Restrictions to the Friedel-Crafts reaction?

[bottleneck]

I am interested in alternatives to formylation in phenethylamine synthesis when the amount of aromatic substrate is a limiting factor.

Does anyone have any ideas on possible sidereactions which would prevent Friedel-Crafts alkylation of 1,2,5-substituted benzenes in the remaining para-position with haloethylamine or haloacetonitrile?

Does Lewis acids react with carboxylic acid derivatives like nitriles?

As far as I understand it, the Lewis acid needs only be present in catalytic amounts in alkylations as opposed to the required molar equivalent amounts in acylation. Would this lessen the likelihood of side-reactions?

[Kinetic]

I've been doing quite a bit of research on Friedel-Crafts, so I'll try and answer your question:

Your haloethylamine route won't work unless you protect the nitrogen, since it will either react with the Lewis acid, or with the other end of the ethylamine chain once the halogen is pulled off. Obviously using only a stoichiometric amount of catalyst instead of 1.2 equivalents won't stop this happening .

The Lewis acid/nitrile interaction is a bit more interesting, and there is very little information here on a reaction which may occur; the Hoesch reaction. GC_MS mentioned it, see

Post 357611

(GC_MS: "Asarone", Chemistry Discourse), and zealot also uses it beautifully in

Post 308020

(Antoncho: "The another way to P2Ps - "the Zealot's pathway"", Novel Discourse), where it seems to be called the Gesch reaction (I'm not sure if there is any difference between the two other than the name). To be honest, I'm surprised it hasn't been talked about more; it looks like a nice reaction to me, and I may have to give it a try soon as an alternative to the highly-prone-to-tar-formation acylation of benzodioxole. Anyway, I'm not sure if it would happen, but theoretically you could end up with your halonitrile adding 'backwards' to your aromatic ring!

I'm assuming you're trying to alkylate a 2-substituted 1,4-dimethoxybenzene. If this is the case, I have a feeling Friedel-Crafts alkylation will be very hard to do without demethylating the methoxies, since the stronger Lewic acids and harsher conditions needed are more likely to do this. It may be possible, but there is probably a reason Shulgin acylated his dimethoxybenzenes then reduces the ketone to the alkane via a Clemmensen reaction.

If anyone has any more info on Frledel-Crafts or can enlighten me, I'd love to hear it. Friedel-Crafts acylation is by far my favourite reaction at the minute .

[bottleneck]

> Your haloethylamine route won't work unless you protect the nitrogen, since it will either react with the Lewis acid, or with the other end of the ethylamine chain once the halogen is pulled off.

Okay, thanks...

> The Lewis acid/nitrile interaction is a bit more interesting, and there is very little information here on a reaction which may occur;

Okay, so acetonitrile survives ZnCl2? That's something. However, diazomethane sounds a little dangerous to handle, I must say.

If one is already going to set up for handling poisonous gasses and everything, I guess one could attempt to make the phenylacetone by Friedel-Crafts with chloroacetone as in

https://www.thevespiary.org/rhodium/Rhodium/chemistry/phenylacetone.html

, although the reported yields for benzene are low.

> I'm assuming you're trying to alkylate a 2-substituted 1,4-dimethoxybenzene. If this is the case, I have a feeling Friedel-Crafts alkylation will be very hard to do without demethylating the methoxies, since the stronger Lewic acids and harsher conditions needed are more likely to do this.

Okay? Well, I think the methoxies are a bit activating and with the methyl also there I think it would be pretty active. In any case, even if a strong catalyst is required, merely adding a drop of bromine to some aluminum foil in a chloroform should be all that is necessary to form a little aluminum tribromide in solution, though obviously not with ketone products which require molar equivalents of the Lewis acid.

> It may be possible, but there is probably a reason Shulgin acylated his dimethoxybenzenes then reduces the ketone to the alkane via a Clemmensen reaction.

You mean instead of just F-C alkylating with alkyl halides? I don't know, didn't he start with 1,4-dimethoxybenzene, which would produce the para-dialkyl derivatives if F-C alkylated?

Actually, that might not be so bad an idea. Dialkylating 1,4-dimethoxybenzene using methyliodide + Lewis acid should produce 2,5-dimethoxy-4-methyltoluene, right?

Oxidation using persulfate like once mentioned by

Post 208719

(Osmium: "Re: The easiest synth of benzaldehyde from toluene", Chemistry Discourse) will probably yield 2,5-dimethoxy-4-methylbenzaldehyde in good yield, since the reaction with xylene is facile.

If 1,4-dimethoxybenzene could be dialkylated using methanol instead of methyl halides, this might not be such a bad route to the benzaldehyde. As a google-search reveals, the alkylation reaction is facile with tert-butanol, but that says nothing about the less branched alcohols of course.

[Kinetic]

If you're happy to work with chloroacetone, then this might well be a good route to choose to the phenylacetone. Benzene gives a low yield due to polyalkylation, but your rather heavily substituted product might be sterically hindered enough to make this less of a problem.

In all the examples I've seen for Friedel-Crafts alkylation, a full molar equivalent of Lewis acid catalyst is still used. To be honest I'm not sure why; theoretically the catalyst will be regenerated at the same rate as the HX gas is evolved, but I'm guesing there is a reason . AlBr₃ though, is an even better demethylation agent than AlCl₃, and it will also complex with the oxygens of the methoxies. AlCl₃ can be used for acylations of (di)methoxybenzenes at around 0^oC without too much demethylation, but I don't know about alkylations.

Yes, Shulgin did start with dimethoxybenzene. I admit I hadn't thought of the reason you gave for using acylation rather than alkylation, but I still think it will be hard to insert a primary alkyl group onto any aromatic ring. I'll have to check, but I don't think it's possible to attach methyl groups in that way; Me⁺ is very unstable as it has no electron donating substituents to stabilise it. Sorry if you know differently, I don't have time at the minute to check if I'm completely wrong or not! I do know that if you tried to acylate benzene with 1-chloropropane, it would rearrange to give the secondary cation, and the acylation product would be isopropylbenzene, excluding any polyacylation which would occur.

Finally, forgive my ignorance, but Osmium mentions the oxidation of toluene to benzaldehyde. I don't know what effect ring substituents have on this reaction, but if you oxidised 2,5-dimethoxytoluene you might end up with both the methyl groups oxidised to aldehydes!

Hope this helps, and sorry if it seems a little incoherent. This 250mg codiene has made me rather sleepy and confused.

[bottleneck]

Well, I do seem to remember methanol and other alcohols are used to Friedel-Crafts-alkylate aromatics. In the patents, usually either solid acids like acid-exchanged clays and zeolites (GB1061775 for example), or high pressures are mentioned. Yields are probably pretty variable.

No, the patent Osmium mentions is indeed supposed to be selective. Xylene gives 4-methylbenzaldehyde.

That codeine sounds like a good idea. I think I'll go and have some as well.

[foxy2]

Xylene gives 4-methylbenzaldehyde.

Only if your using p-Xylene, not mixed Xylenes which are whats commonly available.  Most "generic" xylene is a mix of ortho, para, meta xylenes and also some ethylbenzene.

Here is a good thread on getting p-xylene and the common ratio's in commertial mixed xylenes.

Post 335906

(Antibody2: "how do they isolate p-xylene from its isomers", Chemistry Discourse)