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Krokodil - a lack of synthesis question

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Bluelighter
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Anyone who has seen pinene dripped onto I2 will see that that that I2 adds to the alkene pretty readily. Now the Russian 'Expert Samples' of krokodil show that some variations of the route yield more methyldesorphine than desorphine (and I'm pretty sure it's because I2 in CH3OH is a common source of I2. What I cannot figure is why the I2 doesn't add to the alkene of methyldesorphine yielding 6-methyl-6-deoxydihydromorphine. The beta epimer of that latter compound is some x60 M (but who knows how potent the alpha is).

All I can suggest is that the P has all been oxidized to H3PO3/H3PO4 yielding I2 so that there is little to no free halogen in the reaction. I know the 'cooks' use the colour to detect completion (which only means all the I2 is used, I presume) thus no I2 to add OR the Russian 'expert samples' aren't too expert. The toxicology team at the University of Porto are checking for the presence of WP and for P containing species derived from the codeine (because several impurities with MW 340-469 show up in GC-MS).

I'm asking if others agree that the alkene SHOULD add because I don't think it will add to the allylic group but should add across the 6,7 or 7,8 double-bond in desoxymorphine C/D which explains why no unsaturated constituents are found. If it COULD add to the allylic moiety, plain I2 in CH3OH added before the RP might prevent the formation of the P containing derivatives.

This isn't a case of making a 'how to' guide but Portugal leads the world in HR so I CAN discuss these things with the people at Porto uni. They are keen on new ideas and are very approachable so anyone with insights into the various toxic species would do well to communicate those ideas.
 
It's not uncommon to run into members of classes of compounds which should smoothly undergo a reaction but for some reason they react sluggishly or don't react at all. First thing to do IMO is the simplest thing one can do, take methyldesorphine and react it with iodine, then I2/RP, and so on, i.e. eliminate as many variables as you can, then start putting them back. If it does react, then look into potential reasons why it is not formed using "krokodil" protocol. The formation of methyldesorphine is quite surprising to begin with, its content in "krokodil" is variable and I don't see it mentioned in all papers on the composition of "krokodil", so 6-methyldesomorphine might be formed in small quantities and might have not been detected so far. Another question I would ask is "what is required in the "krokodil" procedure for methyldesorphine to form?". The source of the methyl group is most likely MeI formed from methyl ether cleavage, all other possibilities are unlikely. MeI is volatile, considering the conditions used are harsh, the amount of MeI lost during the reaction may vary from one performer to another. But how is C6 made nucleophilic to react with MeI? Perhaps it's a reaction involving radicals? I certainly wouldn't expect it to be one of the main reactions in this system. So before looking for 6-methyldesomorphine or reasons why it is not formed, I would want to find the conditions under which appreciable amount of methyldesorphine is formed.

If the reagent reduces the 7,8-bond, it should be able to reduce the 6,7-bond even if it's a bit more hindered and differs electronically but we're just extending the reactivity guessing here and in such cases some small details are responsible for differences in reactivity that we can't predict using common sense. Still, the comparison between a-pinene and 7,8- and 6,7-didehydromorphinans is unfortunate IMO because in a-pinene there is much more ring strain responsible for driving the reaction once the carbocation is formed or the olefin is activated with a Lewis or Bronsted acid. There isn't that much ring strain in methyldesorphine.
 
Well adder, the high levels of methyldesoprhine may be because I2 is sold as a solution in methanol in Russia. The deprotection yields a mole of CH3I but I suggest that it takes a large excess for the sample to be 33.7% methyldesorphine, 29.6% desorphine & 29.7% 6-deoxymorphine (DOI: 10.1134/S1061934808040096). Is pinene THAT strained? The cyclohexene appears to be in a near-minimum chair conformation. That said, Chadha & Rapoport proceed via the 6-ethenyl moiety (DOI: 10.1021/ja01578a040) and that was in 1957, after they had spent the whole decade working through the various C-ring substitutions. It seems that as soon as they discovered them, they went on to develop the 14-substituted derivatives (e.g. nalmefene).

Bromine reacts with allyl alcohol to make 1,3-dibromoprop-1-ene and I have a patent in which codeine is 6,8-dichlornated with HCl giving 98% yield... in only 100 hours.

I'm not looking to make krokodil synthesis easier, I'm noting what is and is not being found in samples and trying to work out why. When methyldesorphine is the main product, we need to examine what these 'cooks' are up to because we have no HR plan for the stuff... because we don't really know what the stuff is!
 
