[voidSetup]

Hello,

I'm working on an undergraduate senior project right now, and am having a little trouble here.  I'm trying to turn a TBDMS protected 9-bromo-1-nonanol into a Grignard reagent for use in a cross-coupling reaction, but the Grignard reagent doesn't seem to form.  I ran the reaction at the end of last semester, and the Grignard solution (the alkyl-halide/Mg in THF) was a grey turbid color so I thought that it worked.  I tried the coupling, did the workup, and ran GC-MS on the reaction mixture. Only two compounds were present and they were the two starting materials.  This means that there were no side reactions (elimination, homocoupling..), or the desired product.  The MS shows though that the 9-bromo-1-nonanol still has its halogen on there though. If the Grignard reagent formed then the halogen would have been removed on the NH4Cl workup.

I tried the reaction again today and added a small crystal of iodine to the solution this time. It instantly turned amber.  I brought the solution to reflux for about an hour but all the of Mg would not be consumed.  The solution turned to a more yellow color but a decent amount of Mg was still present.  I tried the cross-coupling again, and worked it up.  I'm going to run some analysis on it tomorrow or Thursday but I don't think the Grignard reagent formed again.

Has anyone else ever encountered trouble with this?

[Doc Oc]

What are you trying to react the Grignard with?

I don't think you can add the iodide whenever you please, you're supposed to mix it with the magnesium first to get the oxidized layer off, THEN add your alkyl halide (anyone who has done this more recently feel free to correct me).

[voidSetup]

I'm reacting the Grignard with another primary alkyl halide, so I'm trying to do sp3-sp3 alkyl coupling.  I'll try that with the iodide next week when I attempt it again.  I think I may need to scrape the top layers off the Mg with a razor blade a little bit more to expose fresh Mg.  When I tried it yesterday I wasn't sure if I was going to use the iodide to initiate it so just tossed it in there once the alkyl halide was already added.  So I should let the Mg in THF stir for a little while with the iodide before adding the alkyl halide?

[stewie griffin]

I'm not so sure that your reaction will work that well. I was under the impression that grignards generally don't do S_N2 on alkyl halides very well... if they did you would never be able to form the gringard in the first place (since it would just homocouple with any unreacted alkyl halide). I think you may have to consider adding Ni (first two ref's) and/or switching to Zn instead of Mg (last ref):
Terao, J.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2003, 125, 5646-5647.
Terao, J.; Watanabe, H.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2002, 124, 4222-4223.
Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 10482-10483.

[voidSetup]

I tried the Ni catalyzed cross coupling last semester but I think I ran it at too low temperature (-78C) and no product or side products were formed.  I'm trying it now under Cu(I) catalysis, but it doesn't seem like the Grignard reagent is forming before I even get to the coupling part. Here's a couple references.

Cahiez, G.; Gager, O.; Buendia, J. SYNLETT 2010, 2, 0299-0303

In this paper they do primary alkyl halide coupling with Cu(I) catalysis and very slow addition of the Grignard reagent to the solution to avoid elimination/homocopuling. In 2000 these guys also published a similar paper but using NMP as a cosolvent which makes the addition rate of the Grignard reagent not important.  I think elimination is more of an issue with secondary/tertiary coupling partners.

Grodner, J. Tetrahedron 2009, 65, 1648-1654

This is a pheromone synthesis paper.  They do a primary alkyl halide coupling using CuBr catalyst.  Its reaction 4.8 in the paper.  The piece turned into the Grignard reagent has an aldehyde protected as dioxane so it's kind of similar to mine.

[Doc Oc]

Yes, let the iodide mix with the Mg first.  Alternatively, you can try to crush the Mg up a little bit once it's in the solvent to expose the fresher Mg underneath.

[voidSetup]

Ok thanks, I'll try that next time I attempt it.  I'll probably let the iodide mix for a little.  Might be hard to crush the Mg once it's in the solvent already because the whole setup is under nitrogen and I don't want to take any of the septums off.

[movies]

I made a lot of Grignard reagents in my undergrad research and I never had success using iodine as an activator.  1,2-Dibromoethane was always superior.  Perhaps more important is the quality of your Mg.  I always used Mg turnings in favor of powdered Mg, and I would submerge the turnings in a bit of THF or ether and then squash them a little with a spatula to expose some of the interior of the metal.  I also had to reflux my mixture for a few hours to form the reagent (although mine was a particularly difficult system).

[voidSetup]

Hm I might be able to try 1,2-dibromoethane if we have some around.  The literature I have uses ethyl iodide as an activator.  How careful do I have to be about keeping the system dry?  I've been drying the glassware and keeping it under nitrogen. Can I open it up for a little to hit the Mg with a spatula? I think I def need to scrape the Mg down with a razor and break it into smaller pieces.

[stewie griffin]

I've opened them up before to *carefully* (don't want to break your flask) grind at some of the Mg so as to assist in the initiation. Just use a two- or three-necked flask so that you can have your nitrogen entering one neck while you insert a spatula into the other neck. Also, temporarily crank up the flow of nitrogen while you have the one neck exposed so as to avoid any moisture/air getting in there.

[movies]

Yup, under a flow of dry N₂ or Ar gas should be fine.  Be sure your glassware is well-dried by heating under vacuum and backfilling with dry, inert atmosphere before you add the solvent and Mg.  Also be sure that you are using good quality dry solvent – it can make a big difference.

[voidSetup]

Ok sounds good.  Unfortunately I think the only two-neck microscale flask I can find in my lab is one of the pear shaped ones and I don't like that.  The Mg kind of just gets stuck in the bottom of it and it doesn't stir well.  I can probably order something though.  I've been drying the glassware in the oven for an hour or two, letting it cool in the desiccator, then putting septums on and flushing it out with nitrogen.  I think the solvent should be good. We ordered it last semester from Fisher and it came sealed and on molecular sieves. I only transfer it with a syringe that's been flushed with nitrogen.

Thank you everyone for the suggestions, I'll let you know if I have any progress.

[orgopete]

… more important is the quality of your Mg.

I second that. I hope you are starting with a fresh bottle of magnesium turnings.

[voidSetup]

I may consider ordering some, the stuff I used was acid washed at some point recently but it's not new.  Is it not good enough to just scrape the surface with a razor blade or something and break it into smaller pieces after?

[OC pro]

What I love with Grignard reactions ist the fact that they are very tolerant. N2 or even argon is absolutely not necessary. The etheral vapours form a layer which keeps moisture away. Also, ether and THF in p.A. quality is good (and dry!) enough. Even the magnesium turnings can be several years old. I never have problems. Last week, I run a reaction on 4-chlorobromobenzene on 750g scale and got >98% conversion into the magnesiated species. Isolated yield of crystalline 4-chlorophenylboronic acid was 70%.
I always add a small iodine crystal before adding the halogen component. That works fine. Mg doesn´t need to be grinded.