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Life in the Drug Labs

Cuprate Voodoo

I may talk a good game, but don’t let me fool you: I really don’t understand some of the things that happen in my lab. I was talking with some colleagues the other day, and told them about a reaction I had in my PhD work. I was using a so-called “higher-order cuprate” reagent, which you make from copper cyanide and lithium reagents, and it worked just fine for me the first time out.
And then it worked just fine again, on a larger scale, and then it worked just fine one more time. And at that point, it stopped working, forever. I never got the tiniest bit of product out of the reaction again, only starting material and varioius forms of junk. It was as if someone had turned a switch.
We’re supposed to be able to work these problems out, and I tried. I checked my solvents, my starting materials, and my technique. I analyzed my lithium reagents, and I tried every bottle of copper cyanide we had. Then I made my own, the most beautiful copper cyanide you’d ever want, assuming that you’d ever want some. Result, zilch. I reversed field, thinking that I’d used an old bottle which might have some oxidation products in it that made things work. But aging the stuff by heating it in an open flask didn’t help, either. Nothing did. I kept looking at my flask of product from before, a key intermediate in my synthesis, and wondering how on Earth I’d ever made it.
Well, as I finally wrote in my dissertations, “cuprate reagents of all sorts were abandoned after this experience.” I never did find out what happened, and eventually worked out another way to get the product (which reminds me, if anyone out there needs to use dimethylmagnesium, talk to me – have I got a recipe for you!) Organometallic reagents are famous for being tricky, but you’d think that a science as old as organic chemistry – we are a science, right? – would be able to deal with such problems. Maybe not.
(Note: the structure and reactivity of all kinds of cuprate reagents have been the subject of food fights for many years. Here’s a sample, but if you’re not seriously into organometallic chemistry you’re going to feel as if you’d stepped into a room full of people discussing Zoroastrian theology. A later and less contentious look at the field can be found here as a PDF.)

4 comments on “Cuprate Voodoo”

  1. Greg Hlatky says:

    We Zoroastrians prefer to keep to ourselves.

  2. Jose says:

    Aha! Did you consider the septa factor? Somewhere in the older cuprate lit there is a footnote saying that some of the “HO” jobbies don’t go if you use the std off-white septa, and the reddish-orange kind are crucial for success… I’ll see if I can dig a reference out….

  3. PsychicChemist says:

    I made many cuprates at one point of time and all of them worked!
    What I found was that cuprates generally do not form very well at -78C. You need to warm the reaction to -40C or so to get the cuprate to form. (This is important as one can imagine what could happen to your molecule if you didnt form the cuprate and you had a lot of very basic organolithium floating in your reaction). Although, you dont want to warm the reaction up too much as some cuprates can decompose at higher temperatures.
    What I found that worked the best was to add the organolithium at -78C and warm the reaction in my hand (it can be fairly unpleasant with a larger colder flask) till I could see the copper salt dissolve in the THF. Then I would stick the flask back into the dry ice/acetone bath. Of course I couldnt write this description in the experimental when I published the paper, I just said warm to -40C
    My question was, why did you use CuCN and not just a simple Gilman cuprate with CuI. I found them to be a lot more reliable. And if you still cant get a good reaction, add some TMSCl. That works like magic.
    So Derek, are you going to try the reaction from grad school again……….

  4. Derek Lowe says:

    Hah! I’d have to be paid very handsomely to revisit anything from graduate school. We actually did try the good ol’ Gilman cuprates on this system, and they didn’t work very well. The cyanocuprate, whatever it is, was a great improvement (for a week or so. . .) But dimethylmagnesium proved to be the high-yielding, 50-grams-at-a-time answer to this problem.

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