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Analytical Chemistry

Small Molecule Structures: A New World

Word has been spreading rapidly about this preprint on Chemrxiv.org, from a joint UCLA/Caltech team. It details the use of the cryo-electron microscopy technique called micro-electron diffraction (MicroED) for the structure determination of small molecules, and it’s absolutely startling. I read it last night, with many exclamations along the way, not all of them fit for print (and that’s in a good way). And it turns out that basically simultaneously, a Swiss/German collaboration has published on the same technique, one day before.

Some quick background on what’s going on here, then we get to the hair-raising stuff. As the chemists in the audience well appreciate, X-ray crystallography is the gold standard for structure determination. If you can grow a good crystal of some substance, you can diffract X-rays through that lattice and work backwards to see what the unit cell of the crystal had to be. The hardware and software to do this have advanced hugely over the years (with worthy Nobel prizes handed out along the way), and although there can still be complications, for most small-molecule substances the main limitation is now contained in that phrase “grow a good crystal”.

That’s the killer for proteins, too, which is why cryo-electron microscopy (cryo-EM) has been getting huge amounts of attention in recent years. The hardware and software techniques in that field (blasting beams of electrons through the sample rather than beams of X-rays) have shown extraordinary improvements, with several no-joke breakthroughs coming right on top of each other. It’s most famous, justifiably so, for being able to deliver structures of huge proteins and protein complexes that can’t even be crystallized, by sampling a huge number of individual protein particles in different orientations and reconstructing the structure (a really impressive computational feat).

There’s another powerful cryo-EM technique, though, that was first reported in 2013: MicroED. That one uses crystals of protein, but ones that are too small to be of any possible use in X-ray diffraction. That happens quite a bit; going from a microcrystalline powder to a suitable single crystal large enough to use has long been one the slogs that protein crystallographers have to go through. Here’s more on MicroED from its discoverers, but the idea is very similar to X-ray work: you rotate the crystals, collecting diffraction data in various positions, and in fact you basically use X-ray structure software to work things up. It’s just that with electron diffraction you can do it on far, far smaller crystals (which are far, far easier to get ahold of!)

Well, what about doing this on small molecules? Would that work? Why the heck not? It’s taken five years for someone to say that, and a lot of people are probably slapping their heads this morning, but what this latest report shows is that it works even better than one might have hoped. If you take microcrystals of some small molecule and floomph them out over a cryo-EM grid (not sure that’s the technical term, but that’s how I’ve always thought of it) you can zoom in on individual particles, fire the electron beam at them, and rotate them (with modern equipment) to get the different angles you need.

The US group first tried it with some progesterone powder right out of the damn bottle off the shelf. Three minutes of data collection from a single nanocrystal (picked at random from the thousands scattered across the grid) gave a data set that produced a one-Ångstrom resolution structure: total powder-to-structure time, less than a half hour. Holy cow. The Swiss/German team reports very similar results on commercial compounds, and also seem to have been taken aback at how straightforward the procedure was. The US team went on to ransack the shelves, and out of eleven small molecule samples, none of them recrystallized for this experiment in any way, they got structures from all eleven (ten using direct methods for the data, one by molecular replacement). This includes complex natural products like brucine, shown at right, and check that resolution. That’s what small-molecule diffraction data can do for you – turn an aryl ring into ping-pong balls and toothpicks like something your kid built on a rainy afternoon. It’s worth noting that electron diffraction tends to give you positions of hydrogen atoms themselves on structures, too (as opposed to X-ray, where it’s definitely less common), since the electrons are strongly affected by those proton nuclei. (Edit: note that reference – others have actually been doing ED on small molecules, although this application to nanocrystals is likely to make it take off even more thoroughly).

