BromicAcid
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Reactions of disulfides to aid in their removal
More work related chemistry issues. Recently I had the pleasure of making a thiochloroformate but something went wrong....
Purity of the final product is only 68% or so with the main impurity being the disulfide (starting material was the mercaptan). The main issue
however is the boiling points. Like most things I make, purification is via distillation but the boiling points differ by, at most, 1°C 
So although a distillation could be done, it would be the biggest headache I could imagine to distill 100 mL of material. So I am looking for a
reaction to take care of the disulfide but leave the R-S-C(O)Cl functional (chlorothioformate) intact. This is problematic from what I've found
because although disulfides contain a weak bond, most of the reaction conditions I've seen are done with bases or use aqueous conditions, both of
which are a 'no go'. I've tried my hand at some crystallization attempts but purity increase is only a % or two. I've also tried sparging, copper
shot (with the hope of complexing the disulfide) and a few separations using immiscible solvents to hopefully pull one constituent into its own layer
to no avail.
I am nowhere near tapped out of ideas, most people here know how it is to want to do a million things at once, but if someone has some guidance I
would really appreciate it.
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Jor
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Can't you reduce the disulfide bond to the thiol?
http://en.wikipedia.org/wiki/2-Mercaptoethanol
Or just hydrolyse your acid chloride, seperate the acid from your impurity and chlorinate it again with SOCl2?
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DJF90
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Its a chloroformate Jor, it doesnt work like that. Practically anything nucleophilic you put in there is going to react with the chloroformate in some
way or another (even if it attacks the disulfide first, you're gonna generate a RS- equivalent).
Perhaps halogenation could aid separation by distillation, but I'm really not sure if this'll affect the chlorothioformate.
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BromicAcid
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I've thought about a halogenation, mostly because Wiki mentions it as a way to form sulfenyl halides. It may work but as you mentioned I wonder if
this will kill my product. I'm assuming that the sulfur is in a much less reactive place on the chlorothioformate similar to the reduced activity of
amides but chlorine can be quite the beast. I'll reserve that option for last but it remains open.
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DJF90
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What other ideas have you had Bromic? I would have thought carrying out the reaction under Argon would have prevented any such issues?
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BromicAcid
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Needle transfers, nitrogen flushed apparatus, supposedly we did our usual air sensitive routine that is used on site successfully for pyrophorics and
the like, but something obviously went wrong. I don't know for sure since I didn't run the reaction myself, just checked up on the person running it,
but it was my procedure that ran so the burden falls on me to fix it. In previous runs the disulfide was always there so it is checked against a
standard when it goes in for final testing, but it's usually only 1-3%. Something <i>different</i> happened this time. What it is, I
don't know. We have hundreds of products in our lines so it really seems like I need to know a bit of everything but this one is throwing me off
pretty well.
Right now the best of the methods might be freezing. The disulfide freezes lower then dry ice and the product freezes just a few degrees higher.
I've done some small scale with just GC vials and dry ice / acetone and the whole mass will freeze at these temps. Trying to go a bit slower I've
managed to get very slight separation, i.e., 72% product in the solid phase and 66% in the liquid. I am hopeful that scaled up, with better
temperature control I might do a bit better but it's still a long shot, even if it works okay to bring it up to even 90%, that's still not going to
cut it and from what I know about hydrogen peroxide concentration (just because it's similar in increasing the concentration through freezing) it will
eventually reach an upper limit where it is no longer effective. I need to do some more solvent tests, I was thinking hexanes and acetonitrile (since
they're immicible) and see if one phase ends up richer.
If I could find a solvent that the chlorothioformate is insoluble in then I could cool that down to -78°C or so then drip in the mixture with the
hope that the disulfide would quickly be removed as the product solidified. I've done similar purification procedures to that one in the past. Of
course what everything comes down to though is that we're a production unit, not a development unit so my time to test in the lab is very very
limited. It doesn't mean I have to take action this second, I could stretch this out over a month, but over that month I might only have 4 or 6 hours
to work on this, which may seem like a lot to some but to those of us who know long hours in the lab there is only so much I'll be able to get done.
Nevertheless, the material needs to be made so if I cannot purify it, it means that we will be doing another run soon enough.
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smuv
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Column?
Edit: I assume both products are soluble in chloroform and ether? Based on this: Dissolve the stuff in chloroform, and add an excess of TEA, the
mixture should stay homogenous. Add ether, I assume the TEA/Thiochloroformate should precipitate. Take up this salt in chloroform, gas with HCl (or
add strong HCl in ether) and add ether to precip the TEA*HCl. Filter. On rotovapping the filtrate you should have your sulfide.
Of course everything needs to be done w/ reasonably dry solvents, under inert atmosphere (especially w/ basic solutions of sulfides!).
[Edited on 5-21-2011 by smuv]
"Titanium tetrachloride…You sly temptress." --Walter Bishop
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BromicAcid
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Nice one smuv, never tired it with a chlorothioformate but you might be onto something. We have several isocyanates that we make using trertiary
amines, however we always have to heat to drive the elimination reaction to get our isocyanate so the formed salt in this case may be stable enough to
work with for at least a short time.
I will give it a shot.
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DJF90
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Sorry guys, hop back a second. Whats the chemistry behind this suggestion? Do chloroformates form an adduct with TEA or something?
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smuv
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The tea simply deprotonates the thiochloroformate. These types of salts are usually insoluble in ether but soluble in chloroform.
