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tupence_hapeny
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n-methyl-3,4-Dihydroxyphenylalanine (orgsyn)
Making my first post, one from which my character can be ascertained, is somewhat daunting.
However, I found this synthesis on orgsyn, and apart from one or two chemicals it is well within the reach of the everyday hobbyist:
http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv3...
It is entirely legal to possess and/or make, although the current synthesis may make use of some chemicals I neither want to acquire or own (namely
HI). One chemical is seriously not something you would want to order, while another is also not a good idea (Ca.Hg(2?)).
Therefore, I would like some assistance, especially from some of the more knowledgeable persons, on this forum, in order to find a more OTC approach
to this interesting, legal molecule.
For instance, I have heard that it is possible to demethylate the vanillin using Lithium Chloride, which is easily prepared from OTC materials
(Lithium Carbonate and Chlorine gas) in dimethyl formamide. I therefore seek information on whether DMSO could be substituted for DMF, and if so, what
effect this substitution could have on the reaction procedure? (currently works by heating to 150-160C and adding portions of Lithium Chloride over 20
hours). I would also be interested in ascertaining whether this reaction could be performed in a microwave, thus reducing the reaction time.
I would like to know whether the double bond reduction by calcium amalgam could be effectively carried out by use of an aluminium amalgam (given the
restrictions upon the use of alkali metals here).
Thanks
[Edited on 26-3-2007 by tupence_hapeny]
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not_important
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| Quote: | | ...Lithium Chloride, which is easily prepared from OTC materials (Lithium Carbonate and Chlorine gas... |
Sounds like an interesting reaction. I've always done it by placing two beakers containing respectively Li2CO3 and water, and tech hydrochloric acid,
in a plastic bucket and loosely placing the lid. My way just release CO2, your's look to pump out O2 or a chlorine oxide as well.
There does not appear to be any mention of calcium amalgam in the article you reference.
You can prepare amalgam electrolytically, although perhaps not of sufficient concentration.
[Edited on 26-3-2007 by not_important]
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Levi
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I understood very little of what you said, tupence, but welcome to sciencemadness.
Chemcrime does not entail death. Chemcrime is death.
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tupence_hapeny
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| Quote: | Originally posted by not_important
| Quote: | | ...Lithium Chloride, which is easily prepared from OTC materials (Lithium Carbonate and Chlorine gas... |
Sounds like an interesting reaction. I've always done it by placing two beakers containing respectively Li2CO3 and water, and tech hydrochloric acid,
in a plastic bucket and loosely placing the lid. My way just release CO2, your's look to pump out O2 or a chlorine oxide as well.
There does not appear to be any mention of calcium amalgam in the article you reference.
You can prepare amalgam electrolytically, although perhaps not of sufficient concentration.
[Edited on 26-3-2007 by not_important] |
The patent it came from makes extensive reference to the need for it to be dry.... (They make the Chloride and dry it in the gas).
They make no reference to calcium amalgam, only to sodium (I chose to use calcium if I do this, I think it requires marginally less mercury (per
potential hydrogen) than sodium amalgam ).
Also, with regard to useful aldehydes this could be applied to, could this synthesis be used (minus the demethylation of course) with piperonal? That
would be an interesting, substituted phenylalanine...
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Nicodem
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Lithium chloride is very hygroscopic and is not easy to dry while it needs to be absolutely dry if the goal is to use it as Lewis acid (same goes for
the DMF solvent). Anyway, even if you "heard" that it can be used to demethylate vanillin this still does not mean one can use such a method to
substitute the HI demethylation step in that Org. Syn. procedure. The amino acid substrate is something completely different and the LiCl would get
quenched by the amino and carboxylic groups. Besides, if your goal is just to play around with amino acids synthesis why you even want to bother with
the last step?
Where did you heard that calcium amalgam reduces conjugated electrophilic double bonds like the sodium amalgam used in the procedure? Aluminium
amalgam is not particularly useful for the reduction of electrophilic double bonds, but if I remember correctly it can do that on some substrates. I
have no idea if it would work on such benzylidenes and besides it would be very, very difficult to work up the reduction due to the acidic phenol
group on this particular substrate. CTH reduction systems, for example HCOOK with Pd/C, can be used to reduce electrophilic benzylidene type double
bonds (as for example in the reduction of cinnamic acids to phenylpropanoic acids). There are a bunch of other CTH systems used specifically for the
reduction of carboxy enamides to amino acid amides, thus suitable to what you want to reduce.
