ascorbic acid and iodinated hydrocarbons

loki · guinea pig

a little gnome i know recently manufactured some desoxyn from pseudoephedrine, which was of a hard but bright yellow crystalline result, and then for the purpose of improving accuracy of dosing for his self-prescribed pharmacotherapy program, he dissolved the yellowy desoxyn crystals in water and added calcium ascorbate to act as an antioxidant to ensure that the desoxyn did not break down too quickly. the next morning he went to his fridge to dish up his morning dose and noticed that the solution had acquired a pink colour, and a tiny bit of precipitation which he assumed must be calcium salts of some kind (being that calcium is a fairly insoluble compound in most but not all salt complexes).

when my gnome friend told me about this i said to him 'that pink is most likely trace iodine liberated somehow from the solution'. as i lay in my bed pondering random thoughts, it returned to this strange observation, and something occurred to me.

it is fairly widely discussed that iodoephedrine is often an impurity in desoxyn manufactured in this method (phosphorus/iodine) and iodoephedrine is an intermediate on the route to the loss of that evil oxygen.

ascorbic acid is known to cause the splitting of elemental iodine, forming hydriodic acid. could it be that this gnome inadvertently stumbled on something interesting - that is, that iodoephedrine is reduced by ascorbic acid? possibly catalysed by calcium ions even?

i am fairly sure that the bright yellow colouring the gnome observed in his product was not the usual hydriodide salts, because unlike the desoxyn hydriodide salt, these salts were not at all hygroscopic, hard and crunchy, the gnome told me.

the speculation i am thus presenting, not based on terribly concrete data, but an indication of something going on is glaringly obvious with the pinkening of that solution.

there are two possibilities: one trace hydriodic acid salts, and maybe the gnome's manufacturing method was faulty, but he assured me that about a match-head quantity of this material was nigh on too much of a dose, and lasted for about 18 hours, thus ruling out hydriodic acid salts because possibly although pseudoephedrine hydriodide may not be a hard non-hygroscopic salt, i cannot say for certain. the other thought that occurs to me is hydriodic esters, but i've not heard of that.

the second possibility is that there was a moderate amount of iodoephedrine in the material. i had been under the impression for quite some time that simply dissolving this substance in water tended to dehydrate back into ephedrine and hydriodic acid, but maybe i am wrong about that.

and so, being that calcium ascorbate, and (bearing in mind the unlikelihood that hydriodic acid salts were significant elements due to the lack of water attracting) possibly iodoephedrine were combined in water, a fair amount of calcium ascorbate, about probably half a gram in 29ml of water, and the result 24 hours later is a pinkened solution, could this mean that the ascorbic acid reduced the iodoephedrine? i seem to distinctly recall that the mechanism of conversion of elemental iodine into hydriodic acid via vitamin C was directly caused by vitamin C being oxidised, donating two hydrogens to I2 and resulting in dehydro ascorbic acid and hydriodic acid.

What, if any, result could occur from the combination of an iodinated hydrocarbon and ascorbic acid? since i may be totally misinformed about the tendency of the iodinated hydrocarbon to dehydrate to the alcohol (or should i call that reduce) in the presence of water, the only other possibility is that the ascorbic acid can reduce the iodoephedrine, just as it does to elemental iodine, by donating two hydrogens to it, resulting in hydriodic acid and desoxyephedrine. the hydriodic acid, in a weak solution would quickly reform iodine and thus would cause a pink tint.

if one could iodinate the aminoalcohol via a means not involving phosphorus (and after much thinking about this i suspect that the conventional iodine/phosphorous reaction proceeds in part through the formation of phosphorus triiodide which, like its other halophosphorus friends is a potent halogenation agent)... then if this mechanism has been correctly surmised, the reduction of the iodinated benzylic amine could proceed via ascorbic acid.

to this end, a method utilising kaolin clay, sulphuric acid and potassium iodide is known to convert benzylic alcohols to methyliodinated benzenes, i can't remember the yield but i think it was somewhere between 80-90% and 5 minutes in a microwave (with proper heat control of course)

it occurs to me that the calcium ions may play a part in this process somehow, but i can't be certain.

