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I need to synthesize some organic compound for my Ph.D. research. Everything went OK during the synthetic route but got messed up at the very end. In my final step (once the final compound has been obtained) I remove a silyl protecting (TBS) group using TBAF. The problem comes when I try to purify the reaction. No matter how carefully I run my flash column (FCC, flash column chromatography), I always obtain my compound with traces of TBA.

I've tried other deprotection procedures (mainly acidic ones) but they hydrolyze my final compounds since they are sensitive to acidic conditions. Does anyone know of an alternative purification technique (or reaction) that would remove the TBA?

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    $\begingroup$ Did you consider using ammonium fluoride instead of TBAF? Article: sciencedirect.com/science/article/pii/S0040403900918896 $\endgroup$
    – Rok Narobe
    Commented Jun 30, 2016 at 19:08
  • $\begingroup$ Did you consider HF-pyridine complex? TBAF looks great on paper, but can be trouble in practice. $\endgroup$
    – jerepierre
    Commented Jun 30, 2016 at 19:59
  • $\begingroup$ FCC = Flash Column Chromatography? TBAF is usually non problematic... unless your compound is incredibly non-polar the by-products of the silyl deprotection wash off the column in hexanes, and then you can modify the polarity to elute your compound $\endgroup$
    – NotEvans.
    Commented Jun 30, 2016 at 22:28
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    $\begingroup$ Though I agree with JerePierre, if you're 20 steps into a synthesis, HF is the way to go. Mild, clean and easy to carry out, the only downside being the potential harm if you get it on yourself. $\endgroup$
    – NotEvans.
    Commented Jun 30, 2016 at 22:34
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    $\begingroup$ @jerepierre I did use it. The results were worse than before with most of my compounds decomposing. $\endgroup$
    – user30064
    Commented Jul 1, 2016 at 14:13

2 Answers 2

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I know it is a relative old issue but I had the same problem with nucleosides during my PhD. I tried a wide range of reagents but all of them lead to the decomposition of compounds or no reaction occurred. The only one that worked was TBAF 1 M in THF. I could not extract them because they are too polar. FCC did not work at all.

Solution (at least it worked for me): after FCC, I dissolved my product with TBAF in water and pass it through a Supelco SPE DSC-C8 3 mL, 500 mg for up to 10 mg of my compound. Use only water and do it slowly. I always get the desired compound from tube one to 6-7 and no TBAF is present. It is useful if you can use a LC-MS to analyze each tube. I tried other brands and no one worked except this one. I don't work for them, just want to share my solution.

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I have the same problem in my Ph.D. research. Whenever I am too lazy to skip the aqueous workup and throw the solid residue from rotavapor directly into a column for chromatography, TBA just penetrate through flash column and exist in every tube I collect. To me, aqueous workup help a lot to remove TBAF if your product is not too soluble or unstable in water. Also, TBAF is mostly used as the floride anion source because its solubility in organic solvent. Other fluoride anion source like KF can be used as alternative to TBAF with proper solvent.

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  • $\begingroup$ That's exactly my case. I can't do water extraction because my products are too polar and would go to the water phase. $\endgroup$
    – user30064
    Commented Jul 1, 2016 at 14:21
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    $\begingroup$ You may just try other fluoride salts. CsF or KF or NH4F may do the deprotection job as well as TBAF while they will not mess up in your column. I remember KF will work in acetonitrile. HF is acidic and may decompose your compound. HF-Pyridine is almost equally messy in column as TBAF a lot of time. $\endgroup$
    – Coconut
    Commented Jul 5, 2016 at 16:06

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