10-21-02 11:24
No 370774
This is a product of strictly retrosynthetic thinking and analysis.
I haven't been around lataly due to the fact that I was burried in litterature, studying to my exam, actually while doing that I got some nice ideas. Earlier I posted in a big hurry some errorous mechanism and that was foolish. Of course I havent tested this synth, I don't posses any lab, and i say no to drugs, but I have however double checked every step, and no rules are violated, but I guess you never know how it looks in practice unless you try it out. This one seriously looks promising since methods applyed are generall and well-known... Lilienthal, please comment if you find something unexpected :)
Step from pre-cursor [1] to [2], is in my opinion most critical step why? We've got a strong activaing ortho-para director in form of a -NH2 (amino) group on p-amino-toluene, incoming nitro (-NO2) groups cannot however be attacked by the para position, that's a positive thing, this inability is due to the occupied para position by (-CH3). What is even more interesting is that we can in this particular synthesis optimally take advantage of the -NH2 group (ortho-para director). In most cases this group needs to be manipulated/treated with Cl-(C=O)-CH3 (acylchloride, acetylated) in order to make it less activating and thereby give it any synthetic value, becose often we don't want to put things on BOTH ortho positions, in this case we want to do just that, and that will most likelty result in quantitave (100%) yeild of the product desired. In this step the NO2 ions are produced "in situ" by H2SO4 dehydrating The HNO3 (-H2O) => NO2.
Warning! 0-5 C should be strictly obeyed becose we are dealing with potentiall explozive [4]. The step from pre-cursor [3] - [4] is where HONO (nitrous acid) is generated "in situ" as well, by reacting HCl (HX) with NaNo2. I didn't show that in the diagram, I wanted to keep it as brief as possible, but the salt formed [4] is actually X(-) N2(+) or if HX used to generate HONO is HCl, Cl(-) N2(+), treating this salt with Cu2O, Cu (2+), H2O, upon gentle heating will generate the best possible leaving group (nitrogen gas), forget triflate, this guy is as inert as a group can get and you don't have to show him the door, he'll allow him self out ;).
Pre-cursor [5] is formed. Since phenols are quite acidic, stealing the hydrogen from their OH isn't that hard, we can modify Williamson ether synthesis and use NaOH instead of elemental Na as with alkane alcohols. This is one more benefit among many in this synthesis.
Going from [6] to [7] is simple introduction of Me groups to form ether, a la Williamson.
About time to treat [7] with NBS, [8] is formed followed by a simple Sn2 mechanism where cyanide ion (:CN -) (love it, hate it, FEAR IT) kicks out Br, and couples to form corresponding nitrile [9], this is treated with Raney Ni or LAH to convert the poision to the most divine psychedelic around => M [10].
It's amazing how organic chemistry and inorganic chemistry come together in this synth :)
...
As complementary synthesis to the one above is the preparation of CN(-) needed for the nucleophilic substitution (nitrile production). Synthesis I came up with would if it worked actually give HCN a deadly gaseus poision, nothing a sensible man wants to mess with. However it could be possible to convert this gas into the CN(-) in situ by treatment with strong base, maybe NaOH in order to strip off the hydrogen and make an anion, prefrably giving NaCN. Preform the reaction at the last step in alkaline solution.
H-CN + NaOH (aq) -> Na(+) :CN(-) + H2O
I'm not familiar with the pKa of H-CN, you should look it up if you are considering to preform my HCN synth.
...
Comment: Oxidation of MeOH with KMnO4 will give formic acid, corresponding acyl chloride by treatment with SOCL2, whereupon treatment with amonia will give formamide, when this material is refluxed with aceticanhydride HCN is evolved, please don't preform this if you are not a trained chemist. Even Death comes in 3 different forms, solid, liquid and gaseous, HCN is gaseous form of Death wich you can't escape from, it will creep up the condenser, hunt you down and kill you. When it's finally satisfied it will creap back to hell where it came from along with your soul. You have to posses certain skills and techniques in order to defeat this demon from the ancient world. Noone knows what HCN smells like, the one who get to know it dies, so don't think "well i'll notice it coming out, it has to have a charasteristic smell". Yeah, the one of death. Please don't fuck with this one, please...