Edit: Any aldehyde without alpha-hydrogens or interfering functional groups can be used instead of vanillin.
[Edited on by Nicodem]
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tupence_hapeny
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| Quote: | Originally posted by Nicodem
Lithium chloride is very hygroscopic and is not easy to dry while it needs to be absolutely dry if the goal is to use it as Lewis acid (same goes for
the DMF solvent). Anyway, even if you "heard" that it can be used to demethylate vanillin this still does not mean one can use such a method to
substitute the HI demethylation step in that Org. Syn. procedure. The amino acid substrate is something completely different and the LiCl would get
quenched by the amino and carboxylic groups. Besides, if your goal is just to play around with amino acids synthesis why you even want to bother with
the last step?
Where did you heard that calcium amalgam reduces conjugated electrophilic double bonds like the sodium amalgam used in the procedure? Aluminium
amalgam is not particularly useful for the reduction of electrophilic double bonds, but if I remember correctly it can do that on some substrates. I
have no idea if it would work on such benzylidenes and besides it would be very, very difficult to work up the reduction due to the acidic phenol
group on this particular substrate. CTH reduction systems, for example HCOOK with Pd/C, can be used to reduce electrophilic benzylidene type double
bonds (as for example in the reduction of cinnamic acids to phenylpropanoic acids). There are a bunch of other CTH systems used specifically for the
reduction of carboxy enamides to amino acid amides, thus suitable to what you want to reduce.
Edit: Any aldehyde without alpha-hydrogens or interfering functional groups can be used instead of vanillin.
[Edited on by Nicodem] |
Sorry Nicodem,
The idea of using Calcium instead of Sodium was not something I had 'heard' anywhere... It was rather my own poorly thought out idea Aside from which , I believe that you're well aware of where I 'heard' about the idea
of demethylating vanillin with Lithium Chloride
Anyhow, thanks for the information regarding the use of HCOOK (Potassium Formate?), that is weird, I was just reading a host of journal articles on
precisely this 'variant' on the leukhardt-wallach(?) reaction yesterday (albeit using formic acid and formamide - also if I remember one used Pt while
another used Ni) in conjunction with the reduction of carbonyl groups.
Sorry if my approach to these compounds offends, however, I believe the WOD is both invalid and immoral (given it is utterly impossible for a country
to maintain laws which 1/2 of the population breach (or have done) and proclaim itself a democracy:mad. The sooner we face facts and end this pointless excuse to provide the government (esp. police and the rest of the
executive) with the excuse to persecute the people they purport to serve, the better
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Nicodem
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I'm not particularly interested in what you heard but in references to what you heard. I'm quite sure any other member who happens to read your post
expects exactly the same.
CTH reductions with formic acid salts are not called Leuckart-Wallach reactions - that is a completely different reaction. The CTH acronym stands for
"catalytic transfer hydrogenation" and it is essentially the same as the usual catalytic hydrogenation with the difference that instead of H2 another
hydride donor is used (cyclohexene, formates, hypophosphites, borohydrides…).
I don't know what all that comments about legislation and war on drugs (assuming WOD means that) has to do with your questions, but if you have an
unstoppable urge to post about that, then it would be preferable if you do that in an appropriate section of the forum (Legal and Societal Issues,
Whimsy and Detritus seem more appropriate). Not surprisingly this Organic chemistry section is reserved to organic chemistry only.
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tupence_hapeny
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I was not suggesting this transfer hydrogenation (and/or deoxygenation) reaction was a leuckart-Wallach reaction, I was mentioning that there appears
to be a great deal of work going into CTH reactions, using the same protocols (albeit with a hydrogenation catalyst) developed for the
Leuckart-Wallach reactions (and others, suprising dithionite has been used very succesfully in the same range of L-W reactions as the formate's as a
hydrogen donor, so could it be the hydrogen donor here?
http://stratingh.eldoc.ub.rug.nl/FILES/root/VriesJGde/1980/J...
I strangely enough presumed that Methyl-DOPA would be a useful chemical target, one which even the more advanced among us here would be interested in
modifying a synthesis of (after all L-DOPA was recently the source of such a lot of interest ).
Now, that out of the way, let us proceed.
I will avoid all reference to the demethylation reaction (although big tip, it does work). Therefore, All that need be discussed is the (1) reduction
of the double bond; (2) hydrolysis of the product with (a) Barium Hydroxide; and (b) Sulphuric Acid. I have stated that I dislike the idea of
utilising HI for the demethylation reaction, for legal reasons especially (if it attacks the COOH you will have a SHITLOAD of explaining to do, not
least as to why you have a seriously controlled (prohibited) acid and how you used that to 'accidentally' make an even more controlled amphetamine
analogue ).
