A potentially revolutionary new technique for chemical structure determination

I am a big believer in science as a tool-driven rather than an idea-driven revolution, and nowhere do you see this view of science exemplified better than in the development of instrumental techniques in chemistry – most notably NMR and x-ray diffraction. NMR and crystallography were not just better ways to see molecules, but in their scope, their throughput, their cost and their speed, they opened up whole new fields of science like genomics and nanomaterials up to investigation that their developers couldn’t even have imagined.

So it is with some interest that I saw a paper from the Nelson group at UCLA and Stoltz group at Caltech that describes a new way to rapidly determine the structures of organic molecules. And I have to say: very few papers in recent times have made me sit up and do a double take, but this one did.

Until now, crystallography has been the gold standard for all kinds of structure determination; it gives you as direct a view of molecules at the atomic level as possible. But the very name “crystallography” implies that you need to get your sample into a crystalline state, and as any chemist who has worked with a headache-inducing list of assorted powders, gels, oils and tars knows, being crystalline is not the natural state of most molecules. In most cases your samples are thus simply not in a convenient form for crystallography.

That’s why NMR has been the primary technique for routine organic structure determination. But NMR is still relatively slow and depends on having a machine that’s expensive and sometimes breaks down. You also cannot do NMR on a benchtop, and getting the sample in a pure enough condition in the right solvent is also key to good structure determination. Then there are all the problems attendant with shimming, water suppression and other artifacts that NMR presents, although sophisticated software can now take care of most of these. Nonetheless, as powerful as NMR is and will continue to be, it’s not exactly a rapid, plug-and-play system.

That’s why this recent paper is so promising. It describes a crystallographic technique that uses cryo-EM and micro-electron diffraction (micro ED) for efficiently finding out the structure of organic molecules. Now, cryo-EM already won the Nobel Prize two years ago for determining the structures of complex proteins, but it has never been routinely applied to small molecule structure determination. This technique could change that landscape in a jiffy. And I mean in a jiffy – the examples they have shown take a few minutes each. The first molecule – progesterone – went from powder to pattern in less than 30 mins, which is quite stunning. And the resolution was 1 Å, and you can’t ask for more. Up to twelve samples were investigated in a single experiment.

But what really made me sit up was the variety of starting points that could be investigated. From amorphous powders to samples straight out of flash chromatography to mixtures of compounds, the method made quick work out of everything. As mentioned above, amorphous powders and mixtures are the rule rather than the exception in preparative organic chemistry, so one can see this technique being applied to almost every chemical purification and synthetic manipulation done in routine synthesis or structure determination. For me the most amazing application however was the determination of a mixture of four different molecules: no other technique in organic chemistry which I know can do mixtures in a few minutes with such high resolution.

There are undoubtedly still limitations. For one thing, cryo-electron microscopes are still not cheap, and while sample preparation is getting better, it’s also not instantaneous in every case. I also noticed that most of the compounds this study looked at were rather rigid, with lots of fused and other rings; floppy molecules will likely cause some trouble, and although thiostrepton is an impressive-looking molecule, it would be interesting to see how this works for beasts like rapamycin or oligopeptides. In general, as with other promising techniques, we will have to see what the domain of applicability of this method is. 

Nonetheless, this is the kind of technique that promises to take a scientific field in very novel directions. It could accelerate the everyday practice of organic chemistry in multiple fields – natural products, chemical biology, materials science – many fold; and at some point, quantity has a quality of its own. It could allow the investigation of the vast majority of compounds that cannot be easily coaxed into a crystal or an NMR tube. And it could perhaps even allow us to study conformational behavior of floppy compounds, which from first-hand experience I know how hard it is to do.

If validated, this technique also exemplifies something I have talked about before, which is how scientific tools and discoveries build on each other; in other words, how scientific convergence is a key driving force in science. When cryogenics was invented, nobody foresaw cryo-electron microscopy, and when cryo-EM was invented, nobody foresaw its application to routine organic synthesis. And so it goes on, science and technology piggybacking in ever-expanding spirals.