and the other thought that occurs to me is that, after the conventional phosphorus/iodine reduction, ascorbic acid, or perhaps calcium ascorbate (if calcium is indeed catalytic to this) could be used to complete the reduction of the intermediate iodoephedrine. Also, along the same lines, methyl phenyl aziridine (a possible and toxic product of hot dry reactions) - maybe it too can be reduced by the same mechanism to afford a complete (apart from any pseudoephedrine which survived somehow without even getting to the intermediate) reduction of the product.

i know it's probably just a total stab in the dark but that pink colour does rather cause a moderate wrinkling of the eyebrows and questions about it's cause. Of course, it is also possible that it is just the residual hydriodic acid salts left over from a quick and dirty post rxn workup.

loki · guinea pig

regarding the source of the bright yellow colour, i have seen pictures before of methedrine as a bright yellow crystalline material. i looked at the possibility that the yellow was just sodium iodide, but sodium iodide is a glassy crystalline substance. the hydriodide salts are hygroscopic so the possibility of the crystals being hydriodic acid salts is pretty low, and the fact that it is known that ephedrine reduction can produce a yellow coloured yet non-hygroscopic crystal would tend to indicate that indeed the yellow material is in fact iodoephedrine.

This does not yet rule out the decomposition of sodium iodide salts in the solution of course, but it does narrow the source of the pink tint to sodium iodide decomposition in water, or alternatively, the speculative suggestion that the ascorbate ions reduced the iodoephedrine, or, alternatively, that the iodinated ephedrine reverted to the ephedrine and liberated HI which decomposed over time into iodine.

However, the preponderance of calcium ascorbate in the solution would not easily permit this decomposition because it would reconvert the iodine back into hydriodic acid and thus should not have been able to return to the elemental form in such a solution, in such a short period of time, unless cool temperatures can accelerate this reaction.

However, if there was a preponderance of iodoephedrine in the solution, and the ascorbate already reduced it, the dehydroascorbic acid would not be able to do this reduction. the amount of precipitate the gnome described did not suggest that this lack of available ascorbates was caused by simple insolubility (maybe 2-5% of the original volume of calcium ascorbate was the amount of precipitate formed).

probably a close to equal amount of calcium ascorbate as alkaloid salts was added, and calcium ascorbate is actually di-ascorbate too. the chances that in 24 hours at 4 degrees C that the hydriodides could have come out so quickly into iodine without there having been a fair excess of iodine atoms around is pretty low i think.

Another thing that may or may not be relevant to this is that the gnome slightly over-acidified upon extraction into the aqueous phase, meaning that the solution would have had a slightly acidic pH. The water was carbon/zeolite filtered water, so although there would have been trace magnesium and calcium in the water as well, the amount would be negligable, at least half or a quarter of what is present in the tap water, which on a TDS meter reads 30ppm.

so, after some further thinking about the possible sources of this iodine, it seems to me that the possibility of ascorbic acid reducing iodoephedrine becomes even more probable.

loki · guinea pig

i know this is a total stab in the dark, i just thought it was worth mentioning because of the novelty factor.

QuickFitAbuser · Quality Control

No, wait a minute loki, this might'nt be such a stab in the dark.
Reading your post brought a distant memory to the frontal lobe.
I recall reading, either in a text book or a patent and it was in drug literature about using Ascorbic acid for reduction , on sensitive molecules. There was I believe a Hydroidic reference there also.
Leave this with me for a while and will try and recall more and hunt down the text.
You never know, this might be developed into the next big thing with all the minds here at work.
There would be riots if they tried to ban the 'ol Vitamin C.

Sadly, there is still that psuedo access problem.

