phlogiston
International Hazard
Posts: 1376
Registered: 26-4-2008
Location: Neon Thorium Erbium Lanthanum Neodymium Sulphur
Member Is Offline
Mood: pyrophoric
|
|
How to improve the chiral purity of my reagent?
I have a chiral derivatization agent that I regularly need to use to resolve chiral compounds on HPLC.
The chiral purity of the reagent itself is critical for my needs. Previous batches of this commercially available reagent had always been perfect, but
my supplier discontinued this product and I am now forced to use an alternative supplier, the only one left selling it. Unfortunately, I purchased a
relatively large amount (3 grams), at significant cost, that turns out to be much less (unacceptably) pure. My analysis indicates the reagent, called
(S)-NIFE, contains about 0.5% of the R-isomer, and I would need at the very least <0.05% R-isomer, but ideally undetectable amounts of R-isomer,
which means <0.0002% with my current limits of detection (and previous commercial batches were actually that pure).
Now the quesion I have is this: what would probably be the best way to purify the 3 gram batch of impure reagent? I have access to a properly equipped
lab.
I am considering recrystalization from a simple (non chiral) organic solvent. Probably ethanol or acetontrile. Bad/good/useless idea?
[Edited on 15-10-2011 by phlogiston]
-----
"If a rocket goes up, who cares where it comes down, that's not my concern said Wernher von Braun" - Tom Lehrer |
|
|
Nicodem
Super Moderator
Posts: 4230
Registered: 28-12-2004
Member Is Offline
Mood: No Mood
|
|
Quote: Originally posted by phlogiston  | | I am considering recrystalization from a simple (non chiral) organic solvent. Probably ethanol or acetontrile. Bad/good/useless idea?
|
Yes, a single recrystallization of compounds with ee > 90% can commonly give practically enantiomericaly pure products (ee > 99%). Given your
starting ee is 99%, I would consider it probable, that with a properly conducted recrystallization, you would get an ee above the desired 99.9%. So,
what you should do is to first check on Beilstein (or Reaxys) what solvent is used for this purpose and then use that, possibly under the same mL/g
ratio used in the published example. Don't waste time reinventing the wheel and trying out solvents on a trial/error basis, because it would be stupid
given the terrifying price of the reagent. Especially, don't try to use protic or otherwise nucleophilic reagents - if you check the structure of the
reagent you can see that it is strongly electrophilic, so it will react with solvents such as ethanol, to give the corresponding ethyl carbamate! (the
institution that paid for the reagent surely would not be happy finding out how stupidly the reagent was destroyed by its employee!)
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
|
|
|
phlogiston
International Hazard
Posts: 1376
Registered: 26-4-2008
Location: Neon Thorium Erbium Lanthanum Neodymium Sulphur
Member Is Offline
Mood: pyrophoric
|
|
Thanks for your advice. It is annoyingly expensive indeed, but it would have been worth the money had it been nice and pure.
Indeed, I also suspected that nucleophylic solvents would react with the reagent (but I am more of a biochemist than an organic chemist), but in the
patent describing its synthesis (USP 7138538, example 2), they recrystallize the raw product from isopropanol ...
Others in our lab also dissolve small amounts of it in ethanol occasionally, and it can be kept in this solution for at least 24 hrs, but I must add
that it is kept on ice for that period of time.
I will test the stability of the reagent in these solvents with a small amount first, both at low and at elevated temperatures to see what happens. If
it reacts at all with the alcohols I will try an aprotic solvent next.
Reaxys does not seem to have more information on its synthesis/purificaiton other than what is in the patent. To access Beilstein is a bit of
traveling for me. Think that is worth it? It it is not very likely to yield more information that the patent, right?
[Edited on 17-10-2011 by phlogiston]
-----
"If a rocket goes up, who cares where it comes down, that's not my concern said Wernher von Braun" - Tom Lehrer |
|
|
Nicodem
Super Moderator
Posts: 4230
Registered: 28-12-2004
Member Is Offline
Mood: No Mood
|
|
When searching for info in regard to recrystallization solvent in databases like Beilstein/Reaxys you need to first look at the mp data where the
solvent is listed.
Isopropanol is somewhat less nucleophilic than ethanol and methanol, so it could be OK though I would take patent examples with a salt of grain.
Consider also that it depends on how fast you heat to the boiling point, how much you keep it there, and how fast you cool. As a practical example, I
had an moderately electrophilic product that I used to recrystallize from ethanol and it worked just fine the first and the second time. The third
time I repeated this, I did it less rapidly than usual and it nearly fully solvolysed (as per Murphy's law, it was also the largest batch). Since
then, I avoid recrystallization from reactive solvents. But in your case, even if part of the compound reacts with the solvent, this will not affect
the ee of the recovered product (the isopropyl carbamate is in any case unlikely to crystallize out as an impurity).
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
|
|
|
phlogiston
International Hazard
Posts: 1376
Registered: 26-4-2008
Location: Neon Thorium Erbium Lanthanum Neodymium Sulphur
Member Is Offline
Mood: pyrophoric
|
|
Thanks for the tip, reaxys also has isopranol as the solvent listed in the melting point data table.
So, perhaps isopropanol would be useable, but I am going to test it first. You are right that some formation of isopropyl carbamate is probably no
problem for my purposes, other than (hopefully) only a little loss of an expensive reagent).
When doing the actual recrystallization I probably should try to prevent keeping the isopropanol solution at elevated temperature as much as possible,
but I do usually like to cool down slowly to aid in the formation of good (and thus more pure) crystals. How slow is slow enough? I guess testing will
tell.
[Edited on 18-10-2011 by phlogiston]
-----
"If a rocket goes up, who cares where it comes down, that's not my concern said Wernher von Braun" - Tom Lehrer |
|
|
phlogiston
International Hazard
Posts: 1376
Registered: 26-4-2008
Location: Neon Thorium Erbium Lanthanum Neodymium Sulphur
Member Is Offline
Mood: pyrophoric
|
|
Just to report the result in case anyone might want do something similar in the future:
I managed to purify the reagent satisfactorily by recrystalization from diethyl ether. This method yielded NIFE reagent with undetectable amounts
(<0.0002 %) of the undesired (R) isomer in a single recrystalization step, with approximately 60% yield of the starting material.
The solvent was chosen after testing a panel of several aprotic solvents and isopropanol. Only hexane, diethyl ether and isopropanol seemed useable
(10% w/v dissolves at elevated temp, but not completely at room temperature in these solvents), whereas the solubility of the reagent was too high
even at room temperature in the other solvents tested (THF, dioxane, MeCN, acetone).
Indeed, isopropanol was found to react with the reagent. However, although micromolar quantities of the isopropyl carbamate could be detected (by
HPLC-MS/MS) after an hour in isopropanol solution, the enantiomeric purity of the reagent recrystalized from this solvent was not much improved over
the starting material. Possibly I did not allow enough time for crystals to form slowly, but I wished to minimize exposure of the reagent to this
solvent.
Thank you very much for your helpful advice nicodem! I greatly appreciated it
[Edited on 16-11-2011 by phlogiston]
-----
"If a rocket goes up, who cares where it comes down, that's not my concern said Wernher von Braun" - Tom Lehrer |
|
|
|
![[*]](images/xpblue/default_icon.gif){kind=icon}