Brucine’s pretty rigid, though. How about this next one, the antibiotic thiostrepton? As you can see, the electron density is a bit more raggy, but jeez, this is powder right out of the vial. That brings up another point: a lot of things that get called “amorphous powders” in organic chemistry are no such thing. As a formulations specialist will tell you, getting a truly (and reproducibly) amorphous powder can be a real pain, because a lot of the time what you have is some sort of microcrystalline powder. Tiny little crystals, of just the sort that MicroED can apparently eat for breakfast. The Swiss/German team demonstrates the structure of a large methylene blue derivative that only forms thin needle crystals that are next to useless for X-ray (a common problem!) but are just fine for MicroED. The crystals used in this paper are thousands of times smaller (!) than the ones typically used for X-ray diffraction, and at that level it’s very much worth putting things under the electron microscope and seeing if you might not have some crystals in there somewhere.

That’s what the US group went on to do: they took solids right off the rota-vap after they’d come off silica gel columns, scraped out some solid and took a look. Two of the four samples of that group gave structures, and honestly, I’d try rota-vapping down the other two from a couple of different solvents if I really wanted their structures, because you never know. How about mixtures of compounds? The different crystals therein show up as different shapes on the EM grid, and you can pick them off one by one, allowing you to get several structure determinations out of a complex mixture if the constituents have managed to form microcrystals of their own. No, really, this is great.

There’s a phrase that leads off a paragraph in the UCLA/Caltech manuscript: “Astounded by the ease with which such high quality data was obtained. . .” and I think “astounded” will go for everyone who reads it. Another line, not many sentences later, is “Based on our findings, we anticipate that MicroED will be enthusiastically received by many types of small molecule chemists“, and buddy, they’ve got that right. The Ang. Chem. paper says that this is “the technique of choice for all unsolved cases in which submicron sized crystals were the limiting factor”, and that’s the truth, too.

Just looking over the paper, I can think of plenty of great experiments, and I’m just one guy. Can you let solutions evaporate right onto an EM grid and use those? Is there an analog to anomalous dispersion, as in X-ray work, to get absolute configurations? What happens to solvates under MicroED conditions? Well, we’re going to find all of these out and more. Congratulations to everyone involved for pushing small-molecule organic structure determination into a new era!

Addendum 1: The authors will probably want to correct that line above to “data were” in the final version and fix several typos and misspelled words, but if I were writing up results like these, God knows I’d have plenty of typos, too, because my hands would be shaking!

Addendum 2: here’s Wavefunction on this paper. He seems to be just as blown away by it as I was.

78 comments on “Small Molecule Structures: A New World”

  1. Martin says:

    So between this and the Fujita methods using MOFs, basically almost ANYTHING can now give you one of those amazing-looking 3D structures?
    When you think that 60 years ago most labs could barely get a usable NMR, and now we have what amounts to 3D pictures of the molecule.
    Mind: blown.
    If I had money to invest, I’d put something in the companies that produce the necessary equipment for this analysis, because now everyone will want one.

    1. myma says:

      I know. In my lifetime in college we had to deduce a structure from he old department beater continuous wave NMR, IR, UV, and bunches of reference tables.
      And now this!

    2. Gustavo Santiso-Quinones says:

      Dear Martin,

      Electron Diffraction is definitively a game changer. Not everything can be measured using this technique. One reason for that is that in an Electron Diffraction experiment, the sample is under high vacuum (< 10 ^ 6) per se, as the electron source of the EM works only under vacuum. Therefore, crystalline systems that loose solvent and therefore loose crystallinity can't be measured using this technique.
      Though, the technique is very promising and will increase the amount of possible structures in a 3 to 4 fold.
      With regards, one of the authors of the paper in the AICE,
      Dr. G. Santiso-Quinones
      Crystallise! AG, Switzerland

    3. CB says:

      I was thinking the same thing Martin, about starting a company!

  2. Name says:

    Awesome work. One thing I noticed… is it just me, or is the microED structure of progesterone the opposite enantiomer of what is expected? Maybe I’m missing something.

    1. AVS-600 says:

      I have no idea what’s involved in deconvoluting EM data, but if it’s similar XRC data then the “typical” analysis doesn’t give you absolute stereochemistry. You have to get that information from a secondary result based on so-called “anomalous scattering”.