Also, on second look, you can just add the TEA to a solution of the thiochloroformate mixture in ether and just filter the salt (it will probably take
some time to precipitate, I recommend letting it come to RT and then refrigerating). Then proceed as specified.
I recommend, allowing the chloroform to sit over CaCl2 before use. Even if it is dry, usually chloroform has some alcohols to stabilize it.
"Titanium tetrachloride…You sly temptress." --Walter Bishop
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BromicAcid
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I wouldn't say it deprotonates it, which proton would it remove? Attached is the usual reaction scheme to make carbonyl chlorides from tertiary
amines, that's what I was banking on from what you suggested smuv and just rewinding it a step after the intermediate is formed.
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smuv
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Oops, I misread the post (I thought it was thiochloroformic acid not a thioester). Can you please post a structure of the disulfide and the
thiochloroformate? It is an interesting problem, but it is hard to provide advice when I don't know what I am dealing with.
Edit: haha sorry about the confusion, I can tell from your post DJF90 it was a WTF? moment 
[Edited on 5-22-2011 by smuv]
"Titanium tetrachloride…You sly temptress." --Walter Bishop
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DJF90
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Yes indeed. It kinda makes sense the way that Bromic suggests, but I'd highly doubt the reversibility on adding HCl (even if anhydrous gas is
employed). I think its a bit of a leap of faith. Depending on the complexity of the thiol involved, it might be better to just cut your losses and
re-do the prep. I'd be pretty confident that the complications have arisen due to someone "dropping the ball".
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BromicAcid
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I tried the experiment today on the small scale and got some interesting results. The process did afford separation but yields look low. First I
took the crude and dissolved in MtBE I also tried EtOAc and Hexanes but MtBE gave the best results. I added TEA and material immediately began to
precipitate and clump together. I just added a few drops, enough to be excess but I didn't measure anything since it was proof of concept.
I put the material in the cooler for an hour and separated off the supernatant. GC of this upper layer showed the disulfide, TEA, and MtBE. There
was a tiny peak of the product and on standing more material precipitated out on the walls of the vial so I might not have given it enough time or the
reaction may have stalled at cold temperatures.
The solids were washed with some more MtBE and then enough MtBE was added to cover the solids. Anhydrous HCl was bubbled into the solids and an
exothermic reaction commenced (there was no cooling). After 10 grams or so of HCl was bubbled in the solids on the walls had dissolved away leaving a
clear / colorless solution. GC of this solution showed 6.7% product and 0.3% disulfide so it did separate dramatically, this may have just been
disulfide due to insufficient washing. So the ratio of product to disulfide had gone from ca. 2 : 1 all the way to 22 : 1. But all was not good, GC
had a number of strange peaks on it, a few high boilers and a few low boilers but two new major peaks stuck out (though nothing that would be too hard
to distill away from). I'm betting that when I acidified the mixture it overheated and started knocking off ethyl chloride leaving behind a
high-boiling impurity of the type R-S-C(O)-N(Et)2 (What the heck would you call that? Would it be classed as a urea? I mean a thiourea has a C=S so
that wouldn't be it...) also some of it is likely the MtBE getting attacked by acid, we never use it as a solvent, just a cleaning agent but I
remember reading it's easy (relatively speaking) to cleave.
Anyway, I'll hopefully be able to wrap this up tomorrow, i.e., find a better solvent. Do the additions by the numbers, and keep things cool during
the reaction and hopefully by the time this is all done I'll have something I can separate from. Purity of the product only has to be 95.5% so if the
ratio of product to disulfide stays the same, the target purity is within reach.
Wish me luck, it's on back order!
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smuv
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I don't understand, TEA*HCl should have precipitated when you gassed with HCl. I assume you did this in an MTBE suspension? Also, MTBE might not be
a great solvent, it is rather acid sensitive; DCM, chloroform or ether might reduce side reactions.
Very interesting though. I can't say I even expected you to recover any precipitate at all when treating w/ TEA. Can you NMR the precip to figure
out what is actually going on?
[Edited on 5-24-2011 by smuv]
"Titanium tetrachloride…You sly temptress." --Walter Bishop
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Nicodem
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Interesting experiment.
Quote: Originally posted by BromicAcid  | | I'm betting that when I acidified the mixture it overheated and started knocking off ethyl chloride leaving behind a high-boiling impurity of the type
R-S-C(O)-N(Et)2 (What the heck would you call that? |
That would be an S-thiocarbamate, the product of the von Broun reaction of your chloride with Et3N. This pathway is likely as you allowed the
temperature to rise during the adduct decomposition step (you should keep it at 0 C). The other product is ethyl chloride.
MTBE reacts easily with HCl, so I suppose most of HCl got consumed in the formation of t-butyl chloride, isobutene and methanol. Your chloride can
react with methanol to give the corresponding thiocarbonate (though this reaction might not be significant).
You could try using diisopropyl ether (cheap) or toluene (even more cheap), but you also need to consider that the solvent will have to be suitable
for separation via fractionation. Hexane, heptane or whatever alkane should be suitable for the adduct with Et3N formation, but I doubt it would work
well as a solvent for the decomposition step (the acidity of HCl in alkanes is poor). You could try the decomposition with conc. H2SO4 as it should be
simpler (1.1 equivalents should do). Sulfuric acid should not interact with the desired product, but the reaction will require good stirring and phase
separation (of the triethyammonium bisulfate slurry) before the fractionation.
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