Now, in order not to upset any one any more, I will suggest that if you wish to carefully reduce the COOH, that you do so carefully and quietly, well
away from me . There are any number of methods that you could use, such as HI which will do the quickly although with copious evolution of betraying
odours (or so I have heard).
Now, Nicodem... If someone can tell me how the hell I upload files I am more than happy to provide you with some of the refereed articles upon which I
have based some of my assumptions (and/or presumptions). Many of them basically describe the use of Leuckart reactants in modified CTH & even
Clemmensen type reactions, although I am stumped as to which article I got the reference to calling them Leuckart 'type' reactions. I realise
professionals and purists may despise such naming methods, nonetheless, they are effective at describing the mechanism so us less professional and
pure 'kitchen kemists', with our limited understanding can decipher how they work.
I do, sincerely, thank you for your interest in broadening the minds of such aspirants as myself and trust me, I ask questions because I do not know,
I don't make suggestions because I am sure that they will work, but because with my limited knowledge they might. As to legal & societal issues,
you appeared to be seeking some response as to why the interest in the MD version of the same, at least that is how I understood it, if so, honesty is
the best policy, wouldn't you agree?
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Nicodem
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I still do not fully understand a lot of your vague talk, but I came to believe that you made quite some terrible confusions:
1.) the end compound in that Org. Syn. procedure is not methyl-DOPA, using the DOPA acronym you could call the product N-methyl-DOPA - thus quite adifferent compound;
2.) neither methyl-DOPA nor this end compound (N-methyl-DOPA) are scheduled in USA (where I assume you live given all the information you gave),
however methyl-DOPA is a pharmaceutical compound and as such is bound to FDA rules;
3.) no product or side product arising from the reaction of N-methyl-DOPA or methyl-DOPA with hydrogen iodide is in anyway scheduled or controlled;
4.) you can not reduce the carboxylic group in amino acids to a methyl group with hydrogen iodide, but if you could reduce it (with some other
reagent) you would obtain N-methyl-3,4-dihydroxyamphetamine which is fully legal though quite certainly similarly cardiotoxic and vascularly active as
3,4-dihydroxyamphetamine;
5.) reaction differences are based on mechanistical pathways and not on the use of specific reagents like you seem to believe (the Leuckart reaction
is mechanistically very different from any CTH reduction even though both can use ammonium formate as reagent) thus calling a CTH reduction as a
Leuckart is complete nonsense and only leads to more confusion.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
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tupence_hapeny
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Ummm, I do not have any interest in this particular compound for the purpose of making amphetamine derivatives per se... It may be do-able, but at
somewhat extraordinary lengths (as with all the other phenylalanine derivatives).
However, I do have a SERIOUS problem with using HI for any HOBBY type reaction... This shit is seriously bad news, leaving aside all of the rather
horrific details of the acid itself (like eating glass), it is worth, all by its lonesome a serious custodial sentence, particularly if the
prosecution could explain to the Court that it was to be (or was being) used to reduce an 'analogue of a controlled substance'. Quite frankly, unless
you have the money to employ serious expert witnesses and brilliant lawyers, YOU ARE FUCKED.
Therefore, I make a suggestion regarding a legitimate synthetic target, I even attempted to phrase the bloody thing appropriately.
Quite frankly, if I wanted to use any part of this reaction to produce the compounds you impute, I would reductively aminate potassium pyruvate with
methylamine (instead of ammonia as in these two patents):
http://www.freepatentsonline.com/4149012.html
http://www.freepatentsonline.com/3972921.html
And then perform the Akabori synthesis using vanillin and n-methyl-d,l-alanine, reducing this sucker with HI (I2/H3PO3) to achieve both the
demethylation and reduction of that pesky OH in one pot (as mentioned elsewhere using hydroquinone to retard polymerisation). Then methylation using
MeI2/Br2/Cl2... Apart from Methylamine (which even I can reach), entirely OTC, and fairly cheap so crap overall yields wouldn't matter.
So, having (hopefully) established that my interest in the title compound is not connected with the synthesis of banned substances, may we proceed?
No, I do not believe that the naming of reactions is dependant upon (or even necessarily related to) the reagents involved. I simply happened to note
(as even a perfunctory search will demonstrate) that others, much more qualified than myself, were describing the formate CTH as a Leuckart type
reaction. This made it a great deal easier for me to grasp the mechanics behind the reaction in this instance, so I thought to adopt that usage.
