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Analytical Chemistry

Crystals and Their Weirdness

Let’s talk crystals for a few minutes. Those of us (like me) who are familiar with chemistry and biology, but who are not crystallographers themselves, will know the broad outlines of X-ray crystallography, and can appreciate its extension to diffracting electrons instead of X-rays. But there are a lot of odd and subtle things that creep into the topic of crystal structure when you look closely, and the better these techniques get, the closer we’re able to look. Several new papers illustrate these, in various ways.

For one thing, how do crystals form, anyway? At some point several molecules (or individual atoms, if it’s that sort of crystal) have to come together in the orderly arrangement that will end up repeating throughout the whole bulk crystal, and start attracting other members from nearby to join the new gathering. This commentary in Nature has some illustrations of the standard model by which this has been thought to happen (at least in many cases): “classical nucleation theory”, which is pretty much what I just described. That is, a very tiny replica of the bulk crystal forms, maybe only a few molecules wide but having the same intrinsic lineup as will repeat in the bulk crystal, and molecules come in from the surrounding solution and arrange themselves on the newly developing surfaces in turn. And that actually is how many crystals form (although it’s already been obvious for some time that deviations from CNT happen a lot under real-world conditions).

This new paper has some painstaking observations in a metal alloy system (iron and platinum) at an unprecedented level of detail, achieved not via diffraction methods, but via atomic electron tomography. Electron tomography (inferring the shape of very small particles via the scattering of an electron beam) is how cryo-EM protein structures are produced, and with the powerful scattering of the heavier elements you can get such data all the way down to particles only a few atoms wide. This new work watches as disordered nanoparticles of Fe/Pt take on the tetragonal crystalline lattice known for this alloy in the bulk phase, and they’re able to follow both the shapes of the individual atom clusters and their evolution over time. The result is. . .well, it’s pretty complicated down there. The early stage nuclei have all sorts of different irregular shapes, for one thing. The very center of these things have the closest fit to the tetragonal structure, but they’re much more fuzzy and variable just outside that – it’s definitely not the orderly stack-up of classical theory. These nuclei vary over a pretty wide size distribution as well, and they’re neither spherical nor tetragonal themselves, which you’d have expected to be the low-energy shapes. These alloy crystals all end up in the same place (a nice tetragonal lattice), but they sure get there through all sorts of pathways.

So there’s one. A couple of other recent papers take on crystal structures of what are actually rather small and simple molecules, but whose crystal forms have been giving people fits for years. One of this is orthocetamol, a structural isomer of the familiar drug paracetamol (known as acetaminophen in the US, Canada, and Japan). This ortho-substituted isomer has been known since 1876 (discovered even before X-rays were!), and it forms what appear to be nice square-shaped crystals (see at right). But experienced small-molecule crystal types would already have been giving that first photo the fish-eye, because those things, while most certainly crystalline, don’t quite look like they’re full of perfect right angles. Sure enough, as you zoom in, what you find is that they’re actually conglomerates of far smaller crystals, and these individual pieces are too small for conventional X-ray crystallography to deal with. If you try to shoot the larger bunches, you get data that can’t be refined to anything useful.

Enter micro-electron diffraction. That’s rapidly turning into the default answer when someone says “My crystals are too small”, and so it proves here, providing what appears to be the first micro-ED-based structure of a small molecule that has been resistant to X-ray techniques. Gently crushing some of those crystals and scattering the pieces across an EM grid allows for data collection on a whole range of pieces, and many of them are tractable (although the authors note, alarmingly, that even pieces less than a micrometer wide showed evidence of inhomogeneity in the diffraction patterns). The data looked sort of like a tetragonal unit cell (which is what you’d have guessed from square crystals), but never really settled into a good one, thanks to plenty of stacking disorder and twinning even on the nanoscale. Dropping down to monoclinic symmetry (a classic move in such situations) allowed for a direct-methods solution, which that was backed up strongly by X-ray powder diffraction and Rietveld refinement – powder diffraction data are very useful for such microcrystalline substances, as you’d imagine.

What you get are infinite ribbons of nearly flat orthocetamol molecules, hydrogen-bonded between the acid of one and the phenol of another. There are a lot of ways that the arrangement can go subtly off – there’s twinning on the scale of about 150nM, for one thing, and the flatness of the molecules (and lack of the some of the intramolecular interactions seen in the other isomers) give them a chance slide around a bit while still maintaining a solid crystalline form. It’s remarkable that there are so many defects and variations in something that is, at first glance, a perfectly reasonable crystalline solid.

And here’s another paper on the crystal structure of a common drug, hydrochlorothiazide. It has more than one crystal form, and one of them look like the photo at left – a sort of two-winged symmetric form. Separation of these “wings” and individual X-ray analysis shows that (weirdly) they are each made up of a single pure enantiomer, and one of the weird things is that you have to stare at hydrochlorothiazide’s structure for a while before you can even see how it could be chiral at all. The sultam nitrogen is nonplanar, and its ring can adopt two different conformations. That and a bond-rotation of the sulfonamide group give you two mirror-image structures, and there they are as two wings of a crystalline butterfly. In solution, the two enantiomers seem to interconvert pretty rapidly, though, so you always have a racemic mixture when the compound is dissolved. It’s remarkable that no one has ever realized this before.

