Sciencemadness Discussion Board

Grignard Degradation Mechanism?

aonomus - 20-10-2009 at 23:56

So I'm attempting to figure out how the Grignard degradation works, I can't find it in any of my textbooks, and a brief recent literature search doesn't turn up anything.

In a paper (see ref below), the authors took dimethylamino sulfonyl (DMAS) protected 4,5-diiodoimidazole, reacted with EtMgBr in DCM, and then intentionally hydrolyzed to give only the 4-iodoimidazole.



Now for a sanity check, the EtMgBr *should* react with the most electrophilic center (in fact shouldn't the Grignard react with the solvent?!). Why would reacting and then quenching, cleave off the most reactive halogen, when the C-C bond is strong and can't simply be hydrolyzed away.


Even if by some leap of thought a Grignard is formed with the imidazole ring, would the magnesium insert itself between the C-I bond, or would the entire MgBr replace the iodine in a metasthesis reaction?

What is more irritating is that the authors don't even address what the particular reaction is, so I'm a little worried I have it by the wrong name, but what information I could find said that the Grignard degradation is used to sequentially remove halogens by reactivity.

Bhandari, M.R., Sivappa, R. et al. 2009. Total Synthesis of the Putative Structure of Nagelamide D. Organic Letters 11:7 1535-1538

Nicodem - 21-10-2009 at 01:13

Quote: Originally posted by aonomus  
So I'm attempting to figure out how the Grignard degradation works, I can't find it in any of my textbooks, and a brief recent literature search doesn't turn up anything.

Never heard about the phrase "Grignard degradation" used for this reaction. Try using the normal name for this reaction: magnesium-halogen exchange or Grignard metathesis. It is a pretty common reaction. It is however uncommon to use it for hydrodehalogenations. More commonly it used to prepare grignard reagents that are otherwise hard or impossible to prepare. Isopropylmagnesium chloride is most commonly employed and this way you can prepare even "impossible" grignards like methoxycarbonylbenzenemagnesium halides, for example (the COOMe group generally slowly reacts with grignards at room temperature, but the Mg-I exchange is rapid enough even at -20°C where such grignards last much longer). For example:

p-MeOCO-C6H5-I + iPrMgCl => p-MeOCO-C6H5-MgCl + iPrI (at -20°C)

This is essentially analogous to the lithium-halogen exchange reaction which however occurs much faster even at -78°C.
Quote:
Now for a sanity check, the EtMgBr *should* react with the most electrophilic center (in fact shouldn't the Grignard react with the solvent?!). Why would reacting and then quenching, cleave off the most reactive halogen, when the C-C bond is strong and can't simply be hydrolyzed away.

The Mg exchanges the most exchangable iodine which is always the one which has the lower C-I bond energy and/or has neighbouring chelating groups (the DMAS protection in this case). I do not know why they used CH2Cl2 as solvent, but there is no reason why not to use it. It does not react with organomagnesium compounds at any useful rate - actually only very few alkyl chlorides react with grignards at all (without transition metal catalysis).
Quote:
What is more irritating is that the authors don't even address what the particular reaction is, so I'm a little worried I have it by the wrong name, but what information I could find said that the Grignard degradation is used to sequentially remove halogens by reactivity.

Currently I do not have the time to check that reference, but I'm sure you will be able to find plenty of literature regarding this reaction if you only use more proper keywords in your search.

aonomus - 21-10-2009 at 04:13

Thanks for pointing me down the right track, I'll look into it when I've gotten more sleep.

As for the solvent issue, I've always made Grignards in diethyl ether before, and 3am was probably another factor.

Arrhenius - 21-10-2009 at 22:03

They probably use DCM to solubilize the imidazole. I'm also willing to bet they used a commercially available grignard reagent solution, so the ethyl grignard was probably not prepared in DCM. As for whether to draw it as MgBr or MgI, this is of little consequence. Not to mention that the mechanism of metal halogen exchange is debated, it would have no effect on the outcome of the product.

The more important question to answer is: Why does it exchange that particular iodine, and not the other?

aonomus - 21-10-2009 at 22:51

Selectivity is always due to either a steric effect, or electronic effect. I spoke with my professor last week and he was siding towards the DMAS group having an electronic effect, but since the mechanism of the magnesium-halogen exchange is debated on and isn't known well, the chelation/coordination proposal by Nicodem seems more reasonable.



It seems reasonable that the electronegative oxygens on the sulfonyl may attract the magnesium, but the arrow pushing described is just proposed, could be a radical mechanism, or just the wrong way around (I'm a little busy to look up whether a C-I bond is more electrophilic/nucleophilic than a C-Mg bond).