Perhaps in order to resolve this debate, it is time for me to demonstrate my ignorance in full (bearing in mind I have no training in chemistry that
will take some time, patience please)
I personally understand (although my understanding of the mechanics of such reactions is unfortunately still somewhat vague) the reaction to proceed
by virtually the same mechanism as a catalytic leuckart (albeit without the amine). Apart from that part of the reaction which forms the imine
(normally formamide/methylformamide), the LW is simply a transfer hydrogenation of a carbonyl type compound from a formate hydrogen donor, giving CO2
and whatever group was attached to the (now reduced) carbonyl. I believe this to be right, so if I am wrong, please advise me where and how this
theory is wrong - that is not a challenge but a request.
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Eclectic
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I think you are confusing HI with HF. AFAIK, HI does not eat glass, although is is very corrosive to metals. While watched, and regulated as far as
sale goes, is HI actually illegal to possess and use for any purpose other than reducing ephedrine and pseudophedrine and phenylpropanolamine to
various amphetamines? No drug precursor and reductant=no illegal drugs.
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tupence_hapeny
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Here, Hyroiodic/Hydriodic acid is certainly prohibited. Possession of more than 0.1g is an indictable offence, and serves as grounds from which to
infer intent to manufacture amphetamines. Whether or not the material it is being used to reduce is 'technically' an amphetamine matters very little,
particularly as you having been in possession of it, are on a hiding to nothing with the jury from the start, so whether they will believe your
version of what you were doing over the version put before them by both police witnesses and the prosecutor. You will require the use of a VERY
EXPERIENCED & QUALIFIED professor in organic chemistry, who is unlikely to wan't to be involved, in order to convince the jury that the chemical
structures are not the same and not able to be, with the materials on hand, turned into illicit drugs. This will be an uphill battle, and success is
not guaranteed, quite frankly, juries are 'normal' people with no knowledge of chemistry, but with the same fear of the unknown as has been instilled
into all of us from birth, the fact that police and the government believe you are guilty puts you behind the 8-ball big time.
PS So SWIM 'imagined' the etching caused by hot, concentrated HI? Perhaps this etching is similar to the effect of concentrated HCl on gold over time?
You know, HCl does not affect gold, right? Yet concentrated HCl will attack it over time, high heat and concentrations make acids and bases do things
that they may not do normally, that doesn't mean it doesn't happen.
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Nicodem
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All that off topic legalistic bullshit in the Organic chemistry section makes me highly upset. Please stop with that crap! Who do you try to fool
anyway? Do you seriously believe that nobody noticed that you confused everything you could confuse and you actually thought that amino acid might be
in anyway a useful precursor to illegal drugs? Your unstoppable off topic diversions into the legal aspects of prohibition and the presumed illegality
of hydrogen iodide possession is nothing but an expression of your bad consciousness and an apologism to your greed just as demonstrated by your
"swimming". Please grow up or if you are unable to mature then just move over to WetDreams. And meanwhile try not to spread misinformation like that
crap about acids properties and hydrogen transfer in the Leuckart reaction. Don't get me wrong, it is not that I'm upset because of your ignorance,
that is fully comprehended, I'm upset because you consider this forum's members plain suckers.
[Edited on by Nicodem]
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not_important
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Another way to get dry LiCl is to make it via conventional wet methods, dry it at 100 C or so, mix with ammonium chloride, and heat while removing
gasses with a slight vacuum, and finally a higher vacuum to get all the NH4Cl. The detailed procedure is in an early Inorganic Synthesis, used to
make anhydrous lanthanide chlorides (or bromides). Works for non-volatile halides - alkali, alkaline earth, and lanthanide metals, manganese, and a
few others; not for Al, Zn, and so on.
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tupence_hapeny
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Nicodem,
So having just stated that HI is illegal here, you would suggest I state that I had noticed the effect of the same substance on glassware, given that
just such an admission would be, in fact, nothing less than a veritable admission to having taken part in an ACTUAL illegal act?
I am sure that nothing would please me more, however and unfortunately, I am utterly incapable of doing so, for as I mentioned, the person who may or
may not have taken part in the commission of an ACTUAL illegal act was somebody other than me.
Not_important,
Thanks for that, it would be useful not to have to work with dry gasses, one of my all time pet hates.
tup
[Edited on 29-3-2007 by tupence_hapeny]
As to the etching of glass by HI, I think I may have discovered the reason why...