Also, on the yellow ting, did the gnome do acetone/alcohol washes etc?

loki · guinea pig

well, the gnome says that the particular shade of yellow was not the same shade of yellow he had seen in previous and commercially acquired materials, it was intensely yellow, just a few shades from fluorescent (maybe he was exaggerating a bit on that point) but he was not sure for sure, what it was. i told him it could possibly be trace amounts of loratidine, but then he retorted 'dood loratidine is a white substance' and also looking at the structure it can't have been modified by the reaction particularly - no hydroxyls anywhere.

er... so anyway, the gnome said because it did not look like the usual yellow that people wash out, and the whole thing formed a nice crunchy rigid crystalline consistency (meaning the colour was not caused by hydriodic acid ions)... and the gnome confessed something important right at the end: that he'd used a bit of an excess of iodine in the reaction, as evidenced by an initial failure to acid/base extract it due to inadequate basification - the toluene turned a murky piss yellow colour, reddish yellow, which reminded the gnome of one time he dissolved iodine in naptha, but not so dark. I said i didn't think an excess of iodine could cause any major problems, but i could have been wrong. in any case the gnome said that the workup was fully basified until it acquired the characteristic milky appearance and funky odour, so there's no way that it could be a component of the product.

...which leads to the conclusion that the product was highly contaminated with iodoephedrine due to an insufficient reaction time possibly.

anyway, knowing the way that ascorbic reacts and forms dehydroascorbate in a redox reaction where it is oxidised by losing two hydrogens, and also the known method of ascorbic acid reducing iodine to hydriodic acid, it does seem possible that a relatively delicate molecule containing a benzylic iodine might be reduced by it.

QuickFitAbuser · Quality Control

Yes, well IMHO the stronger, faster the RXN with RP/I, the better. Burn that Iodo off.
Will probally need a little time over the weekend to find those refs etc.

loki · guinea pig

just been messing around with a molecular mechanics modelling program, built an iodoephedrine molecule and ran the geometry optimisation on it, and then turned on van-der-waals rendering, and sure enough, that iodine sure sticks out like a sore thumb on the side of the molecule. For good measure, i rendered the ascorbic acid molecule and the hypophosphorous acid molecule as well, to get a good look at their comparative geometries. hypophosphorous is clearly a good dehalogenation agent because it has two hydrogens sitting there right next to each other, I imagine that when it comes into contact with that very prominent iodine atom that the reaction with it comes quite easily.

But ascorbic acid has two hydrogens sitting very close to each other there too and it is known to readily lose and form two double bonds in the presence of an oxidiser. According to the geometric optimisation that the molecular modeller did, these two hydrogens normally tend to be bent away from each other towards the axis of the ether ring. But if I placed the two molecules with the iodine atom and these two hydrogens in proximity to each other the geometric optimisation brought those two hydrogens VERY close to each other, and pertinently, in a very similar position as i imagine that hypophosphorus' two reduction capable hydrogens would. I should probably bring those two together to see how they behave as well.

edit: Having done that to both of them I observe some interesting things in common with both of them. It appears that the dehalogenation via hypophosphorous acid proceeds via the attraction of the phosphorous atom to the iodine, and both hydrogens tend to move towards one side.

If you have a molecular modelling viewer plugin which can render .mol files, here is a link to it: https://m0c.no-ip.org/comparison.mol

here is an image taken from a screenshot:

I can't say that this means anything at all, but it does indicate that there is most likely a good chance that when these two chemicals come into contact that the charge characteristics (which is how the optimiser calculates optimal geometry) are such that the hydrogens that ascorbic acid donates in it's redox reaction definitely are drawn towards the iodine atom. If i can figure out how to run the animation feature of the modeller I will post this animation in here so you can see what the geometric dynamics of this reaction, in theory, would be.

loki · guinea pig

i thought i should probably have a look at what water dose when brought close with this geometric optimisation thing and it seems that it does not want to be quite so close to it, it moved sideways and across into a position where one H was near the iodine, but not as close as the other two, and the other hydrogen oriented towards the centre of the benzene ring. ascorbic acid sat it's hydrogens virtually on top of the iodine, whereas hypophosphorous acid seemed to like to put its phosphorous atom right on top of it.

