Final Word on the HI/RP Mechanism

[Rhodium]

no Rhodium - H3PO2 not H3PO3

I wasnt referring to your "...ideas" but to the two pdfs you have on your server which talk on H3PO2 reactions. I am no coward - if I mean you I tell this, ok?

Huh? On the page

https://www.thevespiary.org/rhodium/Rhodium/excellent.ideas/index.html

two PDF files are linked, namely these two:

https://www.thevespiary.org/rhodium/Rhodium/excellent.ideas/h3po2.i2.reduction-1.pdf

https://www.thevespiary.org/rhodium/Rhodium/excellent.ideas/h3po2.i2.reduction-2.pdf

The only thing discussed on that page is the Hypophosphorous acid–Iodine reducing system published in Tet. Lett. 2-3 years ago, and my only effort was to read those two docs and adapt their techniques for use with (pseudo)ephedrine instead of boring benzhydrols.

Actually I cannot find the information on impurities by high HI concentration in the references you provided - the forensic ones are also suspicious per se - or do you you think they provide correct ratios for cookie cookie?

If you check the GC outputs from each and every of those forensic articles, you can see that the main product very often is not methamphetamine, but rather phenylacetone (+ condensation products of that compound), especially in the reference where they analyze the remnants of a "dry reduction" (= high acid concentration, high temperature).

If you then on the other hand take a look at the german patents for the production of phenylacetone from ephedrine alkaloids, you see the same general trend - hydrolysis of ephedrine and its derivatives to the corresponding imine, and in the end phenylacetone from that - that reaction is favored by strong acid and high temperatures.

There is no need to believe the ratios published by the forensic chemists, as they have probably not made any effort towards optimizing the reaction even if they are telling the truth - the main point is to look at the product distibution in their spectra - as they have probably not drawn them by hand, those can be regarded as autenthig data.

I have provided refs to every point.

Except what I have been asking all the time - in what piece of literature can I find a high-yielding reduction of a vicinal amino alcohol to the hydrocarbon where stronger acid than the constant-boiling 57% HI is used (with or without recyclants).

Tell me what information you need to be able to bubble HCl into a reaction at 60°C.

That sentence is enough if taken as instructions, what I felt your description lacked was rather a compelling reason why anyone would go through the trouble of performing the experiment you suggested, as this far we have nothing but your word on that it is a "great modification" to the standard procedure. You have not provided any literature references, nor have you described a controlled trial where you tell us what the return is from the increased effort in terms of absolute yields, reaction times, product purity etc... Only that you describe your variation as "better".

[gluecifer69]

This may bee slightly off topic, but Gluecifer an't fraid of a some bad karma.

Gluecifers point is this, this is the greatest thread I have had the pleasure of learning alot of new info from!

Please Rhodium and Organkium, you are the two (in Glueys opinion in his reads on this site for the past year and Rhodium's for the past three) greatist minds in the hive and please don't get agressive Gluecifer senses that both Rh and Org should keep up the great info exchange, but back off on the personal emotions.

[Organikum]

For the flowers first and for the hint which is right on the point.

So I apologize explicitely for the "below the belt" expressions in my last post, also I was highly pissed - and not without reason - it was unnecessary.
I hope Rhodium you will accept my excuse on this.

Back on topic:
- Rhodium, high HI concentrations AND high temperatures, you name it by yourself. Whereby the high HI concentration is necessary for the reaction and concentrations on the edge of workability lead to unnecessary prolonged reactiontimes which also must lead to byproducts by the timefactor alone, the temperatures are the point you can move something.
- By reading the Gmelin and the old threads on safrole bromination you will find in the end some similarities:
- 48percent aqueous HBr is hardly able to brominate safrole 
- HI with less than 50percent is not able to iodinate ephedrine - you tell this
A working solution was found by Fester, Ritter confirmed it several times:
Dehydration of the HBr by gaseous HCl. As dehydration works the problem will be related to the hydrates formed by HBr as HI. For the HI hydrates see the Gmelin.

There is some logic in this.
I thought.
I tried.
And the proof is in the pudding.

The dehydration fights also another probable problem, which I guess to exist but here I have no direct proof: I believe a part of the the HI is trapped as salt on the aminegroup - a equilibrium with the HCl salt form may be formed. But thats a guess.

I also tried a reaction after the old german reference using a catalytic amount of iodine (10percent of theory) - no reduction at all also at 140°C+. TLC was run using 48/48/2 - ethylalcohol/chloroform/ammonia on standard TLC plates.

I read and learned a lot the last years.