HI generated by the reaction between orthophoric acid and Iodide will generally be accomplished by use of orthophosphoric acid generated by the 'wet
process' (calcium phosphate + sulphuric acid = calcium sulphate and phosphoric acid), one of the contaminants of which is hydroflouric acid:
http://en.wikipedia.org/wiki/Phosphoric_acid
Similarly to that produced by reaction of cheap, hypophosphorus acid (and phosphorus acid) derived from the salts, as these are made by (in one
approach) heating a dry mixture of carbon (charcoal) and absorbed phosphoric acid to white heat and generating phosphorus, which is collected in water
(which is turned into the acid) and forms a slurry which is reacted with calcium carbonate. The phosphite and hypophosphite salts being separated from
the phosphate salts by dissolving in water:
http://www.freepatentsonline.com/4379132.html
There doesn't appear to be any means utillised of separating out the calcium flouride (from the contaminant in the original absorbed acid or the
precipitant), so some of this will remain in the salts - which will also be in the acid generated (H2PO2/H3PO3) from them, so contaminating any HI
generated therefrom.
I presume that the HI generated from RP would be free of this impurity, so this would be the reason why the various reactions differ.
[Edited on 29-3-2007 by tupence_hapeny]
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Nicodem
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I can work with concentrated aqueous HI any time I want without worrying about any legal consequences. You should find the paragraph of the law saying
that working with HI is illegal before making such assumptions based on rumors. If such a paragraph truly exists it would mean that perhaps thousands
of chemists are criminals, but what is naive is that you seem to believe that the law is the same all over the world. Anyway, there are so many
threads on these issues in the "Legal and Societal Issues" section of the forum that I can only consider this discussion as extremely off topic here.
Aqueous HI does not etch glass – actually it is even sold in glass bottles. You seem to have it mixed up with the etching of the glass that happens
with the hot H3PO4 (at >120°C H3PO4 attacks glass and ceramics quite notably and above 150°C where it starts to dehydrate to pyrophosphoric acid
it is able to dissolve your flask in some hours). Hydrogen fluoride on the other hand attacks glass already at room temperature and quite more
efficiently due to the very favorable thermodynamics of the Si-F bond over the Si-O bond (since glasses are amorphous metallic silicates).
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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tupence_hapeny
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A quick look at the legislative changes made post-2004 in the majority of jurisdictions, from which hobbyists contributing to this board would come
from, will demonstrate that HI is a prohibited substance. You (obviously as a result of your employment?) may have access to HI, and frankly I
wouldn't doubt it, however, this does not mean that it is a particularly 'usable' chemical for most amateurs (especially here, as in this jurisdiction
there is not even any allowance for researchers to have it, it is simply verboten).
I honestly did not consider the effect of the hot phosphoric acid, thank you. I think that this may serve as a valuable demonstration of the potential
differences that can occur as the result of using 'non-Lab Grade' (or even tech) reagents.
In relation to the nature of HI, so could it be purified by feeding some powdered silica to the reaction? On the assumption that the more finely
divided sillica will react with the phosphoric (or even pyrophosphoric acid) before it eats too much of the glassware (it should also remove the HF)?
This may be of some significant utility, as the industrial process for hydrogenation of carbohydrates to hydrocarbons uses distillation to remove the
HI from the H3PO4 generated by the reaction between phosphorus acid and iodide. This would be good as the industrial processes for making the
phosphorus require phosphoric acid to be mixed with sillica, so the removal of it from its end use would be a step in the regeneration of it, elegant
is good...
So, back to the title reaction, the double-bond can be reduced with potassium formate and formic acid... I take it an excess of at least one of the
two would be necessary? Do you have any links to articles, etc. describing the reaction? I have some, but they don't go into the reduction of double
bonds, only specific functional groups.
