Single crystals suitable for X-ray crystallographic analysis were obtained when a solution of the salt in EtOAc/nC6H14/MeCN was allowed to stand at 20 °C for about 1 d.
That sentence appears in the X-ray characterization section of only the second paper I published — an Angewandte from 1998.
First of all, I’m embarrassed that the information that is given is not even close to being adequate to repeat the crystallization (if it’s any excuse at all — and it’s not a good one — this paper was submitted within 6 months of me beginning my PhD and was the first paper I had some involvement in writing; my first paper was from a project I did as an undergrad and the paper was written without me). What concentration of the compound was used, and what was the ratio of those three solvents. But secondly, HOW ON EARTH DID I COME UP WITH THAT WEIRD COMBINATION OF SOLVENTS?!
Well, sit back, put your feet up, and get ready for the #overlyhonestmethods version of the story.
I’d been trying to crystallize this particular compound for months — it was something I had made as part of my final-year undergraduate project; a project I was continuing with for my PhD. You don’t really need to know what the structure of the compound was, other than the fact it was a salt, with a large-ish organic cation (the interesting bit) and pretty much any anion you may choose to associate with it. Most compounds of this type in the research group were prepared using a non-coordinating anion such as hexafluorophosphate (‘non-coordinating’ means that the anion doesn’t form a tight ion pair with the cation, and the cation is free to start forming interesting complexes without the anion getting in the way).
The hexafluorophosphate salt was not particularly soluble in most organic solvents. It would go into acetonitrile (up to a point) and it was also soluble in DMSO, but that was pretty much it. So, it could be characterized by NMR spectroscopy, but I had no luck growing crystals from acetonitrile (and it didn’t even cross my mind to try DMSO). Every crystallization attempt would just produce an amorphous white powder — nothing that was going to give me a nice crystal structure. After many months of frustration, I think a postdoc in the group badgered me into running a 13C NMR to try to get a better picture of what was happening in solution (the molecule was a self-complexing one; the idea was that it would form intermolecular complexes that would resemble interwoven chains, and since the 1H NMR spectrum was very complicated, he suggested 13C might be more revealing).
I wanted to make a concentrated sample to get a good spectrum, and I knew that I couldn’t do that in acetonitrile. DMSO would be able to dissolve a large amount of the compound, but the compound didn’t form complexes in DMSO (no matter how concentrated), so that was no good. Instead of using hexafluorophosphate as the anion, I thought I’d give trifluoroacetate a go — I’m not sure why, but perhaps others in the group had been using this anion too. So I made the trifluoroacetate salt and was pleasantly surprised to find out that it was quite soluble in chloroform. Brilliant. I’d run the 13C NMR in CDCl3, the solvent I ran most NMR experiments in.
At that time, the NMR spectrometers in the department ran as a service — you weren’t allowed to touch them yourself. The only time you could run a 13C spectrum was overnight, and they had to be queued up on the carousel before the NMR facility was locked and closed for the night at 6 pm (I just heard a collective gasp from all of the US grad students/postdocs reading this — but yes, the NMR suite was locked shut at 6 pm; no way of getting in). So, you couldn’t run your own NMR spectra and if you wanted a 13C spectrum you had to make sure you got one of the 20 overnight slots.
So there I was in the lab (on the 7th floor of the building) and I glanced at the clock to see that it was about 5:50 pm. I quickly grabbed my bottle of CDCl3 from the shelf on my lab bench and added about 1 mL of it to a sample vial containing about 100 mg of my trifluoroacetate salt. It looked like the stuff wasn’t completely dissolving and because I was in a rush, I just decided to grab my bottle of CD3CN and add a few drops of that. Hey presto, everything dissolved. I dutifully filtered the solution into the NMR tube through a small amount of glass wool stuffed into a pipette, capped the tube, and raced to the lift to head down to the ground floor to get into the NMR suite before it closed.
I just made it. I got my sample on to the carousel and I think they locked the door behind me as I left and returned back to the lab. I went back to my lab bench to clean up and it was then that the horror hit me. Our bottles of CDCl3 were very distinct; they were dark brown glass, big blue screw caps and weren’t cyclindrical, but had a square cross-section. Once I’d finished with one, I’d often re-purpose them to hold TLC solvent mixtures. It turned out that the bottle of ‘deuterated chloroform’ on my bench that I had just used wasn’t actually a bottle of CDCl3 — in my haste, I had grabbed the wrong one off the shelf; one that was clearly labelled, in my own handwriting, as containing a 1:1 mixture of hexane:ethyl acetate. So, my NMR sample had been made up using (non-deuterated) hexane/ethyl acetate and a few drops of deuterated CD3CN. Bugger.
Had this been any other time of the day, I would have trudged back downstairs, retrieved my NMR tube, evaporated off the solvent, and re-made the sample using CDCl3 (and not informed anyone of my utter stupidity). As it was, the NMR lab was locked, there was no way in, and I resigned myself to picking up a nice 13C NMR spectrum of hexane/ethyl acetate the following morning (as well as looking like an idiot). The morning came, I picked up my spectrum (which was as useless as you would expect it to be). I think all of the samples had already been cleared off the carousel and were in a rack waiting for collection. I don’t remember for sure, but the guy who ran the NMR machines might have even written something less that complimentary on my spectrum (yes kids, these were the days of paper spectra; no electronic versions available for students…).
I don’t know when I noticed, but at some point between the NMR suite on the ground floor and the lab on the seventh floor, I looked at the NMR tube and saw what I can only describe as BLOODY HUGE CRYSTALS in there. The boss was away, but the senior postdocs booked me on a train the very next day to carry my precious cargo to Imperial College in London, where our crystal structures were all solved. The rest is history, and the crystal structure got me an Angewandte paper — and ended up being the basis for one of the chapters in my thesis.
So, that’s my #overlyhonestmethods story for you.
As a postscript, I should point out that the deuterated solvent, the strong magnetic field of the NMR machine, the spinning at 20 Hz for 30 minutes and the periodic shunting around an NMR-machine carousel were NOT required for the crystallization. In repeat experiments, a mixture of ethyl acetate and regular acetonitrile produced crystals in a vial sitting quite still on the bench top in the absence of a strong magnet…