Having a racemic mixture crystallize out that way is pretty odd, too. Most of the time you get racemic crystals, 1:1 mixtures on a molecular scale of each mirror-image enantiomer. More rarely, you get separate crystals of each enantiomer (as happened, famously, with tartaric acid when Pasteur investigated it and performed the first chiral resolution). But seeing the two enantiomeric crystals form along a common surface like this – that’s weird. There seems to be only one other example known, hydrobenzoin. The authors believe that this happens as the crystals try to deal with the electric dipole field that forms as things start to line up – having the two “wings” like this allows the dipole to cancel out. It’s thought that some crystal formation routes in general actually end up being unstable due to “uncancellable” dipole charges building up.

But then, there are a lot of ways to build a crystal, and if you’d like to explore those, this recent JACS article will send you to the appropriate literature. There’s a lot to the ordered solid state of matter, a lot that we don’t understand, and a lot to explore. . .


13 comments on “Crystals and Their Weirdness”

  1. Anon says:

    Derek…it is diffracting electrons and not diffracting elections as you write up (3rd line from the top). Thinking of 2020?

    1. Derek Lowe says:

      Geez. Yeah, that’s my fingers completing things on their own!

      1. Polynices says:

        I thought maybe the headline was going to refer in some way to Marianne Williamson so maybe pretend you meant to type elections?

  2. Eugene says:

    First Russian interference now diffracting elections. Whats next?

    1. Hap says:

      Both? “The Russians are sapping the strength of our nation, its precious electrons!”

  3. anon the II says:

    When my wife was in high school, she took one of those skills test that tells you what you’d be most qualified for in life. Her best match was for a “packaging engineer”. She eventually became a crystallographer (brevetoxin B, okadaic acid, et al). It all makes sense now.

  4. Rakesh Arul says:

    Hi Derek! Fantastic article again!
    Just a clarification:
    “twinning on the scale of about 150nM” did you mean “150 nm” as in the nanometre length scale instead of the nanomolar concentration unit?

  5. Barry says:

    two molecules of water can’t form ice
    at best, they share a single hydrogen
    no less than five could possibly suffice
    to sketch the unit right tetrahedron
    thereafter, each incomer’s free to dock
    if its kinetic energy’s alright
    forsaking role as gas for role as rock
    to claim a free coordination site
    six vertices in six directions grow
    each independently hews to the norm
    as building blocks march outwards, row by row
    defining a new snowflake’s starry form
    reductionism picks a thing apart
    to grasp it by the method of Descartes

  6. Paul A van den Bergen says:

    Oh, seeing discussions like this makes me hark for a different career path…

    I studied Materials Engineering right around the time nano-materials and STM first became an thing, so I remember a lot of this stuff with fondness…

    For example, the description above of how crystals grow is talked about in materials engineering terms as nucleation and growth. Nuclei need to be bigger than a certain radius or the energy released from crystallizing is less than the energy required to make new “surface”. “New surface” is that slightly ordered interface between the (mostly) disordered bulk and the (somewhat more) ordered “crystal”. Entropy versus Enthalpy.

    Aside: Talking about crystals is really talking about states of order and entropy, and it’s a bit less cut and dried than folks often like to pretend – Glasses laugh at your notions of crystalline states… and it is much worse in macro-molecules and waxes than in classical crystalline systems… the language lets one down…

    The reason I mentioned STM above is because at the same time I was learning about nucleation and growth I read about the surface of gold forming planar 5-fold symmetry crystals only a few atoms thick due to “surface tension” – fundamentally it’s the same phenomena – there is an imbalance between the forces on the molecules on one side where it’s highly ordered and on the other where it’s not…

  7. willie gluck says:

    Link to “And here’s another paper on the crystal structure of a common drug, hydrochlorothiazide.” ?

  8. Partha Pratim Das says:

    Hi Derek,
    Nice overview, but i need to correct the history on ED a bit. Collecting 3D data by Electron diffraction is proposed by Ute Kolb in 2007 known as Electron Diffraction Tomography, there are many work/many papers on this (structures solved from previously known and unknown system). A slight modification of the original technique (continuous rotation of the crystal instead of step-wise) was proposed by three groups J. P. Abrahams et al, T. Gonen et al, M. Gemmi et al in 2013-2015 and one of group calls it as Micro-ED. There are many published work from different groups either by rotating the crystal stepwise or continuously , but unfortunately in recent years some authors have forgot to acknowledge the work done previously.

  9. P says:

    To be more precise Orthocetamol structure have been solved by electron diffraction tomography combining beam precession with stepwise crystal tilt, same technique (automated electron diffraction tomography) as proposed by Ute Kolb back in 2007.

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