[pH]armacist - Never underestimate the power of retrosynthesis. 1-800-MANTLE-NO-TNX
(Hive Bee)
10-21-02 12:10
No 370789
I'm not going to make statements about the (im)possibility of your proposed reactions, only about the HCN. A rather famous reaction involving HCN is the Gattermann formylation. If you use TFSE, you'll find several matches for Gattermann. I think that Gattermann used HCN in his original 1898 article, but afterwards, he and other chemists proposed safer ways of performing this type of reaction by generating HCN in situ. I often see that zinc cyanide is used for that purpose. So, for your own safety and convenience, I think you might consider in situ generation reactions.
Information on Gattermann's reaction is also available on Rh's site: ../rhodium /formyla
geh in die knie. wackle mit den hueften. klatsch in die haende. und tanz den mussolini.
(Hive Prodigy)
10-21-02 14:19
No 370813
pHarmacist, your reactions are very interesting, and I see nothing really wrong with any of them other than that some might not have wonderful yields. I think they should all work.
I am very interested in your statement on N2+ as a leaving group, being the "best possible leaving group" and you even mentioned it being superior to triflate. I was unaware that N2+ is a good leaving group. Logically speaking, when you look at it it looks like it would be a good leaving group, but I have never seen it specifically mentioned before as one, and triflate is pretty much known as the universal king of leaving groups.
I would love to hear someone else's comments on this as well. Award for most interesting (possible)-factoid of the day goes to pHarmacist for bringing the possibility of N2+ as a wonderful leaving group, to my attention.
PrimoPyro
(Stranger)
10-21-02 17:39
No 370854
I like the route, provided that I have a decent fume hood at hand...
I'm not sure about this, merely a speculation. However if you are going to handle HCN, then perhaps you should consider making the corresponding grignard of 3,4,5-trimethoxybenzyl bromide, add it to HCN (dissolved in ether?) and then reduce the formed iminium salt with NaBH4. That would exclude the hard-to-get-LAH, and if it works (which someone else will have to comment, I'm afraid), it would probably give a good yield (refering to a similar reaction on Rhodium's page, prep of amphetamin from BnMgCl/CH3CN).
Again I'm not sure the reaction works with HCN.
But I would think twice before even considering this route due to the HCN involved... (gaseous or in solution)
If you decide not to go through with it due to HCN, then consider preparation of the grignard, react with CH3CN, reduction with NaBH4 - viola, 3,4,5-TMA.
-Stanley
(Hive Bee)
10-21-02 18:07
No 370861
Do you have a ref. to substantiate the [3] --> [4] transformation?
There may be a problem, since with multiple amine groups in ortho position on the phenyl group, there may be benzotriazole formation when you do the diazotization: the free electron pair of a not diazotized amine does a nucleophilic attack on a vicinal diazonium ion. Furthermore, compound [4] looks like very unstable ... (boom!!!)
It would be more wise to do the Sandmeyer reactions in seperate steps.
And in step [1] --> [2], the amine would get oxidized (so you have to protect it).
A better approach would be, to directly do the diazotation and Sandmeyer reaction on [1], converting p-toluidine to 4-hydroxytoluene, wich can be treated with NaOH so that the oxide ion can be methylated with dimethylsulfate. Then nitrate ($) the 4-methoxytoluene to obtain 3,5-dinitro-4-methoxytoluene, reduce the nitros and then repeat the diazotation and Sandmeyer to get 3,5-dihydroxy-4-methoxytoluene. Methylate and you 've got the precursor.
And now that I think of it, it is probably better to just buy the 4-methoxytoluene. Then you start right here ($) in the synthetic scheme. p-Toluidine is rather toxic stuff. I wouldn't play with it, if I were you.
PrymoPyro, nitrogen gas is the leaving group - not the N2+ ion.
(Chief Bee)
10-21-02 20:10
No 370922
I haven't ever seen a triple-diazotized compound in the literature, to me it feels like that 3,4,5-tris-diazotoluene would spontaneously fall apart...
You cannot make formyl chloride, it is unstable and decomposes in real-time to CO and HCl.
