The metal-oxide framework can be used to cage molecules, such as cyclohexanone, to obtain crystal structures © NPG
X-ray crystallography has
shaped modern chemistry.
It is arguably the most powerful tool for molecular structural
analysis. But it suffers from one big drawback: it can only analyse
materials that form well-defined crystals. This may now be about to
change. Researchers in Japan have used
‘crystal sponges’ to hold molecules that can’t be crystallised, allowing them to be analysed using x-ray crystallography.
For
chemists, trying and failing to crystallise compounds can be a
frustrating task. Yasuhide Inokuma’s experience was no different. So, in
2010, Inokuma and colleagues at the University of Tokyo
came up with a solution.
With the help of metal atoms and organic ligands they built molecular
cages, more commonly known as metal-organic framework (MOF), to trap
fullerenes and analyse their structure using single crystal diffraction
(SCD), a type of x-ray crystallography.
Now, they have gone a step
further and tuned the molecular cages to enable SCD of all sorts of
compounds, even those that are liquid at room temperature. Remarkably,
this can be done with less than 0.1µg of the compound.
Inokuma and colleagues built the molecular cage using either
cobalt(II) thiocyanate or
zinc(II) iodide with
tris(4-pyridyl)- 1,3,5-triazine
to form an octahedral cage. The target molecule can be caged by dipping
a single crystal of the MOF into a solution of it. Once inside the MOF,
the target molecule settles into the most thermodynamically stable
orientation. This is key, because SCD only works when molecules are held
in the same orientation to allow the x-rays to scatter in a reliable
manner.
Parsimony for stereochemistry
In their initial attempts they were able to successfully trap
cyclohexanone and
isoprene, both liquids at room temperature, and analyse their structures. Next they took up the challenge of analysing the structure of
miyakosyne A,
a long chain marine natural product. With only 5µg to hand, they were
not only able to nail down its structure, but also determined the
absolute stereochemistry of its hydroxy groups.
Tiny amounts of complex natural products, such as miyakosyne A, can be analysed using the new technique © NPG
There
are limitations, however. Inokuma admits that ‘data from pure single
crystals, that is without using molecular cages, are usually better than
our method, which is to say that bond length and angle are more
reliable’. But for the many compounds that do not crystallise at all,
this method is still good enough to obtain their structure, especially
when used in conjunction with standard tools like NMR and mass
spectroscopy.
In recent years, combining separation with analysis –
LC–MS, for instance – has proven invaluable for chemists. Inokuma and
colleagues envisage LC–SCD, combining liquid chromatography with single
crystal diffraction to create a powerful new analytical tool.
They’ve
already trialled their LC–SCD technique on dried orange peel. The peel
extract was run through an HPLC machine, with each compound delivered
into a vial containing a single crystal of the molecular cage. The team
were then able to get good structural data on the peel molecules.
The revolution will not be crystallised
So, could Inokuma’s method revolutionise x-ray crystallography? ‘It certainly could,’ says
Richard Cooper,
head of chemical crystallography at the University of Oxford, UK.
‘There will, as ever, be caveats and exceptions, but this certainly
pushes the envelope of what can be studied by SCD in the right
direction.’
But
Amber Thompson,
another crystallographer at Oxford, is less enthused. ‘The key is
matching the size and surface properties of the cavity with the target
molecule,’ she says. Thus, if the cavity is too big the target molecule
will ‘flop’ about rendering the analysis useless. If it is too small the
target molecule may not fit in the cavity.
Inokuma admits that
very large molecules, such as proteins, can’t currently be analysed. ‘We
have to work to make our method more versatile,’ he says. ‘But we hope
that in five years our method will be standard protocol.
27 March 2013Akshat Rathi