[3dem] MicroED on small molecule

[Tim Gruene]

On Thu, 15 Jan 2026 18:37:05 +0000
"Yu, Xiaodi \[JRDUS\] via 3dem" <3dem at ncmir.ucsd.edu> wrote:

> Hi everyone,
> 
> I’d like to consult MicroED experts about a small‑molecule sample:
> the powder contains diffracting microcrystals, but they stick
> together and make data collection difficult. Does anyone have
> recommended approaches or tips to prevent clumping and improve data
> collection?
> 
> Thanks in advance,
> Xiaodi
> 

Dear Xiaodi,

my experience is slightly different from Takanori's. We put a lot of
effort in sample preparation, so as to get as good data as possible
rather than leaving it to the software to deconvolute multiple
lattices. No matter how good the software (even talking SAINT/TWINABS
;-), a dataset from multiple lattices is hardly ever as good as a single
crystal dataset.

Our goal is a sufficiently dilute crystal density on the grid so to
have isolated particles. Like Takanori, match the beam diameter to the
crystal size. For organic and metalorganic samples, this can be 2-3um
in diameter. Smaller diameter is a greater challenge for how good you
can centre the crystal and the stability of the rotation axis.

My personal favourite is a suspension, because it is reproducible. The
liquid must match two requirements:
- it evaporates
- it does not modify the crystal structure

In suspension, we either vortex the sample, or place it in a sonication
bath. This can be up to several minutes, depending on how strongly they
stick. The lab record for a zeolite was about 1-2 hourse.

n-hexane is a good candidate to start, but also isopropanol, MeOH,
EtOH. You can check water, too.

Sometimes particles stick together while you watch the solvent
evaporate. To reduce their time of socialization, you can either dip
the grid vertically to the suspension surface.

Or you add a drop to the grid and suck off the supernatant from
underneath: lacey carbon makes a great sieve for crystals.

By creating a dilution series, we typically get to the ideal density
with 3-5 trials.

Good luck!

Tim

P.S.: in Europe, there is a great number of installation of electron
diffractometers (more than a dozen at least), and the Bruker mailing
list or the CCP4bb may also be great resources for crystallographic
questions. Crystallography is not an imaging techniques, while
TEM is.

-- 
--
Tim Gruene
Head of the Core Facility Crystal Structure Analysis
Faculty of Chemistry
University of Vienna

Phone: +43-1-4277-70202

https://ccsa.univie.ac.at

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