So Rhodium, your interpretation of the data in the references is by will and not by facts, sorry - you cannot blame something on one factor if already two factors are provided, thats unscientific. But usual I know.
The information in the references is unconsistant and contradictary in parts - sometimes HI is produced from the GAA even.... why not, who minds...?
So I refer mainly to physical data and hopefully proofen knowledge:
- Gattermann-Wieland
- Gmelin
- Vogels

In addition - please think through the reaction by my way once - you will see how things suddenly fit together and how a certain (not complete) amount of predictibility is gained all of a sudden - and the predicted changes match with the known facts.
Of course a rather high developed ability of imagination of complex things is needed to do so....
(sorry - couldnt behave..... )


hey - a present for the chief at last:
- the hexamine to methylamine reaction is NOT always the same as ammoniumchloride + formaldehyde to methylamine one. These french chemists in these days were not so stupid and paper to publish was expensive.
The funny thing is you have the answer also pointed out but never followed it experimental: "....if enough water is present" The frenchies did never say stochiometric amounts are enough, how do you come to think so? Try 4l water for 100gram hexamine and use less HCl - if you add some zinc or Al or tin a 40th of theory HCl and roomtemperature is good to go..... or you get ammoniumchloride en masse.
(ever heard of chloropicrin? Thats where I took the trace to haunt this down)

I once tried to spoonfeed the biosynth to the masses.
I swore to myself never ever to spoonfeed something again.

Happy experimenting!

[Rhodium]

There is some logic in this.

Most definitely, it has been a good theory all the time. Hopefully the reaction rate increase by using this modification wins out over the unavoidable increase in hydrolysis rate gotten at the same time.

I thought. I tried. And the proof is in the pudding.

Is this to be read as you did try out this suggestion of yours? If so, then was was the yield difference?

The dehydration fights also another probable problem, which I guess to exist but here I have no direct proof: I believe a part of the the HI is trapped as salt on the aminegroup - a equilibrium with the HCl salt form may be formed. But thats a guess.

Does any amine salts precipitate during the reaction? If not, then all the HI is available for reduction, as in a homogenous solution, the amine nitrogen is merely protonated and not present as a tight RR'NH₂⁺I^- ion pair holding on to the iodide ion.

I also tried a reaction after the old german reference using a catalytic amount of iodine (10percent of theory) - no reduction at all also at 140°C+. TLC was run using 48/48/2 - ethylalcohol/chloroform/ammonia on standard TLC plates.

That's interesting, but do you remember the ratios of reagents/solvents? I believe the problem boils down to an insufficient HI concentration rather than any other factor in this case.

I think this will be my last post regarding this HI hydrate discussion, as my expertise lies in knowledge of the theory and the published literature rather than me having any practical experience with this reaction (something I believe I would need to discuss this further), as I have said before, I have never extracted a single pill and never run a single PIE reaction. I'll wait for others to take up this suggestion and publish more details regarding yield improvement using this procedure.

I'm not sure I understood what you said regarding the HMTA reaction, but let's take that discussion in an appropriate forum in case you want to clarify through what alternative mechanism the reaction would proceed - this is no place for that.

Thanks for your input in this case, hopefully others will embrace your suggestion or at least have learned a thing or two by reading our discussion here - it probably contains a lot of things we know about the reaction but which we haven't written down elsewhere for people to see.

[Organikum]

Please point me in the direction so I can verify this - I cant remember to have up to now read of this being named as a problem in this reaction.

"Does any amine salts precipitate during the reaction? If not, then all the HI is available for reduction, as in a homogenous solution, the amine nitrogen is merely protonated and not present as a tight RR'NH2+I- ion pair holding on to the iodide ion."

Are you sure on this? The HI and the hydrates are also completely dissociated and on the other side bound quite strong together. I believe this a simplified and misleading way to see things - this atoms swimming in a soup picture - I prefer to see it as a interacting assemblation of probabilities.

I told this being science and not fiction.
Now guess if tried it.
And I told about yields already.

nuff now.
anything else would be forced spoonfeeding.

[Rhodium]

Hydrolysis? Please point me in the direction so I can verify this - I cant remember to have up to now read of this being named as a problem in this reaction.

This is the acid-catalyzed hydrolysis of ephedrine alkaloids to phenylacetone and methylamine I have mentioned and linked to repeatedly above.

In regards to ion pair bonding, I am completely sure of the iodide ions not being taken out of the reaction equilibriums by salt formation as long as 1) no precipitation occur, and 2) at least 1 equivalent of H⁺ from another source being present (such as using an amine hydrochloride as starting material).

[Organikum]

As told - I am not sure on the salt formation as problem.
As told - I am sure acid hydrolysis almost not to take place at the low temperatures recommended - for boiling ephedrine in HCl only leads to razemisation on the alpha-carbon and a ephedrine/pseudoephedrine equilibrium is formed, this may be seen as strong hint in this direction. A stronger hint might be the fact that TLC showed no byproducts in my related experiments - but an almost quantitative reduction in several runs.

thats all.

