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Analytical Chemistry

Chiral Separations With Magnets. No, For Real.

Now here is something I didn’t expect: what may well be a completely new way to separate enantiomers, not based in any way on shape recognition versus another chiral substance.

[Quick background for those not in the field: a great many three-dimensional molecules can exist in right-handed and left-handed mirror-image forms (enantiomers), exactly like pairs of shoes. They have the property of “chirality”. When this happens with drug compounds, it’s generally the case that the two have different activities, because proteins in the body are chiral, too. Where that handedness comes from is a rather deep question. Separating enantiomers is generally done by using another chiral substance (making derivatives or salts of the parent compound or passing across a purification column loaded with some chiral solid phase].

There have been a number of proposals in this vein, although it’s a minefield of subtlety (and of irreproducible experiments). But there are some electromagnetic effects that are both theoretically feasible and experimentally real, and this new paper seems to be another one. The paper starts off, I should note, with a brief history on the intersection of chirality and magnetism, a topic that involved heavy hitters like Pasteur, Lord Kelvin, and Pierre Curie in its early days. During my own career, I well recall reports of chiral induction in magnetic fields that had to be retracted to much embarrassment, so it does take some bravery to venture into this area.

The authors, a multicenter team from Israel, the US, Germany, and Poland, are taking advantage of a phenomenon called chirality-induced spin selectivity (CISS). Simply put – and I’m not going to be able to put it at a much higher level – electron movement through molecules is affected by their chirality. And that means that charge distribution in two enantiomers has different spin polarization in each one. That led the group to wonder about the interaction of chiral molecules with perpendicularly-magnetized surfaces, which have been the subject of much research in thin-film “spintronic” applications. In theory, one enantiomer could be attracted to such a surface much more than the other, depending on the direction of the magnetic field.

And that’s just what happens. They picked a test helical polyalanine peptide and a gold-layered ferromagnet film (the gold is to protect it from oxidation, and the behavior of the exact peptide on gold layers had already been studied in other contexts). Attaching nanoparticles to the peptide (for visualization) and exposing these to the surface showed (by electron microscopy) a dramatic difference based on the direction of the perpendicular magnetic field. In one direction, the particles stick, and in the other they don’t. If the magnetization is in-plane (instead of perpendicular), there’s no difference, and there’s no difference if you’re applying an external magnetic field instead. It has to be a field associated with the thin layer, and it has to be in the right direction.

The group also prepared a 50/50 mix of D- and L-peptides, and this (as it should) shows no circular dichroism. But after multiple exposures to fresh magnetic surfaces, the solution was clearly enriched in one enantiomer, and began to show circular dichroism as expected, increasing with the number of exposures. They then set this up as a flow experiment, and the results were unmistakeable: flowing an an enantiomeric mixture of two peptides down an unmagnetized column gave the same racemic mixture out the other end. But when the surface was magnetized “perpendicular down”, they got a strong CD spectrum from the eluent, and when it was magnetized “perpendicular up”, they got the mirror-image CD spectrum: the other enantiomer. The D enantiomers interact with the down-magnetized surfaces and the L enantiomers with the up.

It’s not just peptides, either. A DNA oligomer was shown to bind to one magnetization and not the other, and the effect was reproduced with the single amino acid cysteine. In each case the kinetics are different for different sorts of molecules, different at various concentrations, and different between the enantiomers. The system thus has to be tuned for the best separation, but the effect is real across all of them. And that immediately suggests a whole new kind of chromatography:

The enantioselective interaction of chiral molecules with a magnetic substrate, presented in this article, provides a potentially generic chromatographic method for enantioseparation, which does not require a specific separating column. Because the observed effect depends on the electrical polarizability of the system (that is accompanied by spin polarization) and because this polarization depends on the global structure of the chiral molecule, the method described here may also allow the separation of chiral molecules from a mixture of molecules, either chiral or achiral. In addition, this technique could potentially be applied for separating chiral molecules based on their secondary structure and/or for separating two secondary structures of the same chiral molecule.

It would appear that a completely new analytical method has been invented, and I very much look forward to seeing what can be made out of it. We’re going to have to learn to think about chiral separations in a completely different way than we’re used to!

 

 

22 comments on “Chiral Separations With Magnets. No, For Real.”

  1. I wonder if I’m witnessing history that will be in textbooks in real time.

    *thinking*

    1. Rami says:

      And they will call it: Magnetoration 🙂
      Really impressive work!

  2. DLIB says:

    Finally a reason to save the magnetic disk drive industry 🙂 ( perpendicular magnetic anisotropy magnetic disk materials 🙂

  3. jb says:

    chiral NMR soon?

  4. Rhodium says:

    So does this mean life evolved either in the Northern or Southern Hemisphere depending on the magnetic field’s effects on L amino acids?

    1. CB says:

      I had the same thought too.

  5. Steve says:

    Does it need a large chiral helical molecule (DNA, proteins etc) to work in which case no use at all? Unless it can work on something molecular sized such an amino acid – though thermal effects would probably overwhelm any magnetic discrimination

    1. Magneto says:

      They did it with unadorned cysteine, so it looks like the answer is no.