  3. Brian Stoltz says:

    Thanks for this great write-up Derek! It is awesome to see the excitement from the community about the possibilities of this technique!

    1. Derek Lowe says:

      Glad to! You can be sure that this is getting a lot of attention. . .

    1. Derek Lowe says:

      As mentioned in the post.

  4. Curious Wavefunction says:

    Thanks for the plug Derek. I am thinking what it would take for, say, a small biotech to set up a cryo-EM facility like this for routine use. Even if it’s a million or two dollars, the downstream payoff would be worth it.

    1. Isidore says:

      This would be a good investment for a CRO in an area where there are a lot of small companies and colleges, like Cambridge/Boston, where people can get on the subway and take in their samples fresh off the rotavap. I would combine this with a coffee shop or bar adjacently so one could have a coffee waiting for the results and drinks afterwards to celebrate.

      1. Marcus Theory says:

        Only if the fuzz don’t catch you for illicitly transporting research compounds! I work in Boston and we often ship samples to collaborators in the same zip code, only to see the tracking code wind up in a central postal office in Tennessee before coming right back ’round to Massachusetts.

        1. Isidore says:

          I also work in the area and have often transported samples in an envelope, in a styrofam box filled with dry ice, even in my pockets (nothing particularly toxic or radioactive or explosive, I should clarify), and with the small amounts required for MicroED this will be easy enough. But if I were taking the subway I’d opt for an innocent-looking cooler of the type people use for their lunch instead of the Styrofoam box so as not to make other passengers nervous.

        2. Anonymous says:

          As an undergrad in Boston/Cambridge, I was doing summer synthesis research at University A. The lab AND the stockroom ran out of THF(!). I hopped the Red Line back to University B, used my stockroom card to buy 4L of THF and hopped the Red Line back to the summer research lab. Probably completed the THF run in less than an hour, most of it walking to/from the T. I shudder a little bit, but it was a glass jug, not the metal can of THF. I was extremely careful (newspaper padding, etc.) but it must have been against the law, even then. If I tried it today, I’d be typing this story from Guantanamo.

  5. Curious Wavefunction says:

    I like that bucolic vision, and in the Bay Area you could get about two hundred samples done while you sit in traffic on the 101.

  6. William Lawrence Bragg says:

    William Lawrence Bragg

    1. dorothy hodgkin says:

      no need to boast

  7. Linus pauling says:

    Holy shit

    1. K C Nicolaou says:

      Damn it, still no Nobel.

  8. John Wayne says:

    Pretty soon we are going to be able to drop a pinch of material into a receptacle and look at the hologram of the structure. Fun stuff.

    I am curious as to why some of the compounds don’t work. Is it a requirement to have some small crystals in there? Would 100% amorphous materials not work? Write those grants.

    1. hn says:

      Yes, you still need the tiny crystals. It’s still a crystallography experiment, just with electrons instead of X-rays.

    2. Gustavo Santiso-Quinones says:

      Dear John,
      I’m one of the ones involved in the paper from ACIE.
      Yes, you still need to have nano-crystallinity to see diffraction.
      The experiment runs in the exact way crystal structures are determined using X-rays, but instead we have used electrons.
      With regards,
      Dr. G. Santiso-Quinones
      Crystallise! AG (Switzerland)

  9. Anonymous says:

    I have obtained X-ray powder patterns of small molecules (but needed help from experts to try to interpret the data). I already knew the structures and just wanted info about the crystal packing. But this new tool looks amazing! I still have some old unknown side products (as powders) from reactions gone awry. Maybe MicroED can finally ID them …?

