[atije]

Hi all,

I have recently embarked on trying to synthesize some primary thiols (negligible steric bulk), something I have never worked with before. They are almost all going to be high-boiling liquids. I know all the background theoretical stuff about how thiols are prone to oxidation to disulfides and beyond and how this tendency is lowered when the thiols are kept protonated, cold and under argon. But I have very little knowledge on how much these things actually matter in real life. Therefore, the following questions to the practical organosulfur chemist out there:

1) Can I run a flash column purification of thiols under normal conditions? Should I degas my solvents beforehand? Use argon for pressure instead of air? Do you add a bit of acid to your eluents - e.g. 1% AcOH?

2) Should I always store thiols under argon, or is it good enough to store them in the freezer? And which do you usually use... under argon at room temperature or in the freezer under air? (I don't love argon+freezer, since the temperature/pressure drop may cause air to enter the flask anyway, unless it is incredibly tight)

3) When preparing thiols (as the final product of a reaction), do you always degas solvents beforehand? Is it required?

4) Finally, what sort of stability issues are we looking at here... If I have thiols sitting on my benchtop the entire day, for example as neat liquids, or in solution, will they have formed disulfides the next day? Anything I should be particularly attentive to?

5) Finally, I would assume that thiols are most stable protonated in non-polar solvents (preferably hexane). Can you confirm?

Thanks in advance. Anyone that can answer these or some of these questions with just a tad of confidence will help me greatly!

Best regards,
Andreas

[wildfyr]

I can only answer #2 since I generally only used thiols and didn't synthesize them, that we had thiols that we kept cold under air for many years and never saw any oxidation issues beyond a bit of disulfide bond formation, which I cleared up by distilling. Disulfides can (somewhat expensively) be broken back into thiols with DTT, but then you gotta deal with the DTT and its products being in there.

[Babcock_Hall]

In aqueous solution the oxidation is catalyzed by the presence of certain transition metal ions.  I don't know whether or not this transfers over to organic liquids.

[hypervalent_iodine]

Some thiols are more prone to oxidation than others. Whether or not they will oxidise over night really is variable. I work with many that would, but many others that would be fine over night.

In my own experience, storage in the freezer is best. I also flush with argon before putting them away and after taking them out (after they've warmed to room temp).

Preparation is again variable. I have put an aromatic thiol (thiosalicylic acid) through Fischer esterification conditions with ethanol overnight and had only a small amount of dimer form. If you are concerned, I would degas.

As for purification, my trickiest thiols I could not column effectively. They would dimerise very fast on silica. I found vacuum distillation with a Kugelrohr or sublimation to work much better. This is what I do now with all of them.

[phth]

1) purification with compressed air is fine.  Just store them under argon/N₂.  Normal thiols have half lives on the order of hours (e.g 9 hours for glutathione in aqueous solution), so if you leave the thiol there fore 30 minutes or an hour under argon there will be only trace amounts which are acceptable for publication purposes.
2) answered by Wildfyr.  You can add 2-5% of PPh₃ if you know how much disulfide there is and OPPh₃ will stick to the baseline of the column for hydrophobic eluents on silica gel.
3) no degassing solvents is a waste of time.  Purging the rxn flask with argon is all that is required.
4) compare redox potentials
5) No, thiolates are more stable, and thiolates decompose through a different mechanism than thiols. 

[Babcock_Hall]

I respectfully disagree with phth with respect to thiol/thiolate stability, at least as it pertains to aqueous solutions.  As pH increases from 6.5 to 7.5 to 8.5, the half life of 2-mercaptoethanol in phosphate buffer falls from 100 to 10 to 4 hours (Clarence Suelter, Practical Enzymology, p. 19, and references within).

[atije]

Hello everyone, and thanks a bunch for your answers! It seems that thiols may not be so problematic in practice as I thought. Agreeing with Babcock-Hall, I am also of the opinion that thiols are more stable than thiolates. Most people in my lab agree :-) I have also read a few papers to back it up. If Phth could argue his position that thiolates are more stable, I at least would find that very interesting.

Best,
Andreas