[Edited on 30-3-2007 by tupence_hapeny]
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Nicodem
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| Quote: | Originally posted by tupence_hapeny
So, back to the title reaction, the double-bond can be reduced with potassium formate and formic acid... I take it an excess of at least one of the
two would be necessary? |
Formic acid itself can not be efficiently used in CTH reductions, only its deprotonated form, the formate anion, can be used as a so called hydride
donor. The mechanism for the "hydride donation" requires intramolecular beta-hydride elimination from an L-M-O-CO-H intermediate where M is palladium
or other appropriate transition metal and L any ligand - thus only formate salts work appropriately since HCOOH itself is unable to coordinate well
with the metal. This intermediate usually decomposes to MH2 (if L=H) and CO2 as side product (similar but specific mechanisms go on also with other
hydride donors like hydrazine, cyclohexene, hypophosphates, isopropanol…). Thus the reducing hydride species is usually exactly the same as in
normal hydrogenations except that it is formed from beta-hydride eliminations as opposed to the insertion of the metal in the H-H sigma bond (the
point is mainly in making the use of the Parr apparatus and H2 unnecessary). You do not need to know all that about the mechanism since organometallic
chemistry of transition metals is way beyond the scope of this thread, but as you can already see the mechanism is completely different from the
mechanism of the Leuckart reaction (the mechanism of the Leuckart is discussed in Tetrahedron, 19 (1963) 1789-1799; J. Am. Chem. Soc.,
70 (1948) 1187-1189; J. Am. Chem. Soc., 70 (1948) 1422-1424 and several other papers; as you can see it no hypothesis of its mechanism
ever calls for an organometallic intermediate).
Some relevant CTH reductions papers and reviews:
Synthesis, (1988) 91-95 (DOI: 10.1055/s-1988-27478) and references therein.
http://www.erowid.org/archive/rhodium/chemistry/cth.cinnamic...
Tetrahedron Letters, 41 (2000) 7847–7849 (DOI:10.1016/S0040-4039(00)01365-4).
the "Reduction of the double bond in conjugation to carbonyl moiety" section in http://www.erowid.org/archive/rhodium/chemistry/cth.af.revie...
…and many, many other papers you can find for yourself by searching using the several publisher's search engines.
Only an experiment can confirm you beyond any doubt weather any CTH method for the reduction of electrophilic conjugated double bonds might work
efficiently for your specific case.
PS: I can easily order hydriodic acid, just like anybody else in my country, if I would ever happen to need it. No need to ask my employer to do so.
Edit: I disagree that the majority of contributors to this forum are from the jurisdiction of Texas, USA or any such cowboy jurisdiction. Perhaps the
scientific level of this forum is not particularly high, but I don't think it so bad as to call for such harsh conclusions.
[Edited on by Nicodem]
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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tupence_hapeny
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Nicodem,
Thank you. I am currently reading like mad in order to understand how and why the reaction works. I do appreciate the input.
BTW, here is my post on the legal issues regarding amateur chemistry in Australia at the present time:
http://www.sciencemadness.org/talk/viewthread.php?tid=8228
You may notice that I have taken advantage of the opportunity to place it in the appropriate forum.
tup
We are all the sum of our experiences, and our reactions to the same
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tupence_hapeny
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Now, sorry about the double post, but I don't feel comfortable with editing after the end of the same day (seems dishonest somehow). Anyhow, with
relation to the demethylation I have found some fleeting references in old boards on the use of NMP (n-methylpyrolidone) as a substitute for pyridine
with AlCl3. On a search of this board I have found a 1999 patent (originally posted by CherrieBaby: http://www.sciencemadness.org/talk/viewthread.php?tid=1369&a...) for the methylation of bezodioxoles using NMP and dihalomethane:
http://www.freepatentsonline.com/5936103.html
With regard to the substitution of the pyridine, I refer amongst others to this:
http://www.erowid.org/archive/rhodium/chemistry/allylcatecho...
Which while not using NMP this paper does substitute the pyridine with pet.ether. I also found other references to the demethylation of eugenol and
vanillin (there appears to have been a great deal of interest in this subject over the years?). Some of the chemistry appears sound, and some just
plain dangerous, however, there is even a vague reference to the potential of NMP (although the author seems to believe that an organic base is
necessary which pet-ether ain't so it can't be):
http://www.synthetikal.org/hiveboard/arch/forum/topic/topic_...
(NB Another reference by Wizard X to the use of HI for demethylation, seems he was right all along (btw as per the orgsyn version of the title
compound, use of Acetic Anhydride will obviate the need for hydroquinone, for those here that are simply perverse).
Finally, a reference to a book which is kinda famous to some people here, I won't mention the name of the same as I bumped into a massive bitch
session on this board about the current use (misuse?) of the name of the same by another board:
http://designer-drug.com/pte/12.162.180.114/dcd/chemistry/tc...
This also goes into a number of specific approaches to the demethylation of eugenol/vanillin.
The reason I suggest NMP is basically the reason advanced by the author of the patent cited by CherrieBaby. It is a high boiling bipolar aprotic
solvent, which does not break down at 200C, or form nasty smelly mercaptan like DMSO. It is also freely available as a paint stripper (actually as a
GBL substitute) in anything up to 220L drums and beyond for stuff all. Basically if AlCl3 and petroleum ether work I see no reason why, especially
given my dislike for ether, this wouldn't.