    1. Gustavo Santiso-Quinones says:

      Dear Anonymous,
      We call it Electron Diffraction (others call it Electon Crystallography) as it has nothing to do with Microscopy. The only reason why many people are still referring to it as EM is because you use (for the time being) and electron source which is embedded in an Electron Microscope.
      If we can be of help with your old samples, contact us.
      With regards
      Dr. G. Santiso-Quinones
      Crystallise! AG, Switzerland
      info@crystallise.ch

  10. Anon electrochemist says:

    You can drop a chiral crystal onto a grid and determine absolute configuration by microED as long as you put a couple nanocrystals of chiral reference material on the same grid. Anomalous dispersion doesn’t help you here, the usual answer was chiral cocrystallization.

    We bought one of these microscopes recently, all in was upwards of 30 million USD.

    1. Anon2 says:

      I’m not sure you need that high-end a scope. They used a Tecnai F30 – there’s a refurished one for sale for around $1M. The detector is maybe $1M more. So maybe $2.5M all up.

  11. Curious Skeptic says:

    Was any of the Chemrxiv authors a referee of the angewandte paper?

    1. Nat says:

      Beats me, but Tamir Gonen’s group has been working on MicroED for proteins for at least five years now; it was somewhat surprising that the Angewandte paper didn’t cite any of that work. (Which in turn suggests to me that those authors weren’t among the reviewers either, but who knows?)

  12. An Old Chemist says:

    Derek, For the past tens of years, I have been going to the C&E News site to learn about the ‘Highlights News”, “Most Popular”, and “Recent.” But, I have lately realized that you (your blog) beat them to the punch. I have come to become of the firm opinion that you should be considered for a “Pulitzer Prize”.

    1. Anon says:

      Failing C&ENews. It’s a joke.

  13. David Edwards says:

    Wonder if anyone will re-run Frondosin B through this new technique?

    1. Gustavo Santiso-Quinones says:

      Dear David,
      If you or anybody is interested in the crystal structure of Fromdosin B or any other nano-crystalline material, don’t hesitate to get in contact with us. We would have soon (in Switzerland) the possibility to offer Electron Diffraction as a service. In that sense, if we can help somehow with any kind of small molecule that needs crystallographic characterization, don’t hesitate to get in contact with us.
      With regards, one of the authors of the ACIE paper,
      Dr. Gustavo Santiso-Quinones
      Crystallise! AG (Swizterland)
      info@crystallise.ch (if needed for any inquiries)

      1. Chambers Hughes says:

        Dear Gustavo,

        How many euros will this cost me?

  14. KN says:

    There’s going to be a huge line of natural products soon enough, waiting to be determined/confirmed.

  15. ILoveMakonnen says:

    So if Angew had a better social media team, they would’ve got Twitter goin’ up on Tuesday, instead of Chemrxiv yesterday?

    1. AdV says:

      I suppose ACIE doesn’t tweet about accepted articles, but rather about published articles. I can imagine this to be quite unfortunate for the “Swiss/German team” – as they don’t get the attention and recognition they should get. I wonder if I am the only one curious about the timing of the two papers. It seems like the ACIE article pushed the “american collaboration” to submit/upload their paper on Chhemrxiv. If that should have been the case they should have mentioned and cited the ACIE article.

      1. Anonymous says:

        From Lemieux’s autobiography, his comments about his interactions with WS Johnson (too much to type, so edited down). RUL disclosed unpublished info to WSJ at a meeting. WSJ then forged the collaboration with RUL so as to AVOID trying to scoop RUL (on the L-J reaction). “A major reward of a career in science was the opp to come to know such fine people. This statement about WSJ is not characteristic of many scientists, even perhaps of the majority. … [strong language deleted] … To my mind, the best part of a scientific career is to talk about you have discovered when it is “hot” [and not have to worry about being scooped or ripped off] … I consider this a most precious freedom that must be defended at all times and with great vehemence, if necessary.”

        WSJ (1913-1995); RUL (1920-2000). Sic transit gloria mundi.