While i am fairly sure that this is not a very practical way to determine likely reaction kinetics, in a complete way, it sure did make it clear where these atoms liked to orient themselves to balance charges. And thus, watching that water molecule dance away from the iodine, I conclude that it most likely will not easily rehydroxylate, meaning that indeed it can be brought successfully out of the reaction into dry form with an acid base (ie through wet conditions).

and the similarity of the geometric optimisation of ascorbic acid vs hypophosphorous acid would tend to suggest that ascorbic acid can indeed do the reduction, and may be even more effective (able to do the reaction at lower temperatures or in a shorter time) because it appears that the carbon-oxygen pairs joined at the carbon by the double bond have a strong affinity for the iodine atom, similar to the way that hypophosphorous did, except in doing so they bring the hydrogens even closer.

On a side thought, I am now of the opinion that the phosphorous iodine reaction system works like this:

iodine and phosphorous bond via 3 iodine molecules attaching to two phosphorus atoms forming two moles of phosphorus triiodide, which is a strong iodinating agent, and thus when it comes into contact with the ephedrine's hydroxyl group it readily plants the iodine on it and takes up the hydroxyl.

2(P) + 3(I2) --> 2(PI3)

PI3 + 3(pseudoephedrine) --> P(OH)3 + 3(iodoephedrine)

This can happen to three ephedrine atoms at the same time and the result is the formation, almost, of phosphoric acid. Free phosphorous can, in this system also, at sufficient temperature form phosphine gas by stealing it from whereverthehellitcanfindit (as it is wont), and phosphine gas can react with the intermediate formed to balance itself with the almost phosphoric acid by forming hypophosphorous acid, with an available oxygen molecule:

2(PH3) + P(OH)3 + O2 --> 3(H2POOH) (hypophosphorous acid)

I never thought of writing hypophosphorous acid's formula that way, but it's correct, well, not conventionally but technically, the main thing: it says POOH hehe

Of course there is probably other ways that the same thing can come together, but i think that the pathway i just described is the main one. The iodination requires an iodination reagent, thus the phosphine has nothing to do with it, but after the iodination the phosphorus tri-hydroxide, clearly unstable, has got to move itself into a more stable form, and as you can see 2:1 phosphine to this unstable intermediate product of the iodination recombination comes out to 3 molecules of hypophosphorous, which conveniently enough means we can then immediately reduce those three iodinated hydrocarbons.

Secondary to this the initial iodination probably can occur in the rP/I2 reaction system via the routes that the other two methods work, by direct iodination with HI acid at concentration.

and then these three molecules of hypophosphorous can then reduce our three molecules of iodoephedrine.

As for how this can work with hypophosphorous acid and hydriodic acid instead: it's much faster - the hydriodic acid directly attacks the alcohol forming water, and the hypophosphorous then removes it. which is why the reaction is so much faster, less steps, less complication.

red phosphorous and hydriodic acid would not start a reaction going until some of the iodine re-formed out of the hydriodic acid and reacted with the phosphorous.

iodine and hypo together would react immediately to form hydriodide - the reacted hypo turning into phosphoric acid, and then reacting with water, taking the hydroxyls from the water and creating phosphoric acid.

Ok, so the point of that was to discuss reaction kinetics of the conventional methods, in order to understand the ways by which this reaction system works. It is clearly a complex and multi-faceted reaction system which, as is rare in chemistry, can clearly run a reaction in a good three different ways to achieve the same result.

There is a reaction I found some time ago for direct iodination of benzylic alcohols which did not need phosphorus. It involved kaolin (silica alumina hydroxide) sulphuric acid and potassium iodide. The reaction was very high yielding, and must have been occurring through a very direct route. I considered that maybe it worked via the sulphuric acid binding with the hydroxide, and catalysing the iodination of the alumina to form aluminium tri-iodide which then does the iodination. Since the reaction is high yielding there probably isn't many other pathways for it to run, than the one which does the reaction. I can't think of any other way in which this reaction would work right now, and the parallel of the triiodide molecule with the PI3 which is a good iodination agent too sprung to mind immediately. Possibly this reaction is catalysed by the presence of the silica...

If there was other options for forming the aluminium triiodide they would probably be nicer than this scheme... the first thing that comes to mind is aluminium (powdered) added to ascorbic acid and iodine.

There is probably more than a few ways to do it, but I am all out of further ideas here so ... Some more reading on aluminium chemistry perhaps...

(i've probably embarrassed myself with inaccurate speculations here but... o well Very Happy

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