THF - Safety

[hajdaei]

We are using THF a bit more often now (partly due to the ACN shortage). And I want to get a better handle on the safety issues.

It seems that the only type of preserved THF you can buy is with BHT. But this is problematic: because of the UV cuttoff this stuff is terrible for use with UV detection and is also a problem if BHT is one of your analytes. So I have a handful of questions:

- is there something else that the end user can add to pure THF that will act as a preservative, and not give much background absorption with UV detection.

- if you use the unpreserved stuff, is it sufficient to use the test strips. Does that give you an assurance of safety.

- what happens once THF is mixed with other mobile phases: such as water and methanol. Will any trace peroxides be consumed by these solvents? Or is it possible that these peroxides could even build up in the LC system.

[sassman]

I could be wrong, but I think that you only run into problems with peroxides when your THF has been stored for a long time or stored improperly (especially if you are applying heat or distilling it). For routine HPLC use, I don't think it is much of a safety issue. At least I have used unstabilized THF for many years and not blown up once.

[DR]

Test strips are fine, once THF is mixed w/ water etc, it is actually more stable.

Nitrogen blanketing opened partial bottles of THF is not a bad idea.

[rick1112]

Some points on THF use..

(1)Please make sure you use only glass bottles, measuring cylinders and pipettes as THF (100%) dissolves most of them...

(2)I am not sure regarding peroxide build up in HPLC system, but I recently came across a polymer based column (I think this was from Polymer labs and had PS-DVB as stationary phase…but need to check it up for being 1005 sure) which recommends to avoid use of non BHT treated THF as peroxides could attack the column…i am not sure how much true it is…

[hajdaei]

Thanks for the comments.

What about the one question: 'is there anything the end user can add that will preserve THF and not cause much of a UV problem'.

There must be something?

Thanks

[tom jupille]

What about the one question: 'is there anything the end user can add that will preserve THF and not cause much of a UV problem'.

There must be something?

Water

[freemab]

Actually, it sometimes happens that the presence of a constant level of a component, such as BHT, does NOT interfere with the detection of that component in the sample. So the first thing to do is see whether it's really a problem. The background signal would be the main problem, I would think.

Fresh THF without preservatives is generally clean of peroxides, but the test strips are a good way of double checking. Once opened, peroxides start forming immediately, unless you exhaustively purge out the air.

However, any preservative that intercepts the oxygen faster than the THF might be suitable instead of BHT. Perhaps hydroquinone or another phenolic that happens not to interfere with your assay could work.

I'm a little out of my field here, but it's my understanding that water and perhaps alcohols can also impede the formation of peroxides. Might be worth looking into.

I recall some years ago doing some work with unstabilized BHT in which I placed cobalt sulfate- (?) treated molecular sieve in the THF bottle to stabilize the THF against peroxides. My memory of this is foggy. I believe I never got so far as instituting such a procedure in a method. I vaguely recall using a material from Fluka, perhaps 69828, because all other suppliers use cobalt chloride as indicator and this compound is soluble in ethers.

Should it be necessary, it is possible to clean THF of peroxides using basic alumina. I believe Fieser and Fieser gives a procedure (for ethers, generally). However, if you do this, be aware that the alumina will now contain peroxides, and it is necessary to reduce these before allowing the alumina to dry. I believe I used KI, which visibly is converted to iodine, to do this.

Another thing to consider is to avoid using THF at all, especially if it's acetonitrile you're trying to replace. Look on Snyder's solvent triangle for something more like acetonitrile than THF. If that doesn't work, consider using methyl-t-butyl ether instead of THF, as MTBE does not form peroxides.

[HW Mueller]

Interesting reaction: KF + peroxide > I2 + . . .

More seriously, for those who do not want to dilute THF: Some high grade ether (diethyl) come with Na (metal) wire, whether this is an alternative here should be checked first. I wouldn´t put Na into strongly oxidized THF. Also, diethylether is often provided in aluminum containers, I wonder why this is not done with THF.

[hajdaei]

Tom - it would be great if water did the trick, but...are you sure? It seems to me peroxides are fairly stable in water. For example you can buy 3% hydrogen peroxide in water at any pharmacy. As long as there are stabilizers in there to chew up any easily oxidized species, it is pretty stable.

Hydroquinone is an interesting idea. I also like the idea of adding metallic sodium. If this works it would accomplish the objective without adding anything to the solution. I wonder if there is a safer metal that can be used. If the sodium ever got in contact with water, that would be dangerous.

[tom jupille]

Here's an abstract of Zhao & Carr's 1999 LC/GC article re water inhibiting formation of peroxides in THF:

http://cat.inist.fr/?aModele=afficheN&cpsidt=1800695

Alas, LC/GC's on-line articles don't go back that far.

[hajdaei]

Thanks Tom.

I was thinking in terms of breaking down the peroxides. But I see the point is that it prevents them from forming in the first place.

I will read the article.

[jclark]

hajdaei,
I'm not using THF (we're lucky to still have sufficient ACN), but I have experienced a THF/peroxide explosion in the past. My suggestion is to purge out the headspace of the solvent bottle with a trickle flow of N2 (or Ar, or He). If you flush out the headspace when you first fill the bottle, then maintain a trickle flow thru the headspace (NOT bubbling thru the liquid), you should be able to keep your THF sufficiently free of peroxides. This avoids the whole issue of chemicals & chemical reactions in your THF.
regards,
Jim Clark
AZ Dep't. of Health Svcs.

[HW Mueller]

Tom, I couldn´t find this article in my LC.GC Int. (have a few issues of 1999 misplaced). Do you still have access to it? Is it due to the lower O2 concentration when water is present (that is what I alwayd thought to be the cause)? An inhibition of homolytic reaction by the polar water? Inhibition of autoxidation? Or . . . .?

[ksharp]

Hi, I spent a few years working with large amounts of THF so I have a good background about peroxide-formation in ether solvents.

Peroxide removal is a hassle. I would reiterate what others have said - first make sure that the BHT-inhibited stuff won't work for you.

If you absolutely need uninhibited THF, the best/easiest thing to do is prevention. If you are buying uninhibited solvents, you *must* vigorously exclude oxygen by blanketing with Ar or N2. Store in cool, dark place, and test regularly (strips are fine). A good practice to follow even if it is inhibited. Buy smallest bottles available, as the "clock starts ticking" when the bottle opens. You should have a procedure in place for regular monitoring, as this is a safety issue.

There are ways to remove any peroxides prior to use. Most methods rely on destroying the peroxides by adding chemical reagents; these work well but of course your solvent now requires distillation prior to use for LC. That's inherently risky and time consuming.

One *removal* method involves passing through a column containing activated alumina. The peroxides are selectively adsorbed onto the alumina, leaving clean peroxide. There are a lot of simple ways to do it, but Grubbs et. al. have a highly cited paper for their solvent purification system:

DOI: 10.1021/om9503712

Another involves passing through a zeolite column:

DOI: 10.1021/jo01311a042

A safety note: peroxide formation in THF is not nearly as dangerous as peroxides in, say, diethyl ether. The THF peroxidation reaction comes to equilibrium before they reach dangerous concentrations. Accidents tend to occur when the THF is heated, or quickly evaporated (thereby concentrating the peroxides before the equilibrium has time to be reestablished).

With the diethyl ether (and others), the peroxides tend to crystallize or precipitate out of the reaction, and they accumulate there until dangerous quantities exist and...BANG!

Cheers,
Kenny

[HW Mueller]

ksharp, with what do the peroxides of THF equilibrate?