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If you compare the reactivity of 1-methylcyclohexene and a-pinene towards iodine, there is a great difference and it must be from the ring strain. And it is large IMO in pinenes because of the cyclobutane ring, the methylene bridge forming the cyclobutane ring disturbs the cyclohexene ring and it's far from an ideal half-chair conformation of cyclohexene when you look at the bond angles in this bicyclic system. For the angles between C-C=C bonds the values deviate from 120 degrees a lot, there is no such strain in 4,5-epoxymorphinans and C-C=C bond angles are much closer to 120 degrees, 3D optimization in ChemSketch shows me 121 and 122 degrees for C8-C7-C6 and C5-C6-C7 respectively. Below are some bond angle values in a-pinene for comparison.





As for the C7-C8 reduction in codeine or morphine in the reaction with I2/RP, there may be no 7,8-diiodo derivative formed actually. I like this proposal:

Link to the proposed mechanism of codeine to desomorphine reduction with HI/RP.

Of course this doesn't answer the question why samples with high methyldesorphine content don't contain 6-Me-desomorphine. C7-C8 and C6-C7 double bonds in 4,5-epoxymorphinans differ in sterics and electronics but are those differences solely responsible for different reactivity towards reduction? In the reduction of codeine ether cleavage and 6-OH cleavage likely precede reduction of the C7-C8 double bond, so it's no longer an allyl alcohol that is being reduced. In case of methyldesorphine there is an allyl phenyl ether in the structure. But this brings us back to my previous question - what factor(s) cause methyldesorphine to form under the reaction conditions? Is it the presence of MeI in iodine reagent used or can it form when there is no external MeI present? I like studying reaction mechanisms, I'd certainly like to see more attempts at reproduction of I2/RP reduction of codeine from professional groups, at this point there's just not enough data to answer questions in this thread, I think.
 
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I'm co-responding with the Department of Toxicology at the University of Porto and it looks like the RP/I reduction/deprotection has a toxic impurity. A P is added at thr 6 position - a phosphonate ester (This is also covered by Desoxycodeine Studies by Small & Cohen - Desoxycodeine Studies VII). Their GC-MS has some unexpected products with MW 340-369 which are as yet unexplained so trying to work out the whole system is more complex than it initially seems. When Russian samples show 33% methyldesorphine & 28% of desomorphine/6-desoxymorphine, a lot of a CH3- species is involved, safe to say. The phenol is also reduced in some samples but in not a single case was an I containing product found. Now I know that codeine heated with 37% HCl for 100 hours yields 6,8-dichlorocodeine (classic allyl halogenation) but the double-bond is not reduced. The work of Small & Cohen in the 1930s also an allylic rearrangement takes place so isocodeine/isomorphine is in their (they give beta chloromorphine as their example so halogenation before rearrangement?) so the double-bond is at the 6-7. While there are examples of I2 & CH3I adding across alkenes, it seems to be a limited and fussy stratergy.

Even within Russia, no single method is used. Different regions have signature mixtures of products and for what it's worth, those with a lot of methyldesorphine were seized in bulk (Tass images suggest Kg bags) but even when their is no P or simple P salts in the samples (so the photogenic physical damage is ameliorated), the neurological problems persist. The long and the short of it is that unlike methamphetamine, RP/I can't produce a clean product and the toxicology isn't well investigated).

There are at least half a dozen alternative OTC reagents to reduce I2 to HI but making that information public can't even be discussed in the UK HR community. With Portugal's unique (AFAIK) HR strategy, they MAY have to consider that option.
 
Use the Birch reaction instead. Much healthier!

Metal ions break that epoxide bridge, sadly. OK, so you can go down the metopon path but in almost every case on record, it was people making it for their own use. Granted there were a couple of exceptions but it seems like HR efforts will tend towards the very obvious risks. The people in Porto are now testing for WP (or indeed any P) fumes and NMR on the three trace impurities that may contain P species at the 6 position (I'm guessing that the PI3 isn't donating an I to the 6 position, it's donating -PI2 which undergoes oxidation.

However you look at it, you are using class B drugs to make class A drugs so at anything but eggcup scale, expect a long term at a HMP holiday camp. Be it codeine, pholcodeine or DHC, nobody is going to collect enough to clean it up - mechanical losses being what they are. This isn't going to be the new methlab.
 
BTW - they are now just running a long-term experiment based on the RP/I reduction system to see if WP is produced. Traces of WP have been found in meth labs so it MAY explain a lot of the damage we see although as I have mentioned, a series of studies in 1938 mentioned that a P ester was discovered at the 6 position. Instrumentation was very poor back then so the species hasn't been identified but I harbour the suspicion that it may also be a toxin thus far undetected. Lower temperatures & catalysts might make things safer but I doubt HR agencies will ever consider telling people how to reduce the risks involved in synthesis.
 
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