[elfspice]

could it bee that the relative solubility of the various salts that can form in the reaction flask affects the reaction - specifically, if HI is the majority acid in the reaction (well, about 2x as much HI as the HCl from using E.HCl) then the logical conclusion is that the e.HI would tend to form a lot, and perhaps this salt is less prone to reaction somehow, and let's not forget that if it's ionised, stuck to the ephedrine, then it can't be reducing anything. In fact, you want to optimise conditions so that the least ionised acid in the mix is the HI, and the simplest way i can see of doing that is to eliminate water, use anhydrous acetic acid (which will greatly tilt the balance in favour of the formation of E.acetate and away from E.HI) and adding anhydrous HCl for good measure... if we want every drop of un-ionised HI to be available for reaction, we want to make the HI content about 1% of total acid content, which will mean that virtually none of the ephedrine forms E.HI

As far as i can tell, the reaction depends on un-ionised hydriodic acid coming into contact with the hydroxyl. Water ionises HI. HI in high concentrations at higher temps tears everything up, but what say we created conditions where it was virtually 100% HI (ie no water), and temperatures very low so as to keep the reaction intensity low and reduce side products.

how does this sound:

mix ascorbic acid with iodine with both dry, add small amounts of water to initiate the reaction and agitate it to get it to keep mixing and reacting.

minimal water: if minimal water is used the concentration of HI that forms will rapidly come to saturation and this will lead to fuming. The fumes are bubbled through a solution of anhydrous acetic acid.

The anhydrous acetic acid now nicely saturated with HI is gassed this time with anhydrous HCL (CaCl+HCl) until saturated.

This fuming stinky mixture of acids can now have some pseudo freebase added to it, the whole thing in a flask with reflux running at a nice gentle 50 degrees C or so.

The hydriodic acid, without the water is able to react freely with whatever it finds most interesting (the hydroxyl) and with the lower temperatures, side reactions ring closures and decomposition reactions cannot easily occur, and there is no other reaction available to it, nothing to reduce in the whole reaction system except the hydroxyl

Couldn't this reaction be done in a sealed vessel that lacks a condenser anyway - i can see it working very well inside an earlenmeyer or volumetric flask with a cork held in place with a clamp or somesuch. with the fuming acids i don't think that a condenser would be enough, although i could be wrong... since the reaction works cold it doesn't need to breathe does it? i guess it doesn't matter, the condensing acetic acid will keep most of the HI in there.

I think this would make the reaction possible without using I2 recycling agents as well, since there is nothing but hydroxyls consuming the HI.


maybe i've got this all wrong, but i always remember from highschool chem that ions are different creatures to the un-ionised forms. when HI is dissolved in water it is really a H+ and an I- floating around. But anhydrous HI is exactly what the label says. Why, if it isn't the fact that the reaction requires un-ionised HI to occur, then i can't think what the hell else it could be, otherwise a very near to saturated (saturated enough to be smelly) solution of HI would not be needed. it could be done with a more mildly dissolved solution if it were the case.

HI in water is not HI, it is hydronium ions and iodide ions in equimolar quantities. this mixture of ions does not have the same chemical properties at all. the neccessity for conc HI solution points to this fact - that only the free HI can do the reducing, the iodide is almost unreactive. so clearly, water is the enemy here.

another point to add: ephedrine freebase is also a different beast to ephedrine ionised into a solution with excess acid countering the amine's addion of OH's. Which form of the ephedrine does the HI react more vigourously with? well, i would think that the salt is what you want, for the simple reason that the amine is a potential reductant for the HI.

[elfspice]

um, boiling ephedrine in HCl laden solution is gonna result in a lot of chiral rearrangement. so, no... keep the HCl out, maybe instead use an excess of anhydrous acetic acid

[CharlieBigpotato]

in a plastic bag.
a flask with a ballon on top is a sealed rxn, unless its leaking like a mother.
that 50 cent item (balloon) is evidently up to the task of containing the potential bomb within.

furthar more, there is no advantage in having air in the flask at the on-set

i'd like to see this post rated as dangerous, beecause heating up almost anything in a sealed containor is risky, especially if one doesn't know anything about anything.

heating up water in a sealed containor is just as risky, although not as corrosive on the 'seals'.
when liquids beecome gasses,generaly, ya'got pressure.
this is the secret to our lives, in america.
from wood fired , cast iron steam engines, to nuclear power plants.

[Rhodium]

Preparation of ?,?-Dimethyl- and N,?,?-Trimethyl-?-cyclohexylethylamine
Bernard L. Zenitz, Elizabeth B. Macks, Maurice L. Moore

J. Am. Chem. Soc. 70, 955-957 (1948)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/hi-rp.aminoalcohol2amine.pdf)

A reduction of ?-methyl-norephedrine to ?-methyl-amphetamine (Phentermine) with HI/P (80-88% yield).

They use 20g RP to 0.4 moles of the aminoalcohol (66g, it has the same molar weight as ephedrine) together with 170 mL 57% HI. The mixture is reacted for 25h at reflux and 12h at room temp before workup (filtration, thiosulfate addition, acid/base extraction, distillation, gassing w/ HCl).