      2. Gustavo Santiso-Quinones says:

        Dear AdV,
        I’m one of the authors involved in the ACIE paper. The timing is something I can’t answer. What I can say is that this paper (the first version) was submitted to Science long time ago. Unfortunately it was rejected. Then it was submitted somewhere else without success too. Finally it got accepted in ACIE. If the timing of the two papers was a coincidence, who knows.
        But we were trying for almost half a year before to get this out.
        With regards,
        Dr. G. Santiso-Quinones

        1. AdV says:

          Hi Gustavo,
          thanks for clarifying the “history” of your ACIE paper. And also, congratulations on really exciting work!

          The question of timing is a question that only the authors of the preprint paper can answer. It is, however, obvious from the timestamps that the ACIE paper was online before the preprint was submitted.

          Do you mind asking me if you or any of your co-authors considered publishing a preprint of your article?

          Thanks!

        2. Some idiot says:

          Wow!!! I am astonished that it got rejected, not once, but twice!!! Are you allowed to give grounds for rejection? Just curious…

          To state the obvious, great work!!! Huge practical importance (again, stating the extremely obvious…). Well done!!!

          🙂

    2. Anonymous says:

      Tells you a lot about the times we live in. Promotion and PR>everything else

      1. anon says:

        I also was wondering that. Submitted the same day as the ACIE paper came out online!

  16. tangent says:

    > The authors will probably want to correct that line above to “data were” in the final version

    Okay if you’re taking time from mindblowing shit to go into the wording, I’m taking time from mindblowing shit to go into the wording! Let’s have a go at what grammarians call count nouns and mass nouns.

    I have *five* marbles, the marbles *are* made of tungsten carbide.
    I have *too much* xenon trioxide, this xenon trioxide *is* making me uneasy.

    One datum, two data, and those “two data are…”, if “datum” / “data” is a count noun, like “marble” / “marbles”. But often the usage is like “ketchup” (like “information”). The data is over a gigabyte, the data doesn’t have good provenance metadata. (Will a datum have a metadatum?)

    If I can point to one datum, cool, then “my data are”. But If I have no idea what an individual datum would even mean, it makes good grammatical sense to say “is”. Not going to push “is” on anybody, do what you like or what your local style is, peace out all y’all.

    (and don’t correct people’s “octopuses” to “octopi” plz)

    1. anon says:

      It’s octopodes

  17. Gustavo Santiso-Quinones says:

    Dear Derek,
    First I want to congratulate you and thank you for such a nice blog.
    I’m one of the authors pushing this technique (in Switzerland) to the limits. We have successfully analyzed nano-particles from an industrial inorganic sample which was never before fully characterized. We succeeded during this series of experiments. Unfortunately this results won’t be published until a patent is released.

    I wanted to answer some of your questions that you ask at the end of your blog:

    Yes, if you have evaporation of your solvent and your material remains as nano-crystalline, as long as you find one particle to irradiate, you will most probably get diffraction (within the limitations and other important aspects to consider).

    Absolute configuration confirmation (like in X-ray) is the golden goal. We are working on that and maybe it will be possible to have enough anomalous dispersion signal to confirm the absolute configuration. Though as far as I am aware (now), it is still not possible.

    Yes, you are right, what happens to compounds that could loose solvent and therefore loose their crystallinity? As this technique works only under high vacuum (< 10-^6) this is one of the problems encountered. Though we are working on the possibility to overcome such problems.

    With regards
    Dr. G. Santiso-Quinones
    Crystallise! AG (Swizterland)
    info@crystallise.ch (for any discussion, comments, requests, etc)

    1. Dionysius Rex says:

      Dear Gustavo,
      Can you remind me who you work for? I can’t seem to find this info anywhere!

  18. Haftime says:

    Very cool stuff, as the authors are commenting, could they explain how their paper is an improvement over last years Science paper on locating hydrogens with ED? I’d recommend reading the Angewandte paper because the ChemRxiv paper can be a little light on details and references and sometimes a bit confusing with their terminology. For example, the ChemRxiv paper talks a lot about amorphous materials, but everything they show has sharp Bragg peaks – i.e. is crystalline. If they’d solved *actually* amorphous materials then that would be something to really shout about!

