Assigning enantiomers (mirror-image isomers of a compound, for the non-organic-chemists in the crowd) can be a pain. By definition, no non-chiral technique can tell the difference between such things, and many of the chiral techniques will just tell you that they’re different, but not which one is which. Take, for example, chiral chromatography, in its various forms. You can often get a very nice separation and resolve a racemic mixture into two peaks, but you will have no idea what the absolute stereochemistry of each compound might be. In the drug labs, you’ll see these things labeled as “A” and “B” enantiomers, with the absolute assignment to be determined later. This language makes it all the way to the patents, with notations of “single unassigned enantiomer” and the like.
There are plenty of ways to, uh, resolve this situation, but none of them are completely general. If you can make a derivative of your compound with a chiral reagent, that’ll do the job if it crystallizes and you can get an X-ray structure. All the relative stereochemistries will become clear, and you can work back from the one that you know for sure in the group you’ve added on. “Mosher’s esters” are an example of this technique – those will often crystallize, but you can also read out the absolute chirality from the NMR spectra. The problem is that the group you’re derivatizing really needs to be pretty close to the enantiomeric center for this to work well – if you’re making Mosher esters of some alcohol way off on the other side of the molecule, you may well not see enough of a difference in the NMR to help you out much.
This new paper from Clemson suggests another technique: turn your alcohol into a sulfate (by reaction with sulfur trioxide/pyridine) and crystallize it with a guanidinium counterion. The sulfur atom is large enough for commonly available X-ray diffractometers to use anomalous dispersion to assign the chirality of the salt directly, and the sulfate/guanidinium combination has already been demonstated to be well-suited for growing crystals. It forms plenty of strong hydrogen bonds in all directions, which is just want you want for making the ordered solid phase thermodynamically appealing.
The paper demonstrates this technique on 17 test cases (16 alcohols and an amine, 1-phenethylamine). The chiral center doesn’t have to be right on the OH or NH2-bearing carbon, and the X-ray diffraction data seem robust. If you need to get your compound back, the sulfate hydrolyzes off readily. The paper does these on the tens-of-milligram scale for in-house X-ray equipment, but you could surely get away with less if you have synchrotron time. Overall it looks like a handy method, and we need all of those we can get for this problem.
Of course, if your molecule doesn’t have an OH or NH2 handle, you’re back to square one. The general solution to the which-enantiomer situation remains elusive!