Diastereomeric recrystallisation is a method of chiral resolution of enantiomers from a racemic mixture. It differs from asymmetric synthesis, which aims to produce a single enantiomer from the beginning, in that diastereomeric recrystallisation separates two enantiomers that have already mixed into a single solution. [1] The strategy of diastereomeric recrystallisation involves two steps. The first step is to convert the enantiomers into diastereomers by way of a chemical reaction. A mixture of enantiomers may contain two isomers of a molecule with one chiral center. After adding a second chiral center in a determined location, the two isomers are still different, but they are no longer mirror images of each other; rather, they become diastereomers.
In a prototypical example, a mixture of R and S enantiomers with one chiral center would become a mixture of (R,S) and (S,S) diastereomers. (The R-S notation is explained here.) The conversion of the enantiomeric mixture into a diastereomer pair, depending on the nature of the chemicals, can be via covalent bond formation with the enantiopure resolving agent, or by salt formation, the latter being particularly convenient since acid base chemistry is typically quite operationally simple and high yielding.[2]
The second step, once the diastereomers have formed, is to separate them using recrystallisation. This is possible because enantiomers have shared physical properties such as melting point and boiling point, but diastereomers have different chemical properties, so they can be separated like any two different molecules. It is these, now different, physical properties e.g. Melting point & Enthalpy of fusion which determine the eutectic composition (see Eutectic system) which correlates with the maximum yield of pure diastereomer in the crystallization (Rmax, see example melting point phase diagram of a diastereomeric system across all compositions in Figure 1). Various methods have been developed to screening diastereomeric resolutions by determining the eutectic composition as a means of ranking for yield efficiency.[3]
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Transcription
Today, we'll be talking about how to separate enantiomers from each other. Enantiomers are like your left and right hands. They are mirror images of each other, but they look almost identical. Remember that much like we use right and left to describe which hand is which, scientists use the letters S and R to designate which enantiomer is which, when you only have one chiral center. However, when you have multiple chiral centers, there are other ways of designating enantiomers. But we won't be getting into that today, because that's much more complicated. Here we have a set of enantiomers. This is the S confirmation of thalidomide, and here on the right is the R confirmation. Why does it matter that we have two different confirmations? Well, you can see the difference quite clearly at the chiral center, where one of the groups points into the screen and the other points out of the screen. And just because of the simple change in confirmation, that S version was found to lead to terrible birth defects when consumed by mothers. And because of this, drug companies now try to make sure that the active ingredient in their drug is only one particular enantiomer. So how would we go about separating these two? One technique that you could use is chiral column chromatography. You would need a stationary phase that is chiral, meaning something that will only bind either to the R confirmation or the S confirmation of your desired enantiomer. So how does the chiral stationary phase only bind to one of the enantiomers? Picture the two enantiomers as your right and left hand. If your right hand tries to shake another person's right hand it seems normal, the two fit together properly. But if your right hand tries to shake your own left hand, it doesn't seem like they line up quite right. That's the exact same thing that happens with the chiral stationary phase and the wrong enantiomer. Next, what you do is you'd load that mixture of enantiomers. So on top here, you might see that you have some kind of band of your mixture. This is racemic, meaning that it has a 50/50 mixture of enantiomers. So that's what you're seeing here in the yellow. If we take a closer look, you'll see that this has some of the S confirmation and some of the R confirmation too thrown in. And as this moves through the stationary phase, so once you open up the stop cock, what you'll see is that if the R enantiomer was the one that binds tightly to the stationary phase, it won't move very quickly. But with the S enantiomer, it might be racing through since it's not really interacting that much with the stationary phase, and prefers to interact with the mobile phase. Once you've collected all of the S enantiomers in your flask, all you'll have left in the column is the R enantiomer, which is pretty tightly bound to the chiral stationary phase. Next, what you'd do is when you have this column, you'd want to pour in lots of solvent so that you can get the R enantiomer to come out. Because as this pushes down through the column, it will take the R enantiomer with it, giving you just the R enantiomer in your flask. And there you've done a successful chiral resolution. The same principle can also be applied to gas chromatography. Let's quickly review how gas chromatography works. You insert your sample in here, a gas flows through, and then it goes into this long to that contains the stationary phase and mobile phase, and goes to the detector. And if we were to zoom in on this-- and draw this just kind of a long tube-- again what you'd see is that if this time the stationary phase was attracted to the S enantiomer instead, you'd see that the S enantiomer is sticking to the sides, sticking to the stationary phase, while the R enantiomer races through with the mobile phase. So there are actually a number of other ways you can separate enantiomers, but those tend to be much more complicated. These are just two of the common ways you can do it. And in both of them, whether you're doing column chromatography with a solid stationary phase or gas chromatography was a liquid stationary phase, the important thing to remember is that your stationary phase should be chiral and bind to the enantiomer that you want.
References
- ^ Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates and Resolutions; Wiley and Sons: New York, 1981; ISBN 978-0471080589; doi:10.1002/bbpc.198200035
- ^ CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation, Edited by David Kozma, ISBN 978-0849300196
- ^ DSC Methods (a) Kozma, D.; Pokol, G.; Acs, M. J. Chem. Soc. Perkin Trans. 1992, 2,435. (b) Madarasz, J.; Kozma, D.; Pokol, G.; Acs, M.; Fogassy, E. J. Therm. Anal. 1994, 42, 877. (c) Ariaans, J. A.; Bruggink, A.; Ebbers, E.; Zwanenburg, B. Tetrahedron Asymmetry 1998, 9, 2745. (d) Dyer, U. C.; Henderson, D. A.; Mitchell, M. B. Org. Process Res. Dev. 1999, 3, 161.
This page was last edited on 30 January 2023, at 15:13