  6. Some idiot says:

    Fascinating… Way kl be very interesting to see how this stuff pans out…! One of my main questions is as to how much you can “dilute” the chiral centre with the rest of an achiral molecule and still get a measurable/useful effect…

    This is going to be a good one to follow…!

    🙂

  7. Tom says:

    On reading this a bit more carefully, their separation seems to rely entirely on inducing a difference in the *kinetics* the adsorption of the chiral molecules onto the surface. All their examples involve sulphur-containing compounds adsorbing onto Au surfaces, with separation only possible for the non-equilibrium system (over long timescales, both enantiomers will absorb onto the surface equally).

    So, this technique seems generally applicable for any system involving:
    -A surface that can efficiently transport spins, which also shows
    -Reversible sorption of the chiral substrate (eg Au-S binding)
    along with the stated caveat that separation will depend strongly on the electrical polarisability of the substrate.

    I’m sure we’ll see all sorts of interest in chemically interacting spin-transporting surfaces if this kicks off, but an easy alternative would be to develop some of thiol containing auxiliary that could be easy added to/removed from a variety of different chiral substrates (and use it to tune the Au absorption kinetics to a useful rate).

    Cool stuff, and I’m looking forward to seeing where this goes!

  8. To me, CISS is equal parts fascinating and headache-inducing! The previous efforts were already pretty cool – my favourite probably being water oxidation with zero overpotential (see link in name for recent review). I’m excited to see what other applications people will come up with!

  9. Grimbo Trundleson says:

    What are the chances of this working in the context of a reaction. Say for example, you had a mixture of epimers but wanted the thermodynamically unfavoured one; if you could immobilise a suitably strong base onto the magnetic surface then flow your compound through ,could you funnel all the material to the desired epimer… – a sort of dynamic magnetic resolution 🙂

  10. BiotechFanatic says:

    On the point about chiral drug molecules having different activities because proteins are chiral…would it not be possible for chiral drug molecules to interact differently with macromolecules in cell even if the macromolecules were not chiral? E.g just different steric interactions

    1. kriggy says:

      No that is not possible. Chiral molecules are indistinguishable in achiral enviroment, that is why you cant differentiate enantiomers in RP-HPLC / NMR / MS or IR.

  11. Uncle Al says:

    (@BiotechFanatic: “pro-chiral,” then diastereomeric interaction.)

    A stranger enters a research area, gets the tour, and at the end says, “you can buy that.”

    http://brightspec.com/wp-content/uploads/2015/06/ProductFlier-Chirality-Nov2014-Press.pdf
    … You can buy that. Three crossed fields are chiral discriminant.

    If you want extreme optically resolved solid benzil or thalidomide, stir with some solvent or alkaline solution, respectively, Melt binapthyl, then slowly cool. Crystallize sodium chlorate absent stirring. There’s a footnote, but you do not get to choose which enantiomer.

    1. loupgarous says:

      Gawrsch, how embarrasking. Copyright date’s 2014, so someone’s got priority on getting electromagnetic resonance chiral analysis to work. Not magnetic, specifically, but it means there’s more than one string to that particular bow. Always nice to have more than one tool for a job.

  12. Former Chemist says:

    Magnets are stupid, they dont know right from left, except the right hand rule . Now if you add a catalyst of some kind, it is possible, this is a basic principle of NMR and Chromatography and not surprising. I learned how to used chiral additives with microscopic differences in megnetism/bond strength in 1st year chem college ( tartic acid can be precipitated with a chiral additive selectively ). Later, NM(magnetic)R traces of enatiomers could sometimes be observed as doublets. However, this is all immaterial. Why are we grasping at staws for some meaning in chemistry when biology is all that matters now?

  13. Billidy says:

    The only rule in biology is that there are no rules. –carl woese. I think this summarizes pretty well whats wrong with statements like…..” chiral separations from magnetism…no kidding”. Even quantum physics, king of reduction, ultimately said you cant know with the uncertainty principle. Give up.

  14. Barry says:

    Seems like the next experiment would be to try resolving cysteine on the gold surface, then homo-cysteine, then increasingly longer homologues to ask how far the chiral center can be from the S-Au bond affected (at this magnetic field strength)

  15. OligoMan says:

    very interesting and awesome finding. could be tried to separate PS-oligo into Rp and Sp isomers?? Should Wave Lifesciences be threatened by this technology?

  16. paul Belcher says:

    Fun story I once had a 5kg tub (from the 1960’s) of Pseudoephedrine in my Postdoc. After I had left (the lab closed suddenly), I had the DEA trying to find me (and the tub) concerned I gone breaking bad (and this was pre-breaking bad)….where in fact I was off getting married….fun times!

  17. Barry says:

    To make a new covalent bond, Pauli requires that the two electrons be paired, one up, one down. The implication is that a magnetic field–by aligning the spins of unpaired electrons–could slow the reaction of one radical with another. This would bias free-radical polymerizations towards higher mol. weight by impeding termination w/o impeding propagation.

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