  19. This is fabulous indeed! Does it mean the end of era of ‘classical’ X-ray?

  20. lynn says:

    Amazing!! or some other unprintable positive oath. Immediately thought of the GC trace from “Medicine Man” and how we laughed at the incredible and superfast determination of the structure of a complex natural product.

  21. Kejuan Muchita says:

    I’d also have plenty of typos if I found out I just got scooped and needed to submit something fast 🙂

    1. AdV says:

      So I wasn’t the only one with that thought 😉

  22. Filip says:

    While this is indeed fantastic stuff, these are definitely not the first examples of the structure solution of small organic molecules by electron diffraction. So these results don’t seem particularly novel, which might also explain the initial rejection(s) of the Angewandte paper.
    There’s even been a review, “Structural Characterization of Organics Using Manual and Automated Electron Diffraction”:
    https://www.tandfonline.com/doi/abs/10.1080/15583724.2010.494238
    Am I missing something important?

    1. Derek Lowe says:

      Oh, this isn’t the first time that electron diffraction has been used for structure. But what stands out here is the application to nanocrystals, which are far more common and easier to obtain than the large single crystals used in the past. That was the same thing that made MicroED such big news in protein crystallography in 2013.

  23. Anonymous says:

    I submit that nothing is as fun for an organic chemist as seeing pictures of their molecules. I started smiling about the paragraph on progesterone, and this news may keep me going through the weekend. Hotchy mama, what a world we live in! When do we get the iPhone app?

  24. Anonymous says:

    The new features in MicroED are that the goniometer/compustage is rotated continuously at a constant speed, the diffraction data is written out every few seconds and all the data can be processed using the software from X-ray crystallography.

  25. Prabin says:

    Thanks a lot Derek, digging out info about the MicroED. I used to try 30-40 different solvents to solvent mixtures to get a fine size crystal for x-ray but none worked. And still struggling to get crystal structure of a set of new molecules! This is awesome. Absolute awesome! Hope this is accessible soon.

  26. Some idiot says:

    This is going to make polymorph screening even more interesting/attractive… with each nanocrystal a crystal structure, and an optical image to identify crystal habit. Running a plate over a week or so to get a heap of structures and/or statistics on the structures is going to make one huge difference to crystal design work, and everything associated with it. The combination of IR and XRPD was good, but this is in a class of its own…! For that matter, I can see a whole new era of classical resolution based on this sort of tool. I’m not in that area anymore, but that huge amount of detailed knowledge, plus the ability to realistically develop statistics as well, could really start to nail down some of the hard stuff here…

    If I had X million in my pocket and otherwise a life of luxury in front of me, I would love to buy some of this kit and really get into it… Opens up a whole new way of getting good phase diagram data for polymorphs and solvates… The imagination (and money/gear…) is very clearly the only limiting factor…

  27. Noni Mausa says:

    Woohoo!!! * confetti! *. And I’m not even a chemist.

    Maybe this would be overkill, (shotgun for fruit flies) but I’m wondering if this technique would be useful for forensic purposes? Microscopic amounts of white powders in coat pockets, suspicious clays in boot treads, traces of dust from the Deserted Old Mines, etc etc?

  28. YZ says:

    Why nobody mentions the molecular imaging NC AFM which is also an advanced and fast-progressing technique and allows us to “see” small organic molecules directly? Am I wrong or missing something?

  29. Shazbot says:

    Was is correct, because the subject of the sentence isn’t ‘the data’. It’s ‘the ease’, which is singular.

    Now, I’ve got to get back to gawping. (And wondering why I didn’t think of it first.) And then work. Hot damn.

  30. Todd says:

    Well, someone is going to be in the conversation for a Nobel in about a decade or so. Goodness this is big news. Very impressive.

  31. 345 says:

    NMR and x-ray diffraction – were critical to take synthesis to a new height.

    This tool would have helped the field to further new heights had it not been the case that synthesis is dying in the hands of funding agencies/due to lack of funding than interest!

