Grignard P2Pol In Situ Oxidation

[PrimoPyro]

Hi. Just had a thought, and wanted to get some input. No formalities this time. It's late, and Im tired.  

Reaction: phenyl-magnesium-bromide or a benzene derivative thereof + propylene oxide in ether --> P2Pol, a.k.a. phenyl-isopropanol upon quenching the reaction with HCl.

Mechanism: Ph-MgBr opens the small epoxide ring of propylene oxide; the phenyl attaches to the terminal carbon, and the epoxide becomes an alcohol derivative on the beta carbon, a R-O-Mg-Br group. Normally, to quench this reaction, HCl would be added to cause R-O-Mg-Br --> ROH + Mg(Br)Cl. Then to get the ketone, the alcohol must be carefully oxidized.

I wonder:
PhMgBr + propylene oxide --> PhCH2-(CHO-MgBr)CH3
PhCH2-(CHO-MgBr)CH3 + NaOCl --> PhCH2COCH3 + Mg(Br)Cl + NaOH

Instead of quenching with hydrohalogenic acid to donate the halogen, use hypohalite solution to both rid of the magnesium halide intermediate, and to dehydrogenate the aliphatic chain by NaO- abstracting a hydrogen, thus an oxidation to a ketone.

Perhaps my description is invalid, but what about such a reaction? In reality, hypochlorites are moderate oxidizing agents. The organomagnesium halide adducts are also unstable. The products of this reaction are much more stable than the reactants. Maybe its because Im tired, but I cannot forsee any specific side reactions. Seems good to me.

Whatayathink? I'd like some feedback when the bees get a chance. Thank you, I appreciate it.  

                                                   PrimoPyro
The Water Will Be Your Only Mirror

[PrimoPyro]

Oh come on now, it's been over a week. No one has anything to say? I find that hard to believe, as I find it hard to believe this hasn't been thought of/debated over before at some time. Every other idea I've had has been thought of by someone else before me, so I'm sure this isn't new either, I just can't find anything on it. Don't make me start talking to myself now....

Are there any reasons this wouldn't work? You guys have to realize just how cool it would be to perform this oxidation step all in one with the grignard coupling. You just have to see the beauty, you have to...If not, what the fuck is wrong with you, you sick, cold hearted, joyless bastard?  

                                                   PrimoPyro
The Water Will Be Your Only Mirror

[Rhodium]

We have to ask ourselves some questions first:

1) Can P2Pol be oxidized to P2P with sodium hypochlorite? Yes it can, for example with a PTC:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/ptc.naocl.oxidation.html

By necessity, the sodium hypochlorite needs to be in aqueous solution for the oxidation, but P2Pol is not water soluble, I don't know what the result would be without a PTC. But a two-phase PTC reaction is all right here, the organic phase is already present (if ether was used for the grignard, THF is water miscible and would have to be evaporated and replaced with another solvent) and the hypochlorite solution provides the aqueous phase.

2) How vigorous reaction conditions are needed to decompose the magnesium alcoholate? In some instances, mere addition of water is enough, in other cases long acid reflux is needed. I don't know about this case. If it is easily decomposed to the alcohol, then water may suffice, or perhaps just one molar equivalent of acid would be needed, and the proposed reaction is indeed feasible.

3) Can hypochlorite really oxidize alcoholate salts to ketones? Probably yes, but the formation of increasing amounts of NaOH will inhibit the reaction speed (negligible, or too much? I don't know, testing is in order.

Aqueous sodium hypochlorite (NaOCl), or common household bleach, can be used to oxidize secondary alcohols to ketones. The reaction occurs more rapidly under acidic conditions, so it is thought (we're not actually sure) that the actual oxidizing agent is hypochlorous acid (HOCl), generated by the acid base reaction between sodium hypochlorite and acetic acid. In alcohol oxidations, the reaction probably proceeds via E2 elimination of the alkyl hypochlorite produced by reaction of the initial alcohol with HOCl.

Taken from

http://www.chemistry.mcmaster.ca/~chem2o6/labmanual/expt7/2o6exp7.html

4) Will any of the species in the grignard reaction mixture interfere with the oxidation? Hard to say, but the bromide/iodide from the grignard reagent will likely be oxidized to the free halogen by hypochlorite - and this halogen may again react with the P2P, forming an alpha-halo ketone.

It sounds like it is worth a try, definitely. Who will be the first to perform this reaction?

And finally - No, I haven't seen any discussions about this one-pot P2P synthesis earlier, and there are only 20-something hits in the database on "propylene oxide grignard", and noone of the posters there seems to have performed it, they just mention it as an alternative pathway.

[PrimoPyro]

Rhodium, thank you for your reply! You really put a lot of thought into that post, and I sincerely appreciate it.  

Here I am, feeling all good about a new possibility, and marveling at the simplicity of such an idea, when what I should have known right from the start, finally came crashing down. I'm afraid this idea is doomed to failure, due to a crucial oversight.  

The idea is annihilated with a mere three small words: The Haloform Reaction.

This is a reaction where a methyl ketone is subjected to hypochlorite solution, and the methyl gets trichlorinated with the formation of alkalai as byproduct. The alkalai then causes fission of the trichloromethyl from the carbonyl, forming chloroform and a sodium carboxylate salt.

Sadly, MD-P2P is a methyl ketone... It will further react with the hypochlorite to rip the terminal aliphatic carbon off of the chain, and create 3,4-Methylenedioxy-phenylacetic acid, sodium salt, a major step backwards.  

I can't believe I didn't see this right away when I posted it a week ago. The Haloform was the first name reaction I ever learned, and it has been one of my favorite conversions since I learned of it. It's unbelievable that it escaped my attention here.

I am so disappointed now. I was really happy.

Thank you Rhodium for the extremely thoughtful reply.

                                                   PrimoPyro
The Water Will Be Your Only Mirror

[Rhodium]

That does not need to be an obstacle. The hypochlorite oxidation is favored by low pH, while the haloform reaction is favored by high pH. Just make sure the solution is buffered to neutrality or slightly acidic.

[PrimoPyro]

It will have to be buffered very well to neutrality. Both an acidic or a basic solution would mess with the reaction. Think about:

The dehydrogenation reaction itself, with hypochlorite, will produce alakalai as a byproduct, buildup of alkalai will promote the haloform reaction, which in turn produces more alkalai...

Counteracting this with an acidic medium will quench the grignard on its own, forming MDP2Pol. It will also react with the hypochlorite ion to oxidize it to free chlorine. Perhaps this would help oxidize the alcohol, perhaps it will destroy the reaction, I do not know.

The only thing I can really see now, is to quench the reaction with acid like normal (cringe) nd then oxidize with hypochlorite. But, the whole idea was to do it all as one step. If you still have to make the alcohol, and then oxidize it, why use hypochlorite when there are other methods just as easy, if not better?

This still really sucks. How would you buffer the solution against alkalinity, without introducing an acid that would kill the magnesium alcoholate to make the free alcohol? Im stumped on that one...

                                                   PrimoPyro
The Water Will Be Your Only Mirror

[Rhodium]

What if the buffered solution hydrolyzes some of the Mg alkoxide? It doesn't matter if the alkoxide or the free alcohol is oxidized to P2P, right? It will still be a one-pot reaction without the isolation of P2Pol first.