OTC preparation of MMA and isomers

[phenethyl_man]

.. the way I understand it, the xylene that is sold retail is predominatly m-xylene followed by p-xylene then o-xylene.  It seems to me that oxidation under neutral conditions with one half part potassium permanganate, and utilizing Al2O3 as a solid support to prevent over-oxidation, should give, in the respective order, m-tolualdehyde, p-tolualdehyde, and o-tolualdehyde. 

Bromination of this mixture, and then subsequent reaction with copper and sodium methoxide should give a mixture of predominatly 2-methoxy-4-methylbenzaldehyde, followed by 3-methoxy-4-methylbenzaldehyde and 2-methyl-5-methoxybenzaldehyde.

I believe that all of these aldehydes would lead to active isopropylamines from the usual workup involving EtNO2 condensation followed by reduction, except for perhaps, the 2-methyl-5-methoxybenzaldehyde, originating from o-xylene, which would hopefully only be a small portion of the xylene of commerce.

3-methoxy-4-methylamphetamine, or MMA, has already been shown to be quite active in the 40-60 mg range and I would expect the isomer 3-methyl-4-methoxyamphetamine to be just as active, since 3-Me isomers of DOM are also potent.

... OTC MMA from just a few simple reactions, could this be true?  Any thoughts on this or am I off base here?

[Rhodium]

How do you suggest separating and purifying the intermediates? Even if you would do something as perverse as running three consecutive reactions (oxidation/bromination/methoxylation) on a starting material which already constitute a mixture, you will end up with a tar-ball consisting of a few percent of various methoxy-tolualdehydes and the rest being accumulated byproduct polymers and other crap. There is no way you could run the nitroethane condensation on an impure product, and it is probably futile to try to column chromatograph such a mixture - not to mention the joys of multiple fractional vacuum distillations of a multicomponent mixture of both solids and liquids, of which your desired fraction constitute a minor part...

Perhaps it's time to rethink your strategy, synthesizing one pure product at the time? Have you looked up the necessary reaction conditions for the bromination of p-tolualdehyde? You need to add an excess of elemental bromine to a neat mixture of anhydrous aluminum chloride and p-tolualdehyde, all mechanically stirred without any solvent. You really want to limit yourself there as to not having to react more stuff than the desired tolualdehyde, or you'd need to scale that vile reaction up with at least 10x to get the same output...

[phenethyl_man]

Okay, well.. the isomers may be able to be crystallized out since all three isomers have significantly different melting points..

(from the Merck Index)

m-xylene - -47.4°
o-xylene - -25°
p-xylene - 13-14°

Or, of course you can always buy them already seperated, by the liter, from any decent chem supplier for cheap as hell, but then again, I guess that's off-topic since my subject states "OTC."

As for the bromination of tolualdehyde...  Are the problems you mention with this reaction caused by the introduction of the formyl group deactivating the ring?

Perhaps the direct bromination of p-xylene would proceed smoother, the bromine should still take the same position and the following oxidation should still proceed fine.  just switch the steps..  Even if AlCl3 is required as a catalyst, it's not like that can't be easily synthesized using OTC products.

However, access to the same intermediate from over-the-counter sources might be much more easily achieved by simply formylating toluene; a dozen procedures to choose from and no isomers to deal with..  For example, Chloromethylation followed by the Sommelet reaction could work and uses all OTC reactants; hydrochloric acid, paraformaldehyde, ammonia, and hexamine (formed from the ammonia and paraformaldeyde).

[Rhodium]

As for the bromination of tolualdehyde...  Are the problems you mention with this reaction caused by the introduction of the formyl group deactivating the ring?

Exactly. It's the same thing with 4-methyl-acetophenone, it's very hard to brominate. You also need to use an extra equivalent of lewis acid to coordinate with the carbonyl oxygen when brominating - see

http://www.orgsyn.org/orgsyn/chemname.asp?nameID=40843

Perhaps the direct bromination of p-xylene would proceed smoother, the bromine should still take the same position and the following oxidation should still proceed fine.  just switch the steps.

I wonder if we could use the procedure they describe in

Post 514596

(Rhodium: "Many routes to 3,4,5-Trimethoxybenzaldehyde", Methods Discourse)

They react p-Hydroxytoluene with bromine to give 4-Hydroxy-3,5-dibromotoluene, which continues to become brominated on its methyl group, first forming 4-Hydroxy-3,5-dibromobenzyl bromide and next the benzal bromide (with a -CHBr2 side chain). This is then hydrolyzed with aqueous acid to give 4-Hydroxy-3,5-dibromobenzaldehyde in their example.

I wonder if the same procedure performed on p-Xylene would give 3-Bromo-Tolualdehyde, or if something weird happens?

[phenethyl_man]

I doubt that would work on p-xylene..

the fact that phenols are so highly activated is prob the only reason that reaction works... the hydroxy group is what allows the bromine to go ape shit on the molecule and dibrominate both it's ortho and para substituent(s), via strongly activating these positions..

still an interesting reaction thou seems like it would be hard to keep under control.