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electronegative subst. in 3' on 3,4,5-pattern phens/phets?

Limpet_Chicken

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Anyone care to speculate as to the likely effects of an electron-withdrawing substituent on the 3 position of the phenyl ring of mescaline/TMA derivatives?

In particular, I happen to have a small amount of 3-bromo-4-(1,1-difluoromethoxy)-5-methoxybenzaldehyde. 4-difluoromescaline was examined in that Trachsel paper, and found to be significantly more potent than mescaline. Can't find jack shit where there is an electronegative substituent on the 3' carbon aside from 3-fluoroamphetamine and fenfluramine, But thats as far as it goes. Seems like nobody has tried electronegative substituents at the 3 carbon of the phenyl ring in mescaline analogs.

Anyone know how likely the phen/phet derivatives are to be active?
 
I don't think changing/removing the methoxy groups from mescaline or 2C-x is any good, presumably it decreases activity by a large margin.

Even changing the methoxy to an ethoxy can decrease affinity, going to a bromide is probably not very good.

Also, can you name an active hallucinogen with more than 2 halides on the ring? I can't.
 
Well going from daniel trachsel's paper on fluorinated phenethylamines and derivatives, difluoromescaline is actually quite potent, it seems like the increased lipophilicity (ala amphetamines) where fluorine is situated on an ether linkage, increases potency, general trend is for increasing degree of fluorination (I.e trifluoro>difluoro>monofluoro.) to correlate with increasing potency, in the case of fluorinated mescaline analogues.

Also, in the case of serotonin releasers, at least, it appears that a lone substitutent, trifluoromethyl, at the 3-position is tolerated in the case of N-ethylamphetamine, namely, fenfluramine.

But in Trachsel's paper, unfortunately NO examples of a 3-position electronegative substituent have been evaluated. But extending the methoxy group to di or trifluoromethoxy increase potency, with trifluoromethoxy being the most potent. But there is just nothing tested it seems, bar possibly 3-fluoroamphetamine and fenfluramine that bears an EWG on the 3' phenyl carbon.
Seems like everywhere else has been tested bar 3-X.

Is meta-substitution more difficult in terms of synthetic effort required? because the aldehyde was damnably expensive.

And strictly speaking, there is only one halogen on the ring. The bromine atom, the fluorine atoms are both on the 4-methoxy group carbon.
 
If you are talking about plain 3-position substitutions on its own, then I'm sure the synthesis/pharmacology has been explored.

3-bromo-4-(1,1-difluoromethoxy)-5-methoxyphenethylamine.png


Have you considered using e.g. methoxide to displace the bromide on the ring?
4-(1,1-difluoromethoxy)-3,5-dimethoxyphenethylamine.png
 
Of course I have. But, why do it, at least unless the amphetamine (probably the one that gets made first, as I'm out of nitromethane) shows very low potency or none. Difluoromescaline would be interesting to explore too of course, but whether or not I can manage to get all three, or four if you count the 3-MeO-TMA analog also, out of just 5g of aldehyde, even using TETA as the base and employing the microwave for heating, not sure as I could squeeze it quite that hard.

I want to get the most out of the aldehyde I have, of course, and NOBODY seems to be poking about on the 3 position with EWGs in 3,4,5-trisubstituted phens/phets.
I can't find a damn thing, Trachsel didn't look there, Sasha didn't seem to either, and I'll just bet that nobody has made anything with this particular substitution pattern. Halogens on the ring other than the 4-position, seem almost unknown, likewise the likes of cyano, nitro, thiocyanato etc.
 
It does appear that these compounds have barely been touched. One group appears to have made both 3-chloro-4,5-dimethoxyphenethylamine and 3-chloro-4,5-dimethoxyamphetamine for the purpose of evaluating their psychoactive properties, but it's in an obscure journal and I can't find the full text:

Potential psychotropic drugs. VI. Synthesis of new mescalinoids
Chimica Therapeutica 1970, 5, 55.

Mescalinoids (I)​, where R1 is H or Me; R2 and R5 are H, Cl, or OMe; R3 and R6 are H or Cl; R4 is OMe, OEt, OCH2Ph, OPr, OBu, OCH2CH:CH2, OMe, or H, or (R4R5 =)​OCH2O; n is 1 or 2, and A is HSO4, Cl, SO4, O2CCO2H, O2CCO2, or Cl, useful as psychotropic medicaments for the central nervous system were prepd. by known methods. 2-​(3,​5-​Dichloro-​4-​methoxyphenyl)​ethylamine was prepd. by treating (3,​5-​dichloro-​4-​methoxyphenyl)​acetamide with LiAlH4. The synthesis and phys. properties of the intermediate products are discussed.

It's not clear from the abstract whether they actually tested the activity.
 