(Hive Prodigy)
10-21-02 23:02
No 370984
I know that N2 is the leaving group, but N2+ facilitates the reaction. My questions still stand.
PrimoPyro
(Chief Bee)
10-22-02 02:02
No 371034
PP: What do you mean by "N2+ facilitates the reaction"? Diazotizing an amine (with for example NaNO2/HCl) creates R-N=N+Cl- which upon any disturbance in the force regroups into R+, N2 and Cl- and then the R+ latches onto whatever good nucleophile that is the most abundant in the solution at the moment, and in the absence of any good nucleophile, it makes do with whatever is available (like water to form phenols).
(Old P2P Cook)
10-22-02 07:33
No 371121
This one seriously looks promising since methods applyed are generall and well-known...
While some of the individual transformations may be of theoretical interest this route is hardly practical compared to established routes. Gallic acid or elemicin as starting material are readily available and provide myriad much more facile routes.
Baseline Does Not Exist.
(Hive Bee)
10-22-02 07:53
No 371128
What is this myriad of routes? aurelius knows of one or two, but other than a couple, they all use unholy-hard-to-obtain chemicals (for a layperson) not that any layperson would ever attempt such a feat.
(I'm Yust a Typo)
10-22-02 11:12
No 371177
See the links at the bottom of this webpage? Read PiHKAL and rhodium's website.
When all you've got is a nailgun, every problem looks like a messiah...
(Hive Bee)
10-22-02 12:55
No 371203
Cyrax:
Furthermore, compound [4] looks like very unstable ... (boom!!!)
Like I said in my original post, 0-5 C, this is potential explozive, diazonium salts are known explozives.
do i have any refs on [x] - [x]? no, like i said reference is my head, a dream... but having multiple _equivalent_ type of groups on the ring is no problem, they all undergo same reaktions when manipulated, thats a fact...
Never underestimate the power of retrosynthesis.
(Hive Bee)
10-22-02 13:09
No 371207
Exactly how is LAH harder to obtain than NaBH4?? please tell me.. Besides we are talking total synthesis here not anything industrial, this is more on paper than in practice... Use of exotic chemicals is allowed in this case.
Never underestimate the power of retrosynthesis.
(I'm Yust a Typo)
10-22-02 13:27
No 371209
>they all undergo same reaktions when manipulated, thats a fact
So, how would you make trinitrotoluene? Just take toluene, nitric acid and h2so4?
When all you've got is a nailgun, every problem looks like a messiah...
(Hive Bee)
10-22-02 13:42
No 371211
In this case the one you mention I wouldn't go via oxidation (asuming that I can go from triaminotoluene, if not I prepare it). I wouldn't treat the aminogroups with acids as you suggest (H2SO4/HNO3), i would go: -NH2 ---HONO/0-5 C---> N2(+) ---HONO/Cu---> -NO2 (HONO,prepared in situ). this treatment will transform all 3 -NH2 groups to -NO2 via diamonium salt and N2 will leave. I hope that I didn't missunderstand your question.
Never underestimate the power of retrosynthesis.
(Old P2P Cook)
10-22-02 16:05
No 371251
Besides we are talking total synthesis here not anything industrial, this is more on paper than in practice...
OK, so you understand that this synthesis is completely impractical.
In your first post you seemed to say that you thought this was a practical synthesis:
This one seriously looks promising since methods applyed are generall and well-known...
Baseline Does Not Exist.
(Old P2P Cook)
10-22-02 16:09
No 371254
What is this myriad of routes? aurelius knows of one or two, but other than a couple, they all use unholy-hard-to-obtain chemicals (for a layperson)
What chemicals would these be that are more hard-to-obtain than the dimethyl sulfate, cyanide, bromosuccinimide and lithium aluminum hydride used in the route currently being discussed?
Baseline Does Not Exist.
(Hive Bee)
10-22-02 16:16
No 371255
If I remember correctly the diazonium groups could be converted to methoxies in the first place, by using MeOH instead of water.
(Stranger)
10-22-02 17:35
No 371269
LAH is harder to get hold on in practice. People come up with lots of synthetic routes every day that seem decent in every way, except for the fact that some of the chemicals are hard to get ones hands on.
