There's an absolutely startling new paper out from Makoto Fujita and co-workers at the University of Tokyo. I've written a number of times here about X-ray crystallography, which can be the most powerful tool available for solving the structures of both large and small molecules - if you can get a crystal, and if that crystal is good enough. Advances in X-ray source brightness, in detectors, and in sheer computational power have all advanced the field far beyond what Sir Lawrence Bragg could have imagined. But you still need a crystal.
Maybe not any more, you don't. This latest paper demonstrates that if you soak a solution of some small molecule in a bit of crystalline porous "molecular sponge", you can get the x-ray structure of the whole complex, small molecules and all. If you're not a chemist you might not feel the full effect of that statement, but so far, every chemist I've tried it out on has reacted with raised eyebrows, disbelief, and sometimes a four-letter exclamation for good measure. The idea that you can turn around and get a solid X-ray structure of a compound after having soaked it with a tiny piece of crystalline stuff is going to take some getting used to, but I think we'll manage.
The crystalline stuff in question turns out to be two complexes with tris(4-pyridyl)triazine and either cobalt isothiocyanate or zinc iodide. These form large cage-like structures in the solid state, with rather different forms, but each of them seems to be able to pick up small molecules and hold them in a repeating, defined orientation. Shown is a lattice of santonin molecules in the molecular cage, to give you the idea.
Just as impressive is the scale that this technique works on. They demonstrate that by solving the structure of a marine natural product, miyakosyne A, using a 5-microgram sample. I might add that its structure certainly does not look like something that is likely to crystallize easily on its own, and indeed, no crystal is known. By measuring the amount of absorbed material in other examples and extrapolating down to their X-ray sample size, the authors estimate that they can get a structure on as little as 80 nanograms of actual compound. Holy crap.
Not content with this, the paper goes on to show how this method can be applied to give a completely new form of analysis: LC/SCD. Yes, that means what it says - they show that you can run an HPLC separation on a mixture, dip bits of the molecular sponge in the fractions, and get (if you are so inclined) X-ray structures of everything that comes off your column. Now, this is not going to be a walk-up technique any time soon. You still need a fine source of X-rays, plenty of computational resources, and so on. But just the idea that this is possible makes me feel as if I'm reading science fiction. If this is as robust as it looks like, the entire field of natural product structure determination has just ended.
Here's a comment in the same issue of Nature from Pierre Stallforth and Jon Clardy, whose opinions on X-ray crystallography are taken seriously by anyone who knows anything about the field. This new work is described as "breathtakingly simple", and furthermore, that "One can even imagine that, in the near future, researchers will not bother trying to crystallize new molecules". Indeed one can.
I would guess that there are many more refinements to be made in what sorts of host frameworks are used - different ones are likely to be effective for different classes of compounds. A number of very interesting extensions to this idea are occurring to me right now, and I'm sure that'll be true for a lot of the people who will read it. But for now, what's in this paper is plenty. Nobel prizes have been given for less. Sir Lawrence Bragg, were he with us, would stand up and lead the applause himself.
Update: as those of you reading up on this have discovered by now, the literature on metal-organic frameworks (MOFs) is large and growing. But I wanted to highlight this recent report of one with pore large enough for actual proteins to enter. Will they?
And here's more on the story from Nature News.