, as I say). No, palladium makes for a rather expensive and toxic waste stream on any kind of scale, and recovering it, though that can be worthwhile, is also somewhat painful. If we could keep the synthetic transformations and ditch the Pd, everyone would be happier.

Many have tried. And many have come to grief! The Nature article linked above will give you a good history of these efforts (some of which I’ve also mentioned here on the blog over the years). Over and over, groups have reported that they’ve gotten these Pd-catalyzed carbon-carbon bond formation reactions to run without palladium, huzzah, only to find, some months later, that it was palladium all along. Dante told us that the gate to Hell had the inscription “Abandon all hope, ye who go in by me”, and the gate to Palladium Hell (or perhaps that should be Attempted Palladium-Free Hell) has a simple message: It Doesn’t Take Much.

Early reports of metal-free couplings collapsed because it turned out that parts-per-billion levels of Pd crept into the reaction somehow – a totally different reagent, the stir bars, the glassware. Now the labs that are still brave enough to try this stuff go to extreme isolation measures to try to keep the metal away –  special stocks of glassware and spatulas, hand-purified reagents and solvents, ever more stringent analytical techniques. And that’s where the most recent effort was coming from, a joint effort from labs at Heifi and Anhui universities in China that reported early last year that they’d found Pd-free coupling conditions. As the Nature article details, though, the months that followed featured nothing but bad news from the labs that tried to repeat this work (and the labs that dug into it looking for hidden sources of palladium contamination). It turns out that yes, there was a Pd catalyst species in these reactions, an absolutely fiendish one that (1) is extremely active, so only minute amounts of it can mess up the results, (2) co-chromatographs with the Pd-free catalyst that was supposed to be doing the reaction, (3) evades the palladium scavenger treatment that the teams were using, and (4) is surprisingly resistant to the nitric acid digestion assay that was supposed to liberate trace amounts of Pd metal no matter where it might be hiding in the system. A real nightmare. The original paper was retracted at the end of last year, and the papers showing the actual presence of palladium in the reaction were published simultaneously in the same journal. By that time, though, the preprint versions of those papers had been out for months, and the word had spread within the synthetic organic community online that the original definitely appeared to be flawed.

In fact, I think that’s the default assumption for many people these days – it certainly is for me. When I see a paper reported Pd-free coupling reactions that would normally require the metal, my first thought is that it’s very, very likely not to be a real result. So many of these things have blown up over the years, and this latest example shows that even honest, hard-working research groups who are taking great pains to remove all doubt can be tripped up. By this point, it’s going to take an awful lot to convince me (and a lot of others) that someone really has found a Pd-free system. The real test will come, as it did in this latest case, when the paper is published for the first time and labs around the world try to get it to work with their own hands, their own reagents, and their own glassware. There’s no substitute for that kind of checking; there really never has been. That’s how science is supposed to work, and you can actually be happy that this latest episode worked out the way that it did. The practicioners out in the field kicked the tires and slammed the doors, revved the engine and tested the brakes, and found out what was wrong. And they did it pretty quickly, too. I wish that all nonreproducible papers were worked over this quickly!

But it’s the ones like this that could have great consequences that get the greatest and most immediate scrutiny, which is also as it should be. If you drill a core sample through the synthetic organic chemisty literature, you’ll find a lot of nonreproducible junk buried in the deep strata that no one cared about when it was published and that no one has paid any attention to since. That’s still down there to trip up the machine-learning programs that are mining the synthetic organic chemistry literature, which is why that effort is not going quite as smoothly as it might, but the humans stopped paying attention to them long ago.