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Chemistry Forums for Students => Organic Chemistry Forum => Organic Chemistry Forum for Graduate Students and Professionals => Topic started by: Babcock_Hall on May 26, 2021, 08:00:25 PM

Title: Poor solubility and problems recovering a product on silica
Post by: Babcock_Hall on May 26, 2021, 08:00:25 PM
Our compound is a N-BOC, tert-butylester-protected amino acid.  It was not very soluble in our chromatographic solvent, which was 35/65 ethyl acetate/hexanes.  We added some DCM to solubilize our compound, added about twice the mass of silica, and removed the solvent by rotary evaporation.  We applied the impregnated silica to the top of the column and ran under flash conditions (we more typically use gravity).  The material tailed, and the product was still visible (though dilute, relative to the most intensely staining fractions) even after we finished collecting fractions.  We used permanganate to visualize the product on TLC.  We noticed that the recovery by mass was low; therefore, we flushed the column with 100% ethyl acetate and recovered more permanganate-positive material that had about the same Rf as previous fractions.  We will soon have dry masses on the pools.

In the past we have often dealt with poorly soluble compounds by dissolving in DCM and applying this solution to the column.  On one occasion we used the dry-loading technique.  I have not tried to correlate yield with poor solubility, but suffice it to say that I have not noticed a recovery problem previously.  My admittedly simple model for why poorly soluble compounds usually elute without difficulty is this:  when a compound moves through a column, it is bound to silica for much of the time.  Putting it another way, the silica helps to solubilize such a compound.  Maybe the model is wrong or is only correct some of the time.  However, the most important question is whether or not to change our technique for this compound or other compounds in the future.  Thoughts?
Title: Re: Poor solubility and problems recovering a product on silica
Post by: rolnor on May 27, 2021, 02:15:03 AM
You should avoid hexane if possible, use EtOAc/DCM or DCM/MeOH. Better use wet-loading, making sure everything is dissolved before loading. If you use DCM/MeOH, pack the column with DCM only.
Title: Re: Poor solubility and problems recovering a product on silica
Post by: Babcock_Hall on June 09, 2021, 10:30:25 AM
For an aromatic compound we were trying to repurify yesterday, we used acetone/DCM as the solvent.  The compound was unexpectedly poorly soluble in this solvent, so we decided to dry load at the last minute.  We added silica and removed solvent.  We observed that the product tailed badly, in a qualitatively similar way to the product in my opening post.

I am not sure that we gave the compound enough time to be solvated and bind to the silica.  In retrospect, we might have chosen a silica-loading solvent in which the compound was completely soluble.  This compound has been troublesome to use previously.
Title: Re: Poor solubility and problems recovering a product on silica
Post by: Babcock_Hall on June 09, 2021, 05:51:43 PM
Rolnor,

By wet loading, what do you mean, dissolving completely and applying to wet silica?

By the way, I noticed a typo in my previous comment:  "This compound has been troublesome to us previously."  This compound has poor solubility in a variety of solvents.
Title: Re: Poor solubility and problems recovering a product on silica
Post by: rolnor on June 10, 2021, 01:08:59 AM
Yes, thats what I mean by wet-loading. Have you tried MeOH/DCM? You should pack the column with DCM only.