[bobo]

Hello,

I wonder what will happen if a grignard reagent is in contact with an imidazole ring. It is a heterocycle five ring containing nitrogens and double bonds. It will have to be deprotonated before reaction since one of the nitrogens is SP3. But then what? Would the grignard reagent attack the other atoms?

My goal can be achieved by either preparing a grignard reagent of an imidazole substituted ring with para bromine and letting it react with the molecule I want to connect it to. This would be the case if imidazole is unreactive. If it is reactive and the reaction does not destroy the ring, I could try putting it on the molecule directly.

Anyone who's really into these (obscure) uses of grignard able to help me?

[movies]

The hydrogen on the N-H bond is too acidic to allow the formation of the Grignard reagent.  The pKa is around 18.6 (DMSO solvent and reference) while the pKa of a typical Grignard reagent is more in the neighborhood of 30.  

The reaction you propose would be like trying to make a Grignard reagent with a molecule that had a free -OH in it.

[laotree]

Protected your imidazole NH, and then do lithium-halide exchange might be a good idea.

[bobo]

Thanks for the replies.

Making a grignard reagent would not be problematic with the N atom because a molecule is commercially available with that N atom bound to the para substituted bromobenzene. Therefore, the question becomes whether the grignard reagent would rather attack the bromine atom on the aryl ring, or somehow interfere with the imidazole ring. I have little information about this except for a russian article which describes a grignard reagent attack on one of the carbon atoms of imidazole, but that imidazole molecule is heavily substituted.

I would make a grignard reagent using precisely the stoichiometric amount of Mg to avoid side reactions, but this will only work if the aromatic bromine atom is more readily displaced than any other.

The second option, nucleophilic attack of a grignard reagent onto an imidazole ring seems more unlikely but I would like to know if this is possible at all.

[movies]

So do you want the Grignard functionality on the benzene ring or the imidazole ring?

I think that attack on the imidazole would be relatively slow and you could probably trap out your desired product provided that you are using a good electrophile like an aldehyde.  You might have problems with deprotonation of the imidazole ring though; I'm not sure of the pKa's for the ring protons.

[bobo]

I want the imidazole intact, and a para bromine atom to participate in a grignard reaction, to attack another (aromatic) bromine atom.

Aromatic bromine isn't too happy to react, but in grignard it does so readily, but how readily it reacts if there is another moiety such as imidazole, that is the question.

I found reactions using n-BuLi that attack the 2-H (between the nitrogens). But n-BuLi is stronger than grignard so we'll see. I will do an experiment to find out whether or not it reacts by using cheap reagents and 1-meIm.

If it DOES react, I would have to protect the 2-H somehow. The other hydrogens seem to be unreactive towards n-BuLi so that's good enough.

[Dude]

As movies indicated, the N-H bond will completely inhibit a Grignard reaction.  However, it is not a given that even the nitrogen in the ring will not cause problems in a Grignard reaction.  As a side project when I was in grad school, I wanted to make a "disilane" by reacting by reacting 2,6-dibromopyridine with two equivalents of chlorodimethylsilane and magnesium.  Most of the literature references reported very poor yields due to "nitrogen coordination" with the formed Grignard reagent.  I don't think I ever got around to that reaction because it looked like a lot of purification work.

[movies]

Yeah, that's a good point too.  Heteroatoms can cause strange problems in anion reactions.

So what you are proposing is a Corey-House reaction?  You will need copper then, right?  Or do you mean a Kumada coupling, in which case you need palladium.

Grignard reagents aren't very good at attacking sp² hybridized carbon halides.

Also, Grignard reagents aren't quite as basic as n-BuLi, but they are close.  It still might be a problem.  I found a pKa for 1-methyl imidazole and it is 33.7, which is pretty close to that of benzene (which should be approximately the same as the Grignard you are proposing).

Definitely a risky reaction in my estimation.