For a synthesis I'm performing at the moment, I keep getting an impurity where I can not describe the origine for.
The reaction is as follows:
Work-up is with Na2CO3 in water, where after the formation of an amide is performed.
The impurity I keep getting is a thiosulfate instead of the bromide on the end of the alkyl chain. Ranges between 0.14 - 0.25 wt%
Anybody an idea were the thiosulfate impurity origine can be found? Maybe a impurity in the commercial bought sulfonyl chloride?
Thanks in advance.kavu - 22-1-2013 at 09:42
Have you freshly distilled the thionyl chloride, thiosulphate substitution might arise from hydrolyzed SOCl2? The amount of side product seems to be
negligibly small and a careful fractional distillation of the acid chloride before adding the desired amine should give you a very pure product.
[Edited on 22-1-2013 by kavu]DJF90 - 22-1-2013 at 13:31
Why are you washing with sodium carbonate after the formation of the acid chloride. Use toluene as a solvent, remove the solvent in vacuo (along with
any excess SOCl2) and dilute again with toluene to reconcentrate it several times (just to be sure all the SOCl2 is gone). Then form the amide under
Schotten-Baumann conditions using the toluene solution as-is. (I guess this may not be applicable to your substrate depending on the boiling point of
your acid chloride).
[Edited on 22-1-2013 by DJF90]SteveZissou - 23-1-2013 at 01:55
Speculating on the origin of your thiosulfate, I am honestly stumped. Wild speculation time, it is then! It should not be possible for a thiosulfate
to form under acidic conditions, in HCl thiosulfate breaks down into sulfur dioxide. Perhaps the problem lies in your work up; it may be possible that
neutralization causes a side reaction of some sort. I can't see this forming under acidic conditions. Nernst - 23-1-2013 at 02:13
Refluxing the chloroform for the removal of SO2 and HCl gasses drives the formation of the acid chloride to completion. I made a mistake in my
openingspost: The Na2CO3 is not used for work-up, but is added during the Schotten-Baumann reaction with dimethyl-amine.
Still wondering about the formation of the thiosulfate S-alkyl chain. Anybody an idea if it has something to do with the formation of Bunte Salt,
where still Thiosulfate is needed for the formation of the S-alkyl chain?
[Edited on 23-1-2013 by Nernst]garage chemist - 23-1-2013 at 06:18
Thionyl chloride is not completely stable against heat, slightly decomposing above 100°C, giving S2Cl2, SO2 and Cl2. Perhaps some of this
decomposition has taken place in your reaction. How long and how hot did you run it?
Also, commercial thionyl chloride always contains more or less of the sulfur chlorides as an impurity. If your purity requirements are so high that
you consider 0,25% of a thiosulfate as problematic, perhaps you should try purifying your thionyl chloride by distillation over quinoline and linseed
oil and running your reaction at a lower temperature. Did you use a drop of DMF as catalyst? Nernst - 23-1-2013 at 06:57
The reaction temperature is not allowed to get hotter than +/- 70°C for a maximum running time of 2 hours. No DMF was added.
The impurity itself is not problematic, it does not couple in the next step. But just for my knowledge, I want to find out why this impurity keeps
popping up.
Maybe I should run a reaction with analytical grade SOCl2 (99.75% pure). I'm not that wild about distilling mine SOCl2.
Still, I find it strange that for my SOCl2 only SO2Cl2 (sulfuryl chloride) is mentioned as an impurity, being less than 0.5 wt%.
Anybody any idea of a good analytical method to determine the amount of thiosulfate in my SoCl2? Nicodem - 23-1-2013 at 07:32
What do you mean by this "thiosulfate impurity"? Do you mean ClCO(CH2)4-S-SO2OH? How did you determine that? By
GC-MS (HRMS?) or otherwise? At first glance, it does not appear volatile enough for GC and without derivatisation, it is of no use for reversephase
LC-MS.
Besides, I can't see how could that pass over the Na2CO3(aq) wash. I would more likely expect a sulfinic acid or sulfinic
chloride as an impurity: ClCO(CH2)4-SO2H or ClCO(CH2)4-SOCl.
In any case, without you providing the characterization data, all this discussion is pretty much pointless.Nernst - 23-1-2013 at 08:07
Imp. R-SSO3H is purified by column cromatography and confirmed by NMR.Nicodem - 23-1-2013 at 08:19
Imp. R-SSO3H is purified by column cromatography and confirmed by NMR.
How did you confirm that by NMR? Is ClCO(CH2)4-S-SO2OH a known compound with a published 1H and 13C NMR?ash - 19-2-2013 at 10:41
avoid the impurity by using oxalyl chloride/CH2Cl2 and a few drops of dmf if reaction doesnt proceed fast enough. 100% yield guaranteed.
another perfect method is CDI 1.1 eq/CH2Cl2, then amine. General procedure - on demand.
anyway, unlikely you make any profit from what you observe in your conditions.DJF90 - 19-2-2013 at 13:12
Problem with using DMF even in catalytic amounts ("a few drops" is all that is usually specified, no real quantity) is the potential formation of
nasty carcinogenic compounds such as dimethylcarbamyl chloride. A better alternative is to use stoichiometric benzotriazole as per a paper in
Synthesis, and it is very rapid indeed (https://www.thieme-connect.com/ejournals/abstract/10.1055/s-...)zed - 20-2-2013 at 17:57
Correct me if I am wrong, but I am under the impression that Carboxylic Acid Chlorides are incompatible with H2O.DJF90 - 21-2-2013 at 13:25
Where do you see that as a problem? I dont see anyone advocating the use of water, other than my mention of Schotten-Baumann conditions above, which
works great and is facile.ash - 23-2-2013 at 04:59
no real quantity
potential formation of nasty carcinogenic compounds
real quantity - couple drops. doesnt reaaly matters if you add two or five but not 100ml) I usually see when its enough so the reaction proceeds not
too violently.
abt cancerogenic - that's all true but in such tiny amount - DCM, say, much more dangerous for your liver etc. If you still afraid, just dont use DMF
- the only difference is how long u'll be waiting for reaction completion. Also, benzotriazole, CDI can make you much more harm than DMF-Cl, you know.DJF90 - 24-2-2013 at 05:34
Sorry I should clarify. A drop or two (say, 5 uL) ought to be sufficient for a small scale reaction. But what sort of amount is needed for a bigger
reaction. In terms of mol% or equivalents? Sure, you could scale up the quantity linearly, but it may be that 1-2 drops is still a sufficient amount.
This sort of information is important to people such as myself (I'm a process R&D chemist), and the formation of carcinogenic byproducts would
also be undesirable, no matter how small the quantity, particularly if I'd have to run the reaction in a 20 L flask or if it goes to pilot plant.
Because there, even 0.01% is alot (c.f. the amount of hexavalent chromium supposedly existing in cured concrete, something on the order of 10g from a
75kg batch (I used to do a little construction work...). In my case (at least at work), it'd also be undesirable as we manufacture APIs. So in an
academic setting, yes, the use of DMF or NMP as a catalyst is possible and any carcinogenic products are likely to go unnoticed.
Again, a couple of drops is not a real quantity. Drops from a pipette will likely be a different volume than those from a syringe needle, especially
if a disparate size is used (say, 25 G). A quantified amount would be much more precise and replicable. Benzotriazole is not particularly nasty, and
neither is CDI. At least you know what risks are present when you're dealing with them.
