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How to ensure, that X-ray crystallography structure analysis was done right to provide correct, non-mirrored atomic coordinates?

Example: Following Wikipedia image,

enter image description here

is generated from data taken from the article Redetermination of (+)-methamphetamine hydro­chloride at 90 K.

However, the structure presented by the CIF file represents (R)-methamphetamine, known to be levomethamphetamine, (–)-methamphetamine,

Fig.2 (R)-methamphetamine

the enantiomer of “native” methamphetamine, dextromethamphetamine, (+)-methamphetamine, identified as (S)-methamphetamine.

Fig.2 (S)-methamphetamine

Also, the article does not claim that the absolute configuration of (dextro)methamphetamine has been for so long mistaken and that they come with revolutionary discovery, rather are just focusing on some inter-atomic distances. (Also the “traditional absolute configuration” has been verified e.g. by synthesis from D-phenylalanine.)

As far as I have known, X-ray structure analysis was unable to provide absolute configuration info. But technology evolves. Can one determine from the experimental data, that it's supposed to be “absolute” or “relative” only (so that the coordinates presented can be mirrored)?

UPDATE: After some comments, I should emphasize that the example is just for an example (of case where the reported coordinates seem to be mirrored; I don’t know how rare or common it is), but can be used as an example in the answer as well, of course (e.g. CIF file analysis, e.g. explaining the Flack parameter value meaning, …)

And a subquestion: When hydrogen positions are provided, does it imply that the configuration is absolute? (I presume that the coordinates can still be mirrored even in such case; I mean “uncertain z-coordinate orientation”.)

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    $\begingroup$ X-ray does provide absolute configuration info. It is just that with Mo radiation and light-atom structure it won't be reliable enough. $\endgroup$
    – Ivan Neretin
    Commented Nov 12, 2018 at 13:23
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    $\begingroup$ As Ivan Neretin comments x-ray diffraction is the definitive method to obtain structure. However, x-rays are scattered off the electrons in an atom and this makes it very difficult to detect H atoms, and hence your question. Neutron diffraction could be used instead. $\endgroup$
    – porphyrin
    Commented Nov 13, 2018 at 8:38
  • $\begingroup$ @porphyrin Hydrogen positions are irrelevant to the configuration determination, as the other substituents are carbon and nitrogen based. (Also in the formula there are no hydrogens, yet it’s stereochemically unambiguous ;) ) $\endgroup$
    – mykhal
    Commented Nov 13, 2018 at 8:42
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    $\begingroup$ Ah yes, I mis-read the last two line structures. In that case as long as you have pure crystalline substances x-ray diffraction should be the technique to use. $\endgroup$
    – porphyrin
    Commented Nov 13, 2018 at 13:59
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    $\begingroup$ In the linked crystal structure all atom positions (including hydrogen) have been refined, there is no doubt that the measured compound is (R)-N-methyl-1-phenylpropan-2-amine.What they were sold for measuring the compound is another question; "The material for this work was purchased from Sigma-Aldrich and was used without any further purification." They did not specify they how they assigned (+), so I'd guess that was on the label. I don't really understand what the question is; obviously you cannot ensure that the people did their jobs right without checking the raw data. $\endgroup$
    – Martin - マーチン ♦
    Commented Nov 14, 2018 at 14:18

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As far as I have known, X-ray structure analysis was unable to provide absolute configuration info.

Routine X-ray structure analysis might not, but there are ways to determine absolute configurations from X-ray data.

The reason that routine X-ray structure analysis does not distinguish between enantiomers is that diffraction intensities show inversion symmetry, or obey Fridel's law. If you rotate the crystal by 180 degrees, you expect the same diffraction image. The phases, however, will be distinct.

enter image description here

Friedel's law breaks down for anomalous diffraction, which occurs when the wavelength of the X-rays is close to the absorption edge of one of the atoms in the structure. This has been used in protein crystallography to find positions of selenium for seleno-methionine derivatized proteins (MAD and SAD phasing methods). However, as Ivan mentions in the comments, the elements present in this molecule would not be near their absorption edges in a standard lab experiment using Mo-radiation.

When hydrogen positions are provided, does it imply that the configuration is absolute?

No, that just indicates that the resolution was sufficiently high to model hydrogen atoms. You can have ultra high resolution without resolving absolute configuration.

How to ensure, that X-ray crystallography structure analysis was done right to provide correct, non-mirrored atomic coordinates?

In a standard experiment, where Friedel mates are averaged, both given coordinates and their mirror image are valid solutions that fit to the diffraction experiment.

If you look at the diffraction data (CIF file), they did not measure anomalous data. The headings are "h,k,l, Fc-squared, Fo-squared, sigma(Fo-squared) and status flag".

Finding the absolute configuration

From classical to cutting edge, here are some strategies:

  1. Derivatize the sample with a chiral substance of known configuration: In this case, you could make an amide with lactic acid purified from a biological sample. You will get a diastereomer, and the lactic acid will tell you the absolute configuration.

  2. Use anomolous diffraction, i.e. choose a wavelength close to an absorption edge of nitrogen or carbon, which would be tricky. Other elements are more suitable because they show a larger effect, and at wavelengths that are easier to handle.

  3. Measure the phases. Using a free electron laser or a triple-beam experiment, measure some or all phases of the diffraction intensities.

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