I am aware however, that this is a topic that has been argued to death, so I would expect that others have other ideas as to whether or not it will
work.
With regard to the reduction of the double bond, Nicodem, I am trying to avoid Pd as I just noticed that Palladium chloride is also banned here. Is
there any way around this, such as for instance a dissolving metal reaction (although mercuric chloride (HgCl2) is banned mercury chloride (Hg2Cl2) is
not - easier to make - doesn't work so easily, quickly or well).
Please understand me, I don't intend to BREAK the law, just to give the bastard a mighty stretch (I think the time has come).
BTW Here is a paper that describes the demethylation of vanillin in 92% yield using nitrobenzene and Aluminium Bromide:
Jayne Thesis
[Edited on 31-3-2007 by tupence_hapeny]
2nd Edit
The reason I ask about dissolving metal reaction (namely clemenson type - Zn/Hg) is due to this article which suggests that the formate method of
transfer hydrogenation was developed as an alternative to Wolf/Kischner & Clemmenson reactions:
http://www.erowid.org/archive/rhodium/chemistry/cth.carbonyl...
[Edited on 31-3-2007 by tupence_hapeny]
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Nicodem
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Confusing lots of stuff again? It is getting a habit already.
The US5936103 patent is about methylenation where NMP is only a solvent most appropriate due to its high dielectric constant (thus promoting SN2
substitutions). It has nothing to do with demethylations! (You seem to have confused methylenations with demethylations all over your last post.)
Pyridine can not be used for demethylations. Instead certain pyridinium salts can be used since they are both acids and solvents (they are so called
ionic liquids at the reaction temperature). Usually pyridine hydrochloride is used (being the cheapest) like in the example of eugenol demethylation
you referred to. The other reason for using pyridine salts instead of the usual strong acids otherwise used (like AlCl3, AlBr3, AlI3, BBr3, BCl3, HBr,
HI and so on) is in that they are less harsh and some other functional groups can survive where they otherwise would not (like the double bond in
eugenol if HBr was to be used). So there is no such thing as "substitute the pyridine with pet.ether" for the simple reason that neither pyridine nor
petrol ether can be used as reagents for demethylations. The first can not be used at all (since it is a base) while the second is just an inert
solvent, thus appropriate for the use of AlCl3 as the acid reagent for demethylation.
| Quote: | | With regard to the reduction of the double bond, Nicodem, I am trying to avoid Pd as I just noticed that Palladium chloride is also banned here.
|
Like I already said, chances are that aluminium or zinc amalgam can reduce this double bond, but I would certainly not bet on it.
| Quote: | | Please understand me, I don't intend to BREAK the law, just to give the bastard a mighty stretch (I think the time has come). |
And you want to do that by synthesizing a useless amino acid? You could have at least chosen to make some methyl-DOPA instead, so that you will have
some medicine in case you get Parkinson's.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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tupence_hapeny
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Sorry, may not have been real clear... I'm still trying to get the hang of writing this stuff properly. No, I didn't think that the NMP was anything
other than a solvent, however, I have constantly run into the suggestion here, there and everywhere that a strong organic base is necessary (in
addition to the lewis acid) in order to demethylate vanillin and eugenol. My point in relation to petroleum ether (also not suggesting that it was a
reagent, merely a solvent) was that if it works and is not a strong, organic base (when used in conjunction with a lewis acid) in this reaction -
there is no real reason why NMP would not. I do however grovel in shame in relation to the misuse of pyridine instead of pyridine hydrochloride - that
was not intentional - merely an oversight and not meant to mislead (in fact, given the widespread knowledge of, for instance the microwave
demethylation, I would be rather suprised if it could).
The making of a 'useless amino acid' is precisely what I intend to make Sir... I am currently sueing police where I am and have ABSOLUTELY no
intention of making anything stronger as I confidently expect a visit immediately a 'chemical' smell is noticed. I need to be able to assert in Court
that I was ONLY making a 'useless amino acid' moreover, via a synthetic route which was (1) viable; and (2) completely legal. I assume you of all
people will be able to understand my purpose in doing so?
tup
EDIT: PS Nicodem, I appear to have missed something on my first glance at your post, you say that the double bond from eugenol would not survive
demethylation using a lewis acid.... What precisely would happen to it?