I suppose there is a reason for the "LAH impaired 2c-b-synthesis"-file on Rhodium's page, which employes NaBH4 instead of the hard-to-get-LAH.
I'm sorry if I missinterpreted you, I thought your purpose with the post was to reveal a new practical way to synth mescalin for those who don't have access to all the goodie chemicals in the professional lab.
Again, Sorry.
-Tao
(Hive Bee)
10-22-02 19:42
No 371324
aurelius didn't mean to come across as saying the chems in this thread were easier to obtain than those you (Terbium) listed. in fact, the chems you did list are the very chems aurelius speaking of (in terms of hard-to-obtain). aurelius was wondering if there was another synthesis that aurelius has overlooked that doesn't require such chemicals.
(Chief Bee)
10-22-02 20:49
No 371352
What's wrong with the Vanillin -> 5-Br-Vanillin -> 5-OH-Vanillin -> 3,4,5-TMB route proposed by me and Osmium four years ago? Everything needed are as good as OTC.
(Hive Bee)
10-22-02 23:27
No 371422
Sorry, aurelius missed that one as a result of misreading. one of the steps leading towards the synthesis MMDA involves nitroethane (hard to get). However, aurelius was blind and didn't realize that it was the wrong set of steps AND that nitroethane is never needed for PEAs
(I'm Yust a Typo)
10-23-02 00:38
No 371451
[pharmacist]
>I hope that I didn't missunderstand your question.
You did. My point is that you just can't attach 3 electronwithdrawing groups like NO2/N=N+ to an aromatic ring
and think that the first one adds as easily as the third one.
When all you've got is a nailgun, every problem looks like a messiah...
(Hive Bee)
10-23-02 02:11
No 371499
But having multiple _equivalent_ type of groups on the ring is no problem, they all undergo same reaktions when manipulated, thats a fact...
Yeah right ... check out Vogel's Textbook of practical organic chemistry, 5 the ed., p 1163. I have a ref. to back up what I am saying: since with multiple amine groups in ortho position on the phenyl group, there may be benzotriazole formation when you do the diazotization: the free electron pair of a not diazotized amine does a nucleophilic attack on a vicinal diazonium ion.
Now, the question is: Do you have one?
(Chief Bee)
10-23-02 02:24
No 371508
And for those of you who haven't got that book, it shows the following reaction:
1,2-Diaminobenzene -HNO2-> Benzotriazole
...effectively outruling the possibility of the sandmeyer reaction on polyaminobenzenes.
(Hive Bee)
10-23-02 11:54
No 371690
Cyrax: please ask me about the refs one more time.. I told you I have NO refs, I came up with this synt on my own... is there any such thing as 3,4,5-triamino-toluene, or is it impossible to synthesize?
One more general point, just a moment ago i saw Assholiums synt on ../rhodium /2cb.man
Never underestimate the power of retrosynthesis.
(Hive Bee)
10-23-02 12:13
No 371692
Dude, I can read.
I asked for a ref. about what you were driveling: But having multiple _equivalent_ type of groups on the ring is no problem, they all undergo same reaktions when manipulated, thats a fact...
If what you are saying is a fact, you 'll have to be able to substantiate your argument.
Is there any such thing as 3,4,5-triamino-toluene, or is it impossible to synthesize? Yeah sure it 's possible to synthesize that compound. It's just impossible to diazotize all those the amino groups like you suggested.
Or if you don't believe me, be my guest: do the reaction (I suggest at a molar scale). We see who gets his ass blown up.
You 'd better do a descent literature study, before you post one of your 'great' synthetic pathways in the Serious Chemistry forum.
(Chief Bee)
10-23-02 12:47
No 371706
pharma: The reason to use the mannich route is that you don't have to start with a 2-methylhydroquinone derivative to end up with 2,5-dimethoxyacetonitrile (a hydroquinone derivative is enough) and you don't need NBS.
No synthesis makes another route obsolete, we just add alternative possible ways for us to arrive at our target compound.
11-28-02 11:37
(Rated as: redundant)