Do they list the DOI? if so could nab it with sci-hub.

As for the odd leaving out of these types of compounds, the question is, WHY. Surely, someone like Shulgin, would, if he had made them and found them to be a generally noxious group,akin to say, para-haloamphetamines, para-monosubstituted alkylated or alkoxyl/alkylthiolated compounds, he would have said as much in PIHKAL, since I can hardly envision him leaving out such information, if it might have lead to someone poisoning themselves.

But shit, He might have been the pioneer of such studies, but there are others now, Nichols, for example, I'm really, really surprised given the nature of Trachsel's paper that he didn't fluorinate the bejeesis out of the 3' carbon like he did with pretty much everything else he could perfluorinate.

That multi-party lack of attempts is what lead to ask whether there were specific difficulties with selective meta-monosubstitution.
 
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Do they list the DOI?

Unfortunately not. It may not have been published online at all.

That multi-party lack of attempts is what lead to ask whether there were specific difficulties with selective meta-monosubstitution.

It looks like 3-bromo-4,5-dimethoxybenzaldehyde has been prepared many times in high yield in two steps from vanillin, so the Friedel-Crafts selectivity doesn't seem to be that big of an issue. It is very widely available, although it does seem to be a bit more expensive than the 4-bromo-2,5-dimethoxy- or 4-bromo-3,5-dimethoxybenzaldehydes. I'm stumped as to why Shulgin, Nichols, et al. wouldn't have looked at these.
 
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Yeah, it just doesn't make sense. Especially for a talented chemist like Sasha Shulgin, as soon as I remember where the hell I put the aldehyde, I'm getting on this one, Its just plain weird that such a substitution pattern has been ignored. It can't have been found to be the parent mold for a legion of neurotoxic horrors and fucked off, nfor two reasons, both people's safety, and especially with Shulgin exploring the compounds he made himself, if it had been something like another para-haloamphetamine, it'd have been both warned against, and exploited in creatively unpleasant ways to abuse rats and mice.
 
Theres only 3 fluorinated, 7 brominated, 2 chlorinated and 3 iodised compounds in phikal while theres 41 thionated compounds. Ironically shulgins most praised discoveries turned out to be among his halogenated compounds.Maybe the materials for thionated compounds were easier to get or to synthesise?
 
Theres only 3 fluorinated, 7 brominated, 2 chlorinated and 3 iodised compounds in phikal while theres 41 thionated compounds. Ironically shulgins most praised discoveries turned out to be among his halogenated compounds.Maybe the materials for thionated compounds were easier to get or to synthesise?

A lot of Shulgins work was methyl ethyl propyl butyl futile, the thioethers allowed for a lot of variation of the alkyl part of the ether by divergent synthesis from 2,5-dimethoxythiophenol and an alkylating agent of choice plenty of compounds almost all junk.

There are classics in Pihkal but things like 2-cb are not really Sashas at all, having been discovered by a British chemist Michael Carter who communicated the discovery to Shulgin. Has anyone ever found out what happened to Carter, did he discover anything else?
Shulgin didn't think laterally later on, and probably stopped being cutting edge in the mid 1970's around the time of DOX's. So very few fluorinated compounds because by the time the chemistry became easy Shulgin had stopped creating, None of the chiral phenethylamines were Shulgin, they were Nichols. EthLAD and the alkyl NorLSDs were also Nichols a lot of Pihkal and Tihkal is not Shulgin but was gathered together in one place by Shulgin to make an excellent reference.
 
I tried 3-MeOMA. It was basically inactive.
Check out the META-DOB entry in PiHKAL.
 
Methoxy isn't an EWG dresden.

(question-whilst haloalkylated substituents are (E.g TFM), do haloalkoxy groups still withdraw electron density from aromatic rings?) (such as the difluoromethoxy group in the 3-bromo-4-(1,1-difluoromethoxy)-5-methoxyphenethylamine and amphetamine counterpart?)

I found the aldehyde BTW folks; after a long, thorough search of every reagent cabinet and shelf in the lab and in all the other spare space devoted to reagent storage. Soon as I've some nitromethane and LAH (already have nitroethane) then its on! (want to be able to prepare the nitrostyrene and nitropropene both at the same time, one after the other in the microwave), should take no more than 15-20 minutes each, high yields using microwave irradiation and a good catalyst for the Knoevanagel, then should be able to report back on the effects of these, as well as saving a small portion, a couple of hundred mg of the phenethylamine and amphetamine for displacement of the bromine atom with methoxide so as to try difluoromescaline and difluoro-TMA as well, or if the brominated compounds are inactive, then the rest will be converted into difluoromescaline, known to be active, and 4-difluoro-TMA which should be active just as difluoromescaline is.
 