[Edited on 1-4-2007 by tupence_hapeny]
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Sandmeyer
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| Quote: | Originally posted by Nicodem
Where did you heard that calcium amalgam reduces conjugated electrophilic double bonds like the sodium amalgam used in the procedure? Aluminium
amalgam is not particularly useful for the reduction of electrophilic double bonds, but if I remember correctly it can do that on some substrates. I
have no idea if it would work on such benzylidenes and besides it would be very, very difficult to work up the reduction due to the acidic phenol
group on this particular substrate. CTH reduction systems, for example HCOOK with Pd/C, can be used to reduce electrophilic benzylidene type double
bonds (as for example in the reduction of cinnamic acids to phenylpropanoic acids). There are a bunch of other CTH systems used specifically for the
reduction of carboxy enamides to amino acid amides, thus suitable to what you want to reduce.
Edit: Any aldehyde without alpha-hydrogens or interfering functional groups can be used instead of vanillin.
[Edited on by Nicodem] |
MeOH/Mg is also effective for this sort of reduction... If someone can get this paper: http://www.ingentaconnect.com/content/ben/coc/2004/00000008/...
Magnesium in Methanol (Mg / MeOH) in Organic Syntheses
Authors: G. H. Lee1; I. K. Youn1; E. B. Choi1; H. K. Lee1; G. H. Yon1; H. C. Yang1; C. S. Pak1
Source: Current Organic Chemistry, Volume 8, Number 13, September 2004, pp. 1263-1287(25)
Abstract:
Magnesium in methanol(Mg / MeOH) system is an extremely versatile, efficient, economical and convenient reducing agent for various reactions useful
for organic synthesis such as reductive cyclization, reductive elimination, reductive cleavage, reduction of a conjugated double bond,
desulfonylation, and reduction of various functional groups. This comprehensive review is intended to highlight the use of Mg / MeOH in each of these
organic transformations.
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PainKilla
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| Quote: | Originally posted by Sandmeyer
| Quote: | Originally posted by Nicodem
Where did you heard that calcium amalgam reduces conjugated electrophilic double bonds like the sodium amalgam used in the procedure? Aluminium
amalgam is not particularly useful for the reduction of electrophilic double bonds, but if I remember correctly it can do that on some substrates. I
have no idea if it would work on such benzylidenes and besides it would be very, very difficult to work up the reduction due to the acidic phenol
group on this particular substrate. CTH reduction systems, for example HCOOK with Pd/C, can be used to reduce electrophilic benzylidene type double
bonds (as for example in the reduction of cinnamic acids to phenylpropanoic acids). There are a bunch of other CTH systems used specifically for the
reduction of carboxy enamides to amino acid amides, thus suitable to what you want to reduce.
Edit: Any aldehyde without alpha-hydrogens or interfering functional groups can be used instead of vanillin.
[Edited on by Nicodem] |
MeOH/Mg is also effective for this sort of reduction... If someone can get this paper: http://www.ingentaconnect.com/content/ben/coc/2004/00000008/...
Magnesium in Methanol (Mg / MeOH) in Organic Syntheses
Authors: G. H. Lee1; I. K. Youn1; E. B. Choi1; H. K. Lee1; G. H. Yon1; H. C. Yang1; C. S. Pak1
Source: Current Organic Chemistry, Volume 8, Number 13, September 2004, pp. 1263-1287(25)
Abstract:
Magnesium in methanol(Mg / MeOH) system is an extremely versatile, efficient, economical and convenient reducing agent for various reactions useful
for organic synthesis such as reductive cyclization, reductive elimination, reductive cleavage, reduction of a conjugated double bond,
desulfonylation, and reduction of various functional groups. This comprehensive review is intended to highlight the use of Mg / MeOH in each of these
organic transformations. |
Attachment: 14259790.pdf (208kB)
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tupence_hapeny
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Thanks Sandmeyer and PainKilla, all research is gratefully accepted.
Now back to that bloody double bond,
Would the Zinc/Nickel couple, as is according to this paper, capable of reducing the double bond in cinnamic acid to hydrocinnamic acid (the respective structures are as shown in this electroreductive synthesis from Orgsyn), reduce this double bond?
Tup
PS I have to edit in order to make my links work
PPS Also note that the orgsyn synthesis referred to in this post makes use of an electrolytic process to generate sodium amalgam in situ
(unfortunately needing sulphuric acid which would fuck up this one) and is suitable for the reduction of other compounds which can be reduced by
sodium amalgam
[Edited on 1-4-2007 by tupence_hapeny]
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