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Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: spankytank on April 23, 2018, 12:39:32 PM

Title: Recrystallization in non-chiral solution to improve enantiomeric excess
Post by: spankytank on April 23, 2018, 12:39:32 PM
In the synthesis of (R)-rolipram a chiral intermediate (see attached structure) was recrystallized in hexane:TBME (4:1) to improve the enantiomeric excess from 94 - >99%. How is this possible?

( https://pubs.acs.org/doi/pdf/10.1021/ol800108u the article in question)
Title: Re: Recrystallization in non-chiral solution to improve enantiomeric excess
Post by: Babcock_Hall on April 23, 2018, 02:21:49 PM
According to forum rules, you should supply an answer or give your thoughts first.  It might be helpful to think in terms of solubility.
Title: Re: Recrystallization in non-chiral solution to improve enantiomeric excess
Post by: spankytank on April 23, 2018, 02:56:19 PM
Oh, my bad.
The physical properties of enantiomers are identical, so I wouldnt think it was  possible to separate them by a simple recrystallization. I thought the only way to separate enantiomeres by recrystallization was via diastereomeric recrystallization, but in the procedure described by Hynes et al. the enantiomers was not converted to diastereomeres (which can be separated by solubility).
Title: Re: Recrystallization in non-chiral solution to improve enantiomeric excess
Post by: Babcock_Hall on April 23, 2018, 03:32:14 PM
Just looking this over in a cursory fashion, I think that it is important that they started with one enantiomer already in excess, but the theory is unfamiliar to me.
Title: Re: Recrystallization in non-chiral solution to improve enantiomeric excess
Post by: clarkstill on April 24, 2018, 03:21:18 AM
The lattice energy of a racemic crystal is different from that of a enantiopure one (since the packing is necessarily completely different - racemates must have a centrosymmetric point group while enantiopure compounds must not). So if you have a scalemic mixture and carry out a recrystallization, there are 2 ways this can be used to improve ee:
 
i) the racemate crystallizes preferentially, leaving the mother liquor enriched in the original major enantiomer;
ii) the enantiopure form crystallizes preferentially. Since one enantiomer was originally in excess, it reaches its saturation point before the minor enantiomer so will form crystals first - so the major enantiomer is collected as crystals while the ee of the mother liquor is degraded.
Title: Re: Recrystallization in non-chiral solution to improve enantiomeric excess
Post by: Enthalpy on April 24, 2018, 04:50:43 AM
Would the published figures suffice to choose between methods i) and ii)?

Prior to recrystallization, there is 0.94 of the major enantiomer and 0.06 of the minor.

After, 0.91 (0.87/0.96) of the previous step remain and contain 0.90 of the major and 0.01 of the minor. So 0.05 of the minor was removed while losing only 0.04 of the major.

If an accurate 50/50 recrystallization happens despite the solution is strongly mismatched, then the figures are too close to call. But if the solution mismatch spoils the 50/50, then the recrystallization must operate instead by adding preferentially the major form on itself.
Title: Re: Recrystallization in non-chiral solution to improve enantiomeric excess
Post by: pgk on April 24, 2018, 11:33:24 AM
Additionally, take a look to the publications, below that refer on whether chiral solvents favor or not the selective crystallization of enantiomers.
https://pubs.acs.org/doi/abs/10.1021/cg800356v
https://pubs.acs.org/doi/abs/10.1021/cg801286s


Title: Re: Recrystallization in non-chiral solution to improve enantiomeric excess
Post by: Babcock_Hall on April 24, 2018, 03:22:12 PM
These might be somewhat helpful:

https://onlinelibrary.wiley.com/doi/pdf/10.1002/chir.20327
"Application of Preferential Crystallization to Resolve Racemic Compounds in a Hybrid Process" CHIRALITY 18:828–840 (2006)

https://pubs.acs.org/doi/pdf/10.1021/op700239a
"Enantioenrichment by Crystallization" Organic Process Research & Development 2008, 12, 282–290
Title: Re: Recrystallization in non-chiral solution to improve enantiomeric excess
Post by: kriggy on May 05, 2018, 10:18:55 AM
Thanks for the papers btw. Gonna read them soon-ish. I did struggle with resolution year ago and its looking like Im gonna have to do it again