Yeah, what all other illegal drugs do you manufacture, Limpet?

Do tell us.

Inquiring Minds Want To Know!
 
Thats bloody rich coming from the likes of you, Dresden, what with your (spurious in most cases, utter horse shit at worst (such as compounds that if at all, are barely stable enough to exist)

And besides, this is BL, why would any users of a site of this nature give a shit about licensing? I'd have thought folk would be more interested in the end results?

And BTW, where did you find the abstract, SJP? might help me track down the original paper.
 
Thanks. I think I'll shoot them an email and see if I can get a copy. Thats EXACTLY the sort of info I want, looking at the abstract.

Although got to admit, there is somewhat of a sense of trepidation about treading on such new, unexplored ground. Good to know though that it can be salvaged even if the phen/phet pair turn out inactive, with Sekio's suggestion of rxn with an alkoxide, maybe alkanethiolate (although I'm leaning towards methoxy group, because bugger me if I want to work with cryogenically condensed methanethiol, dumping sodium in there. Because its not going to take much to raise an unholy stench. The neighbors are fine with my chemistry hobby, or at least, they've gotten used to having a neighbor buggering about in hazmat gear in the back garden (for things that are just too dangerous or unpleasant to do in the lab itself)

But I think they'd probably skin me alive and cover me in salt if a flask full of liquid methanethiol or ethanethiol 'got loose', which given the potency of their stenches, isn't saying much
They'll tolerate the odd bit of flying white phosphorus and accompanying P2O5 cloud, a bit of H2S stink, but I doubt they'd be too pleased if I were to dump a load of some low weight mercaptan on their doorstep, so to speak=D
 
(question-whilst haloalkylated substituents are (E.g TFM), do haloalkoxy groups still withdraw electron density from aromatic rings?) (such as the difluoromethoxy group in the 3-bromo-4-(1,1-difluoromethoxy)-5-methoxyphenethylamine and amphetamine counterpart?)

You will enjoy this survey of Hammett parameters from Chemical Reviews. The Hammett equation is based on the equilibrium between benzoic acid and hydronium benzoate in water. Adding an electron-withdrawing substituent to benzoic acid will push the equilibrium towards benzoate by stabilizing the anion, while adding an electron-donating substituent will push the equilibrium towards the undissociated acid. The effect of a given substituent on the equilibrium is assigned to the parameter "sigma," where log(rate constant of substituted benzoic acid/rate constant of benzoic acid) = sigma*rho, rho being a constant. If sigma is positive, the substituent is electron-withdrawing and the equilibrium lies towards the carboxylate relative to benzoic acid. If sigma is negative, the substituent is electron-donating and the equilibrium lies towards the undissociated acid relative to benzoic acid. A great advantage of this equation is that by varying rho, the sigma values can be applied to a wide variety of reactions and equilibria. For example, a substituent with a positive sigma value will be a weaker Friedel-Crafts nucleophile than benzene, while a substituent with a negative sigma value will be a stronger Friedel-Crafts nucleophile. A great number of sigma values have been tabulated, for both the position para to a substituent ("sigma(p)") and meta to a substituent ("sigma(m)"). Values for ortho positions are generally not examined as there are confounding steric effects.

For mono-, di-, and trifluoromethoxybenzene, the sigma values are as follows, according to the Chem. Rev. article:

mono: sigma(p) = 0.02, sigma(m) = 0.20
di: sigma(p) = 0.18, sigma(m) = 0.31
tri: sigma(p) = 0.35, sigma(m) = 0.38

The conclusion, therefore, is that even a monofluoromethoxy group will withdraw electron density from an aromatic ring at the ortho, meta, and para positions, with the withdrawing effect increasing as the number of fluorines increases.

For reference, the values for methoxybenzene are: sigma(p) = -0.27, sigma(m) = 0.12

Alkoxy groups are sigma (inductively) withdrawing while pi (conjugatively) donating. This means that while methoxybenzene, for example, is significantly stronger of a nucleophile than benzene is overall, electrophilic substitution at the meta positions will actually be slower in methoxybenzene than in benzene, as the conjugation from the oxygen lone pair into the aromatic ring can only push electron density to the ortho and para positions. As you add more fluorines to the methyl, the inductive withdrawal gets stronger and the pi donation weaker, making the arene a weaker nucleophile than benzene even at the ortho and para positions. An interesting quirk of this situation, though, is that while pi donation towards the ortho position and that towards the para position are roughly equivalent, the inductive effect of the fluorines weakens with distance. This leads trifluoromethoxybenzene to be a much more para-selective nucleophile than methoxybenzene, as the inductive deactivation is much stronger at the ortho position than the para.

See "Table I" in the Chem. Rev. article for the full list of sigma parameters.
 
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