  32. Anon says:

    EJ Corey will still want melting point and IR.

  33. SSG says:

    Does this sound like end of the total synthesis era?

  34. anon says:

    More or less, one would guess! Now the bigger question to ponder – How about re-purposing that expertise and labs? What do they ought to do? What skills/areas do they need to learn stay active in the research? There should be some direction than closing the shutters on them!

    1. SSG says:

      No more Eribulins?

  35. anon says:

    The utility value seems to dictate the research these days. So, above comment is in light f the following sentiments/perils expressed by a Total Synthesis practitioner/ admirer:

    https://www.chemistryworld.com/news/chemistrys-toughest-total-synthesis-challenge-put-on-hold-by-lack-of-funds/8152.article

    “Does everything have to have an obvious utility? Was there an obvious utility to sending men to the moon? Is there obvious utility in the work produced by artists? These are all accomplishments that reflect upon the creativity and sheer tenacity of motivated, talented people. These are the the accomplishments that people look back to when measuring the contributions of generations. Many argue that money spent on such endeavors is wasted, and there are many more critical needs (feeding the poor, fixing the infrastructure, etc), but I firmly believe we can afford to do all these things if we truly want to. When you go to Europe (or other foreign countries) do you go to see and appreciate the art and architecture that reflects upon the ingenuity of man, or the more utilitarian investments into improvements of their roads and sewer systems?”

    So, what lies ahead?

    1. Medici-nal chemistry says:

      Adopt the Renaissance strategy and get bankrolled by rich patrons and the church.

  36. anon says:

    What would happen if Science/Nature (which I assume is where the authors would have decided to publish next) accepted Stoltz’s but rejected the Swiss/Germans’? Pretty much showing that if you have a big name, you can get anything accepted anywhere. Would Science/Nature now have to reject the paper on the basis that ACIE published it before them and it would also be insulting to the authors of the ACIE paper who worked on the same thing to see the same work accepted into Science/Nature? Just wondering how the ACIE authors would feel if that were to happen is all.

    1. Jon says:

      It’s been published in ACS Central Science
      https://pubs.acs.org/doi/10.1021/acscentsci.8b00760

  37. gippgig says:

    Does this really need high vacuum? A new extra-high resolution electron microscope (MAIA3) gets its extra-high resolution in part by operating at a lower vacuum (which bleeds off charge that would otherwise build up on the specimen and distort the image). Sounds like it might work here too. (There’s an article on this, Focused on the small things, in the May 2017 issue of, of all things. Aerospace America.)

    1. Post-Doc Panda says:

      MAIA3 is an FEG-SEM that peaks at 30kV. Both authors here (preprint and ACIE) used a TEM at 200 kV, and for that, you need the high vacuum. You’re not running an environmental mode on a TEM just yet…hence the whole cryo revolution to reduce beam damage.

      That’s not to say this technique couldn’t be modified for a lower power SEM in environmental mode, but there would be some technicalities to work out, beyond simply larger crystal sizes to compensate for the reduced power. You’d have to run STEM, but you’d think with some tweaking it should be possible.

  38. VICTOR GUALLAR says:

    Maybe it has been already mentioned (could not go over all comments), but when using crystals of small units, I would be quite worried about the artifacts from crystal contacts. We already see them all over the surface of larger units, but in small units the surer is quite the entire molecule. Thus, I would imagine that the conformations obtained in flexible small molecules “could” be quite biased, and not representative of the main structure in solution. I would rather believe some quantum chemistry model…

    1. Derek Lowe says:

      No one will be using these for conformations, though – it’s more for chemical identity, structure, and connectivity. This objection comes up a lot, and to synthetic organic chemists it always sounds like a non sequitar. We really have a lot of situations where we need to know what the compound is, where it has a hydroxy group, etc. Solution conformation is a problem for another day, and another technique.

      1. Victor Guallar says:

        Yes for that purpouse it can make an impact.

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